The effects of general anesthetics on the hypothalamus-pituitary-adrenal (HPA) axis and cortisol release in the setting of surgical stimuli in children are poorly characterized. Etomidate, commonly administered in a single dose as an induction agent, can inhibit the enzyme 11β-hydroxylase responsible for conversion of 11-deoxycortisol to cortisol and 11-deoxycorticosterone to corticosterone.1–3 Previous investigations of the effects of etomidate on cortisol levels have not accounted for the diurnal variation in cortisol excretion, and most have used a single cortisol measurement.4–9 In contrast to etomidate, nearly no effect on cortisol levels has been found postoperatively after propofol administration.10 Several studies have shown that cortisol levels fluctuate greatly throughout the day in adults along with their circadian rhythm.11–14 In any assessment of the effect of etomidate on cortisol levels over time, it is necessary to account for this diurnal variation.
There are several ways to measure human cortisol levels. Urine samples, while easy to obtain, do not reliably reflect rapid changes in serum cortisol levels. Venipuncture samples can be used to directly access serum cortisol, but it is rarely practical to perform serial blood collections throughout the day, and the stress of venipuncture may affect levels. Conversely, salivary samples have the advantage of being easily collected and are considered a reliable surrogate for total serum cortisol in response to rapid changes across a wide range of concentrations.15
In this study, we sought to obtain a more precise determination of the differential effect of 2 drugs on cortisol in children over time by using serial salivary measurements.
The aim of this study was to determine the daytime cortisol secretory pattern in an exploratory subgroup composed of healthy children and children scheduled for urologic surgery, and then to investigate the effects of an induction dose of etomidate compared with propofol on this secretory pattern in a larger cohort of children undergoing urologic surgery.
This trial was registered with ClinicalTrials.gov (NCT02013986), the principal investigator was Yi Du, and the date of registration was December 17, 2013. After receiving approval from the ethics committee of our institution and obtaining written consent from the children’s parents, 80 children scheduled for urologic surgery were recruited. All patients were classified as ASA physical status I and were 3 to 12 years old. We also recruited 11 healthy volunteers who were comparable in age, sex, and body mass index (BMI) to serve as a control group after obtaining written consent from the children’s parents.
Children with a history of HPA axis or liver disease, an infectious disease, who had taken glucocorticoids in the preceding year or drugs known to influence glucocorticoid secretion (such as ketoconazole and dexmedetomidine), who were severely obese (BMI >25), or who had oral cavity disease were excluded from the study.
Patients were randomly assigned in a 1:1 ratio to either the etomidate (Etomidate Fat Emulsion Injection, Nhwa Pharma, Xuzhou, China) group administered as a 0.3 mg/kg IV bolus or the propofol (Diprivan, AstraZeneca, Corden Pharma S.P.A., Italy) group administered as a 2 mg/kg IV bolus. Randomization was done with a computerized random number generator list provided by a statistician not involved in the determination of patient eligibility, drug administration, or outcome assessment.
All anesthesia procedures were scheduled to begin at approximately 11:00 AM in the morning. None of the patients received any premedication before induction of anesthesia. In the anesthesia preparation room, patients were accompanied by their parents and were administered sevoflurane by mask to facilitate placement of an IV catheter. After loss of consciousness, the patients were transferred to the operating bed where IV access was established and standard monitors, including electrocardiogram, pulse oximeter, noninvasive cuff blood pressure monitoring, and bispectral index, were applied for the duration of the procedure. Induction was performed by a senior anesthesiologist with an assistant following a standard protocol taken from a sealed envelope. The anesthesiologists responsible for the care of the child during the procedure were blinded to the induction medications. Other than etomidate or propofol, the induction anesthetics were the same between the 2 groups and included midazolam 0.1 mg/kg, fentanyl 2 μg/kg, and rocuronium 0.6 mg/kg.
After confirmation of tracheal intubation and tube placement, maintenance of anesthesia was initiated by the use of a standardized protocol with sevoflurane (2.5%–3.0% in oxygen 2 L/min) combined with remifentanil (0.2–0.5 μg/kg/min) and rocuronium (0.3 mg/kg as a bolus) with a target bispectral index of 30 to 40. When the surgery was completed, the patients were sent to the postanesthesia care unit (PACU) until they recovered from the anesthesia. All the patients used an IV patient-controlled analgesia (PCA) device to relieve pain. A continuous IV infusion of fentanyl 0.225 to 0.3 μg/kg/h with a lockout interval of 30 minutes was used. A bolus of fentanyl 0.225 to 0.3 μg/kg was given if needed. Nurses performed pain assessment 5 times a day.
We assessed postoperative pain using the FLACC (Face, Legs, Activity, Cry and Consolability) score.16 Each of the 5 criteria is assigned a score of 0, 1, or 2. The scale is scored in a range of 0 to 10, with 0 representing no pain and 10 representing extreme pain. The FLACC score was assessed 5 times a day at 7:00 AM, 8:00 AM, 12:00 PM, 4:00 PM, and 8:00 PM. A PCA bolus was given to the patient for a FLACC score >5.
Cortisol levels measured in saliva were the primary study end point. Saliva samples for cortisol in the absence of physical activity or emotional upset were taken hourly from 7:00 AM in the morning until 9:00 PM from both a group of 10 healthy children over a weekend and from 10 randomly selected patients scheduled for urologic surgery on the day before surgery. Saliva samples of patients undergoing surgery were obtained in the anesthesia preparation room (approximately 11:00 AM), when the patients were discharged from the PACU (approximately 2:00, PM), at 7:00 PM and 8:00 PM on the operative day, and at 7:00 AM, 8:00 AM, 12:00 PM, 4:00 PM, and 8:00 PM during the first 2 postoperative days. To avoid stressing the children, all the saliva samples were taken by the patient’s parents.
Saliva samples of patients undergoing surgery were taken when they were in the anesthesia preparation room (approximately 11:00 AM) and when they were discharged from the PACU (approximately 2:00 PM), at 7:00 PM and 8:00 PM on the operative day, as well as at 7:00 AM, 8:00 AM, 12:00 PM, 4:00 PM, and 8:00 PM during the first 2 postoperative days. All the saliva samples were taken by the parents to prevent fear.
Saliva was collected using the Salivette® cortisol (Sarstedt AG & Co., Nümbrecht, Germany) sampling device, which allows quick and hygienic saliva recovery from a polyester swab through centrifugation at 3000 rpm for 15 minutes. The salivary samples were immediately frozen at −20°C until further analysis. For each sample, duplicate measurements were performed for 1 mL of saliva using commercial enzyme-linked immune sorbent assay kits (IBL, Hamburg, Germany) for the direct salivary assay of cortisol (with a detectable concentration range of 0.414–110.4 nM).
We included a number of secondary end points in our study. Because low cortisol levels are associated with infection,17 we choose the need for nonprophylactic antibiotics as one of the clinical outcomes. As cortisol secretion has been implicated in wound healing,18 we recorded cases of fistula formation in the hypospadias patients. We also recorded clinical outcomes, such as hemodynamic parameters, duration of surgery, administration of vasopressors, need for nonprophylactic antibiotics, and length of hospital stay. We recorded general characteristics of the patients, including demographics, diagnosis, ASA physical status, albumin, and vital signs before surgery.
The sample size calculation was designed to provide sufficient statistical power for analyzing the primary end point, which were cortisol levels. On the basis of a preliminary study, the relevant difference in salivary cortisol to be detected between the 2 treatment groups was considered to be 2.3 nmol/L, and the SD was 5.5 nmol/L. The sample size of 76 patients allowed for 75% power to detect this difference with a repeated-measures analysis of variance with a type I error of 0.05. The time points of sampling postoperatively were 5 and autocorrelation, 0.365. Therefore, we decided to recruit 80 patients for this study, allowing for 5% of the patients with missing data or patients withdrawing for other reasons to discontinue the study, without affecting the statistical power of the study.
For the secondary end point, such as hemodynamic parameters and length of hospital stay after operation, we compared the 2 groups by the Student t test. The Fisher exact test was used to compare the percentage of nonprophylactic antibiotics use and percentage of fistula formation. The results are presented as mean (±SD) for normally distributed variables, numbers, and percentages for categorical variables. All statistical tests were 2-sided. The chosen type 1 error rate was a P value <0.01. We also compared the different cortisol levels at individual time points between the 2 groups and adjusted the type I error as 0.002 using Bonferroni-corrected method. All analyses were performed with SAS statistical software (version 9.2, SAS Institute, Cary, NC).
Eighty patients were initially enrolled and randomly selected from December 2013 to June 2014 in our hospital; of these, 2 patients were subsequently excluded because of oral cavity damage and 1 was excluded because of the lack of parental consent. Of these patients, 39 were assigned to the propofol group and 38 to the etomidate group (Fig. 1). There were no significant differences between the 2 groups with respect to sex, age, BMI, temperature, albumin concentration, length of operation, dosage of opioid analgesics, and FLACC scale. The diagnoses included hypospadias (28 patients in the etomidate group versus 24 in the propofol group) and ureteropelvic junction obstruction (10 vs 15; Table 1).
We recorded the cortisol levels of 11 healthy child volunteers and 15 patients before surgery. The peak cortisol concentration was in the morning upon awakening at approximately 7:00 AM. Levels continued to fall throughout the day until the children went to sleep at 9:00 PM (Fig. 2). No statistical difference between the 2 groups in cortisol levels was detected (interaction between group and time: F = 0.463, P = 0.863).
On the operative day, the cortisol levels of the etomidate group were significantly higher at approximately 11:00 AM (99% confidence interval [CI], 3.96 to 9.80; P < 0.0001; in the preparation room) and were significantly lower at approximately 2:00 PM (99% CI, −5.87 to −2.30; P < 0.0001; at the time of discharge from the PACU), 7:00 PM (99% CI, −4.37 to −1.11; P < 0.0001), and 8:00 PM (99% CI, −3.32 to −0.76; P < 0.0001) compared with those before surgery (interaction between group and time: F = 55.496, P < 0.0001). Compared with before surgery, the cortisol levels of the propofol group were significantly higher at approximately 11:00 AM (in the preparation room; 99% CI, 3.90 to 11.24; P < 0.0001); no significant differences were found at 2:00 PM (99% CI, −1.55 to 2.99; P = 0.476), 7:00 PM (99% CI, 1.21 to 4.99; P = 0.002), and 8:00 PM (99% CI, −0.08 to 3.08; P = 0.042; interaction between group and time: F = 13.176, P < 0.0001). Compared with the propofol group, no significant difference in cortisol levels in the etomidate was found at 11:00 AM (99% CI, −1.85 to 3.24, P = 0.476), but they were significantly lower at approximately 2:00 PM (discharging from the PACU; 99% CI, 3.60 to 6.02; P < 0.0001), 7:00 PM (99% CI, 4.82 to 6.88; P < 0.0001), and 8:00 PM (99% CI, 2.67 to 4.41; P < 0.0001; interaction between group and time: F = 14.703; P < 0.0001; Fig. 3A).
On the first postoperative day, the cortisol levels of the etomidate group were significantly lower at 7:00 AM (99% CI, −9.12 to −2.10; P < 0.0001) and 8:00 AM (99% CI, −6.93 to −2.50; P < 0.0001) in the morning; no significant differences were found at 12:00 PM (99% CI, −3.18 to 0.92; P = 0.148), 4:00 PM (99% CI, −2.22 to 2.99; P = 0.695), and 8:00 PM (99% CI, −0.69 to 2.36; P = 0.150) compared with before surgery (interaction between group and time: F = 11.462; P < 0.0001). Compared with before surgery, no significant differences in cortisol levels in the propofol group were detected (interaction between group and time: F = 2.22; P = 0.086). Compared with the propofol group, the cortisol levels of the etomidate group were significantly lower at the times of 7:00 AM (99% CI, 7.64 to 11.79; P < 0.0001) and 8:00 AM (99% CI, 5.30 to 8.67; P < 0.0001); no significant differences were found at 12:00 PM (99% CI, 0.16 to 2.96; P = 0.004), 4:00 PM (99% CI, 0.23 to 3.67; P = 0.004), and 8:00 PM (99% CI, −0.43 to 1.38; P = 0.171; interaction between group and time: F = 56.013, P < 0.0001; Fig. 3B).
On the second postoperative day, no significant differences in cortisol levels were detected between the interventional groups (interaction between group and time: F = 1.718, P = 0.163); no significant differences were detected between the etomidate (interaction between group and time: F = 0.616, P = 0.611) and propofol (interaction between group and time: F = 0.049, P = 0.990) group compared with before surgery (Fig. 3C).
There was no statistical difference between the 2 intervention groups in clinical outcomes, including hemodynamics (systolic blood pressure P = 0.209, diastolic blood pressure P = 0.137, heart rate P = 0.071), nonprophylactic antibiotics use (P = 0.675), fistula formation (P = 0.658), and length of hospital stay after surgery (P = 0.617; Table 2). We recorded no serious adverse events with either study drug.
Our study revealed that children who underwent induction of anesthesia with etomidate compared with propofol for short urologic procedures had significantly lower saliva cortisol levels at the time of PACU discharge, 3 hours later, and for the early part of the following postoperative day (7:00 AM and 8:00 AM). This difference in levels did not persist after 8:00 AM. Despite these differences in cortisol levels, there were no associated differences in the clinical outcomes between the 2 groups (Table 2).
Cortisol is secreted by the adrenal glands and is distributed to all the water spaces of the body. It can be detected in the serum or saliva.19 Salivary samples have the advantage of being easily collected and are thought to represent only the bioactive fraction. Several studies have shown that saliva is a reliable medium for assessing cortisol under basal and stimulated conditions.15,20,21 Saliva was an ideal medium for use in this study involving children because it is noninvasive, painless, stress free, and easily obtainable. This approach allowed us to conduct frequent analysis of cortisol levels to detect the time course of etomidate-related suppression of cortisol levels.
It is known that the input from the suprachiasmatic nucleus modulates the activity of the HPA axis via circadian rhythm.22,23 A recent study in adult volunteers using a computerized, automated blood sampling system that allows repeated stress-free blood sample collection demonstrated that serum cortisol was low during periods of sleep, increased before wakening, and peaked in the morning; the circadian rhythm actually consisted of an ultradian rhythm of pulses.11 To characterize the cortisol secretory pattern in children during the daytime, we recruited 11 healthy child volunteers and 15 patients randomly selected from the larger group scheduled for urologic surgery on the day before surgery. We characterized the secretion pattern in children by taking saliva every hour during the daytime. To our knowledge, this is the first time salivary cortisol that has been used to describe the secretion pattern of cortisol in healthy children. Salivary cortisol can be detected in infants as early as 8 weeks of age, and this method has been used in one instance to study morning and evening fluctuations of cortisol levels in healthy infants.24 However, because that study recorded cortisol concentrations at only 2 time points a day—in the morning and at night—it was unable to fully characterize diurnal variation. Our study was able to clearly delineate the diurnal variation in cortisol levels of healthy children and of children scheduled for urologic surgery. In this small sample size, there was no difference in either the cortisol levels or the pattern of secretion.
Etomidate is a general anesthetic most frequently used, in a single dose, as an induction agent. However, its continued use has been challenged because it has been found to inhibit 11β-hydroxylase, an enzyme involved in conversion of 11-deoxycortisol to cortisol and 11-deoxycorticosterone to corticosterone. To examine the effects of etomidate on cortisol, a number of studies have assessed baseline cortisol and cortisol after a corticotropin stimulation test, but these studies using serum or saliva samples did not account for daily variation in cortisol levels.25–27 We designed our study to account for these variations so that appropriate, time-based comparisons of levels throughout the day could be undertaken. Our study was organized in order that induction, surgery, recovery, and discharge from the PACU occurred at relatively consistent times in all patients during a time interval in which we had characterized diurnal variation in a control group.
Although it has been reported that one bolus of etomidate is associated with increased morbidity and mortality in adults,6,28 these findings have not been confirmed by other investigators.4,29,30 As a secondary end point, we assessed several clinically relevant outcomes and were unable to demonstrate any association between transient depression of cortisol levels after etomidate administration and outcomes compared with the propofol group.
It is unlikely that differences in intraoperative anesthesia management influenced cortisol levels, given that management was identical in both groups save for the use of either propofol or etomidate. Postoperative pain can also cause a stress response that influences cortisol levels.31,32 However, postoperative pain management was standardized in both groups using PCA, and no differences in FLACC scores were detected during the 2 postoperative days.
We chose propofol as a comparator induction drug because it is the most commonly used induction drug in pediatric patients. Previous studies have shown that propofol only very slightly inhibits cortisol secretion from adrenal cells in a dose-related fashion in vitro.10 In our study, propofol did not reduce cortisol levels after surgery at comparable time points.
Hypospadias repair and ureteropelvic junction obstruction repair are commonly performed urologic surgical procedures in children at Xinhua Hospital. We chose these 2 procedures because their duration and level of surgical stimulus were comparable, and they are generally not associated with confounding factors, such as large blood loss or the need for blood transfusions. It has been reported that minor urologic procedures in pediatric patients have little influence on HPA and cortisol release.33
This study is limited by the fact that we could not analyze the secretion pattern of cortisol during sleep. We did not get nighttime saliva samples postoperatively because we chose not to wake the patients to obtain them.
In conclusion, compared with propofol, a single bolus injection of etomidate for induction of anesthesia suppressed postoperative cortisol levels in healthy children undergoing urologic surgery. This suppression lasted for approximately 24 hours and was not associated with any changes in clinical outcomes.
Name: Yi Du, MD.
Contribution: This author helped design the study, collect the data, and prepare the manuscript.
Attestation: Yi Du attested to the integrity of the original data and the analysis reported in this manuscript and approved the final manuscript. Yi Du is the archival author.
Name: Yi-Jun Chen, MD.
Contribution: This author helped design the manuscript.
Attestation: Yi-Jun Chen approved the final manuscript.
Name: Bin He, MD, PhD.
Contribution: This author helped analysis of the data.
Attestation: Bin He approved the final manuscript.
Name: Ying-Wei Wang, MD, PhD.
Contribution: This author helped design the manuscript.
Attestation: Ying-Wei Wang attested to the integrity of the original data and the analysis reported in this manuscript and approved the final manuscript.
This manuscript was handled by: James A. DiNardo, MD.
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