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Classification of neurodevelopmental outcomes in extreme premature newborns

Canadian Neonatal Network manuals with definitions

Important definitions used in neonatal research

Bronchopulmonary dysplasia (BPD)

Necrotizing Enterocolitis (NEC)

Other important definitions (IVH, ROP, Chorioamnionitis, SGA, Growth failure, etc.)

1. Pulmonary Hypertension (PH): The European Society of Cardiology and the European Respiratory Society established a definition of PH considering all ages. When the mean pulmonary artery pressure at rest is ≥ 20 mmHg or when estimated systolic pulmonary artery pressure is ≥ 40 mm Hg by echocardiography, PH is diagnosed 1, 2. The presence of PH at echocardiography is often established established if any of the following is present: an estimated systolic PAP (sPAP) ≥ 40 mmHg or a LV end-systolic eccentricity index (EI) ≥ 1.3. EI quantifies the degree of septal flattening, and premature newborns with a value ≥ 1.3 were previously described to have impaired RV systolic function 3. Maximal estimated sPAP is usually established as the highest value obtained from either a tricuspid regurgitant jet (TRJ) (plus expected right atrial pressure of 5 mmHg), or a PDA peak systolic velocity gradient (when present) 2. A ratio of the estimated sPAP to the systemic systolic blood pressure (sBP) at the time of the echocardiography is often calculated. Further, a RV systolic pressure to systemic systolic blood pressure of greater than 0.5, any cardiac shunt with bidirectional or right to left flow, or any degree of ventricular septal wall flattening are indirect indicators of potential PH. The presence of significant (or severe) PH, defined as being 2/3 systemic or more, has been advocated as a marker of concern in the premature population4. 

2. Bronchopulmonary dysplasia (BPD): BPD and its severity is often defined as per the National Institute of Child Health and Disease (NICHD) workshop on BPD 5. For preterm infants born less than 32 weeks of gestational age and requiring oxygen or respiratory support at 28 days of life, BPD is classified according to the support needed at 36 weeks of post-menstrual age. BPD is considered severe when the patient still requires mechanical ventilation, continuous positive airway pressure or oxygen supplementation above 30%, moderate if the patient has oxygen requirements below 30%, or mild if the patient is breathing in room air. In 2018 – refinement of the definition: BPD is defined at 36 weeks of post-menstrual age or discharge6 according to Higgins et al7: grade I (nasal flow cannula < 1L/min with FiO2 ≤ 70%; nasal cannula with flow of 1 to 3L/min and FiO2 between 22 to 29%; CPAP, non-invasive positive pressure ventilation [NIPPV] or nasal cannula with flow > 3 L/min with FiO2 of 21%), grade II (nasal flow cannula less than 1L/min with FiO2 > 70%; nasal cannula with flow of 1 to 3L/min and FiO2 ≥ 30%; CPAP, NIPPV or nasal cannula with flow > 3L/min with FiO2 between 22-29%; invasive mechanical ventilation [IMV] with FiO2 of 21%), grade III (NIMV, NIPPV or nasal cannula with flow > 3L/min with FiO2 ≥ 30%, IMV with FiO2 > 21%). 

3. Chorioamnionitis is often defined as having clinical signs of uterine infection or inflammation (maternal fever, uterine sensitivity, white blood cells above 15,000) or suspected or confirmed diagnosis written in mother’s chart as per obstetrical team or confirmed diagnosis on placental pathology. 

4. Small for gestational age (SGA) is often diagnosed if birth weight is below the 10th percentile. At the Neocardiolab, we use the Fenton growth chart 8. 

5. Early (EOS) and late onset sepsis (LOS): Early onset sepsis is defined by a positive bacterial or fungal culture in blood and/or cerebrospinal fluid, in the first two days after birth. Late onset sepsis is defined with the same criteria beyond two days of life. 

6. Necrotizing enterocolitis (NEC): NEC is often defined when established as a stage 2 and above according to the Bell’s classification 9, 10. Another classification is the MD7 criteria11. (MD7: Positive blood culture, acidosis, bandemia, thrombocytopenia, hyponatremia, hypotension, or neutropenia). 

7. Intra-ventricular hemorrhage (IVH): IVH is often graded according to the Papile’s classification 12. Grade I – Germinal matrix alone; Grade II – IVH without ventricular dilatation; Grade III - IVH with ventricular dilatation; Grade IV – IVH with intraparenchymal hemorrhage. 

8. Retinopathy of prematurity (ROP) is defined according to the International Classification for Retinopathy of Prematurity 13. Significant ROP is defined as ROP requiring treatment with laser photocoagulation or intra-ocular injection of bevacizumab. 

9. Length of hospitalization is defined as the number of days from birth to discharge from the neonatal intensive care unit, for those who survived initial hospitalization. 

10. Length of invasive ventilation is defined as the number of days from initial intubation to final extubation for those who survived without a tracheostomy. 

11. Length of positive pressure ventilation is defined from initial respiratory support with continuous positive airway pressure, intubation, high flow nasal cannula above 2 liters per minute or non-invasive positive pressure ventilation, to the last day requiring any of these modalities for respiratory support. 

12. Pulmonary hemorrhage is defined as presence of frank blood in the endotracheal tube, or leading to intubation, with an associated increased in oxygen/respiratory support and a confirmatory chest radiography 14. 

13. Score for Neonatal Acute Physiology (SNAP score), will be recorded and is defined as “an illness severity scoring system which sums up the worst physiological derangement in each organ system in the first 12 hours of admission to the NICU (…) SNAP provides a numeric score that reflects how sick each infant is.” 15, 16 

14. Late-onset sepsis - positive bacterial or fungal culture in blood and/or cerebrospinal fluid following the first 3 days after birth 

15. Early-onset sepsis - positive bacterial or fungal culture in blood and/or cerebrospinal fluid in the first 3 days after birth 

16. Growth failure: Weight, length or head circumference below 3th percentile for corrected age as per Fenton or WHO growth curves (when term corrected-age).

17. Prematurity: Birth before 37 completed weeks of gestation. This is further subdivided on the basis of gestational age into extremely preterm (<28 weeks of gestation), very preterm (28–32 weeks of gestation) and moderate or late preterm (32–37 weeks of gestation). 

18. Very low birth weight (VLBW): Infants who weigh <1,500 g at birth. Most VLBW infants are born at <30 weeks gestational age. 

19. Extremely low birth weight (ELBW): Infants who weigh <1,000 g at birth. Most ELBW infants are born at <28 weeks gestational age. 

20. Extremely low gestational age newborn: Infants born at <28 weeks gestational age. 

21. Post-menstrual age: A measure of the age of an infant that combines gestational and postnatal age, both in weeks. For example, a 23-week gestational age infant at 9 weeks after birth has a postmenstrual age of 32 weeks.

22. Intrauterine growth restriction (IUGR): Also known as fetal growth restriction, IUGR usually refers to infants whose weight is below the tenth percentile for infants of that gestational age or less than two standard deviations below the average weight for infants of that gestational age. 

Vasoactive Index Score

From: McIntosh AM, Tong S, Deakyne SJ, Davidson JA, Scott HF. Validation of the Vasoactive-Inotropic Score in Pediatric Sepsis. Pediatr Crit Care Med. 2017;18(8):750-757. doi:10.1097/PCC.0000000000001191

Stages of Lung Development

Standard Research Echocardiography Protocol at the NeoCardioLab

Important note: As part of our imaging protocol, our TNE team plays piano-derived classical music from a portable device placed on the echocardiography machine holder for every TNE performed, regardless of the infant's condition or age. In addition to music therapy, a multi-strategy approach is implemented at each encounter. This includes the presence of parents and nurses (when possible), a darkened room, coordination with care, bundling of the newborn, warm ultrasound gel, maintaining closed incubator doors and focusing image acquisition to the most essential views during the least amount of time possible.

TnECHO Report at the Montreal Children's Hospital developed by Dr. G. Altit

Echocardiography research definitions at NeoCardioLab

Echocardiography Acquisition:

Echocardiography Analysis

Local raw ECHO images and data will be stored in Digital Imaging and Communications in Medicine format (DICOM). DICOM files will be stored on the hospital servers and on separate encrypted hard-drives kept at the Montreal Children’s Hospital. ECHO will be acquired with electrocardiogram-gating. All the ECHO images will require de-identification prior to transfer of data. All measures will be performed by one masked expert.

Clinical data collection

Systemic blood pressure at initiation of ECHO study will be recorded by both invasive (if clinically in place) and oscillometric methods. Other data gathered at the start of ECHO include: date and time, pre- and postductal saturations, medications (iNO, epinephrine, dopamine, norepinephrine, dobutamine, vasopressin, hydrocortisone, dexamethasone, sildenafil and prostacyclin analogs).

Study measurements and definitions:

a) Cardiac dysfunction:

Left ventricular systolic dysfunction will be defined as any of these factors:

-       Estimated ejection fraction of LV less than 55% by either method (Simpson’s) (1)

-       Estimated peak longitudinal strain of the LV ≤ -16% (2).

-       Estimated circumferential strain of the LV ≤ -19 % (2).

Right ventricular systolic dysfunction will be defined as any of these factors:

-       Fractional area change of the RV ≤ 30 % (3).

-       Tricuspid annular plane excursion with Z-score less than 2 (4, 5)

o   Calculator: http://dev.parameterz.com/tapse

-       Longitudinal strain of the RV of ≤ -13% (6) (free wall and septum).

b) Degree of pulmonary hypertension:

-       Suprasystemic pulmonary pressures will be defined as sPAP/sBP ratio > 110%.

-       Isosystemic pulmonary pressures will be defined as sPAP/sBP ratio 90-110%.

-       Infrasystemic pulmonary pressures will be defined as sPAP/SBP ratio < 90%.

a) Evaluation of PDA significance:

Echocardiography remains the tool of choice for the diagnosis and characterization of the PDA anatomy. Coupled with clinical hemodynamic evaluation, echocardiography informs on the volume and direction of the trans-ductal shunt, while eliminating ductal-dependent pathologies. The diameter of the PDA is measured at the end of the systole in black and white, at its narrowest part. Its measure is often indexed to the measurement of the left pulmonary artery  (small if ratio < 0.5, moderate if 0.5 to 1 and large if ³ 1 (7)) or to the weight of the patient (8). Doppler evaluation allows for assessment of directionality and degree of restrictiveness. A significant left to right volume that persists beyond the first days of life may result in dilation of left cardiac cavities by increased pulmonary venous return. The ratio of the size of the left atrium to the size of the aortic root (LA/Ao ratio) by M-mode equal or above 1.5 has been associated with systemic arterial hypotension in preterm newborns (9, 10). Progressive dilation of the left ventricle may lead to loss of coaptation of the mitral valve and / or of the aortic valve, leading to valvular insufficiency. Diastolic steal can lead to retrograde flow in the abdominal aorta and to decrease flow in the middle or anterior cerebral artery with an increase in the resistance index (11).

b)    Measures of LV function and size:

Ejection fraction (EF) will be calculated using the Simpson’s method. When using the modified Simpson’s method, the LV EF is calculated using the summation of disks to estimate the end-diastolic and end-systolic volume from the apical 4 chamber endocardial area tracing. Size of the LV will be assessed by longitudinal measurement from mitral valve to apex at end of diastole in apical 4 chamber view and by measuring the largest opening of the mitral valve. Estimated LV-end diastolic volume will be derived using Simpson’s.

Strain by Speckle-Tracking Echocardiography (STE): Strain analysis allows for segmental systolic and diastolic functional assessment in different planes, looking at longitudinal, circumferential, radial and rotational mechanics. Strain is the incremental distance change between two myocardial areas at two specific time points (%), and strain rate is the speed at which this deformation occurs (1/second) (12). Values of regional right and left ventricular strain have been reported in the normal pediatric and adult populations (12-14). The software used for strain assessment by STE identifies gray-scale speckles (echodensities) that compose the ultrasound images. Speckles are composed of ultrasound reflectors of myocardial tissue (13). They are tracked on a frame by frame basis to measure the magnitude (or percentage) of deformation of individual myocardial segments (15). TomTec software allows for speckle-tracking echocardiography derived strain and strain rate assessment by tracking endocardial border speckles through cardiac cycles and in a perpendicular motion to the trace (inward and outward) (12). In the context of shortening during systole (longitudinal and circumferential), the strain and strain rate values are negative, while during lengthening (diastolic relaxation) or thickening (radial contraction), they are positive (15, 16).

Images of the apical 4-chamber and parasternal short axis view at the level of the papillary muscle of the mitral valve or tricuspid valve will be stored as DICOM on MUHC server and transferred on the TomTec platform for strain analysis. Images will be stored above 100 frames per second (Hz). Tracing of the RV and LV will be done manually, point-by-point, of the endocardium for the longitudinal analysis and of the endocardium and epicardium for the radial and circumferential analyses. Tracing will be repeated multiple times to ensure appropriate tracking (14). Peak global longitudinal systolic strain and strain rate, as well as global endocardial circumferential and radial strain and strain rate will be provided by the platform. Peak diastolic e’ strain rate (early diastolic peak) value, a marker of diastolic function, will be extracted from the average strain rate curve (14, 17). In the context of shortening during systole (longitudinal and circumferential), the strain and strain rate values are negative, while during lengthening (diastolic relaxation) or thickening (radial contraction), they are positive. Full volume acquisition by 3D echocardiography of the LV will be done in Apical 4 Chamber view. This clips will be used to assess: ejection fraction, 3D volumes, 3D deformation indices and 3D rotational analysis (18).

c)     Measures of RV function and size:

Fractional area change (FAC) of the RV will be calculated from the endocardial area tracing of the RV in the apical 4 chamber view (19). Tricuspid annular plane systolic excursion (TAPSE) will be measured from the lateral tricuspid valve annulus by M-mode with the line of interrogation crossing through the apex of the RV (20). Measurements of the RV size (basal diameter, mid-cavity diameter and longitudinal dimension) will performed at end diastole (21). End diastolic area will be measured as well as maximal tricuspid valve annulus in 4 chamber view when opened in diastole. Strain by STE will also be measured for the RV peak longitudinal strain and strain rate as well as early diastolic strain rate, as mentioned previously. Full volume acquisition by 3D echocardiography of the RV will be done in Apical 4 Chamber view. This clips will be used to assess: ejection fraction, 3D volumes and 3D deformation indices (18).

d)    Pulmonary pressures:

Pulmonary pressures will be assessed by patent ductus arteriosus (PDA) flow velocity-derived gradient during systole or, if no ductus is present, tricuspid regurgitation jet (TRJ) velocity plus estimated right atrial pressure (5 mmHg (22, 23)), when a full Doppler envelope is available. In the presence of mild pulmonary valve regurgitation, a similar approach can be used to estimate the mean pulmonary artery pressure by measuring the diastolic peak Doppler gradient between the main pulmonary artery and the RV. In the presence of a PDA or a VSD and with an appropriate Doppler derived envelope across the shunt, pulmonary artery pressure can be estimated as a gradient between pulmonary and systemic pressure. The estimation of systolic pulmonary arterial pressure in the context of a VSD or a TR jet should only be done if there is no associated right or left ventricular outflow tract obstruction. Pulmonary hypertension has traditionally been defined as a mean pulmonary arterial pressure above 25 mmHg or a systolic pulmonary arterial pressure above 40 mmHg (24). However, this definition does not take into account the transitional physiology of the newborn. Hence, in this population of newborns with prematurity, estimated systolic main pulmonary artery pressure will be compared to the systolic systemic blood pressure at the time of the echocardiography (sPAP/sBP ratio) as a mean to assess pulmonary hypertension. The tricuspid valve systolic-diastolic duration (TVSD) ratio will be measured as it is a marker of systolic function in healthy neonates and measureable even in the absence of a complete TR jet. An elevated TVSD ratio is associated with poor clinical outcomes in the pediatric PH population (worse catheterization hemodynamics, shorter 6-minute walk distance, and increased risk for lung transplantation or death). TVSD ratio was also significantly increased in the PH group compare to those with BPD or without BPD (25).

LV end-systolic eccentricity index (EI) will be measured. LV-EI is the ratio of largest LV dimension (parallel to the septum at the mid-papillary muscle view in the parasternal short axis) to the dimension perpendicular to the septum at end systole (20). It is a quantification of septal configuration and the transmural pressure gradient. Recently, left ventricular eccentricity index (LVEI) has been recognized as a marker of PH in patients with bronchopulmonary dysplasia (26). LVEI quantifies the septal distortion with a tendency to be increased in the context of RV overload secondary to high pulmonary pressures. LVEI allows for a better appreciation of LV-RV cross-talk and quantifies the degree of septal flattening and/or bowing during systole. As a measure of RV dilation secondary to RV afterload, the LV to RV ratio will be calculated as the ratio of the distance from the IVS to the LV free wall and the distance from the IVS to the RV free wall at end of systole in the parasternal short axis at papillary level (6). LV/RV ratio has been used to quantify the degree of RV dilation by ECHO due to the high subjectivity associated with qualitative assessment of RV dimensions (19). In a pediatric cohort with PH, a LV/RV ratio at end of systole of less than 1.0 has been associated with adverse outcomes (initiation of intravenous prostacyclin treatment, atrial septostomy, transplant or mortality) (19, 27). Magnitude of LV/RV ratio was also correlated to PVR, mean PAP, sPAP and sPAP/sBP ratio by cardiac catheterization (27).

e)    Ventricular output:

Right ventricular outflow tract (RVOT) acceleration time to right ventricular ejection time (AT/RVET) ratio will be measured from the pulsed wave (PW) Doppler envelope of the RVOT. This ratio, a surrogate of pulmonary vascular resistance, compares the time to reach peak stroke distance in the pulmonary artery to the overall RV ejection time, but is influenced by cardiac output (20, 28, 29). In the pediatric population, this ratio is inversely related to the pulmonary artery pressure measured at cardiac catheterization (30). Indeed, a short acceleration time of RV ejection into the pulmonary artery is associated with PH (23). Thus, with increasing pulmonary arterial pressures, the Doppler pattern obtained at the RV outflow tract changes from a smooth curved pattern to a triangular pattern (19).

Velocity time integral (VTI) of the pulsed wave Doppler in the RVOT, sampled at the level of the pulmonary valve attachments, will be measured in the parasternal short axis view. VTI of an outflow tract indicates red blood cells stroke distance travelled per cardiac contraction, as a surrogate measure for output in the corresponding vessel (31). LVOT VTI of the pulsed wave Doppler, measured at the level of the aortic valve attachments, will be measured in the apical 3 chamber view. Aortic valve (AV) will be measured in the parasternal long axis view and the pulmonary valve (PV) in the parasternal short axis view. Calculated stroke volume will be derived from the VTI multiplied by the corresponding outflow cross-sectional area: (PV or AV/2)2 x Pi. The cardiac output (CO) will then be estimated by multiplying the resultant stroke volume by the heart rate and dividing by body weight in kilograms (kg) (32).

f)     Inter-atrial shunt

The presence of a shunt and direction of flow at the level of the foramen ovale (or atrial septal defect) will be assessed. Direction of atrial shunting is an indicator of ventricular compliance/pressure. If the atrial shunt is bidirectional, the end-diastolic pressures are assumed to be similar; if right to left, the assumption is that end-diastolic pressures of RV are higher than LV, and if left to right, the inverse. In the presence of increased end-diastolic pressure, restricted filling of the ventricle can impact atrial pressure and emptying. Right atrial planimetry will be measured to quantify degree of RA dilation.

Conferences to apply for poster - abstracts - presentation

Pediatric Academic Societies

NeoHeart

America Society of Echocardiography

American Thoracic Society

Canadian Pediatric Society

Canadian National Perinatal Research Meeting

UCSF Pulmonary Vascular Disease

Data collection from Echocardiography for research at the NeoCardioLab

Data Dictionary for RedCap

NeoCardioLab Atlas for Measurements

At the NeoCardioLab, our commitment to transparency in our research procedures is paramount. Therefore, we are openly sharing our data extraction and echocardiography measurement methodologies for all our research projects, and our targeted neonatal echocardiography. These measurements are designed to align with the established literature and adhere to the guidelines set forth by the American Society of Echocardiography and the Canadian Society of Echocardiography. The NeoCardioLab Atlas of measurements is now available here.

Le 9 septembre 2023 - Au NeoCardioLab, notre engagement envers la transparence dans nos procédures de recherche est primordial. C'est pourquoi nous partageons ouvertement nos méthodes d'extraction de données et de mesure en échocardiographie pour l'ensemble de nos projets de recherche, y compris pour nos échocardiographies néonatales ciblées. Ces mesures sont conçues pour être en accord avec la littérature établie et conformes aux directives énoncées par la Société américaine d'échocardiographie et la Société canadienne d'échocardiographie. L'Atlas des mesures du NeoCardioLab est désormais disponible ici.