In this study, we have revealed the relationships between the decrease in CBV during HI insult and the increase in CBV within 6 h of the insult in HIE piglets. This CBV decrease during insult and increase within 6 h after it was correlated. HR showed a similar tendency to CBV but MABP did not.
During HI insult, CBV increases rapidly in a compensatory fashion, followed by impaired cerebral blood flow autoregulation and vasoparalysis that result in gradually decreased CBV due to decompensation (20, 21). In our previous translational HI piglet studies, greater decreases in CBV from baseline during insult were associated with severe brain damage or death (17).
With respect to the increase in CBV after HI insult, we have two theories to explain why greater decreases in CBV during insult were followed by greater increases in CBV after insult.
The first is severe cerebral vasoparalysis due to impaired cerebral autoregulation. Cerebral hypoperfusion, and thus decreased CBV, which are induced by severe systemic hypotension, would impair cerebral vascular autoregulation during the HI insult. After the initial resuscitation, cerebral blood flow would become passive due to a rise in systemic BP and result in an increase in CBV in the acute period immediately after resuscitation. The second is cerebral venous congestion due to heart failure, although we failed to identify a relationship between the CBV increase and the severity of the cardiac dysfunction from the data obtained in the present study, such as HR and BP. Our previous studies showed that increases in CBV at 1, 3, and 6 h after insult were associated with depressed neurocortical activity at the respective time points (18) and also histopathological brain injury at 5 days after insult (19).
Hence, this sequence of more pronounced cerebral hypoperfusion during insult being followed by greater cerebral hyperfusion after insult reflected impaired cerebral autoregulation and resulted in severe brain injuries.
In clinical practice, HIE neonates are at risk of cerebral blood flow dysregulation. Several studies have shown that impaired cerebral autoregulation (pressure-passive cerebral blood flow) after birth was associated with poor neurological outcomes (22) and increased mortality (23). Therefore, our work additionally suggests that CBV monitoring with TRS within the first 6 h after birth can estimate the degree of hypoperfusion during labor in HIE neonates and, further, can categorize the severity of brain injuries by recognizing the patterns of sequential changes in CBV during and after insult.
Significant cardiovascular dysfunction with redistribution of blood flow occurs in HI. In the initial stages of HI, cardiac output (CO) is well compensated and the distribution of blood to organs is maintained. However, blood is gradually redistributed to vital organs such as the brain and heart (24, 25). Myocardial ischemia results in ventricular dysfunction, which leads to a fall in stroke volume. Despite this reduced stroke volume, CO remains unchanged due to increased HR in the compensation phase. In the decompensation phase, HR also falls. Based on the literature, we speculated that the function of the HR increase after insult is to deliver the necessary oxygen to compensate for the HI. This would explain the association in the present study between the decrease in HR during the insult and the increase in HR after it.
MABP changes during HI constitute a complex phenomenon. MABP is influenced by multiple factors, including CO, autonomic function, neuroendocrine response, degree of vasoparalysis, and peripheral resistance (24, 26). In HI neonates, autonomic dysfunction with attenuation of parasympathetic activity and increased sympathetic activity influence the hemodynamic changes (27, 28). During HI, due to the autonomic dysfunction, compensatory tachycardia and increased BP occur initially and are followed by decompensation with a fall in HR and BP. After resuscitation, an initial reduction in myocardial contractility is accompanied by increased ventricular resistance to maintain the redistribution of the blood supply to the brain and heart.
A graphical summary of this study and our previous work with the HI piglet model is shown in Fig. 5. We can categorize three patterns of changes in CBV during and within 6 h after HI insult.
A schematic representation of the patterns of changes in CBV are shown according to severity of insult: (A) in mild HI insults, a slight CBV decrease during the insult and a decrease to baseline after the insult; (B) in moderately severe insults, a CBV decrease during the insult above the baseline and a decrease after the insult that is smaller than that of (A); and (C) in severe insults, a CBV decrease during the insult to below the initial basal level of CBV and an increase after the insult.
The angles of the CBV changes from the basal horizontal line after insult are α < β < γ (angle values of α and β are negative, whereas that of γ is positive). The categorization of each group was related to the prognosis within 5 days after insult. In pattern (A), the piglets all survived 5 days after the insult with no obvious neural pathological damage. In pattern (B), the piglets survived, but they had neural pathological damage. In pattern (C), the piglets did not survive after the insult due to severe convulsions or cardiac and respiratory failure. Thus, we can categorize the animals into groups by using the changes in CBV measured by TRS within 6 h after the insult to estimate future prognosis. This categorization could be applied to neonates with asphyxia to predict prognosis and we will plan to investigate this in future work.
The limitations of this study are as follows. In HIE, the important determinants of outcomes are not only the severity of HI during insult, but also the duration and frequency of the insult, sexual dimorphism, and the presence of infection/inflammation (5, 25, 26). We could only assess HI severity in this study.