Protective Ventilation of Preterm Lambs Exposed to Acute Chorioamnionitis Does Not Reduce Ventilation-Induced Lung or Brain Injury

Abstract

BackgroundThe onset of mechanical ventilation is a critical time for the initiation of cerebral white matter (WM) injury in preterm neonates, particularly if they are inadvertently exposed to high tidal volumes (VT) in the delivery room. Protective ventilation strategies at birth reduce ventilation-induced lung and brain inflammation and injury, however its efficacy in a compromised newborn is not known. Chorioamnionitis is a common antecedent of preterm birth, and increases the risk and severity of WM injury. We investigated the effects of high VT ventilation, after chorioamnionitis, on preterm lung and WM inflammation and injury, and whether a protective ventilation strategy could mitigate the response.MethodsPregnant ewes (n = 18) received intra-amniotic lipopolysaccharide (LPS) 2 days before delivery, instrumentation and ventilation at 127±1 days gestation. Lambs were either immediately euthanased and used as unventilated controls (LPSUVC; n = 6), or were ventilated using an injurious high VT strategy (LPSINJ; n = 5) or a protective ventilation strategy (LPSPROT; n = 7) for a total of 90 min. Mean arterial pressure, heart rate and cerebral haemodynamics and oxygenation were measured continuously. Lungs and brains underwent molecular and histological assessment of inflammation and injury.ResultsLPSINJ lambs had poorer oxygenation than LPSPROT lambs. Ventilation requirements and cardiopulmonary and systemic haemodynamics were not different between ventilation strategies. Compared to unventilated lambs, LPSINJ and LPSPROT lambs had increases in pro-inflammatory cytokine expression within the lungs and brain, and increased astrogliosis (p<0.02) and cell death (p<0.05) in the WM, which were equivalent in magnitude between groups.ConclusionsVentilation after acute chorioamnionitis, irrespective of strategy used, increases haemodynamic instability and lung and cerebral inflammation and injury. Mechanical ventilation is a potential contributor to WM injury in infants exposed to chorioamnionitis.

Diffusion Tensor Imaging Colour Mapping Threshold for Identification of Ventilation-Induced Brain Injury after Intrauterine Inflammation in Preterm Lambs

“…LPS was successfully injected into the amniotic sac as confirmed by electrolyte analysis of amniotic fluid aspirated at the time of injection and the presence of thickened fetal membranes characteristic of this experimental intervention observed at delivery (12). …”

“…We have previously demonstrated that acute (2 days) exposure to intra-amniotic (IA) lipopolysaccharide (LPS) increases the incidence and severity of ventilation-induced brain injury in preterm lambs (11). Furthermore, a protective ventilation strategy did not reduce the severity of brain injury, assessed histologically, after IA LPS (12) compared to control lambs (5). These results support clinical findings that intrauterine inflammation increases the risk and severity of postnatal white matter injury (13), periventricular leukomalacia, and periventricular/intraventricular haemorrhages (14–17).…”

Optimizing the Dose of Erythropoietin Required to Prevent Acute Ventilation-Induced Cerebral White Matter Injury in Preterm Lambs

“…Clinically, diffuse white matter injury in infants has been associated with adverse neurological outcomes such as cerebral palsy [37,38] . VIBI is further characterized by increased microglial activation, denser microglial aggregations, and increased astrogliosis [5,18,39] . EPO administration did not alter microglial aggregation in the PVWM and SCWM, nor were the number of ramified and ameboid microglia different.…”

A Critical Review of Models of Perinatal Infection

“…Acute exposure to intra-amniotic LPS 2 days before birth was associated with impaired oxygenation during subsequent ventilation after birth, with increased lung and cerebral inflammation and injury. These findings suggest that exposure to chorioamnionitis may indirectly increase injury during mechanical ventilation after birth [24]. …”

“…The precise reasons are unclear, although we may speculate that killing bacteria will release more inflammatory bacterial fragments. Infection/inflammation can also either dramatically exacerbate or alleviate neural damage from subsequent insults such as hypoxia-ischemia, hyperoxia and mechanical ventilation, depending on the precise timing and pattern of the insults [21,22,23,24]. Moreover, whereas brief hypoxia or low-dose Gram-negative lipopolysaccharide (LPS) exposure alone or in combination did not cause neural injury in very immature (postnatal day (P)1) rat pups, brief hyperthermia superimposed on combined hypoxia/LPS upregulated apoptosis and increased cell loss [25], illustrating the potential importance of multimodal injury.…”