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

Recruiting

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

• Registration Number: NCT06611254
• Lead Sponsor: University of Erlangen-Nürnberg Medical School

Brief Summary

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.

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 Timeline

• Study First Submitted: 2024-06-21
• Study Start: 2024-06-24
• Status Verified: 2024-09
• Study First Submitted QC: 2024-09-20
• Last Update Submitted: 2024-09-20
• Study First Posted: 2024-09-24
• Last Update Posted: 2024-09-24
• Primary Completion: 2027-07-01
• Study Completion: 2027-12-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 20

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 & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
Neonates with perinatal asphyxia and indication for hypothermia treatment	Contrast enhanced ultrasound imaging (CEUS) and post processing with ULM	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.

Primary Outcome Measures

Name	Time	Method
CEUS Time intensity curves	before(T1, within the first 6hours of life), during hypothermia treatment(T2, 6-78hours of life), after treatment (T3, within first week of life)	All CEUS outcomes will be generated in order to achieve time intensity curves in contrast enhanced ultrasound analysis
CEUS Measurement1	before(T1, within the first 6hours of life), during hypothermia treatment(T2, 6-78hours of life), after treatment (T3, within first week of life)	PE (Peak-Enhancement)
CEUS Measurement2	before(T1, within the first 6hours of life), during hypothermia treatment(T2, 6-78hours of life), after treatment (T3, within first week of life)	WiAUC (Wash-in Area Under the Curve (AUC(TI: TTP)))
CEUS Measurement3	before(T1, within the first 6hours of life), during hypothermia treatment(T2, 6-78hours of life), after treatment (T3, within first week of life)	WiAUC (Wash-in Area Under the Curve (AUC(TI: TTP)))
CEUS Measurement4	before(T1, within the first 6hours of life), during hypothermia treatment(T2, 6-78hours of life), after treatment (T3, within first week of life)	RT (Rise Time)
CEUS Measurement5	before(T1, within the first 6hours of life), during hypothermia treatment(T2, 6-78hours of life), after treatment (T3, within first week of life)	mTT (mean Transit Time local) (mTT-TI))
CEUS Measurement6	before(T1, within the first 6hours of life), during hypothermia treatment(T2, 6-78hours of life), after treatment (T3, within first week of life)	TTP (Time to Peak)
CEUS Measurement7	before(T1, within the first 6hours of life), during hypothermia treatment(T2, 6-78hours of life), after treatment (T3, within first week of life)	WiR (Wash-in-Rate )
CEUS Measurement8	before(T1, within the first 6hours of life), during hypothermia treatment(T2, 6-78hours of life), after treatment (T3, within first week of life)	WiPI (Wash-in Perfusion Index (WiAUC/RT))
CEUS Measurement9	before(T1, within the first 6hours of life), during hypothermia treatment(T2, 6-78hours of life), after treatment (T3, within first week of life)	WoAUC (Wash-out AUC (AUC(TTP:TO)))
CEUS Measurement10	before(T1, within the first 6hours of life), during hypothermia treatment(T2, 6-78hours of life), after treatment (T3, within first week of life)	WiWoAUC (Wash-in- und Wash-out-AUC (WiAUC+WoAUC))
CEUS Measurement11	before(T1, within the first 6hours of life), during hypothermia treatment(T2, 6-78hours of life), after treatment (T3, within first week of life)	FT (Fall Time - (TO-TTP))
CEUS Measurement12	before(T1, within the first 6hours of life), during hypothermia treatment(T2, 6-78hours of life), after treatment (T3, within first week of life)	WOR (Wash-out-Rate) QOF (Quality Of Fit between the echo-power signal and f(t)
CEUS Measurement13	before(T1, within the first 6hours of life), during hypothermia treatment(T2, 6-78hours of life), after treatment (T3, within first week of life)	QOF (Quality Of Fit between the echo-power signal and f(t)
Near-infrared spectroscopy	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 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.
Visualization and quantification of cerebral perfusion with CEUS	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 imaging for cerebral perfusion in asphyxia
Visualization and quantification of of renal perfusion with CEUS	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 imaging for renal perfusion in asphyxia

Secondary Outcome Measures

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

Trial Locations

Locations (1)

FAU Erlangen-Nuernberg; 🇩🇪 Erlangen, Bavaria, Germany