388 - Cerebrovascular dysfunction and mediation of neurological injury in response to perinatal asphyxia in growth restricted lambs

Publication Number: 388.4287

Beth J. Allison, Hudson Institute of Medical Research, Clayton, Victoria, Australia; Beth Piscopo, Monash University, Clayton, Victoria, Australia; Zahrah Azman, The Ritchie Centre, Hudson Institute of Medical Research and Monash University, Melbourne, Victoria, Australia; Amy Sutherland, Hudson Institute of Medical Research, Melbourne, Victoria, Australia; Atul Malhotra, Monash University, Melbourne, Victoria, Australia; Graeme Polglase, Monash University, Melbourne, Victoria, Australia; Suzanne Miller, Monash University, Clayton, Victoria, Australia

Background: Fetal growth restriction (FGR) occurs secondary to chronic hypoxia and can result in serious neurological consequences in the offspring. FGR is associated with higher rates of perinatal asphyxia compared to appropriately grown infants. Currently, it is unknown whether the cerebrovascular response and pathological impacts of asphyxia are similar in FGR and appropriately grown offspring.

Objective: We aimed to investigate cerebrovascular dysfunction and the mediation of neurological injury in response to perinatal asphyxia in FGR lambs.

Design/Methods: FGR was induced via single umbilical artery ligation at 89 days gestation (dGA) in twin fetal sheep (term=148dGA, unoperated twin - control). Preterm lambs were delivered by caesarean section (126dGA) and immediately euthanised (fetal control, n=8), or ventilated for 8 hours (vent, n=6) with or without asphyxia induced via cord occlusion at birth (asphyxia, n=6). During asphyxia, resuscitation was withheld until diastolic blood pressure (DBP) reached 10mmHg. Cerebral and systemic BP, flow and oxygenation were measured throughout the experiment. At postmortem middle cerebral arteries (MCA) were collected for assessment of vascular function using wire myography and brains were underwent neuropathological assessment.

Results: Time taken to reach asphyxia (cord occlusion and withholding ventilation until DBP=10mmHg) was significantly longer in the FGR cohort (FGR=17min vs control=15min, p=0.04). Carotid blood flow at 12 mins post asphyxia was elevated 3-fold in FGR vs control (p < 0.0001, Fig 1B), however this was not accompanied by increased cerebral oxygenation (Fig 1C). Asphyxia, but not growth restriction, significantly increased maximum vasodilation in MCA’s (p=0.003) compared to fetal and vent groups. However, analysis of brain bleeds showed a significant increase in microbleeds in the white matter of FGR brains compared to controls in all groups (p=0.04).

Conclusion(s): FGR lambs have subtle but physiologically important differences in their cerebral hemodynamic responses to perinatal asphyxia. Our data suggests that despite maintained carotid blood flow, FGR lambs were unable to maintain cerebral oxygenation throughout asphyxia. This implies the cerebrovascular response to asphyxia is different in FGR lambs, potentially underlying a mismatch in metabolic uptake and/or delivery. Despite the robust physiological response to asphyxia, the growth restricted brain is vulnerable to injury. The findings of this study have important implications for detecting asphyxia and the subsequent clinical care of growth restricted newborns that have experienced asphyxia.

Figure 1.
PAS Fig 1.pdfAsphyxia characteristics and cerebrovascular physiology. Data presented as mean ± standard error of the mean for; femoral blood pressure (mmHg, A), carotid blood flow corrected for brain weight (ml.min-1.g-1, B), femoral blood flow corrected for body weight (ml.min-1.kg-1, C) and total oxygen index in the cerebral circulation derived from near infrared spectroscopy (%, D), length of asphyxia (mins, E), maximum change in mean arterial blood pressure (mmHg, F) and maximum change in oxygen saturation (SaO2 %, G). Groups are fetal growth restricted with asphyxia (FGR, red, n=16) and control asphyxia (control, blue, n=15). Dotted line represents the onset of umbilical cord occlusion (UCO), the beginning of the asphyxia. Grey boxes represent data variability of non-physiological origin caused by moving of the lamb for weighing. Experimental time measured in minutes of asphyxia. A-D Analysis performed using mixed effect analysis with uncorrected Fishers least significant difference test. E-G Analysis performed used unpaired Student’s t-test. *p < 0.05, **p < 0.01, ****p < 0.0001.