Evaluating perioperative stresses in children by noninvasive modalities using salivary cortisol and autonomic reactivity

doi:10.21203/rs.3.rs-4842527/v1

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Research Article

Evaluating perioperative stresses in children by noninvasive modalities using salivary cortisol and autonomic reactivity

https://doi.org/10.21203/rs.3.rs-4842527/v1

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Journal Publication

published 05 Aug, 2024

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Purpose

Salivary cortisol (SalC) and low to high pulse ratio (LHR) were used for evaluating perioperative stresses in children.

Methods

Children aged 6 months-16 years having elective general (thoracic/abdominal) or minor (open/minimally invasive: MI) procedures underwent pulse monitoring during AM (08:00–12:00) and PM (17:00–21:00) saliva collections from the day before surgery (S-1) to 3 days after surgery (S + 3). SalC/LHR were correlated with age, sex, caregiver attendance, operative time, and surgical site/approach using mixed model analysis and face/numeric pain rating scales (FRS/NRS).

Results

Mean ages (years): minor-open (n = 31) 4.7 ± 2.0, thoracic-open (n = 2) 8.7 ± 4.9, thoracic-MI (n = 6) 9.6 ± 6.1, abdominal-open (n = 14) 4.3 ± 4.1, and abdominal-MI (n = 32) 8.0 ± 5.0. Postoperative SalC increased rapidly and decreased to preoperative levels by S + 3 (p < 0.001). LHR increased slightly without decreasing (p = 0.038). SalC correlated positively with operative time (p = 0.036) and open surgery (p = 0.0057), and negatively with age (p < 0.0001) and caregiver attendance (p < 0.001). SalC correlated positively with FRS (n = 51) at S + 2(PM) (p = 0.023), S + 3(AM) (p < 0.001), S + 3(PM) (p = 0.012) and NRS (n = 34) at S + 1(AM) (p = 0.031), S + 3(AM) (p < 0.044). LHR positively correlated with age (p = 0.0072), female sex (p = 0.0047), and caregiver attendance (p = 0.0026). Postoperative SalC after robotic-assisted MI was significantly lower than after open surgery at S + 2(AM) (p = 0.020).

Conclusions

SalC correlated with pain. Caregiver attendance effectively alleviated stress.

Perioperative stress

Pediatric surgery

Mixed linear model effect analysis

Cortisol

Autonomic nerve response

Pain scale.

Systemic stress responses triggered by surgical intervention (i.e., surgical stress) are characterized by neuroendocrine activation, autonomic reactivity, and inflammatory cytokine production regulated by the central nervous system or the hypothalamic-pituitary-adrenal axis [1] to maintain physiological homeostasis [2]. As a result, stress may be implicated in the breakdown of the physical or immune system [3, 4], which could influence the recovery of pediatric surgical patients. A spectrum of factors such as age, type of procedure, surgical approach, duration of surgery, body mass, anxiety, environmental issues related to hospitalization and separation from caregivers [5], and limited communication skills can compound the effects of stress and evaluating stress in children can be challenging because of this complex interplay.

Noninvasive markers are considered the best for assessing stress responses directly without extraneous aberrations caused by invasive assessment techniques, such as blood collection. To date, several studies have assessed the stress responses to medical/surgical intervention. For example, cortisol reflects physical and psychological stress well [1, 6] and is sensitive enough for scientific and medical research [7–9]. Salivary cortisol (SalC) reacts in parallel with plasma cortisol [10], and increases immediately after surgery [11]. In infants, it can remain elevated for several hours, decreasing within 48 hours of surgery [12].

Autonomic reactivity (AR) can be measured using a small, lightweight, non-intrusive wearable device [13, 14] that continuously monitors the heart rate and respiratory variability to determine whether the sympathetic or parasympathetic state is dominant [15]. For example, there is a report of a wearable device applied for perioperative monitoring of an adult patient with gastric cancer for 5 days to assess autonomic/psychological disturbances induced by fear, fasting, environmental change, or pain before and after tumor resection surgery [16, 17]. However, no similar study could be identified for pediatric surgical patients.

Despite technological developments in evaluating surgical stress using noninvasive methods in pediatric patients, there appear to be no such studies involving infants who are particularly sensitive to environmental factors and have limited communication skills. Data on responses to perioperative stress associated with more routine activities related to medical attention, such as physical examination, could improve the management of infants undergoing surgery. Therefore, in the current study, the impact of perioperative stress on children undergoing various types of elective open (OP) or minimally invasive (MI) minor (cutaneous), or major (thoracic/abdominal) procedures was monitored noninvasively using SalC and AR estimated by a wearable monitor to clarify which perioperative factors may strongly influence stress responses using multivariate statistical analysis and successive univariate analysis. Furthermore, stress responses and postoperative pain were correlated to determine whether SalC and AR had clinical relevance for postoperative pain management.

Study design and patient selection

Patients were identified from all pediatric patients aged between 6 months and 16 years booked for elective internal or minor OP or MI surgery between June 2022 and June 2023 at a single institute with 10 complete SalC results (n = 85). Patients under six months of age or with intellectual disabilities were excluded because their diurnal fluctuations in cortisol secretion may be at risk of disruption [18]. Caregivers were hospitalized with their children when requested.

Patients who underwent elective general (thoracic/abdominal), or minor procedures had pulse monitoring and saliva collections from the day before surgery (S-1) to 3 days after surgery (S + 3). Correlations between SalC or AR and age, sex, hospitalization with caregivers, operative time, surgical site (cutaneous, abdominal, or thoracic), and surgical approach (OP or MI) were determined using mixed model analysis. SalC and AR were correlated with the Numeric Rating Scale (NRS) or Face Rating Scale (FRS) for pain, white blood cell count (WBC; /µL), C-reactive protein (CRP; mg/dL), and creatine kinase (CK; U/L) as general indicators of stress at S + 1(AM) and S + 3(AM).

Surgical procedures

The MI procedures were either laparoscopic, thoracoscopic, or robotic-assisted. Minor (cutaneous) procedures (n = 31) included penile shaft chordectomy (n = 11; all OP) and urethroplasty (n = 20; all OP). Internal procedures (n = 54) were thoracic (th; n = 8; OP = 2, MI = 6) or abdominal (ab; n = 46; OP = 14, MI = 32). Specifically, th were: lung lobectomy (n = 3; OP = 1, MI = 2), Nuss procedure (n = 4; all MI), and bar removal after Nuss procedure (n = 1; OP); and ab were: interval appendectomy (n = 17; all MI), pyeloplasty (n = 7; OP = 4, MI = 3, all robotic-assisted), colostomy takedown (n = 6; all OP), hepaticojejunostomy (n = 3; all MI including 2 robotic-assisted), urachal resection (n = 2; all OP), endorectal pull-through (n = 2; all MI), anoplasty (n = 1; MI), sacrococcygeal teratoma excision (n = 1; MI), hepatectomy (n = 1; OP), ovarian cystectomy (n = 1; MI), excision of enteric duplication (n = 1; MI), vaginoplasty (n = 1; MI), nephrectomy (n = 1; MI), ureterocystostomy (n = 1; OP), and varicocelectomy (n = 1; MI).

Pain management and sedation

Patients who underwent minor (cutaneous) procedures received a caudal epidural block with a 1mL/kg bolus of 0.2% ropivacaine or 0.25% levobupivacaine after the induction of general anesthesia. Acetaminophen (15mg/kg) was administered transanally as required for postoperative pain. For Patients who underwent interval appendectomy, urachal resection, ovarian cystectomy or varicocelectomy, postoperative pain was managed by 3 routine doses of acetaminophen (15mg/kg) administered intravenously or orally, followed by an additional 15mg/kg dose as required. For patients who underwent thoracic or other abdominal procedures, postoperative pain was managed by intravenous fentanyl 1µg/kg/min (S0) and 0.5µg/kg/min (S + 1) and 3 routine doses of acetaminophen 15mg/kg/time administered (S + 2 and S + 3). Nonsteroidal anti-inflammatory drugs (1mg/kg) were also administered intravenously or orally as required for pain. Sedation was achieved with dexmedetomidine infusion at 1µg/kg/hour administered until S + 1 8:00 a.m.

Saliva collection, sample processing, and SalC measurement

Saliva was collected using commercially available saliva assay kits (Salimetrics LLC, USA) and age-appropriate techniques according to the manufacturer’s instructions. Samples were collected twice daily between 8:00–12:00 (AM) and 17:00–21:00 (PM) for 5 days from one day before surgery until 3 days after surgery (S-1, S, S + 1, S + 2, and S + 3), 30 minutes after eating or oral care by healthcare staff or caregivers. If the samples could not be collected correctly for any reason, the patients were excluded from this study.

Saliva samples were processed as follows. 200µL of saliva was extracted and frozen at -80℃ following centrifugation at 1500g for 15 minutes. SalC was determined in each sample using a Salivary Cortisol Enzyme-Linked Immunosorbent Assay (ELISA) kit (Salimetrics LLC, USA) according to the manufacturer’s instructions.

Assessing AR

AR was evaluated by calculating low to high heart rate ratios (LHR) using a “My Beat” wearable monitoring device (Union Tool Co., Tokyo, Japan) [13] worn on the left chest constantly during the 5-day study period except for surgery and transfer to and from the operating room. Data were recorded continuously during saliva collection times on all 5 days. The software provided by the manufacturer was used to determine the low and high heart rates to calculate LHR. A high LHR signified sympathetic dominance and a low LHR signified parasympathetic dominance [19].

Assessment of the pain scale score

To evaluate postoperative pain, two pain scales [20, 21] were used; the NRS for patients who were able to explain their pain verbally (n = 34) and the FRS for patients who could point (n = 51). NRS was scored from 0 = no pain to 10 = maximum pain. FRS was scored from 0 = smiling (no pain) to 5 = crying (maximum pain).

Statistical analysis

The influence of preoperative (age, sex, and caregiver attendance) and intraoperative (operative time, surgical site, and approach) factors on SalC/LHR was evaluated by a mixed linear model effect analysis for repeated measurements using JMP Pro 17. Based on the statistically significant results derived from the multivariate analysis, univariate analyses for each factor were performed successively. Each factor, pain scale scores, and blood test results (WBC, CRP, and CK) were independently compared with SalC and LHR using the Kruskal-Wallis test, Spearman coefficient test, ANOVA test, and Student’s t-test using GraphPad Prism 6.0, respectively. Differences were considered significant when p < 0.05. Data were expressed as mean ± standard deviation.

Ethical approval

Informed consent to participate in this study, attach a wearable device, and undergo saliva/blood sample collection was obtained from all caregivers. This study was approved by the Institutional Review Board of Juntendo University School of Medicine (E21-0351) and complied with the Helsinki Declaration of 2008.

Table 1

Table 1 summarizes the patient data. Mean ages (years) at surgery were minor (cutaneous)-OP: 4.7±2.0; th-OP: 8.7±4.9, th-MI: 9.6±6.1; and ab-OP: 4.3±4.1, ab-MI: 8.0±5.0; there were no statistically significant differences between the 5 groups. Mean operative times (minutes) were minor (cutaneous)-OP: 160±53; th-OP: 153±103, th-MI:265±190; and ab-OP: 239±76, ab-MI: 268±270; there were no statistically significant differences between the 5 groups. None of the patients developed a postoperative wound or systemic infection or other serious complication requiring reoperation within 3 days of surgery.

Table 2

Fig. 1A

Fig. 1B

Overall, SalC increased rapidly after all surgeries and decreased to preoperative levels by S+3 in all 85 patients (p<0.001) (Fig. 1A). In contrast, the postoperative increase in LHR was transient followed by an indistinct decrease or increased and remained increased (p=0.038) (Fig. 1B). The analysis of the mixed linear model effect showed that SalC was negatively correlated with age (95% confidence interval (CI) = -0.05982 to -0.03126, p<0.0001), caregiver attendance (95% CI = 0.05850 to 0.21019, p<0.001) and MI surgery (compared to OP, 95% CI = -0.18005 to -0.03083, p=0.0057) while for OP, SalC was negatively correlated with age (95% CI = -0.05982 to -0.03126, p<0.0001), and positively correlated with longer operative time (95% CI = 0.00002 to 0.00059, p=0.036), but not with sex or surgical site (Table 2). On the other hand, LHR was positively correlated with age (95% CI = 0.04533 to 0.28784, p=0.0072), female sex (95% CI = 0.25646 to 1.41022, p=0.0047) and caregiver attendance (95% CI = -1.64936 to -

Table 3

0.35156, p=0.0026), and not correlated with operative time, surgical site, or type of procedure (Table 3).

Fig. 2C

Fig. 2B

Fig. 2A

Table 4

On univariate analyses, the Spearman coefficient test between age at surgery and SalC showed a negative correlation from S-1(PM) to S+3(AM) except at S+1(PM) i.e., (S-1(PM), p=0.016; S(AM), p=0.012; S(PM), p=0.034; S+1(AM), p=0.0013; S+1(PM), p=0.1076; S+2(AM), p=0.031; S+2(PM), p=0.018, and S+3(AM), p=0.028, respectively, despite the correlation between LHR and age being negative only at S-1 (AM and PM) (p=0.034 and 0.029, respectively) (Table 4). Furthermore, when all SalC samples were classified according to age at surgery, there was a change in distribution at 5 years old (<5), with the mean SalC being significantly higher at S(PM), S+1(AM), S+1(PM), and S+2(AM) in patients aged up to 5 years old compared with patients aged 5 or older; (p=0.028, p<0.001, p=0.092, and p=0.015, respectively) (Fig. 2A). Similarly, SalC was significantly higher in internal-OP less than 5 at S+1(AM) and S+1(PM) compared with 5 or older (p<0.001 and p=0.027, respectively) (Fig. 2B) and internal-MI less than 5 at S(AM), S(PM), S+1(PM), and S+2(AM) compared with 5 or older (p=0.033, p<0.001, p=0.012, and p=0.043, respectively) (Fig. 2C).

For hospitalization with caregivers, SalC was significantly lower in patients less than 5 years old hospitalized with caregivers at S-1(AM), S-1(PM), S(PM), and S+1(PM) (p=0.045,

Fig. 3A

p=0.012, p=0.007, and p<0.001, respectively) (Fig. 3A). However, SalC in patients 5 or older hospitalized with caregivers was higher on S-1(PM) compared with those hospitalized without

Fig. 3B

caregivers (p=0.026) (Fig. 3B). There were no statistically significant differences for LHR in based on age or attendance of caregivers.

Table 5

Fig. 4A

The Spearman correlation coefficient between operative time and SalC showed a positive correlation immediately after surgery at S(PM) and also at S+1(PM) (p=0.0098 and p=0.018, respectively) whereas there was no correlation between LHR and operative time (Table 5). When all SalC samples were analyzed according to the operative time, there was a change in the distribution at 3 hours. The mean SalC after surgery taking less than 3 hours was significantly lower at S(PM) compared with surgery taking 3 or more hours; (p=0.014) (Fig. 4A).

Fig. 4B

Comparison between internal-OP and MI showed that MI had consistently lower postoperative SalC than OP throughout the study, with a statistically significant difference between robotic-assisted and OP surgery at S+2(AM) (p=0.020) (Fig. 4B).

Table 6

For the pain scale and SalC, SalC correlated positively with FRS at S+2(PM) (p=0.023), S+3(AM) (p<0.001), and S+3(PM) (p=0.012) and NRS at S+1(AM) (p=0.031) and S+3(AM) (p=0.044) (Table 6). The LHR did not correlate with postoperative pain.

For postoperative blood test results for abdominal surgery cases, WBC was 9905±2966/µL at S+1(AM) and 8271±2183/µL at S+3(AM); CRP was 2.1±2.2mg/dL at S+1(AM) and 3.1±3.7mg/dL at S+3(AM); CK was 363±288U/L at S+1(AM) and 176±167U/L at S+3(AM), while for thoracic surgery cases, WBC was 11833±5145/µL at S+1(AM) and 9433±2021/µL at S+3(AM); CRP was 3.1±2.7mg/dL at S+1(AM) and 3.1±0.62mg/dL at S+3(AM); CK was 1616±1858U/L at S+1(AM) and 1577±2482U/L at S+3(AM). These data did not correlate statistically with SalC/LHR at S+1(AM) and S+3(AM) using the Spearman coefficient test.

In the present study, multiple environmental and surgical factors were identified as causing distinct perioperative stress responses in pediatric patients using SalC and LHR. The postoperative increase in SalC was rapid and more impactful than LHR. The patients for the present study were all clinically stable and all surgeries were elective. As a result, the baseline data on S-1, was considered to be the same as for healthy children of the same age. In fact, SalC data on S-1 was similar to data from healthy children available from the manufacturer of the Salivary Cortisol ELISA kit at https://salimetrics.com/wp-content/uploads/2018/03/salivary-cortisol-elisa-kit.pdf. SalC on S+1, was higher than normal (baseline) because of surgical intervention. Thus, the present study precisely evaluated the stress response to surgical intervention from normal baseline levels preoperatively back to normal on S+3.

Additionally, multivariate statistical analyses revealed that high SalC levels were correlated with younger age at surgery, absence of caregivers, longer operative time, and OP. On the other hand, high LHR was correlated with older age at surgery, female sex, and caregiver attendance, but not with surgical factors. Thus, SalC appears to reliably assess the perioperative stress response, whereas LHR appears to reflect multiple environmental influences not just surgery-related influences.

In general, physical stress is assessed by the WBC count, CRP, or CK. They did not correlate with cortisol and LHR at S+1(AM) and S+3(AM). Neutrophils in particular are known to increase following the secretion of cortisol and adrenaline [22], whereas lymphocyte production correlates with mood states such as depression and anxiety [23]. CRP is an acute-phase protein that responds to systemic inflammation and correlates with the secretion of interleukin-6, a major cytokine [24], and its half-life in plasma is reported to be 19 hours. Although postoperative CK elevation is considered a stress response to surgical intervention, it is dependent on muscle mass, wound size, and duration of surgery [25,26]. This means that they lack specificity and are unlikely to be reliable indicators like cortisol or autonomic nervous system monitoring although these are subject to diurnal fluctuation. The SalC and LHR data in the present study reflect the characteristics of the endocrine and autonomic nervous systems, respectively, and are unique in that they are both sensitive to changes and respond readily. These data suggest that SalC and LHR can distinguish between the effects of various stress alleviating and stress inducing factors such as caregiver attendance and differences in surgical approach, respectively that may not be reflected by blood samples taken routinely during clinical practice.

Surprisingly, the influence of the age at surgery and the attendance of caregivers on SalC and LHR were opposite in the multivariate statistical analysis. It was reasonable that younger patients had higher SalC, as cortisol is known to predominantly respond to physical stress, and the main stress in the present study was surgery with some associated psychological stress [17]. On the contrary, high LHR correlated with older age on the mixed model effect analysis, while high LHR correlated only with younger age preoperatively on the Spearman test, indicating that LHR is non-specific, dependent on the type of data analysis and thus of questionable clinical relevance. SalC was consistently lower when patients were hospitalized with caregivers, particularly when they were less than 5 years old. This finding supports the general observation that children less than 5 years old become agitated if separated from their caregivers [5]. Research has also shown that 2-year-olds cared for by their caregivers have lower salivary cortisol levels than those cared for by others [27]. This finding also supports the findings of the current study hinting that younger children benefit from caregiver attendance in a medical setting. However, hospitalization with caregivers was correlated with high LHR and high SalC in patients 5 or older, which can be explained partly by a report that found caregivers may not be effective at reducing mental agitation in older children such as school-aged children because they are mature enough to be sensitive about things and concerned about the stress that might inflict on their caregivers [28]. Data from the present study suggest that hospitalization with caregivers is critically effective for alleviating the perioperative stress response in children less than 5 years old, but for older children, it might be better for them to be separated from their caregivers.

Common sense would dictate that more complex, longer, more invasive, larger scale procedures should be more stressful. Some investigators have demonstrated that cortisol levels may be lower in adult patients after a laparoscopic or thoracoscopic procedure for the resection of colorectal cancer or for the treatment of rib fractures compared with laparotomy or thoracotomy group [29, 30]. Although there is little reported evidence in pediatric patients, including those having robotic-assisted surgery, univariate analysis showed that SalC was lower after MI, especially robotic-assisted surgery, compared with OP. This is reported for the first time. In contrast, a longer operative time only correlated with high postoperative SalC and LHR, for a very short, limited period only. Thus, the surgical stress associated with longer procedures appears to resolve promptly, although most surgeons are conscious that longer procedures cause greater physical impact.

Interestingly, postoperative pain scales were positively correlated with SalC, but not with LHR. This is reasonable because cortisol significantly reflects physical stress [17], suggesting that SalC may be a scientifically reliable indicator of postoperative pain with potential for application to the administration of on-demand or self-administered analgesia.

A limitation of the present study was the strict protocol for saliva sample collection and heart rate monitoring. In particular, accurately collected samples to record the diurnal rhythm of cortisol secretion were considered mandatory. The importance of ensuring that a collection was completed within the stipulated time was strictly enforced and could itself have been stressful. Another reason was the differences in pain management and sedation that could affect autonomic activity. Unfortunately, other incidental stress-inducing factors and endocrine-mediated stress responses were beyond the scope of the present study. A separate study on the effects of pain relief and sedation on SalC is planned.

In conclusion, the present study identified that SalC correlated specifically with perioperative stress and could be a useful indicator for monitoring postoperative pain, while LHR possibly reflects surgical stress factors less. The advantage of robotic-assisted surgery, as evidenced by postoperative low SalC, is reported for the first time. Of particular interest was the negative correlation between high stress response and age and the benefit of caregiver attendance. In other words, the stress experienced by younger pediatric surgery patients was readily relieved by hospitalization with a caregiver.

Acknowledgments

The authors thank the Laboratory of Molecular and Biochemical Research, Research Support Center, Juntendo University Graduate School of Medicine, for technical assistance. This study was supported by a University President's Grant for Young Researchers, Juntendo University Grant Numbers YP22-33 and YP2022-42, and a University President's Grant, Juntendo University Grant Number P22-04.

Authors’ contributions

AA and KS designed the study. AK, TY, HI, SN, HK, HK, and AY provided conceptual advice. AA, KF, HW, AI, MS, and KS collected saliva samples. AA, KF, and KS analyzed data. AA, AY, and KS wrote the manuscript. GL revised the English of the manuscript as a native English speaker to be faithful to the style of the authors.

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Manou-Stathopoulou V, Korbonits M, Ackland GL (2019) Redefining the perioperative stress response: a narrative review. Br J Anaesth 123(5):570-83.
Finnerty CC, Mabvuure NT, Ali A, Kozar RA, Herndon DN (2013) The surgically induced stress response. JPEN J Parenter Enteral Nutr 37(5 Suppl):21s-9s.
Lachmann G, von Haefen C, Kurth J, Yuerek F, Spies C (2018) Innate immunity recovers earlier than acquired immunity during severe postoperative immunosuppression. Int J Med Sci 15(1):1-9.
Lutgendorf SK, Weinrib AZ, Penedo F, Russell D, DeGeest K, Costanzo ES, et al (2008) Interleukin-6, cortisol, and depressive symptoms in ovarian cancer patients. J Clin Oncol 26(29):4820-7.
Ouellet-Morin I, Tremblay RE, Boivin M, Meaney M, Kramer M, Côté SM (2010) Diurnal cortisol secretion at home and in child care: a prospective study of 2-year-old toddlers. J Child Psychol Psychiatry 51(3):295-303.
Lee T, Shimizu T, Iijima M, Obinata K, Yamashiro Y, Nagasawa S (2006) Evaluation of psychosomatic stress in children by measuring salivary chromogranin A. Acta Paediatr 95(8):935-9.
Taşar S, Dikmen N, Bulut İ, Haskılıç YE, Saç R, Şenes M, et al (2022) Potential role of salivary cortisol levels to reflect stress response in children undergoing congenital heart surgery. Cardiol Young :1-7.
de la Rubia Ortí JE, García-Pardo MP, Iranzo CC, Madrigal JJC, Castillo SS, Rochina MJ, et al (2018) Does Music Therapy Improve Anxiety and Depression in Alzheimer's Patients? J Altern Complement Med 24(1):33-6.
Sabatini L, Nicolaci G, Atzori F, Oliva A, Aprato A, Terzolo M, et al (2018) Biochemical stress evaluation after medial parapatellar and subvastus approach in total knee replacement. Musculoskelet Surg 102(2):185-90.
Kim JH, Kim YJ, Lee SM, Lee J (2020) Comparison of salivary and serum cortisol levels in mechanically ventilated patients and non-critically ill patients. Acute Crit Care 35(3):149-55.
Nakamura M, Suita S, Yamanouchi T, Masumoto K, Ogita K, Taguchi S, et al (2003) Cortisol and cytokine responses after surgery in different age groups of pediatric patients. Pediatr Surg Int 19(3):194-9.
Okur H, Küçükaydin M, Ustdal KM (1995) The endocrine and metabolic response to surgical stress in the neonate. J Pediatr Surg 30(4):626-5.
Itao K, Komazawa M, Luo Z, Kobayashi H (2017) Long-Term Monitoring and Analysis of Age-Related Changes on Autonomic Nervous Function. Health, 9:323-344.
Akimoto K, Ailing H, Yamaguchi T, Kobayashi H (2018) Effect of 528 Hz Music on the Endocrine System and Autonomic Nervous System. Health, 10:1159-1170.
Hinde K, White G, Armstrong N (2021) Wearable Devices Suitable for Monitoring Twenty Four Hour Heart Rate Variability in Military Populations. Sensors (Basel) 21(4).
Cheng W, Liu J, Zhi M, Shen D, Shao M, Zhang C, et al (2022) Stress and autonomic nerve dysfunction monitoring in perioperative gastric cancer patients using a smart device. Ann Noninvasive Electrocardiol 27(1):e12903.
Eda N, Ito H, Akama T (2020) Beneficial Effects of Yoga Stretching on Salivary Stress Hormones and Parasympathetic Nerve Activity. J Sports Sci Med 19(4):695-702.
Tryphonopoulos PD, Letourneau N, Azar R (2014) Approaches to salivary cortisol collection and analysis in infants. Biol Res Nurs 16(4):398-408.
Shaffer F, Ginsberg JP (2017) An Overview of Heart Rate Variability Metrics and Norms. Front Public Health 5:258.
Buvanendran A, Fiala J, Patel KA, Golden AD, Moric M, Kroin JS (2015) The Incidence and Severity of Postoperative Pain following Inpatient Surgery. Pain Med 16(12):2277-83.
Cravero JP, Fanciullo GJ, McHugo GJ, Baird JC (2013) The validity of the Computer Face Scale for measuring pediatric pain and mood. Paediatr Anaesth 23(2):156-61.
Tahir N, Zahra F (2023) Neutrophilia. StatPearls, Treasure Island (FL).
Park JE, Kim SW, Park Q, Jeong DU, Yu BH (2005) Lymphocyte subsets and mood states in panic disorder patients. J Korean Med Sci Apr 20(2):215-9.
Thompson D, Pepys MB, Wood SP (1999) The physiological structure of human C-reactive protein and its complex with phosphocholine. Structure 7(2):169-77.
Wallimann T, Hemmer W (1994) Creatine kinase in non-muscle tissues and cells. Mol Cell Biochem 133-134:193-220.
Griffith M, Shaw KA, Baird M, Rushford P, Shaw V, Roberts A, Gloystein DM (2019) Defining the Normal Trends of Serum Creatine Kinase Levels Following Spinal Surgery. Asian Spine J 13(3):386-394.
Ouellet-Morin I, Tremblay RE, Boivin M, Meaney M, Kramer M, Côté SM (2010) Diurnal cortisol secretion at home and in child care: a prospective study of 2-year-old toddlers. J Child Psychol Psychiatry Mar 51(3):295-303
van der Geest IM, van den Heuvel-Eibrink MM, Passchier J, van den Hoed-Heerschop C, Pieters R, Darlington AS (2014) Parenting stress as a mediator of parents' negative mood state and behavior problems in children with newly diagnosed cancer. Psychooncology 23(7):758-65.
Wang D, Xu Y, Wang Q, Wang X (2022) A Cohort Study on the Comparison of Complications, Short-Term Efficacy, and Quality of Life between Thoracoscopic Surgery and Traditional Surgery in the Treatment of Rib Fractures. Contrast Media Mol Imaging 2022:2079098.
Chen Y, Xi D, Zhang Q (2022) Laparoscopic Radical Resection versus Routine Surgery for Colorectal Cancer. Comput Math Methods Med 2022:4899555.

Table 1 Types of surgery

	Minor (Cutaneous) (n=31)	Major (Thoracic) (n=8)		Major (Abdominal) (n=46)
	OP (n=31)	OP (n=2)	MI (n=6)	OP (n=14)	MI (n=32)
Male:Female	31:0	2:0	6:0	10:4	15:17
Mean age (years)	4.7±2.0	8.7±4.9	9.6±6.1	4.3±4.1	8.0±5.0
Operative time (minutes)	160±53	153±103	265±190	239±76	268±27

OP: Open; MI: minimally invasive

Table 2 Mixed linear model effect analysis for SalC

SalC
	Coefficient	Standard error	t	p value	95% CI
Age	-0.04554	0.007272	-6.26	<0.0001	-0.05982	-0.03126
Sex (Female)	-0.0154	0.033529	-0.46	NS	-0.08124	0.05045
Caregiver absence	0.134344	0.038623	3.48	<0.001	0.05850	0.21019
Operative time	0.000303	0.000144	2.1	0.036	0.00002	0.00059
Site (Abdominal)	0.011596	0.043665	0.27	NS	-0.07425	0.09744
Type (MI)	-0.10544	0.037949	-2.78	0.0057	-0.18005	-0.03083

SalC: Salivary cortisol; MI: minimally invasive; CI: confidence interval; NS: not significant

Table 3 Mixed linear model effect analysis for LHR

LHR
	Coefficient	Standard error	t	p value	95% CI
Age	0.166585	0.061737	2.7	<0.0072	0.04533	0.28784
Sex (Female)	0.833336	0.29372	2.84	<0.0047	0.25646	1.41022
Caregiver absence	-1.00046	0.33039	-3.03	<0.0026	-1.64936	-0.35156
Operative time	0.000986	0.001455	0.68	NS	-0.00188	0.00385
Site (Abdominal)	-0.18883	0.372198	-0.51	NS	-0.92076	0.54311
Type (MI)	0.355749	0.347766	1.02	NS	-0.32814	1.03964

LHR: low to high heart rate ratio; MI: minimally invasive; CI: confidence interval;

NS; not significant

Table 4 Correlative analysis between mean age at surgery and stress response

Spearman	SalC		LHR
	r	p	r	p
S-1(AM)	-0.1303	NS	-0.2931	0.034
S-1(PM)	-0.3136	0.016	-0.3342	0.029
S(AM)	-0.5169	0.012	-0.2442	NS
S(PM)	-0.3121	0.034	-0.1486	NS
S+1(AM)	-0.4195	0.0013	-0.0058	NS
S+1(PM)	-0.2235	NS	-0.0813	NS
S+2(AM)	-0.2785	0.031	0.0515	NS
S+2(PM)	-0.2806	0.018	0.0355	NS
S+3(AM)	-0.2894	0.028	0.1030	NS
S+3(PM)	-0.1975	NS	0.0942	NS

SalC: Salivary cortisol; LHR: low to high heart rate ratios; r: correlation coefficient;

NS; not significant

Table 5 Correlative analysis between operative time and stress response

	SalC		LHR
	Operative time		Operative time
Spearman	r	p value	r	p value
S (PM)	0.3771	0.0098	0.1459	NS
S+1 (AM)	0.0947	NS	0.0206	NS
S+1 (PM)	0.3261	0.018	0.0040	NS
S+2 (AM)	0.1666	NS	0.0267	NS
S+2 (PM)	0.1743	NS	-0.0026	NS
S+3 (AM)	0.1030	NS	-0.1811	NS
S+3 (PM)	0.1257	NS	0.2103	NS

SalC: Salivary cortisol; LHR: low to high heart rate ratios; r: correlation coefficient;

NS; not significant

Table 6 Correlative analysis between postoperative pain scales and stress response

	SalC				LHR
	FRS (n=51)		NRS (n=34)		FRS (n=51)		NRS (n=34)
Spearman	r	p value	r	p value	r	p value	r	p value
S (PM)	0.2592	NS	-0.1136	NS	-0.0122	NS	0.0477	NS
S+1 (AM)	0.1659	NS	0.4515	0.031	0.0539	NS	0.0344	NS
S+1 (PM)	0.147	NS	0.0209	NS	-0.1350	NS	0.1874	NS
S+2 (AM)	0.2612	NS	-0.2674	NS	0.0382	NS	-0.0040	NS
S+2 (PM)	0.5533	0.023	0.0412	NS	0.0787	NS	-0.1248	NS
S+3 (AM)	0.7218	<0.001	0.4457	0.044	-0.0253	NS	-0.0932	NS
S+3 (PM)	0.6140	0.012	-0.1669	NS	0.0097	NS	0.1189	NS

SalC: Salivary cortisol; LHR: low to high heart rate ratio; r: correlation coefficient; FRS: Face pain rating scale; NRS: Numeric pain rating scale; NS; not significant

No competing interests reported.

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published 05 Aug, 2024

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Editorial decision: Accepted
02 Aug, 2024
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02 Aug, 2024
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Evaluating perioperative stresses in children by noninvasive modalities using salivary cortisol and autonomic reactivity

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Abstract

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Results

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Introduction

Materials and Methods

Study design and patient selection

Surgical procedures

Pain management and sedation

Saliva collection, sample processing, and SalC measurement

Assessing AR

Assessment of the pain scale score

Statistical analysis

Results

Discussion

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References

Tables

Additional Declarations

Status:

Journal Publication

Version 1