Assessment of salivary cortisol concentrations for procedural pain monitoring in newborns

Abstract

Objectives The study aimed to evaluate the usefulness of salivary cortisol (SC) for the assessment of procedural pain intensity in preterm and term newborns. Methods Three groups of neonates (term, 370–416 weeks; moderate to late preterm, 320–366; and very preterm, <320) hospitalized in neonatal intensive care unit were assessed for the study. Response to nappy change, lung ultrasound (LUS), and blood sampling was analyzed. The intensity of pain was evaluated using continuous heart rate and blood oxygen saturation (SpO2) monitoring, Neonatal Infant Pain Scale (NIPS), and SC concentrations. Saliva samples were collected before and 20 min after the procedure’s end. Results Seventy-one infants were examined: 30 term, 21 moderate to late preterm, and 20 very preterm. SC has increased significantly in response to nappy change only in very preterm newborns (2.13 ng/mL [1.55–3.68] vs. 2.84 ng/mL [1.93–9.06], p = 0.01). LUS did not affect concentrations of SC in any group. Significant increase in SC was observed after blood sampling in term and very preterm infants (2.2 ng/mL [1.45–2.92] vs. 4.29 ng/mL [3.88–5.73], p = 0.002, and 1.88 ng/mL [1.47–4.13] vs. 5.3 ng/mL [3.42–8.02], p = 0.002, respectively). A significant correlation between values of SC increase and NIPS scores was found (Spearman’s rank correlation coefficient [rs] = 0.31, p = 0.001). Conclusions We observed the increase in SC concentrations in response to painful stimulus. The presence of a correlation between NIPS scores and SC increase suggests that SC can be used as an objective parameter to assess pain in neonates.

Repetitive neonatal procedural pain affects stress‐induced plasma corticosterone increase in young adult females but not in male rats

“…Unfortunately, clinical studies did not include possible gender differences in their analysis. Altogether, our results and previous clinical and preclinical studies suggest an age‐ and sex‐dependent effect of repetitive neonatal procedural pain on the HPA axis (Brummelte et al., 2015; Chen et al., 2016; Green & McCormick, 2016; Grunau et al., 2004; Lowe et al., 2023; McLean et al., 2023; Mooney‐Leber & Brummelte, 2020; Olszewska et al., 2022). Given that many studies did not include longitudinal and gendered effects, conclusions must be taken with precaution and additional longitudinal research including gender‐related aspects is required.…”

“…This outcome adds to previous studies demonstrating that early‐life moderate stressors, such as repetitive neonatal procedural pain, lead to adult resilience in rodents (e.g., reduced state anxiety, fear conditioning, and stress response) (Davis et al., 2018; de Kort et al., 2021; Palermo et al., 2020; Pfau & Russo, 2015; Victoria et al., 2015; Zuke et al., 2019). This effect of repetitive neonatal procedural pain on cortisol levels was also shown in school‐age children with former NICU history (Brummelte et al., 2015; Lowe et al., 2023), although other clinical studies highlight cortisol level increase in young children (Grunau et al., 2004; Olszewska et al., 2022; Ranger et al., 2014). Unfortunately, clinical studies did not include possible gender differences in their analysis.…”

“…Furthermore, the HPA axis response depends on negative feedback from glucocorticoids on the glucocorticoid receptors (GR) and the mineralocorticoid receptors (MR), an adaptive response under the influence of sex hormones and epigenetically sensitive to early-life events (De Kloet et al, 1998;Goel et al, 2011;Keller-Wood & Dallman, 1984;Nicolaides et al, 2015). Early-life adversities, including repetitive neonatal procedural pain, promote continued increase of glucocorticoids levels in rodents and human alike (Grunau et al, 2004;McLean et al, 2023;Mooney-Leber et al, 2018;Olszewska et al, 2022;Victoria, Karom, et al, 2013). Rodent females may be more sensitive to the heightened glucocorticoids levels as suggested by their higher ACTH response at P8 following ether inhalation (Hary & Dupouy Isabelle Grégoire, 1986).…”

“…Clinical studies have shown that continued neonatal procedural pain shifts the level of the main stress hormone cortisol in former NICU patients (Brummelte et al, 2015;Grunau et al, 2004Grunau et al, , 2005McLean et al, 2023;Mörelius et al, 2016;Olszewska et al, 2022;Stoye et al, 2022). Nevertheless, the long-term effects of repetitive neonatal procedural pain on the HPA axis are still unclear and the directionality of this effect seems to depend on exposure intensity in combination with gender and age (Grunau, 2013;LaPrairie & Murphy, 2010;Matthews, 2002).…”

Biomarkers for assessing pain and pain relief in the neonatal intensive care unit

“…Salivary cortisol levels in neonates peak 20–25 min after the stressful event ( 100 ), which limits their clinical usefulness for pain assessment in neonates admitted to the NICU. Out of three studies that evaluated the use of salivary cortisol measurements for monitoring procedural pain in the NICU, two identified a significant correlation between pain scores during the procedure and peak cortisol levels and the third found no such correlation ( 27 , 101 , 102 ). However, in the latter study, pain was assessed using the CRIES score, which has been developed for assessment of postoperative rather than procedural pain ( 103 ).…”