Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT03841929 |
| Other study ID # |
Pro00084238 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
February 15, 2019 |
| Est. completion date |
March 30, 2022 |
Study information
| Verified date |
May 2022 |
| Source |
University of Alberta |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Low blood pressure is a common problem in the premature newborn and can affect over 30% of
all Extremely Low Gestational Age Neonates (ELGAN) babies delivered less than 28 weeks
completed. Neonatal clinicians assess the hemodynamic status of the infant using clinical
signs and physiological parameters including heart rate, blood pressure, capillary refill
time, urine output and laboratory parameters (base deficit and lactate). While urine output
and laboratory parameters do not provide real-time assessment of the hemodynamic status,
heart rate and capillary refill time could be non-specific, inaccurate and
observer-dependent, respectively. Blood pressure (BP) continues to be used as a common
physiological marker for cardiovascular state in neonates.However, there is increasing amount
of evidence that monitoring blood pressure alone is not enough to ensure adequate systemic
and cerebral perfusion and oxygenation. Indeed, preterm babies may have "low blood pressure"
triggering pharmacological treatment while still maintaining adequate systemic flow-
especially cerebral and other organ perfusion as shown by other noninvasive measures like
targeted neonatal echocardiography (TNE) and near infrared spectroscopy (NIRS).
Using mean BP alone as the indication of treatment of neonatal cardiovascular compromise
without taking into consideration the status of tissue perfusion may lead to unnecessary
exposure of neonates to vasoactive medication. This medication can be potentially harmful to
these extremely vulnerable patients. Analysis of a large neonatal database has demonstrated
that treatment of hypotension was associated with an increase in serious brain injury. This
held true even after the blood pressure was included in the regression mode, suggesting that
it is treatment of hypotension, rather than the presence of hypotension which is harmful. The
common interventions, fluid boluses followed by inotropes, could as well be harmful.
Observational data has shown an association of fluid boluses with intracranial bleeding and
in animal models intraventricular haemorrhage after hypotension can be induced by rapid
volume infusion. Fluctuations in blood pressure when inotropes are introduced are well known
and could also trigger haemorrhage.
Current standard approaches to evaluation and treatment of transitional circulatory problems
in the preterm infant may be harmful. Therefore it is essential that these approaches are
adequately investigated. This research study is trying to find out if having a detailed
hemodynamic understanding using a multimodal assessment consisting of Targeted Neonatal
Echocardiogram, Cerebral NIRS and clinical-biochemical data, will result in less inotrope use
in ELGAN population during the first 72hours of transitional period.
Description:
Background:
Neonatal transition from the intra-uterine to extra-uterine environment is a complex,
multi-organ process. The heart of a term neonate is anatomically and functionally mature to
make the transition. However, the feto-neonatal transition of Extremely Low Gestational Age
Neonates (ELGAN) may have significant challenges in the context of the physiologically "less
than adequate" myocardial function and a delicate balance between pulmonary and systemic
blood flow. Further, the brain and cerebrovascular state of ELGAN are particularly vulnerable
to the effects of an unbalanced transition. Despite advances in neonatal intensive care that
have contributed to a decline in mortality and morbidity, preterm birth remains a major cause
of mortality and long term neurological sequelae. Brain injury in preterm infants is often
caused by disturbances in cerebral blood flow (CBF) and oxygenation that happen early in the
transition when the majority of intraventricular bleeds and parenchymal infarcts occur.
Therefore, it is important to evaluate the systemic and regional hemodynamic state of ELGAN
in order to facilitate the neonatal transition.
Neonatal clinicians assess the hemodynamic status of the infant using clinical signs and
physiological parameters including heart rate, blood pressure, capillary refill time, urine
output and laboratory parameters (base deficit and lactate). While urine output and
laboratory parameters do not provide real-time assessment of the hemodynamic status, heart
rate and capillary refill time could be non-specific, inaccurate and observer-dependent,
respectively. Blood pressure continues to be used as a common physiological marker for
cardiovascular state in neonates. However, there is increasing amount of evidence that
monitoring blood pressure alone is not enough to ensure adequate systemic and cerebral
perfusion and oxygenation. Indeed, preterm babies may have "low blood pressure" triggering
pharmacological treatment while still maintaining adequate systemic flow- especially cerebral
and other organ perfusion as shown by other noninvasive measures like targeted neonatal
echocardiography (TNE) and near infrared spectroscopy (NIRS). Interestingly, studies have
demonstrated that independent of early blood pressure changes, anti-hypotensive therapy
exposure in ELGAN was associated with an increased risk of death/NIDD at 18-22 months'
corrected age even after controlling for risk factors known to affect survival and
neurodevelopment.
The use of targeted neonatal echocardiography (TNE) by neonatal clinicians to evaluate
cardiovascular state in neonates is common in many tertiary neonatal intensive care units.
When used in combination with clinical findings, neonatal echocardiography may be an
invaluable tool for the identification of hemodynamic compromise, guiding therapeutic
intervention, and monitoring treatment response. There are an increasing number of
prospective studies that highlight the potential merits of TNE in identification of
cardiovascular compromise and guiding neonatal cardiovascular care. In addition, it has been
shown that the use of early echocardiography to provide targeted PDA treatment may result in
a reduction of severe intraventricular hemorrhage and pulmonary hemorrhages. The role of TNE
to study organ blood flow including cerebral, renal and the gut is largely limited.
Near-infrared spectroscopy (NIRS) is a technique that can be used to monitor regional
cerebral oxygen saturation (rScO2), being both a measure of cerebral oxygenation as well as a
surrogate of cerebral blood flow. NIRS monitoring can be applied for prolonged periods of
time, even in the most vulnerable infants. It uses multiple wavelengths of NIR light and
relies on the distinct absorption spectra of oxygenated (O2Hb) and deoxygenated. NIRS offers
the ability to assess target organ blood flow. It offers additional information regarding
organ perfusion, which supplements data provided by echocardiography and other modalities. In
preterm infants, NIRS-derived fractional tissue oxygen extraction and regional cerebral
oxygen saturation reference values, particularly over the first 72 hours of life, are
emerging. NIRS is being used in many centers including ours, in an ad-hoc manner. In a
multicenter, randomized, controlled trial, infants monitored with NIRS and treated for
evolving cerebral hypoxia had a lower cerebral hypoxic burden when compared with infants who
were not treated based on NIRS findings. The long-term benefit of this approach has yet to be
elucidated.
There have been attempts to combine the TNE and NIRS studies in preterm neonates to guide
management, showing benefits including reduced inotrope use and length of stay. There is a
clear need for a systematic evaluation of the hemodynamic state using a combination of TNE,
NIRS and clinical assessment that will result in better clinical understanding of the
physiology especially during the transitional period by the neonatal clinicians. The
assessment of ELGAN hemodynamics without considering data regarding systemic flow, cardiac
output and organ perfusion is incomplete and may result in unnecessary and potentially
harmful management strategies.
Various scoring measures have been used in neonates and children to objectively categorize
the cardiovascular support using inotrope use as a surrogate. Vasoactive inotrope score (VIS)
which provides a numerical sum of inotrope doses used, has been used in preterm infants to
quantify cardiovascular support in the perioperative period. A more comprehensive score -
Vasoactive Ventilation Renal score (VVR) that incorporates ventilation support and renal
function assessment has been used to evaluate children during the perioperative period. There
are no neonatal studies using VVR scores in the transitional period after birth.
The hypothesis is having a detailed hemodynamic understanding using a multimodal assessment
will result in less inotrope use in ELGAN as evidenced by lower VVR and VIS scores.
Objectives:
Primary Objective:
1. To determine whether a multimodal hemodynamic monitoring using combined TNE and cerebral
NIRS can reduce inotrope use as evidenced by decreasingVasoactive-Ventilation-Renal(VVR)
scores in ELGAN within the first one week of life
2. To investigate whether a multimodal hemodynamic monitoring using combined TNE and
cerebral NIRS can reduce the VIS scores in the subset of ELGANS receiving inotropes in
the first 72hours of life
Secondary Objective
To validate the use of VVR scores during the neonatal transition period in ELGAN population
Study design: Non-blinded Randomized Control Trial
Study site: This study will be conducted at the Stollery Children Hospital (RAH-Site NICU)
NICU which is a 69-bed unit that specializes in the care of very premature infants. On an
average, about 150 ELGAN less than 29 weeks are admitted per year to the RAH-Site NICU for
specialized neonatal care.
Methodology: This will be a Non-blinded Randomized Control Trial.
The study will involve the following steps (APPENDIX 1)
1. The study population will be assigned by simple randomization to either Study arm to
receive multimodal hemodynamic assessment using the study guideline (APPENDIX 5) or
Standard arm to be treated according to the standard approach operative in the Neonatal
Intensive Care Unit (NICU) of the Royal Alexandra Hospital.
2. ELGANs recruited into
A) Standard arm:
1. .Continuous cardiorespiratory monitoring using ECG leads or via an arterial line, and
pulse oximetry and intermittent non-invasive blood pressure monitoring as standard of
care in the NICU. Continuous arterial blood pressure monitoring will also be obtained as
appropriate when an arterial line has been placed under the clinical team's discretion.
2. .TNE studies will be performed at the discretion of clinical team for concerns on
cardiorespiratory status of the study population.
3. . Cerebral NIRS monitoring for regional Cerebral Oxygen saturation (rScO2) using
Neonatal sensors attached to the forehead of the infant as per current practice
4. . The current treatment protocol for hemodynamic compromise at our NICU is starting
inotropic support if Mean Blood Pressure is less than the gestational age of the infant
in the first 72hours of life.
B) Study Arm:
1. ELGANs recruited to the study group will have the same monitoring outlined in 2a in a
standardized manner. Zubrow's Normative BP chart will be used and MBP less than the
third centile for the gestational age will be taken as low BP for the study
2. .Continuous cerebral NIRS monitoring for regional Cerebral Oxygen saturation (rScO2)
using Neonatal sensor will be attached to the forehead of the infant (APPENDIX 2) for
the first 72 hours of life.
3. .Hemodynamic assessment using TNE (APPENDIX 3) will be performed at 18-24 hours and
66-72 hours of life. Additional TNE studies will be performed at the discretion of
clinical team for concerns on cardiorespiratory status of the study population.
4. .A hemodynamic report will be provided by the research team integrating the findings of
the multimodal monitoring (ie Cardio-respiratory parameters, NIRS and TNE) within the
clinical context (APPENDIX 5). No management suggestions will be provided in the report
4.All neonates will have standardized assessment for lead related skin abrasions as per
standard practice, neonatal pain and stress assessment (NPASS score) as part of their
standard care
5.Developmentally support care will be given by the support person during the TNE
assessment as per standard unit practice
6.The discontinuation of either or both NIRS and TNE will depend on the discretion of
clinical team. Reason for the discontinuation will be sorted. This does not constitute a
deviation from the study protocol.
7.The admission, 24hrs, 48 hours, 72 hours and 7days mean and median VVR and VIS scores
will be calculated in both Study and Standard arms. (APPENDIX 4)
8.Urine output will be monitored during the study period as a surrogate for renal
function and urine output less than 1ml/k/hr will be considered as oliguria.
9.Score for Neonatal Acute Physiology with Perinatal Extension-II (SNAPPE-II) score
which is a validated disease severity score in preterm babies will be calculated in both
study and standard arm at admission, 72hours and 7days of life.
10.Data on NIRS changes with normal saline bolus and blood products will also be
collected in the study arm whenever appropriate.
Data collection: The following patient demographics will be recorded: gestation, birth
weight, type of pregnancy, type of delivery, antenatal morbidities (Pregnancy Induced
Hypertension, placental abruption, chorio-amnionitis), antenatal steroids, antenatal
Magnesium Sulphate, Apgar scores, and gender. Information will be collected about the
active clinical issue and disease states at the time of the hemodynamic assessment. Data
pertaining to cardiorespiratory support, ventilation requirement, inotropes requirement
will be recorded during the first week of life. Data for the TNE cardiac function
studies will be collected in a separate datasheet and continuous NIRS data will be
collected for the first 72 hours of life. Major morbidity data like Chronic lung
disease, Necrotizing Enterocolitis, Retinopathy of Prematurity, severe brain injury,
Patent Ductus Arteriosus management and mortality will be collected for the purpose of
validation of VVR score in the transitional neonatal period.
Sample size:
Sample size calculation for VVR scores
Assuming 25% reduction in VVR in intervention arm with mean VVR score of 30 in control
arm and 22.5 in intervention arm, sd-15; t test assuming sd1 = sd2 = sd; Ho: m2 = m1
versus Ha: m2 != m1
Study parameters:
alpha = 0.0500; power = 0.8000; delta = -7.5000; m1 = 30.0000; m2 = 22.5000
sd = 15.0000
Estimated sample sizes: N = 128; N per group = 64
Sample size calculation for VIS scores
Assuming 30% reduction in VIS in intervention arm with mean VIS score of 5 in control
arm and 3.5 in intervention arm, sd-15; t test assuming sd1 = sd2 = sd; Ho: m2 = m1
versus Ha: m2 != m1
Study parameters:
alpha = 0.0500; power = 0.8000; m1 = 5 ; m2 = 3.5 sd = 15.0000
Estimated sample sizes: N = 56; N per group = 28
Analysis: All statistical analyses will be performed with the intercooled Stata Version
14.0 (College Station, Texas). All data will be anonymized for analysis. All the tests
will be two-sided (where applicable) and significance will be defined as p-value <0.05.
Univariate and bivariate analysis will be done to describe the sample. Categorical
variables will be compared by Fisher's exact test and continuous variables by Student's
t-test (two-sided). Logistic and linear regression models will be developed using
statistical techniques to examine the association between arterial blood pressure,
Cerebral oxygen saturation, the use of inotropes, VVR and VIS scores. Receiver Operating
Curve will be used for the purpose of validation of the VVR scores in neonates during
the neonatal period.
