Elavazhagan Chakkarapani

Xenon Enhances Hypothermic Neuroprotection in Asphyxiated Newborn Pigs

To investigate whether inhaling 50% xenon during hypothermia (HT) offers better neuroprotection than xenon or HT alone.

Association of prenatal diagnosis of critical congenital heart disease with postnatal brain development and the risk of brain injury

IMPORTANCE The relationship of prenatal diagnosis of critical congenital heart disease (CHD) with brain injury and brain development is unknown. Given limited improvement of CHD outcomes with prenatal diagnosis, the effect of prenatal diagnosis on brain health may reveal additional benefits. OBJECTIVE To compare the prevalence of preoperative and postoperative brain injury and the trajectory of brain development in neonates with prenatal vs postnatal diagnosis of CHD. DESIGN, SETTING, AND PARTICIPANTS Cohort study of term newborns with critical CHD recruited consecutively from 2001 to 2013 at the University of California, San Francisco and the University of British Columbia. Term newborns with critical CHD were studied with brain magnetic resonance imaging preoperatively and postoperatively to determine brain injury severity and microstructural brain development with diffusion tensor imaging by measuring fractional anisotropy and the apparent diffusion coefficient. Comparisons of magnetic resonance imaging findings and clinical variables were made between prenatal and postnatal diagnosis of critical CHD. A total of 153 patients with transposition of the great arteries and single ventricle physiology were included in this analysis. MAIN OUTCOMES AND MEASURES The presence of brain injury on the preoperative brain magnetic resonance imaging and the trajectory of postnatal brain microstructural development. RESULTS Among 153 patients (67% male), 96 had transposition of the great arteries and 57 had single ventricle physiology. The presence of brain injury was significantly higher in patients with postnatal diagnosis of critical CHD (41 of 86 [48%]) than in those with prenatal diagnosis (16 of 67 [24%]) (P = .003). Patients with prenatal diagnosis demonstrated faster brain development in white matter fractional anisotropy (rate of increase, 2.2%; 95% CI, 0.1%-4.2%; P = .04) and gray matter apparent diffusion coefficient (rate of decrease, 0.6%; 95% CI, 0.1%-1.2%; P = .02). Patients with prenatal diagnosis had lower birth weight (mean, 3184.5 g; 95% CI, 3050.3-3318.6) than those with postnatal diagnosis (mean, 3397.6 g; 95% CI, 3277.6-3517.6) (P = .02). Those with prenatal diagnosis had an earlier estimated gestational age at delivery (mean, 38.6 weeks; 95% CI, 38.2-38.9) than those with postnatal diagnosis (mean, 39.1 weeks; 95% CI, 38.8-39.5) (P = .03). CONCLUSIONS AND RELEVANCE Newborns with prenatal diagnosis of single ventricle physiology and transposition of the great arteries demonstrate less preoperative brain injury and more robust microstructural brain development than those with postnatal diagnosis. These results are likely secondary to improved cardiovascular stability. The impact of these findings on neurodevelopmental outcomes warrants further study.

Neonatal rat model of intraventricular haemorrhage and post-haemorrhagic ventricular dilatation with long-term survival into adulthood

K. Aquilina, E. Chakkarapani, S. Love and M. Thoresen (2011) Neuropathology and Applied Neurobiology37, 156–165
Neonatal rat model of intraventricular haemorrhage and post‐haemorrhagic ventricular dilatation with long‐term survival into adulthood

The feasibility of using a portable xenon delivery device to permit earlier xenon ventilation with therapeutic cooling of neonates during ambulance retrieval.

BACKGROUND:Therapeutic hypothermia is the standard of care after perinatal asphyxia. Preclinical studies show 50% xenon improves outcome, if started early. METHODS:During a 32-patient study randomized between hypothermia only and hypothermia with xenon, 5 neonates were given xenon during retrieval using a closed-circuit incubator-mounted system. RESULTS:Without xenon availability during retrieval, 50% of eligible infants exceeded the 5-hour treatment window. With the transportable system, 100% were recruited. Xenon delivery lasted 55 to 120 minutes, using 174 mL/h (117.5–193.2) (median [interquartile range]), after circuit priming (1300 mL). CONCLUSIONS:Xenon delivery during ambulance retrieval was feasible, reduced starting delays, and used very little gas.

Therapeutic hypothermia delays the C-reactive protein response and suppresses white blood cell and platelet count in infants with neonatal encephalopathy

Background Therapeutic hypothermia (HT) delays the cytokine response in infants with neonatal encephalopathy (NE). Objective To determine if HT delayed the C-reactive protein (CRP) response and altered white blood cell (WBC), neutrophil and platelet count course during the first week of life in infants with NE. Design Retrospective cohort study. Setting Regional neonatal intensive care unit, UK. Patients 104 term infants with NE (38 normothermia (NT) and 66 HT) born between 1998 and 2010. Infants not exposed to prenatal sepsis risk factors were classified as group ‘A’ and exposed infants to group ‘B’. CRP >10 mg/L was defined as significant response. Main outcome measures Time to CRP >10 mg/L, peak CRP, WBC, neutrophil and platelet count. Results Blood cultures were negative in all the infants. In babies who had CRP response, HT delayed time to CRP >10 mg/L (median (95% CI): group A, HT: 36 h (28.3 to 48.0); NT: 24 h (0.0 to 24.0); p=0.001; group B, HT: 30 h (15.2 to 56.8); NT: 12 h (0.0 to 24.0); p=0.009) and time to peak CRP (median (95% CI): group A, HT: 60 h (60.0 to 72.0); NT: 36 h (0.0 to 48.0); p=0.001; group B, HT: 84 h (62.1 to 120.0); NT: 24 h (0.0 to 36.0); p=0.001). Compared with NT, HT was associated with reduction in slope of CRP elevation by 0.5 (95% CI 0.04 to 0.97), WBC by 2.18×109/L (95% CI 0.002 to 4.35) and platelet count by 32.3×109/L (95% CI 2.75 to 61.8) independent of exposure to sepsis risk, meconium aspiration and severity of asphyxia. Conclusions Therapeutic hypothermia delayed the initiation of CRP and its peak response, and depressed the WBC and platelet count compared with NT.

Effects of xenon and hypothermia on cerebrovascular pressure reactivity in newborn global hypoxic-ischemic pig model

Autoregulation of cerebral perfusion is impaired in hypoxic-ischemic encephalopathy. We investigated whether cerebrovascular pressure reactivity (PRx), an element of cerebral autoregulation that is calculated as a moving correlation coefficient between averages of intracranial and mean arterial blood pressure (MABP) with values between −1 and +1, is impaired during and after a hypoxic-ischemic insult (HI) in newborn pigs. Associations between end-tidal CO2, seizures, neuropathology, and PRx were investigated. The effect of hypothermia (HT) and Xenon (Xe) on PRx was studied. Pigs were randomized to Sham, and after HI to normothermia (NT), HT, Xe or xenon hypothermia (XeHT). We defined PRx >0.2 as peak and negative PRx as preserved. Neuropathology scores after 72 hours of survival was grouped as ‘severe’ or ‘mild.’ Secondary PRx peak during recovery, predictive of severe neuropathology and associated with insult severity (P = 0.05), was delayed in HT (11.5 hours) than in NT (6.5 hours) groups. Seizures were associated with impaired PRx in NT pigs (P = 0.0002), but not in the HT/XeHT pigs. PRx was preserved during normocapnia and impaired during hypocapnia. Xenon abolished the secondary PRx peak, increased (mean (95% confidence interval (CI)) MABP (6.5 (3.8, 9.4) mm Hg) and cerebral perfusion pressure (5.9 (2.9, 8.9) mm Hg) and preserved the PRx (regression coefficient, −0.098 (95% CI (−0.18, −0.01)), independent of the insult severity.

Reliability of Early Magnetic Resonance Imaging (MRI) and Necessity of Repeating MRI in Noncooled and Cooled Infants With Neonatal Encephalopathy

In cooled newborns with encephalopathy, although late magnetic resonance imaging (MRI) scan (10-14 days of age) is reliable in predicting long-term outcome, it is unknown whether early scan (3-6 days of life) is. We compared the predominant pattern and extent of lesion between early and late MRI in 89 term neonates with neonatal encephalopathy. Forty-three neonates (48%) were cooled. The predominant pattern of lesions and the extent of lesion in the watershed region agreed near perfectly in noncooled (kappa = 0.94; k = 0.88) and cooled (k = 0.89; k = 0.87) infants respectively. There was perfect agreement in the extent of lesion in the basal nuclei in noncooled infants (k = 0.83) and excellent agreement in cooled infants (k = 0.67). Changes in extent of lesions on late MRI occurred in 19 of 89 infants, with higher risk in infants with hypoglycemia and moderate-severe lesions in basal nuclei. In most term neonates with neonatal encephalopathy, early MRI (relative to late scan) robustly predicts the predominant pattern and extent of injury.

Differential Tiam1/Rac1 Activation in Hippocampal and Cortical Neurons Mediates Differential Spine Shrinkage in Response to Oxygen/Glucose Deprivation:

Distinct neuronal populations show differential sensitivity to global ischemia, with hippocampal CA1 neurons showing greater vulnerability compared to cortical neurons. The mechanisms that underlie differential vulnerability are unclear, and we hypothesize that intrinsic differences in neuronal cell biology are involved. Dendritic spine morphology changes in response to ischemic insults in vivo, but cell type-specific differences and the molecular mechanisms leading to such morphologic changes are unexplored. To directly compare changes in spine size in response to oxygen/glucose deprivation (OGD) in cortical and hippocampal neurons, we used separate and equivalent cultures of each cell type. We show that cortical neurons exhibit significantly greater spine shrinkage compared to hippocampal neurons. Rac1 is a Rho-family GTPase that regulates the actin cytoskeleton and is involved in spine dynamics. We show that Rac1 and the Rac guanine nucleotide exchange factor (GEF) Tiam1 are differentially activated by OGD in hippocampal and cortical neurons. Hippocampal neurons express more Tiam1 than cortical neurons, and reducing Tiam1 expression in hippocampal neurons by shRNA enhances OGD-induced spine shrinkage. Tiam1 knockdown also reduces hippocampal neuronal vulnerability to OGD. This work defines fundamental differences in signalling pathways that regulate spine morphology in distinct neuronal populations that may have a role in the differential vulnerability to ischemia.

A Randomized Controlled Trial of the Use of Oral Glucose with or without Gentle Facilitated Tucking of Infants during Neonatal Echocardiography

Objective To compare the effect of oral glucose given with or without facilitated tucking (FT), versus placebo (water) to facilitate image acquisition during a targeted neonatal echocardiography (TNE). Design Factorial, double blind, randomized controlled trial. Setting Tertiary neonatal intensive care unit (NICU). Patients Infants born between 26 and 42 weeks of gestation (GA). Interventions One of four treatment groups: oral water (placebo), oral glucose (25%), facilitated tucking with oral water or facilitated tucking with oral glucose, during a single, structured TNE. All infants received a soother. Main Outcome Measure Change in Behavioral Indicators of Infant Pain (BIIP) scores. Results 104 preterm infants were randomized (mean ± SD GA: 33.4 ± 3.5 weeks). BIIP scores remained low during the echocardiography scan (median, [IQ range]: 0, [0 to 1]). There were no differences in the level of agitation of infants amongst the treatment groups, with estimated reductions in mean BIIP relative to control of 0.27 (95%CI -0.40 to 0.94) with use of oral glucose and .04 (-0.63 to 0.70) with facilitated tucking. There were also no differences between treatment groups in the quality and duration of the echocardiography scans. Conclusions In stable infants in the NICU, a TNE can be performed with minimal disruption in a majority of cases, simply by providing a soother. The use of 25% glucose water in this context did not provide further benefit in reducing agitation and improving image acquisition. Clinical Trial Registration Clinical Trials.gov: NCT01253889

Minimal systemic hypothermia combined with selective head cooling evaluated in a pig model of hypoxia-ischemia

Background:Selective head cooling (SHC) with moderate hypothermia (HT) and whole-body cooling are beneficial following perinatal asphyxia. SHC with systemic normothermia (NT) or minimal HT is under-investigated, could obviate systemic complications of moderate HT, and be applicable to preterm infants. We hypothesized that minimal systemic HT with SHC following hypoxia-ischemia (HI) would be neuroprotective compared with systemic NT.Methods:Newborn pigs underwent global HI causing permanent brain injury before being randomized to NT (rectal temperature (Trectal) 38.5 °C) or minimal HT (Trectal 37.0 °C) with SHC (cooling cap and body wrap) for 48 h followed by 24-h NT with 72-h survival.Results:SHC did not reduce global or regional neuropathology score when correcting for insult severity or compared with a NT group matched for HI severity but increased mortality by 26%. During 48 h, the SHC mean ± SD Trectal was 37.0 ± 0.2 °C, and Tdeep brain and Tsuperficial brain were 35.0 ± 1.1 °C and 31.5 ± 1.6 °C, respectively, with stable Tbrain achieved ≥3 h after starting cooling.Conclusion:This is the first study in newborn pigs of minimal systemic HT with SHC for 48 h and a further 24 h of NT following HI. Mortality was increased in the cooled group with no neuroprotection in survivors.