Association of cerebral metabolic rate following therapeutic hypothermia with 18-month neurodevelopmental outcomes after neonatal hypoxic ischemic encephalopathy.

BACKGROUND: Therapeutic hypothermia (TH) is standard of care for moderate to severe neonatal hypoxic ischemic encephalopathy (HIE) but many survivors still suffer lifelong disabilities and benefits of TH for mild HIE are under active debate. Development of objective diagnostics, with sensitivity to mild HIE, are needed to select, guide, and assess response to treatment. The objective of this study was to determine if cerebral oxygen metabolism (CMRO2) in the days after TH is associated with 18-month neurodevelopmental outcomes as the first step in evaluating CMRO2's potential as a diagnostic for HIE. Secondary objectives were to compare associations with clinical exams and characterise the relationship between CMRO2 and temperature during TH. METHODS: This was a prospective, multicentre, observational, cohort study of neonates clinically diagnosed with HIE and treated with TH recruited from the tertiary neonatal intensive care units (NICUs) of Boston Children's Hospital, Brigham and Women's Hospital, and Beth Israel Deaconess Medical Center between December 2015 and October 2019 with follow-up to 18 months. In total, 329 neonates ≥34 weeks gestational age admitted with perinatal asphyxia and suspected HIE were identified. 179 were approached, 103 enrolled, 73 received TH, and 64 were included. CMRO2 was measured at the NICU bedside by frequency-domain near-infrared and diffuse correlation spectroscopies (FDNIRS-DCS) during the late phases of hypothermia (C), rewarming (RW) and after return to normothermia (NT). Additional variables were body temperature and clinical neonatal encephalopathy (NE) scores, as well as findings from magnetic resonance imaging (MRI) and spectroscopy (MRS). Primary outcome was the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III) at 18 months, normed (SD) to 100 (15). FINDINGS: Data quality for 58 neonates was sufficient for analysis. CMRO2 changed by 14.4% per °C (95% CI, 14.2-14.6) relative to its baseline at NT while cerebral tissue oxygen extraction fraction (cFTOE) changed by only 2.2% per °C (95% CI, 2.1-2.4) for net changes from C to NT of 91% and 8%, respectively. Follow-up data for 2 were incomplete, 33 declined and 1 died, leaving 22 participants (mean [SD] postnatal age, 19.1 [1.2] month; 11 female) with mild to moderate HIE (median [IQR] NE score, 4 [3-6]) and 21 (95%) with BSID-III scores >85 at 18 months. CMRO2 at NT was positively associated with cognitive and motor composite scores (ß (SE) = 4.49 (1.55) and 2.77 (1.00) BSID-III points per 10-10 moL/dl × mm2/s, P = 0.009 and P = 0.01 respectively; linear regression); none of the other measures were associated with the neurodevelopmental outcomes. INTERPRETATION: Point of care measures of CMRO2 in the NICU during C and RW showed dramatic changes and potential to assess individual response to TH. CMRO2 following TH outperformed conventional clinical evaluations (NE score, cFTOE, and MRI/MRS) at predicting cognitive and motor outcomes at 18 months for mild to moderate HIE, providing a promising objective, physiologically-based diagnostic for HIE. FUNDING: This clinical study was funded by an NIH grant from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, United States (R01HD076258).

Improving Infant Hydrocephalus Outcomes in Uganda: A Longitudinal Prospective Study Protocol for Predicting Developmental Outcomes and Identifying Patients at Risk for Early Treatment Failure after ETV/CPC.

Infant hydrocephalus poses a severe global health burden; 80% of cases occur in the developing world where patients have limited access to neurosurgical care. Surgical treatment combining endoscopic third ventriculostomy and choroid plexus cauterization (ETV/CPC), first practiced at CURE Children's Hospital of Uganda (CCHU), is as effective as standard ventriculoperitoneal shunt (VPS) placement while requiring fewer resources and less post-operative care. Although treatment focuses on controlling ventricle size, this has little association with treatment failure or long-term outcome. This study aims to monitor the progression of hydrocephalus and treatment response, and investigate the association between cerebral physiology, brain growth, and neurodevelopmental outcomes following surgery. We will enroll 300 infants admitted to CCHU for treatment. All patients will receive pre/post-operative measurements of cerebral tissue oxygenation (SO2), cerebral blood flow (CBF), and cerebral metabolic rate of oxygen consumption (CMRO2) using frequency-domain near-infrared combined with diffuse correlation spectroscopies (FDNIRS-DCS). Infants will also receive brain imaging, to monitor tissue/ventricle volume, and neurodevelopmental assessments until two years of age. This study will provide a foundation for implementing cerebral physiological monitoring to establish evidence-based guidelines for hydrocephalus treatment. This paper outlines the protocol, clinical workflow, data management, and analysis plan of this international, multi-center trial.

Predictability matters: on the stimulus-driven account of the multiple-cue effect.

To examine the issue of whether attentional focus can split among noncontiguous locations, Wright and Richard (2003) used a multiple-cue display and found the validity effect for each of the multiple cues. However, they argued against the multiple foci account by claiming that the multiple-cue effect they obtained was stimulus-driven. We doubt whether their cues were indeed exogenous as they claimed since their target could appear in any one of the eight possible locations but the cue validity was set at 50%. In this case, the cue was in fact predictive as to the target location. In the current study, we showed that when the cues were designed to be truly nonpredictive (12.5%), the multiple-cue effect was eliminated (Experiment 2). We replicated the multiple-cue effect when the cue validity was 50%, as in Wright and Richard (Experiment 1), and showed that there was a cue-triggered, attentional-orienting effect but not visual search advantage when the cue remained on the target display (Experiment 3). Our results, therefore, highlight the possibility of involvements of top-down controls in the validity effect found for multiple-cue displays and the importance of taking predictability into consideration in the testing of hypotheses derived from attention theories.