Multimodal Monitoring of Hemodynamics in Extremely Low Birth Weight Preterm Infant in a Canadian Tertiary Level Unit
Condition: Hemodynamic Instability
MeSH terms: Birth Weight
Study type: Interventional

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.
    

Detailed 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.
    

Intervention name(s): Hemodynamic report
Intervention type(s): Other
Intervention description(s): The multimodal data comprising the clinical, biochemical, NIRS data and TNE where available will be used by the study team in such cases to reach a description of the hemodynamic status of the study infant and will be provided to the Clinical team.
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Prevention
Keywords: Multimodal hemodynamic assessment