Hypothermia During ECMO to Decrease Brain Injury

Term and late preterm neonates with severe hypoxemic respiratory failure [NHRF] receive
extracorporeal membrane oxygenation (ECMO), a modified form of cardiopulmonary bypass, when
maximal conventional therapy fails. Although ECMO significantly improves survival and
decreases disability, 15-50% of survivors nevertheless have poor neurodevelopmental [ND]
outcomes due to hypoxemia and cerebral hypoperfusion occurring prior to and during ECMO.
Hypothermia [HYP] (33 deg-34 deg C for 48-72 hours) has been shown to improve ND outcomes
and following neonatal hypoxic-ischemic encephalopathy [NE]. Whether the addition of
hypothermia to ECMO for severe NHRF will improve ND outcomes is unknown. Long-term
evaluation of ND outcomes is the gold standard for determining the full spectrum of
developmental disabilities as neonatal clinical findings; biochemical and
electrophysiological tests; and cranial sonography have limited predictive value.
Conventional magnetic resonance imaging [MRI] has a predictive accuracy of > 0.8 for death
and disability following NE. MR abnormalities in infants undergoing ECMO for NHRF differ
from those seen in NE and there are no systematic reports on the ND implications of MR
abnormalities seen in NHRF treated with ECMO. Given the societal and economic costs
associated with poor long-term ND outcomes and the challenges of neurologic assessment in
critically ill neonates receiving ECMO for NHRF, there is an urgent need for (i)
neuroprotection pre-/during ECMO to decrease brain injury and (ii) innovative diagnostic
modalities to enable early diagnosis and intervention.

Our goal is to improve the treatment and ND outcomes in neonates with NHRF. The overall
objectives of this proposal are to establish the neuroprotective role of hypothermia during
ECMO for NHRF as evaluated by ND assessment at 18-22 months [mo] of age and to validate the
use of conventional and advanced MR techniques as biomarkers of brain injury. The central
hypotheses are that (i) HYP to 33.5°C during the 1st 72 hours of ECMO in NHRF will reduce
the extent and severity of brain injury as evaluated by Bayley Scales of Infant Development
(BSID-III) cognitive scores at 18-22 mo and proportion of normal MRI studies in the neonatal
period and at 18-22 mo; and (ii) conventional and advanced MR techniques in the neonatal
period and at 18-22 mo will be biomarkers of brain injury allowing prediction of ND
outcomes, and monitoring of post-injury brain growth and plasticity.

The specific aims are to evaluate:

1. Safety and efficacy of hypothermia combined with ECMO for NHRF in improving
neurodevelopmental outcomes at 18-22 months of age

2. MR abnormalities in the neonatal period and at 18-22 months of age and their predictive
accuracy for neurodevelopmental outcomes at 18-22 months of age following hypothermia
during ECMO for NHRF

MRI will be obtained in the neonatal period as part of routine clinical care; MRI will be
repeated at 18-22 mo of age on an outpatient basis if funding is available to assess
longitudinal changes in brain structure and metabolite profile following ECMO for NHRF and
to correlate these with ND outcomes at 18-22 mo of age.

Inclusion Criteria:

- Neonates ≥ 34 weeks gestational age and postnatal age ≤ 28 days

- Presence of severe reversible NHRF qualifying for ECMO based on institutional
guidelines including:

- Oxygenation Index > 35 ([mean airway pressure in cmH2O x Fractional inspired O2
concentration x 100]/Arterial O2 tension in mmHg) or

- Alveolar-arterial oxygen gradient > 600 mmHg for 4 h

- Infants undergoing veno-arterial or veno-venous ECMO

Exclusion Criteria:

- Lethal chromosomal and congenital anomalies including congenital diaphragmatic hernia
(CDH) Infants with CDH, who constitute a third of neonates undergoing ECMO, have been
excluded because the high mortality and morbidity is related more to the underlying
lung abnormality and practice variation in timing of CDH repair rather than to NHRF.

- ECMO for post operative cardiac support

- Neonates with a birth weight < 1.8 kg

- Initiation of HYP for NE prior to initiating ECMO for NHRF