Abstract
Hyperbilirubinemia (HB) occurs in 90% of preterm newborns. Moderate HB can induce acute neurological disorders while severe HB has been linked to a higher incidence of apneas of prematurity. The present study aimed to test the hypothesis that even moderate HB disrupts cardiorespiratory control in preterm lambs. Two groups of preterm lambs (born 14 days prior to term), namely control (n = 6) and HB (n = 5), were studied. At day 5 of life, moderate HB (150–250 μmol/L) was induced during 17 h in the HB group after which cardiorespiratory control as well as laryngeal and pulmonary chemoreflexes were assessed during baseline recordings and during hypoxia. Recordings were repeated 72 h after HB induction, just before euthanasia. In addition, neuropathological studies were performed to investigate for cerebral bilirubin deposition as well as for signs of glial reactivity in brainstem structures involved in cardiorespiratory control. Results revealed that sustained and moderate HB: (i) decreased baseline respiratory rate and increased the time spent in apnea; (ii) blunted the cardiorespiratory inhibition normally observed during both laryngeal and pulmonary chemoreflexes; and (iii) increased heart rate in response to acute hypoxia. These acute physiological changes were concurrent with an activation of Alzheimer type II astrocytes throughout the brain, including the brainstem. Concomitantly, bilirubin deposits were observed in the leptomeninges, but not in brain parenchyma. While most cardiorespiratory alterations returned to normal 72 h after HB normalization, the expression of glial fibrillary acid protein (GFAP) and ionized calcium binding adaptor molecule 1 (Iba1) was still increased within the nucleus tractus solitarius. In conclusion, moderate and sustained HB in preterm lambs induced cardiorespiratory alterations, the latter of which were associated with neurohistopathological changes. These changes are indicative of an inflammatory response in the brainstem neuroanatomical substrates involved in cardiorespiratory control.
Highlights
Hyperbilirubinemia (HB) is one of the most common problems encountered in neonates, preterms (Watchko, 2009)
We aimed to further elucidate the mechanisms involved in these alterations by assessing whether neurohistopathological alterations are present in the region of the nucleus tractus solitarius, which is devoted to central processing of cardiorespiratory afferent inputs (Kubin et al, 2006)
On day 0 (D0), moderate HB significantly blunted the cardiorespiratory inhibition normally observed during laryngeal chemoreflexes (LCR), including a decrease in the number and duration of apneas, lesser cardiac inhibition and a lesser decrease in SpO2
Summary
Hyperbilirubinemia (HB) is one of the most common problems encountered in neonates, preterms (Watchko, 2009). A few studies have suggested an association between HB and apneas and/or bradycardias in newborn infants (Johnson et al, 2009; Amin et al, 2014; Amin and Wang, 2015). A study in rat pups provided evidence that acute HB influences respiratory control; the degree of HB was much higher and more transient than levels clinically encountered in neonates (Mesner et al, 2008). The above studies suggest that HB induces respiratory alterations in the neonate. The main objective of the present study was to test the hypothesis that moderate HB, at a level similar to that commonly observed in newborn infants, induces acute and delayed alterations in cardiorespiratory control. We aimed to further elucidate the mechanisms involved in these alterations by assessing whether neurohistopathological alterations are present in the region of the nucleus tractus solitarius, which is devoted to central processing of cardiorespiratory afferent inputs (Kubin et al, 2006)
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