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Cerebrovascular Pressure reactivity: biomarker in newborn global hypoxia-ischemia pig model

Presented at the Neonatal Society 2011 Spring Meeting.

Chakkarapani E1, Liu X1, Dingley J2, Porter H3, Thoresen M1

1 School of Clinical Sciences, University of Bristol, Bristol BS2 8EG, UK
2 School of Medicine, Swansea University, Singleton Park, Swansea SA2 8PP, UK
3 Leicester Royal Infirmary, UK

Background: Cerebrovascular pressure reactivity (PRx) is a key element of cerebral autoregulation and illustrates the reactivity of cerebral vasculature to spontaneous low-frequency fluctuations of mean arterial blood pressure (MABP). PRx is associated with mortality and disability after traumatic head injury in children (1) and adults (2). When the PRx is intact, under finite pressure-volume compensatory reserve as in a closed skull of a newborn pig, rise in MABP leads to vasoconstriction with a concomitant reduction of cerebral blood volume and intracranial pressure (ICP) and vice-versa when the PRx is impaired. We aimed to investigate the effect of a hypoxic-ischaemic (HI) insult on PRx and whether post insult PRx is associated with neuropathology as outcome in a global newborn hypoxic-ischaemic pig model. The study was conducted under UK home office license and approved by the University of Bristol Ethical review panel.

Methods: Sixteen newborn pigs were maintained normothermic (rectal Temp 38.5ºC) before, during and after a 45 min global HI insult, during which inhaled FiO2 was reduced to ~ 5% depressing the amplitude integrated EEG to 7μV. All animals were ventilated under intravenous anaesthesia until 30h and weaned from the ventilator by 48h. The PRx, calculated as a linear (Pearson’s) moving correlation coefficients (values:-1 to +1) between 40 consecutive 8-second averages of ICP and MABP was recorded from baseline to 34h. At 72h, pigs underwent terminal perfusion fixation of the brain under deep anaesthesia. Neuropathology from 7 brain regions was assessed by a pathologist blinded to clinical details and the score ranged from 0.0 to 4.0 for each region with a summated range from 0.0 to 28.0.3 Poor outcome were values 8-28 and good outcome <8. Three sham animals underwent all procedures except the HI insult.

Results: The median (range) age was 15(11,30)h and mean(sd) weight was1510(237)g. Lactate (15.8 vs 2.22) mmol/L and arterial pH (7.0 vs 7.46) at the end of the insult period differed significantly between the experimental pigs and the sham. Median PRx during the insult was significantly higher (0.36 vs -0.05 p<0.00001) compared to the sham group. PRx normalised within 90 min after the insult. Median PRx post insult was significantly associated with summated neuropathology (r =-0.6, p=0.02). The Positive Predictive Value for poor outcome of a post insult median PrX >0.003 is 100%.

Conclusion: Cerebrovascular pressure reactivity was impaired both during and after the hypoxic ischaemic insult and positive median PRx value post HI is a biomarker with PPV of 100% in the global hypoxic-ischaemic newborn pig model.

Corresponding author: marianne.thoresen@bristol.ac.uk

1. Brady, KM et al. Pediatrics 2009.
2. Zweifel, C et al. Neurosurg focus 2008.
3. Chakkarapani E, et al. Annals of Neurology, September 2010.

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