Post-hypoxic hypoperfusion is associated with suppression of cerebral metabolism and increased tissue oxygenation in near-term fetal sheep

Abstract

Secondary cerebral hypoperfusion is common following perinatal hypoxia-ischaemia. However, it remains unclear whether this represents a true failure to provide sufficient oxygen and nutrients to tissues, or whether it is simply a consequence of reduced cerebral metabolic demand. We therefore examined the hypothesis that cerebral oxygenation would be reduced during hypoperfusion after severe asphyxia, and further, that the greater neural injury associated with blockade of the adenosine A(1) receptor during the insult would be associated with greater hypoperfusion and deoxygenation. Sixteen near-term fetal sheep received either vehicle or 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) for 1 h, followed by 10 min of severe asphyxia induced by complete occlusion of the umbilical cord. Infusions were discontinued at the end of the occlusion and data were analysed for the following 8 h. A transient, secondary fall in carotid artery blood flow and laser Doppler flow was seen from approximately 1-4 h after occlusion (P < 0.001), with no significant differences between vehicle and DPCPX. Changes in laser Doppler blood flow were highly correlated with carotid blood flow (r(2)= 0.81, P < 0.001). Cortical metabolism was suppressed, reaching a nadir 1 h after occlusion and then resolving. Cortical tissue P(O(2)) was significantly increased at 1, 2 and 3 h after occlusion compared to baseline, and inversely correlated with carotid blood flow (r(2)= 0.69, P < 0.001). In conclusion, contrary to our initial hypothesis, delayed posthypoxic hypoperfusion was associated with suppression of cerebral metabolism and increased tissue P(O(2)), and was not significantly affected by preceding adenosine A1 blockade. These data suggest that posthypoxic hypoperfusion is actively mediated and reflects suppressed cerebral metabolism.

Figure 1. Time sequence of changes in tP_O2 (mmHg), cortical heat production and EEG intensity (dB) in DPCPX and vehicle control fetuses for 2 h before, during and 8 h after a 10-min umbilical cord occlusion

The two vertical dashed lines depicted in the bottom graph indicate the start and finish of occlusion. The horizontal bars indicate significant hourly averages. Values are the mean ±s.e.m.*P < 0.05 versus baseline values for both groups, ^aP < 0.05 versus baseline values for controls, ^bP < 0.05 versus baseline values for DPCPX infused fetuses.

Figure 2. Time sequence of changes in carotid blood flow (ml min⁻¹), cortical blood flow (% baseline) and mean arterial blood pressure (mmHg) from 2 h before, during and up to 8 h after a 10-min umbilical cord occlusion

The two vertical dashed lines depicted in the bottom graph indicate the start and finish of occlusion. The horizontal bars indicate significant hourly averages. Values are the mean ±s.e.m.*P < 0.05 versus baseline values for both groups.

Figure 3. Relationships between carotid blood flow and tP_O2, and carotid blood flow and cortical blood flow (% baseline)

Individual animals from both groups are plotted at hourly time points after occlusion. Note that some animals had missing data for tP_O2 or cortical flow. Carotid blood flow showed a negative within subjects linear correlation, calculated using the method of Bland & Altman (1995), with tP_O2 (r² = 0.69, P < 0.001, A) in this 8 h recovery period. Carotid blood flow was positively correlated with cortical blood flow (r² = 0.81, P < 0.001, B).