Quantification of Brain and Kidney Perfusion Before, During, and After Hypothermia Treatment in Neonates With Perinatal Asphyxia Using Contrast-enhanced Ultrasound

In this clinical study vascular dynamics in the neonatal brain and kidney will be monitored by CUES and ULM before, during and after hypothermia treatment in neonates with asphyxia.

Study Overview

• Status: Recruiting
• Conditions: Perinatal Asphyxia; Hypothermia Treatment; Gestational Age Min. 36SSW
• Intervention / Treatment: Device: Contrast enhanced ultrasound imaging (CEUS) and post processing with ULM

Detailed Description

Perinatal asphyxia (PA) is the reduced supply of oxygen to vital organs during or immediately after birth. PA is one of the most common causes of neonatal mortality in full-term infants worldwide and of hypoxic-ischemic encephalopathy (HIE) with subsequent neurological deficits (spastic cerebral palsy). In addition to brain damage, perinatal asphyxia often leads to dysfunction of other organs. It is not uncommon for this to be accompanied by transient renal failure.

Hypothermia treatment is an established therapeutic measure for neuroprotection in clinical indications of HIE. This involves lowering the core body temperature of affected children to 33.5°C for 72 hours. The therapeutic effect is thought to be due to multifactorial mechanisms, including a reduction in endothelial dysfunction, reduced excretion of free radicals and attenuation of the inflammatory cascade.

In the guidelines for hypothermia treatment in neonatal asphyxia, regular ultrasound examinations are prescribed to clarify damage to the central nervous system (CNS) before, during and after hypothermia treatment.1 In infants, transfontal ultrasound makes it possible to visualize brain structures, vessels and their flow velocities.

The intravenous use of ultrasound contrast enhancers as an aid also opens up the possibility of recording the tissue perfusion of the CNS and kidneys, including the smallest vessels.8 This could provide significantly more information compared to conventional methods and expand our knowledge of the pathophysiology and individual status of tissue perfusion in patients.

For example, two studies at Erlangen University Hospital have successfully used contrast-enhanced ultrasound (CEUS) with the contrast agent known as SonoVue® to visualize postoperative perfusion of the brain after pediatric cardiac surgery.

In this clinical study, the new CEUS measurement and imaging technique will be used before, during and after hypothermia treatment in neonates with asphyxia. A contrast agent (SonoVue®) will be administered during the routine ultrasound examination and improved tissue visualization will be achieved. The aim is to gain new insights into brain and kidney perfusion as part of the treatment and to better assess the extent of organ damage in the individual patient through more specific vascular imaging. Improved visualization and assessment of the end-stream area will provide information on processes that promote the development of HIE and renal failure. Finally, the aim is to compare diagnostic and prognostic methods with the currently recommended measures. The CEUS is to be examined as a possible diagnostic imaging tool and possibly a supplement to existing diagnostic methods.

• Study Type: Observational
• Enrollment (Estimated): 20

Contacts and Locations

• Study Contact: Name: Ferdinand Knieling, MD; Phone Number: 0049 9131 85 33118; Email: ferdinand.knieling@uk-erlangen.de
• Study Contact Backup: Name: Gregor Hanslik, MD; Phone Number: 0049 9131 85 33118; Email: gregor.hanslik@uk-erlangen.de

Study Locations

• Germany
  • Bavaria
    • Erlangen, Bavaria, Germany, 91054
      • Recruiting
      • FAU Erlangen-Nuernberg
      • Principal Investigator: Ferdinand Knieling, MD
      • Contact: Ferdinand Knieling, MD; Phone Number: 0049 9131 85 33118; Email: ferdinand.knieling@uk-erlangen.de
      • Principal Investigator: Gregor Hanslik, MD
      • Sub-Investigator: Henriette Mandelbaum

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: N/A

• Sampling Method: Non-Probability Sample

Study Population

One study population. Anticipated approx. n=20 neonateswith above mentioned inclusion criteria with perinatal asphyxia and inclusion criteria for hypothermia treatmentaccording to the AWMF guideline.

Description

Inclusion Criteria:

• Fulfillment of the inclusion criteria for hypothermia treatment according to the AWMF guideline
• Severe acidosis (pH ≤7.0 or a base deficit ≥16 mmol/l) in umbilical cord blood or a blood sample from the first hour of life, and
• clinical signs of moderate or severe encephalopathy (severity grade 2 or 3 according to Sarnat & Sarnat), and
• postnatal age ≤6h, and
• gestational age ≥36 weeks' gestation
• Consent of the parents/legal guardians

• Time 1 (before the start of hypothermia treatment)

  • Informing the parents/legal guardians present on site despite an emotionally stressful situation with high individual benefit for the patient
  • If only one parent is present and able to provide information, their consent is sufficient - the second parent is informed repeatedly when they regain the ability to provide information
  • Information adapted to the emergency situation, addressing the personal situation and comprehensible presentation of the plan

• Time 2 (during hypothermia treatment)

  -->Offer of a further informative discussion/repeated explanation with the parents/legal representatives before the second measurement in order to answer any questions that may have arisen

• Suitable acoustic window
• Availability of the qualified examiner

Exclusion Criteria:

• Lack of consent of at least one parent
• Pre-existing brain malformations
• Absence of the competent examiner

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Intervention / Treatment

Neonates with perinatal asphyxia and indication for hypothermia treatment; Included will be neonates with perinatal asphyxia that get an indication for hypothermia treatment (severe azidosis and signs of encephalopathy and under 6h of age and >36 gest. weeks). They will be monitored with CEUS/ULM at three different time points (T1: within first 6h of life/before hypothermia treatment, T2 = during hypothermia treatment/6-78h of life, T3 = after hypothermia treatment/within first week of life.

Device: Contrast enhanced ultrasound imaging (CEUS) and post processing with ULM; CEUS is a contrast based ultrasound technique and ULM (Ultrasound Localization Microscopy) is a post-processing bioinformatical method to quantify microvascular architecture and perfusion dynamics.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
CEUS Time intensity curves	All CEUS outcomes will be generated in order to achieve time intensity curves in contrast enhanced ultrasound analysis	before(T1, within the first 6hours of life), during hypothermia treatment(T2, 6-78hours of life), after treatment (T3, within first week of life)
CEUS Measurement1	PE (Peak-Enhancement)	before(T1, within the first 6hours of life), during hypothermia treatment(T2, 6-78hours of life), after treatment (T3, within first week of life)
CEUS Measurement2	WiAUC (Wash-in Area Under the Curve (AUC(TI: TTP)))	before(T1, within the first 6hours of life), during hypothermia treatment(T2, 6-78hours of life), after treatment (T3, within first week of life)
CEUS Measurement3	WiAUC (Wash-in Area Under the Curve (AUC(TI: TTP)))	before(T1, within the first 6hours of life), during hypothermia treatment(T2, 6-78hours of life), after treatment (T3, within first week of life)
CEUS Measurement4	RT (Rise Time)	before(T1, within the first 6hours of life), during hypothermia treatment(T2, 6-78hours of life), after treatment (T3, within first week of life)
CEUS Measurement5	mTT (mean Transit Time local) (mTT-TI))	before(T1, within the first 6hours of life), during hypothermia treatment(T2, 6-78hours of life), after treatment (T3, within first week of life)
CEUS Measurement6	TTP (Time to Peak)	before(T1, within the first 6hours of life), during hypothermia treatment(T2, 6-78hours of life), after treatment (T3, within first week of life)
CEUS Measurement7	WiR (Wash-in-Rate )	before(T1, within the first 6hours of life), during hypothermia treatment(T2, 6-78hours of life), after treatment (T3, within first week of life)
CEUS Measurement8	WiPI (Wash-in Perfusion Index (WiAUC/RT))	before(T1, within the first 6hours of life), during hypothermia treatment(T2, 6-78hours of life), after treatment (T3, within first week of life)
CEUS Measurement9	WoAUC (Wash-out AUC (AUC(TTP:TO)))	before(T1, within the first 6hours of life), during hypothermia treatment(T2, 6-78hours of life), after treatment (T3, within first week of life)
CEUS Measurement10	WiWoAUC (Wash-in- und Wash-out-AUC (WiAUC+WoAUC))	before(T1, within the first 6hours of life), during hypothermia treatment(T2, 6-78hours of life), after treatment (T3, within first week of life)
CEUS Measurement11	FT (Fall Time - (TO-TTP))	before(T1, within the first 6hours of life), during hypothermia treatment(T2, 6-78hours of life), after treatment (T3, within first week of life)
CEUS Measurement12	WOR (Wash-out-Rate) QOF (Quality Of Fit between the echo-power signal and f(t)	before(T1, within the first 6hours of life), during hypothermia treatment(T2, 6-78hours of life), after treatment (T3, within first week of life)
CEUS Measurement13	QOF (Quality Of Fit between the echo-power signal and f(t)	before(T1, within the first 6hours of life), during hypothermia treatment(T2, 6-78hours of life), after treatment (T3, within first week of life)
Near-infrared spectroscopy	Near-infrared spectroscopy Non-invasive measurement of oxygen saturation in tissue using a probe that is attached to the head.62 This procedure is already firmly established in the field of pediatric surgery and pediatric cardiology interventions at the University Hospital Erlangen. The probe is attached before the start of the first measurement time point and removed after the end of the third measurement time point. There is no risk of side effects.	before(T1, within the first 6hours of life), during hypothermia treatment(T2, 6-78hours of life), after treatment (T3, within first week of life)
Visualization and quantification of cerebral perfusion with CEUS	CEUS imaging for cerebral perfusion in asphyxia	before(T1, within the first 6hours of life), during hypothermia treatment(T2, 6-78hours of life), after treatment (T3, within first week of life)
Visualization and quantification of of renal perfusion with CEUS	CEUS imaging for renal perfusion in asphyxia	before(T1, within the first 6hours of life), during hypothermia treatment(T2, 6-78hours of life), after treatment (T3, within first week of life)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
CEUS and NIRS	Correlation coefficient (R) between CEUS curve and NIRS	T1,T2,T3
Neurological status assessment (Bayley Score)	Neurological status of the patients will be assessed by the score "Bayley Scales of Infant and Toddler Development"	Month of life: 3-4 and 6-24
MRI imaging in asphyxia	MRI Weeke Score	once within first two years of life
Comparison of the CEUS time-intensity curve between three timepoints	CEUS curve at T1,T2, T3	T1,T2, T3
Assessment of blood Lactate	Lactate (mmol/l)	T1, T2, T3
EEG signs of seizures	Number (n) of ETPs in EEG	T1 -T3 and through study completion
EEG activity	frequency EEG (Hz)	T1 -T3 and through study completion
Assessment of renal function GFR	GFR (ml/min/1,73 m2)	T1 -T3 and through study completion, an average of 3 years
Assessment of renal function urea	urea (mg/dl)	T1 -T3 and through study completion, an average of 3 years
Assessment of renal function urinary status	standardized urinary status	T1 -T3 and through study completion
Assesment of renal function kreatininekinase	kreatininekinase (U/l)	T1, T2, T3
Assessment of metabolic LDH	LDH (U/l)	T1, T2, T3

Collaborators and Investigators

• Sponsor: University of Erlangen-Nürnberg Medical School
• Investigators: Principal Investigator: Ferdinand Knieling, MD, FAU Erlangen-Nuernberg; Principal Investigator: Gregor Hanslik, MD, FAU Erlangen-Nuernberg

Study record dates

Study Major Dates

• Study Start (Actual): June 24, 2024
• Primary Completion (Estimated): July 1, 2027
• Study Completion (Estimated): December 1, 2027

Study Registration Dates

• First Submitted: June 21, 2024
• First Submitted That Met QC Criteria: September 20, 2024
• First Posted (Actual): September 24, 2024

Study Record Updates

• Last Update Posted (Actual): September 24, 2024
• Last Update Submitted That Met QC Criteria: September 20, 2024
• Last Verified: September 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Wounds and Injuries; Infant, Newborn, Diseases; Death; Body Temperature Changes; Hypothermia; Asphyxia; Asphyxia Neonatorum
• Other Study ID Numbers: Neo_CEUS_ULM

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