Background

Many studies have been conducted recently to identify biomarkers that could potentially be used to objectively evaluate pain.

Objective

To synthesize and critically analyze primary studies of endogenous biomarkers and their associations with pain to identify suitable biomarkers for the objective evaluation of pain in critically ill children.

Methods

PubMed, Scopus, and Ovid databases were searched; searches were restricted by publication date, language, species, and participant age. Critical appraisal tools and the Strengthening the Reporting of Observational Studies in Epidemiology checklist were used to evaluate quality of evidence.

Results

All included articles were coded according to methods and findings. Saliva, blood, cerebrospinal fluid, and gingival crevicular fluid were used to detect biomarkers. Enzyme-linked immunosorbent assays were used in most studies (64%). Appropriate statistical analyses were performed at a significance level of P < .05 in included studies. Cytokines, peptides, and hormones were associated with pain, stress, and inflammatory response, suggesting that they can be used to screen for pain in children during painful conditions. Only 1 study in neonates did not show any correlation between saliva biomarkers and pain.

Conclusion

According to this literature review, various biomarkers that are easily obtained and measured in a clinical setting are associated with pain in children. Further investigation of these biomarkers through observational studies is suggested to evaluate their suitability for pain assessment in critically ill children.

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Use of Biomarkers to Evaluate Pain in Critically Ill Children

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Use of Biomarkers to Evaluate Pain in Critically Ill Children

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Critically ill children in a pediatric intensive care unit (PICU) experience multiple painful conditions due to either the nature of their disease or a variety of therapeutic procedures.1,2  Adequate analgesia and sedation are required to ensure the physiological and psychological comfort of pediatric patients in the PICU by reducing anxiety and increasing tolerance of clinical procedures and compliance with mechanical ventilation.3,4  Various validated behavioral pain scales are used routinely to assess pain intensity and the effectiveness of analgesia and sedation in PICUs.57  However, there is strong evidence that clinical severity can affect the behavioral pain response due to a patient’s limited communication, oversedation, and pathophysiology of the disease.8,9  Nurses’ perceptions of children’s pain during routine painful procedures can also affect the accuracy of behavioral pain scores.1012  According to the available literature, behavioral pain scales cannot always distinguish distress and anxiety from pain in PICU patients.6 

An objective method for evaluating pain would be useful for nurses, other clinicians, and pediatric patients in ICUs. Many studies have been conducted in recent years to identify biomarkers that could potentially be used as objective indicators of pain.13,14  An objective pain measurement tool would ideally be able to provide clinicians with standardized information with no or limited variation between patients.15  A biomarker that could be used as a pain indicator rather than as additional confirmation of the physiological and subjective characteristics of pain would benefit patients and enable health care professionals to choose the best course of action in pain management.16 

Some biomarkers can indicate pain intensity, whereas others can reveal an underlying painful pathobiological condition.

Although pain is subjective, physiological indicators of pain are considered pain biomarkers.15  Over the past 2 decades, research data have shown a significant correlation between the autonomic nervous system and the pain response. Heart rate, cortisol, β-endorphin, and inflammatory agents are associated with the pain and stress response. According to the US Food and Drug Administration (FDA),17  a biomarker is a defined characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or biological responses to an exposure or therapeutic intervention. Some biomarkers can indicate pain intensity, whereas others can reveal an underlying painful pathobiological condition.16  The FDA17  has identified 3 types of pain biomarkers: prognostic biomarkers (used to determine the risk of pain progression in the future), response biomarkers (used to evaluate analgesic drugs’ effectiveness or detect painful conditions), and predictive biomarkers (used to predict response to treatment, including beneficial or adverse effects).

Hormones and neuropeptides are released during tissue injury, activating the proinflammatory response in microglial cells and enhancing the painful stimulus (proinflammatory action). In experimental models, specific neuropeptides, such as substance P, have been found to increase pain sensitivity by promoting the proinflammatory response in spinal cord cells.18 

The aim of this scoping review was to synthesize primary studies that explored associations between endogenous biomarkers and pain in children with painful medical conditions. A secondary aim of the review was to identify suitable pain biomarkers to objectively evaluate pain intensity in critically ill children in the PICU who cannot verbally communicate their pain level. We conducted a scoping literature review to investigate this secondary aim according to the population, exposure, and outcomes framework (population, children in the PICU; exposure, pain; outcomes, levels of biomarkers).19 

We searched the PubMed and Scopus scientific databases in November 2020. We used combinations of the keywords pain biomarkers, measurement, and evaluation as follows: pain, biomarker’s OR biomarkers OR biomarker, measure’s OR measured OR measurement’s OR measurements OR measuring OR measuring OR measurment OR measurments, evaluate OR evaluated OR evaluates OR evaluating OR evaluation OR evaluation’s OR evaluations OR evaluative OR evaluatively OR evaluatives.

Due to the limited results from the initial review, we searched the same databases using terms for pain biomarkers identified in previous reviews in adult populations. We performed the search in November 2020 using the key terms pain neuropeptides, pain, and inflammatory as follows: pain OR pain AND (neuropeptid OR neuropeptides OR neuropeptides OR neuropeptide) AND (inflammatories OR inflammatory).

We limited the search by publication date (within the past 10 years), language (English), species (human), and participant age (up to 18 years). We limited the publication date to the preceding 10 years to exclude older laboratory and experimental studies that could have affected the reliability of the results. We excluded systematic reviews and other secondary studies. We conducted the final online search on November 28, 2020.

We conducted a further search of the Ovid platform to retrieve articles from the MEDLINE database that might have been missed because of differences in truncation between PubMed and Ovid.20  We also manually searched the journals Pain and Pain Management Nursing to identify articles relevant to our study.

We assessed the quality of the studies with recognized critical appraisal tools.19  We assessed risk of bias for the randomized trials with the revised Cochrane risk of bias tool.20  We selected articles for inclusion on the basis of title, aims and objectives, methods, sampling method, participant age, data collection strategy, data analysis, statistical analysis, findings, and conclusion.

To ensure that we reviewed the most appropriate biomarkers, we set 4 predefined criteria according to the results of previous studies in the adult population.16,21  These criteria were as follows:

  • The studies were quantitative to ensure transparency and the utility of the biomarkers.

  • The biomarkers were measured during a painful procedure to ensure their sensitivity.

  • The biomarkers were measured in the absence of pain to ensure their specificity.

  • The biomarkers were analyzed with a quantitative method easily performed in a hospital setting on sample sources such as plasma, saliva, and cerebrospinal fluid.

After removing duplicate records, we examined titles and abstracts of 376 articles for eligibility. We excluded 341 articles due to study design, methods (systematic reviews or other secondary studies), or a nonspecified study population. We also excluded studies of children with cancer because the inflammatory response to cancer progression might alter the response to pain.22 

We reviewed the full texts of 35 articles for eligibility in this scoping review. We excluded 5 articles after assessing their quality with the Strengthening the Reporting of Observational Studies in Epidemiology checklist. We excluded 6 irrelevant studies that explored disease-related biomarkers or risk biomarkers. To reduce the heterogeneity of the included articles, we excluded 5 studies because the researchers used a neuroimaging method to observe the pain biomarkers. Eight studies were ineligible because they investigated behavioral measures of pain or did not measure pain. We included 11 primary studies (1 randomized controlled study, 5 cohort studies, and 5 cross-sectional studies) in this review (Figure 1). We synthesized the included articles and coded them on the basis of first author’s name, publication date, study aims, methods, studied population, participant age, and strengths and weaknesses according to Critical Appraisal Skills Program and Joanna Briggs Institute critical appraisal tools19  (Table 1).

We categorized the ages of participants in the included studies into 5 age groups. The population studied were mainly children aged 5 to 12 years (870 of 1251 children (70%) (Figure 2). Of a total of 1300 collected samples, the most frequently obtained sample type was blood, 1163 times (89%). Only 67 of 1300 collected samples (5%) were saliva samples, although saliva samples are more convenient to obtain from children. Cerebrospinal fluid and gingival crevicular fluid were also collected in some studies (Figure 3). Enzyme-linked immunosorbent assay (ELISA) was the method most commonly used to analyze samples (used 7 of 12 times [64%]; Figure 4). The researchers used reliable and validated pain tools to evaluate pain intensity levels between groups under conditions of pain and no pain.

Researchers measured levels of hormones, proteins, neuropeptides, and enzymes under conditions of pain and no pain to investigate their roles in pain pathways. The synthesis of sample types, measured biomarkers, and methods of sample analysis is presented in Table 2.

Seven of the included studies met all 4 of the predefined criteria for eligibility of investigated biomarkers. Hormones, cytokines, and neuropeptides were observed in conditions of both pain and no pain, ensuring the sensitivity and the specificity of these pain markers. They were analyzed with ELISA, a quantitative method easily obtained in a hospital setting (Table 3).

Ferland et al25  found a significant difference (P < .05) between preoperative and postoperative catecholamine levels in plasma and cerebrospinal fluid in children aged 12 to 18 years who had received spinal surgery. A numeric pain scale was used to assess pain at 4 time points (before the surgical procedure, on postoperative days 1 and 2, and at the 6-week follow-up). Catecholamines were measured during conditions of pain (to assess sensitivity) and no pain (to assess specificity). The levels of epinephrine and norepinephrine were highest at the 6-week follow-up. Two years later, Ferland et al26  investigated the correlation between levels of monoamines and their metabolites with the pain response in children and adolescents with back pain. They found that higher plasma levels of these biomarkers were correlated with greater pain modulation efficacy (P < .05).25,26 

Symons et al33  used a novel method to identify multiple molecules associated with the pain response in children with cerebral palsy. They observed that the levels of several biomarkers, including salivary metabolites, neuropeptides, cytokines, and hormones, were higher in children with pain than in those with no pain. Interleukin 1α (IL-1α), IL-8, and cortisol were present in the group with pain.33 

Naguib et al29  investigated the roles of hormones and cytokines in the pain and stress response in children by conducting a prospective, randomized, double-blinded study in children with congenital heart disease. They measured the levels of metabolic and hormonal stress markers at 5 time points during a cardiac surgical procedure in 3 groups randomized to receive a low dose of fentanyl, a high dose of fentanyl, or a low dose of fentanyl plus dexmedetomidine. Plasma adrenocorticotropic hormone, cortisol, and epinephrine levels were lowest in the group who received higher doses of fentanyl. The investigators found no significant differences in cytokine levels among the groups at the 5 time points.29 

Heidari et al27  compared the levels of substance P and neurokinin A in gingival crevicular fluid of intact and decayed permanent teeth in children 7 to 12 years old. They found significantly higher levels of substance P and neurokinin A in the gingival crevicular fluid of decayed teeth. The authors used a visual analogue scale to evaluate pain; however, they did not compare pain scores and neuropeptide levels. Brandow et al23  also investigated the role of substance P in pain. In their prospective cohort study, they found that substance P levels in plasma were significantly elevated in pediatric patients with sickle cell disease compared with the healthy control group (P < .001) and significantly higher in patients with sickle cell disease during the acute crisis than at baseline (P = .004).23,27 

Maan et al28  also investigated pain biomarkers in saliva samples in children older than 12 years and adults before and after orthodontic treatment. Correlations between pain and the levels of IL-1β and prostaglandin E2 during different periods were assessed by using the Spearman rank correlation coefficient with a significance level of P < .05. Elevated concentrations of IL-1β and prostaglandin E2 were found 1 hour after orthodontic treatment. The concentrations were higher in adults than in children.28 

Hormones, cytokines, and neuropeptides were observed in conditions of both pain and no pain, ensuring the sensitivity and the specificity of these pain markers.

Rochette et al31  investigated plasma inflammatory markers in a study in children with juvenile idiopathic arthritis at rest and after exercise. Concentrations of calprotectin and IL-6 fluctuated during the first, second, and third days of the experiment, suggesting that these markers have a role in inflammatory pathways. However, a clear correlation with the pain response could not be confirmed.31 

Perrone et al30  investigated pain biomarkers in a healthy population. The researchers conducted a prospective cohort study to evaluate whether oxidative stress biomarker levels increased in term newborns after a painful procedure and whether nonpharmacological treatments or sex influenced the level of pain. Oxidative stress biomarker levels increased during heel prick, the painful procedure. The researchers also observed a positive correlation between oxidative stress biomarker levels and pain scores measured on the acuteness of first cry, burst rhythmicity, and constancy of crying scale. On the other hand, Shibata et al32  did not find significant differences in salivary biomarker levels before and after heel prick in term newborns. However, the results of their study are debatable because they performed only simple descriptive statistical analysis.

All of the referenced biomarkers appear to have characteristics of predictive, response, or prognostic biomarkers.

Ersig et al24  conducted a novel study to examine genomic variations associated with pain, anxiety, and distress in children aged 4 to 10 years undergoing intravenous catheter insertion. The researchers investigated 34 genes with known or suspected roles in pain, anxiety, and distress pathways. Genes for corticotropin-releasing hormone (P = .04) and opioid receptor mu 1 were associated solely with pain, whereas other genes, like those for IL-1β and endothelin receptors, were associated with both pain and distress (P < .05). According to the authors, their findings could improve nursing care via pain screening protocols, analgesia delivery, and nurse-driven research.24 

All of the referenced biomarkers appear to have characteristics of predictive, response, or prognostic biomarkers. Neuropeptides, interleukins, prostaglandin E2, and other proteins can be characterized as response biomarkers because they were present or increased during conditions of pain. Cytokines and genes can potentially be used as predictive biomarkers. In the 2 studies in which the role of neuropeptides in pain was investigated, substance P worked as a response biomarker. Hormones like epinephrine, norepinephrine, and cortisol had both predictive and response characteristics.

The investigation of pain biomarkers is challenging. Pain is a complex and subjective phenomenon involving many different biological functions.34  In this scoping literature review, observational studies with good methodological quality were synthesized to identify quantitative pain biomarkers in children during painful conditions. Although the pathophysiological characteristics of the populations in the included studies were not homogeneous, most of the studies used similar methodological approaches, ensuring the validity of the conclusions.

We found no evidence to favor any of the sampling methods. The sample analysis techniques were chosen according to study design. Mass spectrometry and ELISA were the most common methods. Both techniques can be used to discover new biomarkers, are widely used in research, and have many advantages.35,36  Nuclear magnetic resonance spectroscopy was used to identify molecules associated with pain in the study by Symons et al,33  but this method seemed to be time-consuming and costly and seemed to yield less clear results, according to the researchers. However, nuclear magnetic resonance spectroscopy is a new technique still under development, with many potential advantages in clinical diagnostics.37 

According to our predefined criteria to identify the most appropriate biomarkers to assess pain in children in the PICU, the study characteristics were as follows:

  • Quantitative study: All of the included studies used quantitative methods, with appropriate statistical analysis in most cases.

  • Measured during painful procedure (sensitivity): The investigated biomarkers were observed during painful procedures in all of the included studies. Epinephrine, norepinephrine, cytokines, and neuropeptides were significantly correlated with painful conditions, and interleukins were correlated with the stress response. These results are analogous to the findings of similar studies in adults.38,39 

  • Measured in the absence of pain (specificity): In 7 of the 11 included studies, the biomarkers were measured in the absence of pain, ensuring their specificity. Those biomarkers were substance P, cytokines, and hormones like epinephrine, norepinephrine, and cortisol. Their pathophysiological role in pain pathways has been previously reported in the literature.15  The levels of these biomarkers differed significantly between conditions of pain and no pain. The study by Shibata et al32  showed no differences between painful and nonpainful conditions in newborns, but because it was the only included study in which salivary enzymes were measured, conclusions about their suitability as pain biomarkers cannot be reached, and further investigation is suggested.

  • Quantitative method readily performed in hospital: All of the methods appeared to be suitable and easily performed in a hospital setting.

The most commonly reported biomarkers in research in adults are neuropeptides, endogenous opioids that are mainly involved in pain regulation within the central nervous system.34  The central nucleus of the amygdala is rich in key neuropeptides that are essential for excitatory or inhibitory modulation of pain neuroactivity. Calcitonin gene-related peptide, corticotropin-releasing factor, neuropeptide S, oxytocin, vasopressin, and opioids are some of these neuropeptides, and their role in pain modulation has been explored in experimental models and clinical settings.40  Additionally, inflammatory mediators such as IL-1β, IL-6, and tumor necrosis factor α have been correlated with pain in adults.41  Similar observations made by the researchers in this review confirm that they also function in pain pathways in children. The role of these biomarkers in pain pathways in newborns has also been investigated, but this work is as yet unpublished or has many limitations, so this role cannot be confirmed.34,42,43  The usefulness of these biomarkers for identifying pain in children in the PICU cannot be confirmed with this scoping review. Only 1 of the studies was performed in an ICU, but the studied biomarkers were mostly associated with the stress response rather than with pain. Severe illness might affect the pain response due to the activation of multiple pathophysiological cascades and the extended use of opioids.44,45  Further investigation of the use of biomarkers to assess pain in children in the PICU is essential, considering the multiple factors that could influence pain pathways in this population. In most of the included studies, researchers addressed possible confounding variables. Some of these identified variables were patient age, patient sex, time of sample collection, and comorbidities that could affect the secretion of hormones and metabolites.

In most of the studies, researchers used reliable and previously validated pain tools to evaluate pain in the pediatric population.6,44,46  Most used pain scores to confirm the presence of pain in the studied group. However, correlations of pain scores with biomarker levels were performed only by Perrone et al,30  who found a strong positive correlation between oxidative stress biomarker levels and pain scores measured on the acuteness of first cry, burst rhythmicity, and constancy of crying scale. This correlation could theoretically indicate that these biomarkers could be used in a clinical setting as response or predictive biomarkers to evaluate pain intensity.

Although biomarkers are not currently used to assess pain in intubated and sedated children, knowledge of their role in pain pathways can promote objective evaluation of pain in children who cannot verbally communicate their pain level. Nurses can consider the effectiveness of behavioral pain assessment tools and evaluate other indicators of pain, like an increase in heart rate or blood pressure resulting from increased catecholamine levels during inflammatory responses and pain stimuli.25,47  This scoping review can help guide further nurse-led research and other studies of the use of interleukins, hormones, and the neuropeptides substance P and neurokinin A to evaluate pain.

One limitation of this review is that differences in the pathophysiology of acute and chronic pain were not considered. The same biomarkers appear to be involved in both pathways, and studies in this review revealed similar biomarkers in patients with acute and chronic pain.15,40  However, neuropeptides appear to play a significant role in acute pain, as has been previously confirmed by researchers studying patients with acute migraine,48  but interleukins appear to be more associated with the stress response in patients with inflammation and chronic pain.49 

Obtaining blood samples in an ICU is usually painless and efficient because patients have central venous or arterial catheters. Blood and saliva samples can both be used to measure pain biomarkers. Various methods of analysis described in this scoping review can easily be performed in a hospital setting. We strongly believe that identifying pain biomarkers in children in the PICU would improve pain management, pain assessment, and the effectiveness of analgesia and would promote personalized care. We suggest that observational quantitative studies be conducted to confirm the diagnostic role of biomarkers of pain in children in the PICU. We hope that in the future biomarkers can be used routinely to measure pain in critically ill children who cannot verbally communicate their pain level.

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Footnotes

To purchase electronic or print reprints, contact the American Association of Critical-Care Nurses, 27071 Aliso Creek Rd, Aliso Viejo, CA 92656. Phone, (800) 899-1712 or (949) 362-2050 (ext 532); fax, (949) 362-2049; email, reprints@aacn.org.

 

Financial Disclosures

None reported.

 

See Also

To learn more about pain assessment in children, read “Pain Assessment and Management for a Chemically Paralyzed Child Receiving Mechanical Ventilation” by Laures et al in the American Journal of Critical Care, 2023; 32(5):346-354. https://doi.org/10.4037/ajcc2023403. Available at www.ajcconline.org.