The hypoxia-asphyxia protocol reflects the most common etiology of pediatric cardiac arrests (20
). Moreover, the pattern of regional brain injury in this piglet model (21
) corresponds to the selective vulnerability of primary sensorimotor cortex, striatum, and thalamus seen in newborns with hypoxic-ischemic encephalopathy (23
). Here, we positioned the LDF probe over vulnerable primary sensorimotor cortex. LDF measurements permit relative changes in RBC flux to be tracked in cerebral cortex to estimate changes in CBF and have been correlated with radioisotope tracer (24
) and microsphere (25
) measurements of regional changes in cortical CBF. A limitation of the LDF technique is that it measures RBC flux in a small volume of tissue (approximately 1 mm3
) and may be subject to variability arising from regional heterogeneity in autoregulatory behavior (26
). Nevertheless, a close correspondence has been reported between the autoregulatory range determined by LDF and autoradiographic tracer at diffferent postnatal ages in rabbits (12
). Moreover, we observed a close correspondence between the regional LDF measurements and the NIRS-based indices, which are derived from a much larger tissue volume. NIRS techniques have been shown to correlate with arterial spin-labeling MRI (27
) and computed tomography perfusion imaging measures of CBF (28
Given these limitations, we did not find a difference in the LDF-derived LLA between sham-operated piglets and those resuscitated from arrest with normothermic recovery. Past studies in humans (2
) and rats (4
) demonstrated impaired autoregulation after cardiac arrest with a shift in the LLA to a higher MAP (3
). It is likely that the degree of cerebral injury affects the extent of disruption in autoregulation. Although neuronal injury occurs in this model (21
), neuronal cell death in cerebral cortex largely evolves beyond the 6–9 hour period when autoregulation was measured in the present study. In addition, these piglets did not have substantial intracranial hypertension, which can exert an independent effect on LLA (16
). Moreover, the piglets are capable of regaining consciousness in the absence of anesthesia, whereas many patients will remain unconscious at 6–9 hours after arrest. Thus, it is possible that a more severe insult or longer recovery period would reveal a shift in the LLA. We did not extend the duration of asphyxia because the ability to resuscitate the heart becomes markedly difficult.
We identified a significant decrease in the LLA in post-arrest piglets that recovered during hypothermia compared to the other three groups. This observation suggests that hypothermia may enable pressure-reactive CBF at perfusion pressures that would normally result in pressure-passivity after arrest. At normal CPP, the post-arrest hypothermic group had a nearly 50% decrease in LDF from pre-arrest baseline. Consequently, increases in baseline cerebrovascular resistance during hypothermia may also expand the range of perfusion pressures at which cerebrovascular reactivity remains intact. The slightly elevated PaCO2 in the hypothermic groups would act to increase LDF and to increase the LLA. Therefore, PaCO2 does not account for the decrease in the LLA seen in the post-arrest hypothermic group.
The LLA between normothermic and hypothermic shams did not differ. It is possible that our sample size was too small to detect a difference. Post-hoc power analysis indicated a power of detecting a difference at alpha 0.05 as 74%. Although the power values for these comparisons are lower than the traditional 80%, some differences in LLA are large enough to be detected with this sample size. However, smaller differences may not be detectable. Additional studies are needed to further evaluate the effects of hypothermia on the LLA.
Delayed decreases in CBF are often present in humans and adult animals after global cerebral ischemia. By pooling normothermic cohorts, a moderate decrease in LDF could be detected. Although there was a trend toward a small increase in ICP over 6 hrs of recovery, CPP was not significantly affected. Moreover, autoregulation was intact. Thus, the lower LDF was not secondary to low CPP.
Hypothermia showed significantly reduced LDF in post-arrest and sham animals despite similar CPP. This decrease is likely related to decreases in oxygen demand (30
). Moreover, Cheng et al. (31
) demonstrated decreased CBF coupled with decreased metabolic rate in a piglet model of cerebral hypoxia and hypothermia. Our results indicate that this decline in CBF also occurs when the initiation of hypothermia is delayed until 2 hrs after ROSC and remains sustained throughout 6 hrs of moderate hypothermia.
The NIRS-derived autoregulation indices detected the LLA across cohorts. CPP below the LLA was detected by index values of COx 0.41 and HVx 0.22 in sham animals and COx 0.42 and HVx 0.21 in arrested animals. This was in agreement with our previous work demonstrating optimal sensitivity and specificity at a COx threshold of 0.42 in naïve piglets (8
). Our results indicate that continuous autoregulation monitoring with NIRS can identify the CPP limits at which the cerebral vasculature is most responsive to changes in CPP. This has important clinical implications and could guide clinicians in clarifying individual patient hemodynamic goals.
In unanesthetized piglets, increasing MAP to 90 mmHg by aortic balloon inflation has been reported to result in no change in CBF, whereas increases in MAP to 100–120 mmHg produced increases in CBF that were attributed to increased prostanoid production (14
). In the present study on anesthetized piglets, we did not observe a consistent increase in LDF in the CPP range of 100–120 mmHg. Perhaps anesthesia reduces the release of vasodilator prostanoids during hypertension or extends the autoregulatory upper limit by effects on baseline myogenic tone. We were unable to increase CPP above 100–120 mmHg because heart failure occurred. To fully examine the autoregulatory response to hypertension in this model, more aggressive cardiopulmonary support, such as bypass, or a different anesthetic regimen that does not affect cardiac contractility may be needed. Moreover, it is unclear if our results in neonatal piglets apply to older children. Juvenile animals with a greater range of cardiac function may be required to model arrest in children older than infants.