Premature infants display discriminable behavioural, physiological and brain responses to noxious and non-noxious stimuli

Abstract

Pain assessment in preterm infants is challenging, as behavioural, autonomic and neurophysiological measures of pain are reported to be less sensitive and specific than in term infants. Understanding the pattern of preterm infants' noxious-evoked responses is vital to improve pain assessment in this group. This study investigated the discriminability and development of multi-modal noxious-evoked responses in infants aged 28-40 weeks postmenstrual age. A classifier was trained to discriminate responses to a noxious heel lance from a non-noxious control in 47 infants, using measures of facial expression, brain activity, heart rate and limb withdrawal, and tested in two independent cohorts with a total of 98 infants. The model discriminates responses to the noxious from the non-noxious procedure from 28 weeks onwards with an overall accuracy of 0.77-0.83 and an accuracy of 0.78-0.79 in the 28-31 week group. Noxious-evoked responses have distinct developmental patterns. Heart rate responses increase in magnitude with age, while noxious-evoked brain activity undergoes three distinct developmental stages, including a previously unreported transitory stage consisting of a negative event-related potential between 30-33 weeks postmenstrual age. These findings demonstrate that while noxious-evoked responses change across early development, infant responses to noxious and non-noxious stimuli are discriminable from 28 weeks onwards.

Toward personalized medicine for pharmacological interventions in neonates using vital signs

“…We find that in some infants there is no change in heart rate while in others there is a large drop. When comparing the change in heart rate with measures of efficacy (behavioral, physiological and neurophysiological responses to the painful procedure for which the analgesic was given 23 , 43 , 44 ) we find that there is a strong relationship, and in this particular case the analgesic does not have any adverse effects. We use machine learning to demonstrate that the rate of change of heart rate shortly after drug administration is predictive of analgesic efficacy.…”

“…15 , 16 , 17 , 18 Furthermore, due to rapid development across the neonatal period, there is large variability in the way in which a single infant responds to painful procedures across their stay in neonatal care. 19 , 20 , 21 , 22 , 23 Predicting individual differences in pain sensitivity and titrating the dose of an analgesic accordingly will be an important step toward individualized analgesic treatment. This could be achieved, for example, by using low level experimental noxious stimuli prior to a painful clinical procedure to gage an individual infant's nociceptive sensitivity.…”

“… 42 Nociceptive input elicits responses at many different levels of the nervous system and a multimodal approach, including assessment of changes in vital signs, has been advocated to assess analgesic efficacy. 23 , 43 , 44 The specific measure(s) that should be used to assess analgesic efficacy are still much debated and a discussion of this is beyond the scope of this article. 4 …”