Factors modulating neonatal pain responssiveness

To relieve pain in newborn infants, particularly preterm infants, is essential in modern neonatology. However, there are a number of innate difficulties related to pain assessment and pharmacological treatment, which includes in this thesis work. It emanated from our participation in an international team that designed and conducted the NEOPAIN multicenter trials, testing the effects of morphine analgesia in 898 preterm mechanically ventilated neonates.

Primary neurological outcomes were defined as death, severe IVH and PVL that were not affected, respectively. However, intermittent doses with morphine increased the incidence of composite outcome 24% vs. 15%. The preemptive morphine infusion did not improve short-term pulmonary outcomes; it extended the mechanical ventilation time with one day. Additional morphine doses aggravated the respiratory outcomes in preterm neonates with RDS and severity of illness. Because these neonates were sicker and had greater physiological instability, they required more frequent procedures and pain assessments by caregivers, consequently an increased use of additional doses of morphine analgesia. However, the pre-emptive morphine infusions reduced pain responsiveness, measured by changes in heart rate (HR) p<0.005, blood pressure p<0.001, and decreased PIPP scores (p<0.02), as compared with placebo.

The ability of professional NICU staffs to correctly estimate analgesia treatment is limited. Neither education (63% to 54%, p=0.60) nor experiences (65% to 55%, p=0.28) in the NICU affected their ability to assess whether the neonates had received analgesia or not, highlighting the difficulties in assessment of prolonged neonatal pain.

Term newborn infants delivered vaginally (VD) reacted with less responsiveness (facial expression 36.6%, cry 21.6%, and HR 4.2%, p=0.04-0.001) after injection of vitamin K as compared to the infants delivered by caesarean section (CS). VD infants showed increased physiological reactivity to graded painful stimuli in the first hours following birth (p<0.001 and p=0.04, for high- and lowintensity stimuli, respectively) but no such increase occurred in the CS newborn infants (p=0.96 and p=0.52). These findings suggest that vaginal delivery leads to a foetal inhibition of pain and thermal sensory processing soon after birth.

Both painful and tactile stimuli resulted in hemodynamic responses in the parietal (somatosensory) cortex, monitored by NIRS in preterm neonates, but did not occur in the occipital (visual) cortex. This sensory perception was accentuated responses in preterm neonates with male sex (p<0.05), lower gestational ages (p<0.05), or greater postnatal ages (p<0.001). These nuanced responses of preterm infants at the cortical level indicate conscious perception of pain.

List of scientific papers

I. Anand KJ, Hall RW, Desai N, Shephard B, Bergqvist LL, Young TE, Boyle EM, Carbajal R, Bhutani VK, Moore MB, Kronsberg SS, Barton BA; NEOPAIN Trial Investigators Group (2004). Effects of morphine analgesia in ventilated preterm neonates: primary outcomes from the NEOPAIN randomised trial. Lancet. 363(9422): 1673-82.
https://pubmed.ncbi.nlm.nih.gov/15158628

II. Bhandari V, Bergqvist LL, Kronsberg SS, Barton BA, Anand KJ; NEOPAIN Trial Investigators Group (2005). Morphine administration and short-term pulmonary outcomes among ventilated preterm infants. Pediatrics. 116(2): 352-9.
https://pubmed.ncbi.nlm.nih.gov/16061589

III. Bartocci M, Bergqvist LL, Lagercrantz H, Anand KJ (2006). Pain activates cortical areas in the preterm newborn brain. Pain. 122(1-2): 109-17. Epub 2006 Mar 13.
https://pubmed.ncbi.nlm.nih.gov/16530965

IV. Bergqvist L, Eriksson M, Kronsberg S, Schollin J, Barton B, Anand K (2007). Seeing through the blind! Ability of hospital staff to differentiate morphine from placebo, in neonates at a placebo controlled trial. Acta Paediatr. 96(7): 1004-7. Epub 2007 May 10
https://pubmed.ncbi.nlm.nih.gov/17498195

V. Bergqvist LL, Katz-Salamon M, Hertegård S, Anand KJ, Lagercrantz H (2008). Mode of delivery modulates physiological and behavioral responses to neonatal pain. J Perinatol. Sep 4: Epub ahead of print
https://pubmed.ncbi.nlm.nih.gov/18769380