CEUS Evaluation of Hypoxic Ischemic Injury

Improved Diagnosis and Prognostication of Hypoxic Ischemic Injury in Neonates and Infants Using Contrast-Enhanced Ultrasound

Neonates presenting with neurologic symptoms require rapid, non-invasive imaging with high spatial resolution and tissue contrast. The purpose of this study is to evaluate brain perfusion using contrast-enhanced ultrasound CEUS in bedside monitoring of neonates and infants with hypoxic ischemic injury. Investigational CEUS scan will be performed separately from clinically indicated conventional US, in the ICU. Subjects will be scanned with CEUS at two different time-points (at the time HII is first suspected or diagnosed and at time of MRI scan), separately from clinically indicated ultrasound. The CEUS scan will be interpreted by the sponsor-investigator.

The study will be conducted at one site, The Children's Hospital of Philadelphia. It is expected that up to 100 subjects will be enrolled per year, for up to two years, for a total enrollment of up to 200 subjects.

Study Overview

• Status: Recruiting
• Conditions: Hypoxic-Ischemic Encephalopathy; Brain Ischemia Hypoxia
• Intervention / Treatment: Drug: Sulfur hexafluoride lipid-type A microspheres

Detailed Description

Contrast-enhanced ultrasonography (CEUS) is a novel imaging technique in which gas-filled microbubbles, smaller than red blood cells, generate increased signal due to the acoustic impedance mismatch. Injection of ultrasound contrast agents into blood increase the echogenicity, allowing enhanced visualization of a blood vessel. Ultrasound contrast agents have been approved for use in Europe for almost two decades. In the case of SonoVue (now called LumasonTM), a second-generation lipid/sulfur hexafluoride US contrast agent (Bracco, Milan, Italy), European Union approved its intravenous use in adults in 2001. The FDA in the United States just recently approved the use of LumasonTM for evaluation of focal hepatic lesions in pediatric population in 2016, and very recently (Jan 2017) approved its use in children for the evaluation of the urinary tract in pediatric patients with known or suspected vesicoureteral reflux. For the remainder of clinical applications, the ultrasound contrast agents are being used off-label in both Europe and the United States.

There is already good evidence in the literature that CEUS may be very valuable in children, and that is why it is routinely performed off-label for this purpose in the USA. However, there are ways in which it could be improved, and more studies are needed to definitively establish its diagnostic performance.

Sulfur hexafluoride lipid-type A microspheres (LumasonTM, Bracco Inc) is an FDA-approved ultrasound contrast agent. The study duration per subject will be approximately 15 minutes including the time to prepare LumasonTM contrast agent and perform the CEUS, as well as the 60 minute monitoring period after the first and second injection of LumasonTM. CEUS will be performed at the time HII is first suspected or diagnosed and within 24 hours of clinically indicated MRI (which occurs approximately on day 5 of life) for a total of two CEUS exams of 1 hour and 15-minute duration each. Study participation will be complete when the 60 minute monitoring period after the second CEUS is complete.

Injection of LumasonTM contrast agent will be performed via the existing peripheral intravenous line or central line using the FDA-recommended dose of up to 0.03 mg/kg. Contrast-agent injection will be performed twice per CEUS scan to ensure image quality and test reproducibility. In the case of more stable patients without an IV line, a peripheral IV line will be started to conduct the investigational CEUS. Two bolus injections will performed to evaluate for dynamic brain perfusion and several 2-minute cine clips as well as static images will be acquired during the exam.

Qualitative analysis with visual assessment and quantitative analysis of the acquired CEUS scans will be performed and interpreted by the PI. The scans will be assessed for diagnostic quality of images, artifacts encountered, and the presence of additional contributory diagnostic information.

• Study Type: Interventional
• Enrollment (Estimated): 200
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Misun Hwang, MD; Phone Number: 267-425-7129; Email: hwangm@email.chop.edu

Study Locations

• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Recruiting
      • The Children's Hospital of Philadelphia
      • Contact: Misun Hwang, MD; Phone Number: 267-425-7110; Email: hwangm@email.chop.edu
      • Principal Investigator: Misun Hwang, MD
      • Contact: Santiago Martinez Correa, MD; Phone Number: 2674257139; Email: martinezcs@chop.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 minute to 1 year (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Males and females aged 1.5 years or younger with open fontanelles and known or suspected hypoxic ischemic injury.
2. Post menstrual age of 34 weeks or older
3. Patient in the CHOP NICU or PICU
4. Parental permission

Exclusion Criteria:

1. Medical history of Lumason hypersensitivity
2. Hemodynamic instability as defined by rapid escalation of cardiopulmonary support in the past 12-24 hours, as defined by the clinical care team including ≥ 1 intensive care physician not part of the study team
3. Pulmonary insufficiency as defined by FiO2 requirements of > 40% and/or subjects with pulmonary hypertension requiring nitric oxide

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Contrast-enhanced Ultrasonography; Intravenous administration of contrast agent Sulfur hexafluoride lipid-type A microspheres before performing contrast-enhanced ultrasound (CEUS). In pediatric patients, after reconstitution 0.03 mL per kg is administered intravenously. The weight-based dose of 0.03 mL per kg will be repeated one time during a single examination. Following each injection, an intravenous flush of 0.9% Sodium Chloride is injected. The study duration per subject will be approximately 15 minutes including the time to prepare the contrast agent and perform the CEUS, as well as the 60 minute monitoring period after the first and second injection of the contrast agent.

Drug: Sulfur hexafluoride lipid-type A microspheres; Injection of Sulfur hexafluoride lipid-type A microspheres (Lumason) contrast agent will be performed via the existing peripheral intravenous line using the FDA-recommended dose of 0.03 mg/kg.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Qualitative and quantitative assessment of CEUS evaluation of brain perfusion	Specific analysis plan consists of both qualitative and quantitative assessment in which description of focal perfusion deficit or lesion, for instance, is reported in correlation with clinical information. Perfusion abnormalities will be qualitatively evaluated (absent - 0, mild hypoperfusion - 1, normal - 2, hyperperfusion - 3) and quantitatively (region of interest placed on brain regions for acquisition of wash-in curves using Matlab software).	2 years

Collaborators and Investigators

• Sponsor: Children's Hospital of Philadelphia
• Collaborators: Bracco Diagnostics, Inc

Publications and helpful links

General Publications

• Hwang M, Piskunowicz M, Darge K. Advanced Ultrasound Techniques for Pediatric Imaging. Pediatrics. 2019 Mar;143(3):e20182609. doi: 10.1542/peds.2018-2609.

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2020
• Primary Completion (Estimated): September 1, 2024
• Study Completion (Estimated): September 1, 2024

Study Registration Dates

• First Submitted: May 25, 2018
• First Submitted That Met QC Criteria: May 25, 2018
• First Posted (Actual): June 8, 2018

Study Record Updates

• Last Update Posted (Actual): August 15, 2023
• Last Update Submitted That Met QC Criteria: August 13, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: Ultrasound; Contrast-enhanced ultrasound
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Central Nervous System Diseases; Nervous System Diseases; Signs and Symptoms, Respiratory; Hypoxia, Brain; Brain Ischemia; Ischemia; Brain Diseases; Hypoxia; Hypoxia-Ischemia, Brain
• Other Study ID Numbers: 18-014912

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No