Preterm infants can be inadvertently exposed to high tidal volumes (V_T) in the delivery room, causing lung inflammation and injury, but little is known about their effects on the brain. The aim of this study was to compare an initial 15 min of high V_T resuscitation strategy to a less injurious resuscitation strategy on cerebral haemodynamics, inflammation and injury. Preterm lambs at 126 d gestation were surgically instrumented prior to receiving resuscitation with either: 1) High V_T targeting 10–12 mL/kg for the first 15 min (n = 6) or 2) a protective resuscitation strategy (Prot V_T), consisting of prophylactic surfactant, a 20 s sustained inflation and a lower initial V_T (7 mL/kg; n = 6). Both groups were subsequently ventilated with a V_T 7 mL/kg. Blood gases, arterial pressures and carotid blood flows were recorded. Cerebral blood volume and oxygenation were assessed using near infrared spectroscopy. The brain was collected for biochemical and histologic assessment of inflammation, injury, vascular extravasation, hemorrhage and oxidative injury. Unventilated controls (UVC; n = 6) were used for comparison. High V_T lambs had worse oxygenation and required greater ventilatory support than Prot V_T lambs. High V_T resulted in cerebral haemodynamic instability during the initial 15 min, adverse cerebral tissue oxygenation index and cerebral vasoparalysis. While both resuscitation strategies increased lung and brain inflammation and oxidative stress, High V_T resuscitation significantly amplified the effect (p = 0.014 and p<0.001). Vascular extravasation was evident in the brains of 60% of High V_T lambs, but not in UVC or Prot V_T lambs. High V_T resulted in greater cerebral haemodynamic instability, increased brain inflammation, oxidative stress and vascular extravasation than a Prot V_T strategy. The initiation of resuscitation targeting Prot V_T may reduce the severity of brain injury in preterm neonates.

Background Physiologically based cord clamping (PBCC) has advantages over immediate cord clamping (ICC) during preterm delivery, but its efficacy in asphyxiated infants is not known. We investigated the physiology of PBCC following perinatal asphyxia in near-term lambs. Methods Near-term sheep fetuses (139±2 (SD) days’ gestation) were instrumented to measure umbilical, carotid, pulmonary and femoral arterial flows and pressures. Systemic and cerebral oxygenation was recorded using pulse oximetry and near-infrared spectroscopy, respectively. Fetal asphyxia was induced until mean blood pressure reached ~20 mm Hg, where lambs underwent ICC and initiation of ventilation (n=7), or ventilation for 15 min prior to umbilical cord clamping (PBCC; n=8). Cardiovascular parameters were measured and white and grey matter microvascular integrity assessed using qRT-PCR and immunohistochemistry. Results PBCC restored oxygenation and cardiac output at the same rate and in a similar fashion to lambs resuscitated following ICC. However, ICC lambs had a rapid and marked overshoot in mean systemic arterial blood pressure from 1 to 10 min after ventilation onset, which was largely absent in PBCC lambs. ICC lambs had increased cerebrovascular injury, as indicated by reduced expression of blood–brain barrier proteins and increased cerebrovascular protein leakage in the subcortical white matter (by 86%) and grey matter (by 47%). Conclusion PBCC restored cardiac output and oxygenation in an identical time frame as ICC, but greatly mitigated the postasphyxia rebound hypertension measured in ICC lambs. This likely protected the asphyxiated brain from cerebrovascular injury. PBCC may be a more suitable option for the resuscitation of the asphyxiated newborn compared with the current standard of ICC.

Background and objectives: Delivery of inadvertent high tidal volume (V_T) during positive pressure ventilation (PPV) in the delivery room is common. High V_T delivery during PPV has been associated with haemodynamic brain injury in animal models. We examined if V_T delivery during PPV at birth is associated with brain injury in preterm infants <29 weeks’ gestation. Methods: A flow-sensor was placed between the mask and the ventilation device. V_T values were compared with recently described reference ranges for V_T in spontaneously breathing preterm infants at birth. Infants were divided into two groups: V_T6 mL/kg (normal and high V_T, respectively). Brain injury (eg, intraventricular haemorrhage (IVH)) was assessed using routine ultrasound imaging within the first days after birth. Results: A total of 165 preterm infants were included, 124 (75%) had high V_T and 41 (25%) normal V_T. The mean (SD) gestational age and birth weight in high and normal V_T group was similar, 26 (2) and 26 (1) weeks, 858 (251) g and 915 (250) g, respectively. IVH in the high V_T group was diagnosed in 63 (51%) infants compared with 5 (13%) infants in the normal V_T group (P=0.008). Severe IVH (grade III or IV) developed in 33/124 (27%) infants in the high V_T group and 2/41 (6%) in the normal V_T group (P=0.01). Conclusions: High V_T delivery during mask PPV at birth was associated with brain injury. Strategies to limit V_T delivery during mask PPV should be used to prevent high V_T delivery.

Mechanical ventilation is a risk factor for cerebral inflammation and brain injury in preterm neonates. The risk increases proportionally with the intensity of treatment. Recent studies have shown that cerebral inflammation and injury can be initiated in the delivery room. At present, initiation of intermittent positive pressure ventilation (IPPV) in the delivery room is one of the least controlled interventions a preterm infant will likely face. Varying pressures and volumes administered shortly after birth are sufficient to trigger pathways of ventilation-induced lung and brain injury. The pathways involved in ventilation-induced brain injury include a complex inflammatory cascade and haemodynamic instability, both of which have an impact on the brain. However, regardless of the strategy employed to deliver IPPV, any ventilation has the potential to have an impact on the immature brain. This is particularly important given that preterm infants are already at a high risk for brain injury simply due to immaturity. This highlights the importance of improving the initial respiratory support in the delivery room. We review the mechanisms of ventilation-induced brain injury and discuss the need for, and the most likely, current therapeutic agents to protect the preterm brain. These include therapies already employed clinically, such as maternal glucocorticoid therapy and allopurinol, as well as other agents, such as erythropoietin, human amnion epithelial cells and melatonin, already showing promise in preclinical studies. Their mechanisms of action are discussed, highlighting their potential for use immediately after birth.

Amyotrophic lateral sclerosis (ALS) is characterised by progressive motor neuron degeneration. Although there are over 40 genes associated with causal monogenetic mutations, the majority of ALS patients are not genetically determined. Causal ALS mutations are being increasingly mechanistically studied, though how these mechanisms converge and diverge between the multiple known familial causes of ALS (fALS) and sporadic forms of ALS (sALS) and furthermore between different neuron types, is poorly understood. One common pathway that is implicated in selective motor neuron death is enhanced α‐amino‐3‐hydroxyl‐5‐methyl‐4‐isoxazole‐propionate (AMPAR)‐mediated excitoxicity. Specifically, human in vitro and pathological evidence has linked the C9orf72 repeat expansion mutation to a relative increase in the Ca²⁺‐permeable AMPAR population due to AMPAR subunit dysregulation. Here, we provide the first comparative quantitative assessment of the expression profile of AMPAR subunit transcripts, using BaseScope, in post‐mortem lower motor neurons (spinal cord, anterior horn), upper motor neurons (motor cortex) and neurons of the pre‐frontal cortex in sALS and fALS due to mutations in SOD1 and C9orf72. Our data indicated that AMPAR dysregulation is prominent in lower motor neurons in all ALS cases. However, sALS and mutant C9orf72 cases exhibited GluA1 upregulation whereas mutant SOD1 cases displayed GluA2 down regulation. We also showed that sALS cases exhibited widespread AMPAR dysregulation in the motor and pre‐frontal cortex, though the exact identity of the AMPAR subunit being dysregulated was dependent on brain region. In contrast, AMPAR dysregulation in mutant SOD1 and C9orf72 cases was restricted to lower motor neurons only. Our data highlight the complex dysregulation of AMPAR subunit expression that reflects both converging and diverging mechanisms at play between different brain regions and between ALS cohorts. © 2019 Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.