Due to the continuous nature of the CRP level variable, we assessed correlations between CRP level and EMG and EEG responses.
Newborn infants in the Neonatal Inflammation Group had significantly greater spinal cord mediated reflex withdrawal EMG activity and noxious-evoked EEG brain activity in response to heel lancing (within 24 h from presentation of risk factors) compared to neonates who do not have raised inflammatory markers (magnitude of noxious-evoked reflex withdrawal activity: Neonatal Inflammation Group: n = 21, mean = 42.1, SD = 30.9 Neonatal Control Group: n = 36, mean=30.2, SD = 20.6 Δ = 11.9, 95%CI = , t test t = 1.74, p = 0.048 magnitude of noxious-evoked brain activity: Neonatal Inflammation Group: n = 19, mean=1.04, SD = 0.68 Neonatal Control Group: n = 32, mean = 0.64, SD = 0.52 Δ = 0.41, 95%CI = , t = 2.4, p = 0.022, p values corrected for multiple comparisons using Holm’s method, Table 2, Fig. Inflammation is associated with increased reflex withdrawal and brain activity in response to a heel lance The threshold of 10 mg/l was selected because in our local unit prophylactic antibiotic treatment was discontinued 36-hours after the first dose if the CRP was below 10 mg/l and there were no other clinical or laboratory signs of infection (Fig. The ‘Neonatal Inflammation Group’ presented with CRP > 10 mg/l or evidence of infection, whereas the ‘Neonatal Control Group’ presented with CRP < 10 mg/l and no evidence of infection. They were grouped according to the level of CRP in their blood or other laboratory or clinical evidence of infection within 24 h from the start of antibiotic treatment.
We studied neonates who presented with risk factors for suspected early-onset neonatal infection (see 18 for guidelines that were in place during the study period) and received prophylactic antibiotic treatment (Table 1). Here, we have generated such human neonatal data-capitalising on our team’s access to a rare resource: well-matched cohorts of newborn infants (with similar perinatal histories) who can be differentiated based on the C-reactive protein (CRP) levels in their blood (Fig. Moreover, given the many known inter-species differences in both immune and nociceptive systems 17, it is of vital importance that we generate data in human neonates, which can be relevantly back-translated into future rodent models. However, studies investigating how the acute phase of early-life inflammation impacts pain sensitivity are scarce. There are, for instance, reports that experimental activation of the neonatal immune system in rat pups, via lipopolysaccharide (LPS) administration, causes long-term increased pain sensitivity 12, 13, 14, 15, 16. Evidence from the preclinical literature suggests that neonatal inflammation might have very serious consequences 11. Suspected infection is very prevalent in neonates 8, affecting 13–20% of infants in the postnatal wards 9, yet the consequences that such early-life inflammation may have on human nociceptive circuitry are not known 10. How the development of these two systems influences each other is much less clear, even though it is a highly relevant clinical question. For example, deficiencies in the exposure to certain microorganisms can pre-dispose us to immune-mediated diseases 2 like asthma and type-1 diabetes 4, while repeated painful procedures in neonates may negatively affect nociceptor sensitivity 5 and have been associated with altered behavioural, motor, and cognitive neurodevelopment 6, 7. Adverse events during this delicate developmental process can have deleterious and long-lasting consequences. In infants and children, both systems undergo extensive fine-tuning and maturation 2, 3. Our nociceptive and immune systems are intimately intertwined, working together to protect us from injury or disease 1.
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