Anxiety and cortisol levels during circumcision

Abstract

AimIn this study, we aimed to investigate whether circumcision is a stressor ambulatory surgical intervention for children and demonstrate the relationship between pre- and post-operative anxiety levels, blood cortisol levels (BCL), and salivary cortisol levels (SCL) in these children.MethodsBoys aged between 5 and 17 years, with a plan of circumcision, were prospectively included. Their preoperative anxiety levels, salivary cortisol levels (SCL), and blood total cortisol levels (BCL) were measured. After the operation, the same parameters were measured and preoperative values were compared with postoperative values. Also, the correlation between anxiety scores, SCL, and BCL was assessed. The Yale Preoperative Anxiety Scale was used to calculate the anxiety scores.ResultsThe mean age of 81 patients was 6.62 ± 1.40 years. The preoperative anxiety scores, SCL, and BCL were significantly lower than post-operative values (p<0.001 for each). The preoperative SCL were positively correlated with BCL and anxiety scores. Postoperative SCL were positively correlated with BCL and anxiety scores.ConclusionCircumcision is a cause of increment in anxiety, serum, and salivary cortisol levels in children. Salivary cortisol levels were correlated with simultaneously drawn serum cortisol levels. The preoperative and postoperative anxiety scores were correlated with BCL and SCL in children with circumcision operation.

Keywords

Introduction

Circumcision is the surgical removal of the foreskin of the penis. Motivation arising from either some personal or religious reasons makes the procedure prevalent in especially Muslim and Jewish populations. It is also one of the oldest surgical procedures, performed for medical indications, such as phimosis, balanitis xerotica obliterans, recurrent balanoposthitis, paraphimosis, and urine outlet obstruction, as well.¹ Recommendations of American Academy of Pediatrics, American College of Obstetricians and Gynecologists, Centers for Disease Control and Prevention, and World Health Organization are present, based on its long-term benefits which outweigh any risks.²
Circumcision is performed as an ambulatory surgery, which can provide more improved patient satisfaction, reduced complications, and more efficient care. Anyway, as well as many other surgical procedures, circumcision is a source of anxiety, fear, and pain for children.³ Increased preoperative anxiety levels result in negative consequences, such as challenges in the induction of anesthesia, increase in the need of anesthetic drugs during the operation and analgesic drugs after the operation, and increased risk of infections.⁴ Following any surgical interventions and trauma, the stress response is triggered by impulses sent from the injured site to the hypothalamus. As well as activation of hypothalamic-pituitary-adrenal (HPA) axis, the serum levels of glucagon, catecholamines, and host of inflammatory cytokines are increased.⁵
Total serum cortisol is the main parameter that is routinely measured in the assessment of HPA axis. Due to the changes in levels of the affinity of corticosteroid-binding globulin and misinterpreting in some patient groups, underestimation of the cortisol response in stress may happen.⁶ Measuring salivary cortisol level (SCL) is a promising alternative, because of its strong correlation with serum-free cortisol, hence safe, easy, and non-invasive, and rapid method that is especially appropriate for pediatric patients.⁷ Previously, SCL has been shown to reflect the stress in obstructive sleep apnea syndrome, dental caries, and burn wounds in children.^8-9-10
In this study, we aimed to investigate and confirm whether circumcision is a stressor ambulatory surgical intervention for children, and also we aimed to demonstrate the relationship between pre- and post-operative anxiety levels and blood and salivary cortisol levels in these children.

Materials and Methods

A prospective, observational study was planned to conduct in Erzurum Palandoken Government Hospital, between January 1, 2017 and December 31, 2017. Boys aged between 5 and 17 years, with a plan of circumcision, were included. Children with a known chronic disease (cardiac, respiratory, endocrinologic, and neurologic, etc.) and history of receiving any kind of corticosteroid therapy during the last month, were excluded. Local ethical committee approved the study protocol (Date:06/21/2016, Number: 2016/12-79) and the patients were included in the study after written informed consent was obtained from the parents of each child.
Preoperative anxiety levels of all children were calculated by means of the Yale Preoperative Anxiety Scale Modified – Short form (M-YPAS-SF), just 30 minutes before the surgery.¹¹ Additionally, salivary cortisol levels (SCL) and blood total cortisol levels (BCL) of all children were measured three times; between 08.00-13.00, on the day before the surgery (basal level); 30 minutes before the surgery (preoperative level); 2 hours after the surgery (postoperative level)
For sedation of the children, the protocol for anesthetic drugs was as follows: midazolam (after an initial intravenous dose (0.05 mg/kg), careful titration up to 0.4 mg/kg total dose was used (not exceeding 10 mg) until appropriate sedation and anxiolysis were achieved before the procedure); propofol (repeated bolus method; after an initial intravenous induction dose (2 mg/kg, 0.5 mg/kg) was given, additional bolus doses in every 3-5 minutes were applied until moderate sedation could be achieved).
No additional sedatives were used. During the monitorization, the duration of procedure, sedation, and recovery, and the doses of propofol and midazolam were recorded. And after the surgery, the Aldrete (recovery) scores were calculated.¹² Deep sedation/general anesthesia was defined as the state of blunted consciousness produced by anesthetic medications, resulting in partial loss of protective reflexes and purposeful responses to various stimuli.¹³ During and after the surgery, complications such as apnea, O2 desaturation, bradycardia, hypotension, cough, nausea, and vomiting were recorded and managed accordingly.
All SCL samples were drawn from the patients after at least 6 hours of fasting. For basal SCL samples, patients rinsed their mouth or drank water 10 minutes before sampling, between 08.00-13.00 am. Examination of cortisol levels (ng/ml) in saliva were performed in clarified saliva supernatants, which centrifuged (at 3500xg for 20 minutes) after sampling and stored at -80°C until analysis. ELISA kit (DRG Salivary Cortisol ELISA; DRG International, Inc., USA) was used following the manufacturer’s instructions. BCL’s were measured by Cobas e 601 (Roche Diagnostics GmbH; Manheim, Germany). Blood samples were centrifuged (at 3500 rpm for 10 minutes) and serum samples were stored at -80°C until analysis.
The statistical analyses of the data of the present study were performed by means of IBM SPSS 20.0 software. The Kolmogorov–Smirnov test was used to evaluate the data distribution. To evaluate the changes in anxiety and cortisol levels, paired samples T-test was used to check differences before and after the surgery, at a significance level of 5% for normally distributed continuous variables. The correlation between anxiety, blood, and salivary cortisol levels was evaluated with the Pearson correlation test. Differences were considered significant if the p-value was < 0.05. Descriptive statistics were expressed as a mean ± SD.

Results

Eighty-one patients were included in the study. Mean age of the patients was 6.62 ± 1.40 years. The data regarding the intra- and post-operative properties of the children were shown in Table 1. The preoperative anxiety scores, SCL, and BCL were significantly lower than post-operative values (p<0.001 for each) (Table 2). The pre-operative SCL were positively correlated with BCL and anxiety scores (Table 3). Similarly, post-operative SCL were positively correlated with BCL and anxiety scores. During and after the surgery, no serious complications, such as hypotension, arrhythmia, and cardiopulmonary arrest were experienced. Fifteen (18.5%) patients had a cough and 12 (14.8%) patients had nausea and vomiting in the post-operative period.

Discussion

In this study, postoperative anxiety, blood, and salivary cortisol levels were higher than preoperative levels. It is expected that a surgical procedure can induce a physiological stress response. Nevertheless, an increased level of anxiety may reflect the surgical and anesthetic experience. Increased postoperative cortisol levels are assumed as instant values without long-term effects. A healthy and functional HPA axis has been proven in adulthood after circumcision.¹⁴ Similar to this study, Hsu et al.¹⁵ reported that sedation and anesthesia induced a significant rise in SCL in children, independent from the level of sedation or the type of procedure performed. Additionally, it was reported that preoperative anxiety of parent and child, the child’s temperament, birth order, previous experience of hospitalization for surgery, preoperative premedication and preparation, the presence of parents at the induction of anesthesia and in the post-anesthetic care unit, or the different use of anesthetic drugs provided at induction in anesthesia may help to predict the postoperative anxiety of the children.³ Anyway, general anesthesia without surgical intervention may not induce a stress response in children.¹⁶
The measurement of hormones in saliva has been in development since the last decades. SCL is correlated with serum cortisol levels and displays a circadian rhythm similar to that of BCL, with a nadir at night and a peak level just after awakening.⁷ Similarly, in this study, it was shown that preoperative SCL was correlated with preoperative BCL, while postoperative SCL was correlated with postoperative BCL. In a recent review, SCL has been proposed to asses cortisol excess, deficiency and hydrocortisone replacement in clinical settings, having the advantage of detection when serum cortisol levels are low.¹⁷ SCL has been shown to correlate with BCL in response to stress, similar to this study.^18-19-20
The anxiety of the children in this study was evaluated by modified YPAS, which included the assessments including the child’s interaction with the environment, vocalization, expression of emotions, and interaction with family members.⁴ The preoperative and postoperative anxiety scores were positively correlated with BCL and SCL in this study. It was noted that children who experience perioperative anxiety become prone to altered immunity, hence increased sensitivity to infections and subsequent consumption of analgesics postoperatively.^21-22 These parameters were not studied because they were beyond the scope of this study. The use of SCL as a stress marker has been supported by previous studies.^15,23
Although Jewish communities perform circumcision on the 8th day of life in accordance with the rules of Judaism given in Torah, many Muslims are circumcised in different ages.² The mean age of the study population was seen to correspond to the school ages. Younger ages could increase the risks of mental disorders, developmental delay, and attention deficit hyperactivity disorders, related to general anesthesia.²⁴ Additionally, greater behavioral distress and more pain, hence higher BCL and SCL would be experienced.²⁵ Nevertheless, this evaluation is beyond the scope of this study.
This study should be evaluated with accompanying limitations. Although the associations between the anxiety levels and cortisol levels were assessed, their association with anesthetic drug doses and durations of anesthesia and operation could not be evaluated. Anyway, this is a well-designed study to show an increased stress burden of circumcision, although it is a simple, ambulatory surgery.
As a conclusion, the results of this study have shown that circumcision induced an increment in anxiety, serum, and salivary cortisol levels in children. Salivary cortisol levels were in correlation with simultaneously drawn serum cortisol levels. Also, the preoperative and postoperative anxiety scores were correlated with BCL and SCL in children with circumcision operation.

References

1. Bastos Netto JM, de Araújo JG Jr, de Almeida Noronha MF, Passos BR, de Bessa J Jr, Figueiredo AA. Prospective randomized trial comparing dissection with Plastibell circumcision. J Pediatr Urol. 2010;6(6):572-577. doi:10.1016/j.jpurol.2010.01.005
   Article · PubMed · Google Scholar
2. Prabhakaran S, Ljuhar D, Coleman R, Nataraja RM. Circumcision in the paediatric patient: a review of indications, technique and complications. J Paediatr Child Health. 2018. doi:10.1111/jpc.14206
   Article · PubMed · Google Scholar
3. Zavras N, Tsamoudaki S, Ntomi V, Yiannopoulos I, Christianakis E, Pikoulis E. Predictive factors of postoperative pain and postoperative anxiety in children undergoing elective circumcision: a prospective cohort study. Korean J Pain. 2015;28(4):244-253. doi:10.3344/kjp.2015.28.4.244
   Article · PubMed · Google Scholar
4. Guaratini AA, Marcolino JA, Teixeira AB, Bernardis RC, Passarelli ML, Mathias LA. A transversal study on preoperative anxiety in children: use of the modified Yale scale. Rev Bras Anestesiol. 2006;56(6):591-601.
   PubMed · Google Scholar
5. Finnerty CC, Mabvuure NT, Ali A, Kozar RA, Herndon DN. The surgically induced stress response. JPEN J Parenter Enteral Nutr. 2013;37(5 suppl):21S-29S. doi:10.1177/0148607113496117
   Article · PubMed · Google Scholar
6. Perogamvros I, Keevil BG, Ray DW, Trainer PJ. Salivary cortisone is a potential biomarker for serum free cortisol. J Clin Endocrinol Metab. 2010;95(11):4951-4958. doi:10.1210/jc.2010-1215
   Article · PubMed · Google Scholar
7. Jeong JH, Guilleminault C, Park CS, et al. Changes in salivary cortisol levels in pediatric patients with obstructive sleep apnea syndrome after adenotonsillectomy. Sleep Med. 2014;15(6):672-676. doi:10.1016/j.sleep.2013.12.019
   Article · PubMed · Google Scholar
8. Park CS, Guilleminault C, Hwang SH, Jeong JH, Park DS, Maeng JH. Correlation of salivary cortisol level with obstructive sleep apnea syndrome in pediatric subjects. Sleep Med. 2013;14:978-984. doi:10.1016/j.sleep.2013.05.012
   Article · PubMed · Google Scholar
9. Caruso S, Gatto R, Cinque B, Cifone MG, Mattei A. Association between salivary cortisol level and caries in early childhood. Eur J Paediatr Dent. 2018;19(1):10-15.
   PubMed · Google Scholar
10. Brown NJ, Kimble RM, Rodger S, et al. Biological markers of stress in pediatric acute burn injury. Burns. 2014;40(5):887-895. doi:10.1016/j.burns.2013.12.001
    Article · PubMed · Google Scholar
11. Jenkins BN, Fortier MA, Kaplan SH, Mayes LC, Kain ZN. Development of a short version of the modified Yale Preoperative Anxiety Scale. Anesth Analg. 2014;119(3):643-650. doi:10.1213/ane.0000000000000350
    Article · PubMed · Google Scholar
12. Ead H. From Aldrete to PADSS: reviewing discharge criteria after ambulatory surgery. J Perianesth Nurs. 2006;21(4):259-267. doi:10.1016/j.jopan.2006.05.006
    Article · PubMed · Google Scholar
13. Inverso G, Dodson TB, Gonzalez ML, Chuang SK. Complications of moderate sedation versus deep sedation/general anesthesia for adolescent patients undergoing third molar extraction. J Oral Maxillofac Surg. 2016;74(3):474-479. doi:10.1016/j.joms.2015.10.009
    Article · PubMed · Google Scholar
14. Ullmann E, Licinio J, Barthel A, et al. Circumcision does not alter long-term glucocorticoids accumulation or psychological effects associated with trauma- and stressor-related disorders. Transl Psychiatry. 2017;7(3). doi:10.1038/tp.2017.23
    Article · PubMed · Google Scholar
15. Hsu AA, von Elten K, Chan D, et al. Characterization of the cortisol stress response to sedation and anesthesia in children. J Clin Endocrinol Metab. 2012;97(10). doi:10.1210/jc.2012-1499
    Article · PubMed · Google Scholar
16. Rains PC, Rampersad N, De Lima J, et al. Cortisol response to general anaesthesia for medical imaging in children. Clin Endocrinol (Oxf). 2009;71(6):834-839. doi:10.1111/j.1365-2265.2009.03591.x
    Article · PubMed · Google Scholar
17. Blair J, Adaway J, Keevil B, Ross R. Salivary cortisol and cortisone in the clinical setting. Curr Opin Endocrinol Diabetes Obes. 2017;24(3):161-168. doi:10.1097/med.0000000000000328
    Article · PubMed · Google Scholar
18. Estrada-Y-Martin RM, Orlander PR. Salivary cortisol can replace free serum cortisol measurements in patients with septic shock. Chest. 2011;140(5):1216-1222. doi:10.1378/chest.11-0448
    Article · PubMed · Google Scholar
19. Arafah BM, Nishiyama FJ, Tlaygeh H, Hejal R. Measurement of salivary cortisol concentration in the assessment of adrenal function in critically ill subjects: a surrogate marker of the circulating free cortisol. J Clin Endocrinol Metab. 2007;92(8):2965-2971. doi:10.1210/jc.2007-0181
    Article · PubMed · Google Scholar
20. Gunnala V, Guo R, Minutti C, et al. Measurement of salivary cortisol level for the diagnosis of critical illness–related corticosteroid insufficiency in children. Pediatr Crit Care Med. 2015;16(4). doi:10.1097/pcc.0000000000000361
    Article · PubMed · Google Scholar
21. Ader R, Cohen N, Felten D. Psychoneuroimmunology: interactions between the nervous system and the immune system. Lancet. 1995;345:99-103. doi:10.1016/s0140-6736(95)90066-7
    Article · PubMed · Google Scholar
22. Caumo W, Broenstrub JC, Fialho L, et al. Risk factors for postoperative anxiety in children. Acta Anaesthesiol Scand. 2000;44:782-789. doi:10.1034/j.1399-6576.2000.440703.x
    Article · PubMed · Google Scholar
23. Fenol A, Jebi S, Krishnan S, et al. Association of stress, salivary cortisol level, and periodontitis among the inmates of a central prison in Kerala. Dent Res J (Isfahan). 2017;14(4):288-292. doi:10.4103/1735-3327.211625
    Article · PubMed · Google Scholar
24. Ing C, Sun M, Olfson M, et al. Age at exposure to surgery and anesthesia in children and association with mental disorder diagnosis. Anesth Analg. 2017;125(6):1988-1998. doi:10.1213/ane.0000000000002423
    Article · PubMed · Google Scholar
25. McCarthy AM, Kleiber C, Hanrahan K, Zimmerman MB, Westhus N, Allen S. Factors explaining children’s responses to intravenous needle insertions. Nurs Res. 2010;59(6):407-416. doi:10.1097/nnr.0b013e3181f80ed5
    Article · PubMed · Google Scholar

Tables

Additional Information

Publisher’s Note
Bayrakol MP remains neutral with regard to jurisdictional and institutional claims.

Rights and Permissions

Creative Commons License

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0). To view a copy of the license, visit https://creativecommons.org/licenses/by-nc/4.0/

View full license details →