Clinical trial NCT03786497: Protecting Brains and Saving Futures - the PBSF Protocol
Official title: Protecting Brains and Saving Futures - the PBSF Protocol: a Prospective Multicenter and Observational Study on the Use of Telemedicine for Neurocritical Care in High-risk Newborns in Brazil.
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Brain Injuries
Congenital Heart Disease
Newborn Morbidity
Intraventricular Hemorrhage
CNS Infection
Neonatal Seizure
Nosocomial Infection
Hypoxic-Ischemic Encephalopathy
Extreme Prematurity
Brain Malformation
Congenital Infection
Neonatal Stroke
Hemodynamic Instability
Extracorporeal Membrane Oxygenation Complication
Inborn Errors of Metabolism
Respiratory Complication
Neonatal Death
Keywords: Newborn
Neonatal Neurocritical Care Units
Neonatal Brain Monitoring
Brain Injury
Neuroprotection
Telemedicine
Electroencephalography
Amplitude-Integrated Electroencephalography
Near Infrared Spectroscopy
Neurodevelopmental Problems
Lead sponsor: Protecting Brains Saving Futures
Sponsor class: OTHER
First posted: 2018-12-26
Enrollment: 2268
Sex: ALL
Maximum age (years): 3
Standard ages: CHILD
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: This will be a multicenter, prospective, observational study in a cohort of high-risk neonates treated at 20 different Neonatal Intensive Care Units in terciary hospitals in Brazil.

Brief summary: Background: Multiple neonatal disorders are associated with risks of neurological injury. Thus, management of these infants should involve a coordinated approach to permit early diagnosis with improved clinical care. Such initiative involves the use of standardized protocols, continuous and specialized brain monitoring with electroencephalography (EEG), amplitude integrated EEG (aEEG) and Near Infrared Spectroscopy (NIRS), neuroimaging and training. Brazil is a very large country with disparities in health care assessment; some neonatal intensive care units (NICUs) are not well structured and trained to provide adequate neurocritical care. However, the development and implementation of these neurocritical care units requires high expertise and significant investment of time, manpower and equipment. In order to reduce the existing gap, a unique advanced telemedicine model of neurocritical care called Protecting Brains and Saving Futures (PBSF) protocol was developed and implemented in some Brazilian NICUs.

Methods: A prospective observational cohort study will be conducted in 20 Brazilian NICUs that have adopted the PBSF protocol. All infants receiving the protocol during January 2021 to December 2023 will be eligible. Ethical approval will be obtained from the participating institutions. The primary objective is to describe the use of the PBSF protocol and clinical outcomes, by center and over a 3 years period. The use of the PBSF protocol will be measured by quantification of neuromonitoring, neuroimaging exams and sub-specialties consultation. Clinical outcomes of interest after the protocol implementation are length of hospital stay, detection of EEG seizures during hospitalization, use of anticonvulsants, inotropes, and fluid resuscitation, death before hospital discharge, and referral of patients to high-risk infant follow-up. These data will be also compared between infants with primarily neurologic and primarily clinical diagnosis.

Discussion: The implementation of the PBSF protocol may provide adequate remote neurocritical care in high-risk infants with optimization of clinical management and improved outcomes. Data from this large, prospective, multicenter study are essential to determine whether neonatal neurocritical units can improve outcomes. Finally, it may offer the necessary framework for larger scale implementation and help in the development of studies of remote neuromonitoring.

Detailed description: METHODS Objectives The aim of this multicenter, prospective, cohort study is to describe the use of the PBSF protocol and clinical outcomes, by center and over a 3 years period (2021 to 2023) in the NICUs that have adopted it. We hypothesize that the use of the PBSF protocol will increase over time with improvement of some specific short-term outcomes (see methods below). Results of this study may provide the necessary background information for larger studies and initiatives aiming to protect neonatal brains and save futures.

Study Design and Setting This will be a multicenter, prospective, observational study in a cohort of high-risk neonates treated at 20 different NICU's in Brazil. The intended period of patient recruitment and data collection will be 3 years (January 2021 to December 2023). The study followed the precepts of good clinical practice and was approved by the Research Ethics Committee of the Irmandade da Santa Casa de Misericórdia de São Paulo. In addition, the project has received formal authorization from the Clinical and Administrative Board of each center. When selecting a participant, the principal investigator of the study or one of the co-investigators will contact the parents or guardians and obtain informed consent. All data will be treated anonymously and confidentially, and in no phase of the study any name, image, or data that allows participants identification will be disclosed.

Participants In this cohort study, all the infants admitted to any of the 20 NICUs from birth up to three months of life and receiving the PBSF protocol are eligible. Indications for the use of the protocol are provided on Box 1. Patients with genetic syndromes or malformation incompatible with life, or older than three months old will be excluded. Details on the PBSF protocol are provided in supplemental material. Briefly, the protocol includes provision of equipment and resources, connection between the associated NICU and the remote monitoring center called the Central of Surveillance and Intelligence (CSI), training and teaching of all health care professional team of each NICU, and customized multiparametric recordings of biological signals of each patient monitoring. At the CSI, a team is available 24 hours a day all year around, allowing for case discussions and simplified reports of brain monitoring information on the patient monitor's display every 6 hours.

Variables Population demographics: gender, gestational age at birth, gestational age ≤ 32 weeks and \< 37 weeks, Apgar score at 1 min, 5 min and 10 min, birth weight, current weight, inborn or outborn, use of antenatal steroids and magnesium sulfate, type of birth.

Primary diagnosis: seizure, anoxia/mild HIE, moderate or severe HIE/cooling, neurologic abnormalities without specific diagnosis, congenital central nervous system (CNS) anomalies, grade III or IV intraventricular hemorrhage (IVH) or hydrocephalus, periventricular leukomalacia, meningitis, neural tube defects, stroke, cyanotic congenital heart defect (CHD), prematurity, gestational age ≤ 32 weeks, meconium aspiration syndrome, cardiorespiratory instability, necrotizing enterocolitis, metabolic disease, extracorporeal membrane oxygenation (ECMO)/pre-ECMO and any other medical conditions not listed here.

For descriptive analysis of the 2 main outcomes (use of the PBSF protocol and clinical outcomes) patients will be them divided into two groups accordingly to their primary diagnosis: neurological or clinical.

Data sources / measurement Patient demographics, diagnosis and clinical outcomes will be extracted from the medical charts of each patient enrolled and entered in the PBSF database. The use of the PBSF protocol will be measured with the data collected by the CSI center continuously. Details of these recordings are provided on Appendix 2.

Bias To address potential source of bias related to financial availability, the 2 main outcomes of interest will be also adjusted based on the unit primary profile: private, foundation or public.

Study size Based on our current experience, there are an average of 5 patients per month with criteria for neurocritical care on each center, making a total of 3,240 eligible patients during a three years period. Considering a 30% loss due to refusal to consent, non-availability of the research team or missing data, we expect to recruit 2,268 infants from all study centers (around 756 patients per year).

Statistical methods Categorical variables will be analyzed by descriptive statistics and presented as number of valid cases and percentage (%). Numeric variables will be analyzed as mean and standard deviation, median and interquartile ranges, or coefficient intervals. Chi-square test (or Fisher's exact test) will be performed to analyze categorical variables and the Student's t test, or Wilcoxon rank sum test will be used to check for significant differences between the two groups. A p value of \<0.05 will be considered statistically significant. The confidence interval considered will be 95%. Analysis of variability (distribution) per site for each variable of the 2 main outcomes will also be performed. ANOVA with post hoc Bonferroni will be used to compare outcomes over time, i.e. between years 1, 2 and 3 and Kaplan Meier curves will be generated to follow the evolution of outcomes over time for the 2 groups of patients: neurologic and clinical.

Results Participants. A flow chart of all eligible and enrolled patients will be produced, and the total number of patients will be reported, overall and per center.

Descriptive data Population demographics: male, n (%); gestational age at birth, weeks, mean (SD); gestational age ≤ 32 wk, n(%); Gestational age \< 37 wk, n (%); Apgar score at 1 min, at 5 min, and at 10min, median (IQR); birth weight, grams, mean (SD); current weight, grams, mean (SD); Inborn, n (%); use of antenatal steroids and magnesium sulfate, n (%); Caesarean, n(%).

Primary outcomes:

Use of the PBSF protocol

1. Use of aEEG/EEG monitoring
2. Duration of aEEG/EEG monitoring
3. Number primary neurologic or medical patients with aEEG or EEG monitoring and the duration of the monitoring (hours)
4. Number of primary neurologic or medical patients with NIRS monitoring and the duration of the NIRS monitoring (hours)
5. Number of primary neurologic or medical patients with brain MRI, neurology consult, and neurosurgery consult.
6. Number of clinical case discussions and videoconference meetings

Clinical outcomes

1. Length of hospital stay
2. Number of electroencephalographic seizures during hospitalization
3. Use and types of anticonvulsants administered
4. Number and types of anticonvulsants prescribed at discharge
5. Use and types of inotropes administered during NICU stay
6. Use and types of fluid resuscitation administered during NICU stay
7. Death before hospital discharge
8. Number of patients referred to neurology or neurosurgery
9. Number of patients referred to high-risk infant follow-up\*

Secondary outcomes:

Use of the PBSF protocol

1. Number of remote communications between CSI and local team
2. Number of reports issued for aEEG / EEG exams with or without the use of NIRS
3. Number of patients who performed Therapeutic Hypothermia
4. Association of pathological brain monitoring findings (aEEG/EEG and NIRS) and alterations in imaging exams including brain magnetic resonance imaging (brain MRI) and cranial ultrasonography (cranial US) performed during hospitalization
5. Association of pathological brain monitoring findings with morbi-mortality and length of hospital stay
6. Adverse effects of therapeutic hypothermia measured by cardiac arrhythmia, thrombocytopenia and coagulation disorders in general, skin lesion and pulmonary hypertension
7. Adverse effects of brain monitoring expressed by skin lesion due to electrode / sensor positioning
8. Association of pathological brain monitoring findings with evaluation of neurodevelopment by application of the Bayley test between 18 and 24 months of life

Eligibility criteria: - Inclusion criteria:

In this cohort study, all the infants admitted to any of the 20 NICUs from birth up to three months of life and receiving the PBSF protocol are eligible. Following are the indications for use of the PBSF protocol in the participating centers

1. Extreme prematurity
2. Peri-intraventricular Hemorrhage
3. Hypoxic-ischemic encephalopathy (mild, moderate or severe)
4. Congenital heart disease
5. Neonatal stroke
6. Congenital infections
7. Nosocomial infections
8. Inborn errors of metabolism
9. Severe hemodynamic/ventilatory instability
10. Seizures
11. Brain malformations
12. CNS infection
13. ECMO

    * Exclusion criteria:

Patients with genetic syndromes or malformation incompatible with life, or older than three months old will be excluded.

Primary outcomes:
measure: Applicability of telemedicine model for monitored infants
timeFrame: 3 years period
measure: Applicability of telemedicine model for recorded remote monitoring
timeFrame: 3 years period
measure: Use of aEEG/EEG monitoring
timeFrame: 3 years period
measure: Duration of aEEG/EEG monitoring
timeFrame: 3 years period
measure: Number primary neurologic or medical patients with aEEG or EEG monitoring and the duration of the monitoring (hours)
timeFrame: 3 years period
measure: Number of primary neurologic or medical patients with NIRS monitoring and the duration of the NIRS monitoring (hours)
timeFrame: 3 years period
measure: Number of primary neurologic or medical patients with brain MRI, neurology consult, and neurosurgery consult.
timeFrame: 3 years period
measure: Number of clinical case discussions and videoconference meetings
timeFrame: 3 years period
measure: Length of hospital stay
timeFrame: 3 years period
measure: Number of electroencephalographic seizures during hospitalization
timeFrame: 3 years period
measure: Use and types of anticonvulsants administered
timeFrame: 3 years period
measure: Number and types of anticonvulsants prescribed at discharge
timeFrame: 3 years period
measure: Use and types of inotropes administered during NICU stay
timeFrame: 3 years period
measure: Use and types of fluid resuscitation administered during NICU stay
timeFrame: 3 years period
measure: Death before hospital discharge
timeFrame: 3 years period
measure: Number of patients referred to neurology or neurosurgery
timeFrame: 3 years period
measure: Number of patients referred to high-risk infant follow-up
timeFrame: 3 years period
Secondary outcomes:
measure: Number of remote communications between CSI and local team
timeFrame: 3 years period
measure: Number of reports issued for aEEG / EEG exams with or without the use of NIRS
timeFrame: 3 years period
measure: Number of patients who performed Therapeutic Hypothermia
timeFrame: 3 years period
measure: Association of pathological brain monitoring findings (aEEG/EEG and NIRS) and alterations in imaging exams including brain magnetic resonance imaging (brain MRI) and cranial ultrasonography (cranial US) performed during hospitalization
timeFrame: 3 years period
measure: Association of pathological brain monitoring findings with morbi-mortality and length of hospital stay
timeFrame: 3 years period
measure: Adverse effects of therapeutic hypothermia measured by cardiac arrhythmia, thrombocytopenia and coagulation disorders in general, skin lesion and pulmonary hypertension
timeFrame: 3 years period
measure: Adverse effects of brain monitoring expressed by skin lesion due to electrode / sensor positioning
timeFrame: 3 years period
measure: Association of pathological brain monitoring findings with evaluation of neurodevelopment by application of the Bayley test between 18 and 24 months of life
timeFrame: 3 years period
Other outcomes:
Locations:
city: São Paulo
country: Brazil
facility: Irmandade da Santa Casa de Misericórdia de São Paulo
state: SP
city: São Paulo
country: Brazil
facility: Protecting Brains and Saving Futures - PBSF
Study officials:
affiliation: McGill University Health Centre/Research Institute of the McGill University Health Centre
name: Guilherme M Sant'Anna, PhD
role: STUDY_DIRECTOR
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