No Pain No Gain or More Pain Less Gain?
Bishr Haydar MD and Rita Agarwal MD
For most of human history, neonates and premature infants were thought to neither experience nor remember pain. Some of the reasons: their nervous system is too immature and not fully myelinated, they are not cognitively able to process painful stimuli, they will have no memory of the pain, and besides the drugs used to treat pain have were more harmful than pain itself. It wasn’t until the early 80’s that the deleterious effects of pain and stress in the neonate was recognized. Several visionary researchers and clinicians including Drs. Sunny Anand, Charles Berde, Ruth Grunau , Maria Fitzgerald, Anne Lynn, Myron Yaster, and many others through both basic science and clinical research revealed that neonates, and premature infants not only experienced pain, but often had exaggerated responses to noxious stimuli that may have long term consequences, including hyperalgesia, decreased pain thresholds and sensory or motor processing changes (1-4). Neonatal pain has been associated with poorer cognitive and motor outcomes, changes in the frontal cortices, subcortical gray, and white matter development and alterations in thalamic metabolic development (5-7). Emma Duerden Ruth Granau and their colleagues at Vancouver Children’s Hospital have been studying a cohort of very premature and extremely premature infants for several years and the today’s paper examines thalamic development and sensory processing in these infants as a result of exposure to “skin breaking procedure”.
Original article
Duerden EG, Mclean MA, Chau C, Guo T, Mackay M, Chau V, Synnes A, Miller SP, Grunau RE. Neonatal pain, thalamic development and sensory processing behaviour in children born very preterm. Early Hum Dev 2022;170:105617. PMID: 35760006
Preterm infants are at elevated risk for sensory and motor development issues, which are more common in infants with brain injury, severe illness, infection, steroids, and sensory stimulation including procedural pain. Pain-related stress while in NICU has been correlated to worsened cognition and more anxiety/depression (8). The thalamus is a major sensory relay hub, and abnormalities in the thalamus can be linked to both pain and neurodevelopmental outcomes.
This study evaluated 130 preterm neonates born 2006-2013 who did not have congenital malformations/syndromes, antenatal infections or large parenchymal infarctions or hemorrhages. They underwent MRI to measure the size of the thalamus when the patient was stable, typically at 32 weeks gestational age (GA) and then again at 40 weeks GA. They also collected NICU data including invasive procedures (heel lance, IV/CVL placement, IM injection or intubation), morphine, and dexamethasone equivalents. Subjects returned at age 4.5 years for sensory processing and neurodevelopmental assessment.
81 infants were born between 24-28 weeks GA and 59 were born between 29-32 weeks GA. The 24-28 week group had more postnatal infections (52% vs 17%), invasive procedures (127 vs 52), and more morphine and dexamethasone exposure than 29-32 week GA infants. Most 29-32 week infants received no dexamethasone. 38% of the 24-28 week group had abnormal sensory processing (SSP scores) at age 4.5 years, compared to 25% of the 29-32 week group. There was no association between invasive procedures and SSP scores for the entire cohort. However, for the 24-28 week cohort, low SSP scores were predicted by increased invasive procedures, even after adjusting for the factors listed above.
Next, they looked at the MRI results - did the thalamus grow between the two scans? Thalamic growth predicted greater SSP scores. The authors then did an exploratory analysis looking at the interaction between invasive procedures and thalamic growth, showing those with a high number of invasive procedures had slower thalamic growth and lower SSP scores.
What does this all mean? Sunny Anand and Paul Hickey showed that treating pain reduces neuroendocrine stress in infants undergoing cardiac surgery (8). In their 1987 New England Journal review, they reiterated that nociception and the physiologic and stress response that follows has deleterious effects on the infant (9). The study we are discussing today shows a clear association between painful procedures and changes in thalamic growth and long term neurocognitive outcomes. However, this study did not include other variables that might influence the experience of nociception, pain and stress. We do not know if patients were pre-treated to reduce the experience of pain, such as sucrose prior to a heel lance, or morphine or fentanyl prior to intubation. Most importantly for us, they did not include exposure to surgical procedures and/or anesthetics in this study (although in previous studies they do note that these were recorded) So, we are left with a possible correlation that those additional awake intubation attempts, IV attempts, lab draws or capillary blood gasses are correlation that painful procedures lead to an increased risk to the infant’s development and changes in hypothalamic growth.
We subject patients to invasive or painful procedures only when there is a clinical need or question. We intubate for respiratory failure or re-check labs to follow and correct clinically important derangements, or in an effort to restore homeostasis. Perhaps the conditions that prompted painful procedures might be the driver of worsened thalamic growth, rather than the painful procedures themselves. As Jim DiNardo constantly reminds us in his PAAD reviews: “correlation does not equal causation”. This study cannot answer that question. Studies such as this provide more evidence for the deleterious effects of pain to further our understanding of pain physiology in developing humans. They are not designed to provide guidance on how to prevent or treat these changes…..yet. Medications and even sucrose prior to painful procedures come with their own set of side effects and complications; comfort measures, while helpful are often not enough to prevent a stress response to noxious stimuli.
This study does support our work caring for this incredibly fragile population. Our anesthetics can cause such hemodynamic struggles in preemies and neonates, but we fight the good fight and blunt the surgical stress response for good reason.
From Myron: Many of you in PAAD-land have true expertise and clinical experience in this topic. I invite you to write in with your commentary (and corrections as needed)!
References:
Anand, Kanwaljeet J., S.. "Discovering Pain in Newborn Infants". Anesthesiology, vol. 131, no. 2, August 2019, pp. 392–395
Anand KJ, Coskun V, Thrivikraman KV, Nemeroff CB, Plotsky P, (1999) Long-term behavioral effects of repetitive pain in neonatal rat pups. Physiol Behav 66:627–637. doi:10.1016/S0031-9384(98)00338-2 pmid:10386907
Taddio A, Katz J, Ilersich AL, Koren G. Effect of neonatal circumcision on pain response during subsequent routine vaccination. Lancet. 1997 Mar 1;349(9052):599-603. doi: 10.1016/S0140-6736(96)10316-0. PMID: 9057731.
Walker, SM. Seminars in Fetal and Neonatal Medicine 24 (2019) 101005
Fitzgerald M, Walker SM (2009) Infant pain management: a developmental neurobiological approach. Nat Clin Pract Neurol 5:35–50. doi:10.1038/ncpneuro0984 pmid:19129789
Duerden EG, Grunau RE, Guo T, Foong J, Pearson A, Au-Young S, Lavoie R, Chakravarty MM, Chau V, Synnes A, Miller SP Early Procedural Pain Is Associated with Regionally-Specific Alterations in Thalamic Development in Preterm Neonates. .J Neurosci. 2018 Jan 24;38(4):878-886
Brummelte S, Chau CM, Cepeda IL, Degenhardt A, Weinberg J, Synnes AR, Grunau RE Cortisol levels in former preterm children at school age are predicted by neonatal procedural pain-related stress. Psychoneuroendocrinology 2015 51:151163. doi:10 pmid:25313535
Anand KJ, Hickey PR Halothane-morphine compared with high-dose sufentanil for anesthesia and postoperative analgesia in neonatal cardiac surgery. N Engl J Med. 1992 Jan 2;326(1):1-9. PMID: 1530752
Anand KJ, Hickey PR. Pain and its effects in the human neonate and fetus. N Engl J Med. 1987 Nov 19;317(21):1321-9