Effects of Etomidate Combined With Dexmedetomidine on Adrenocortical Function in Elderly Patients: A Double-Blind Randomized Controlled Trial

Introduction Etomidate has been advocated to be used in anesthesia of the elderly and the critically ill patients due to its faint effect on cardiovascular system. But the dose-dependent suppression of etomidate on adrenal cortex function leads to the limitation of its clinical application. Clinical research shows that dexmedetomidine can reduce the dose requirements for intravenous or inhalation anesthetics and opioids, and the hemodynamics is more stable during the operation. The objective is to observe the effect of etomidate combined with dexmedetomidine on adrenocortical function in elderly patients. Methods 180 elder patients scheduled for elective ureteroscopic holmium laser lithotripsy were randomly allocated to PR group anesthetized with propofol- remifentanil, ER group anesthetized with etomidate-remifentanil, and ERD group anesthetized with dexmedetomidine combined with etomidate-remifentanil. Patients in each group whose operation time was less than or equal to 1h were incorporated into short time operation group (PR1 group, ER1 group and ERD1 group), and whose operation time was more than 1h were incorporated into long time operation group (PR2 group, ER2 group and ERD2 group). The values of SBP, DBP, HR and SpO2 were recorded at T0, T1, T2, T3, T4, T5, T6 and T7.The time of operation, the dosage of etomidate and remifentanil administrated during surgery, the time to spontaneous respiration, recovery and extubation, and the duration of stay in the PACU were recorded. The serum cortisol and ACTH concentration was measured at t0, t1, t2, t3, t4 and t5. Results The dosage of etomidate was significantly lower in ERD1 group and ERD2 group compared with ER1 group and ER2 group(P < 0.05), respectively. The SBP in ER2 and ERD2 group were higher at T1 and T3 compared to PR2 group (P < 0.05). The DBP in ER1 and ERD1 group were higher at T1compared to PR1 group (P < 0.05). The Serum cortisol concentration were higher at t1 ~ 2 in ERD1 group compared to ER1 group (P < 0.05). The Serum cortisol concentration were higher at t1 ~ 3 in ERD2 group compared to ER2 group (P < 0.05).The Serum ACTH concentration were lower at t1 ~ 2 in ERD1 group compared to ER1 group (P < 0.05). The Serum ACTH concentration were lower at t1 ~ 3 in ERD2 group compared to ER2 group (P < 0.05). Conclusion The administration of dexmedetomidine combined with etomidate can attenuate the inhibition of etomidate on adrenocortical function in elderly patients and maintain intraoperative hemodynamic stability.

Diagnostic Accuracy of Dehydroepiandrosterone Sulfate and Corticotropin in Autonomous Cortisol Secretion

Autonomous cortisol secretion (ACS) affects up to 50% of patients with adrenal adenomas. Despite the limited evidence, clinical guidelines recommend measurement of serum concentrations of dehydroepiandrosterone-sulfate (DHEA-S) and corticotropin (ACTH) to aid in the diagnosis of ACS. Our objective was to determine the accuracy of serum concentrations of DHEA-S and ACTH in diagnosing ACS. We conducted a retrospective single center study of adults with adrenal adenoma evaluated between 2000−2020. Main outcome measure was diagnostic accuracy of DHEA-S and ACTH. ACS was defined as post-dexamethasone cortisol >1.8 mcg/dL. Of 468 patients, ACS was diagnosed in 256 (55%) patients with a median post-DST cortisol of 3.45 mcg/dL (range, 1.9–32.7). Patients with ACS demonstrated lower serum concentrations of DHEA-S (35 vs. 87.3 mcg/dL, p < 0.0001) and ACTH (8.3 vs. 16 pg/mL, p < 0.0001) compared to patients with non-functioning adrenal tumors (NFAT). Serum DHEA-S concentration <40 mcg/dL diagnosed ACS with 84% specificity and 81% PPV, while serum ACTH concentration <10 pg/mL diagnosed ACS with 75% specificity and 78% PPV. The combination of serum concentrations of DHEA-S <40 mcg/dL and ACTH <10 pg/mL diagnosed ACS with the highest accuracy with 92% specificity and 87% PPV. Serum concentrations of DHEA-S and ACTH provide additional value in diagnosing ACS.

The dysregulation of the hypothalamic-pituitary-adrenal axis in diet-induced prediabetic male Sprague Dawley rats

Background: Altered function of the hypothalamic-pituitary-adrenal (HPA) axis in type 2 diabetic patients, a condition preceded by pre-diabetes, has been shown to increase the risk of depression as well as cause downstream effects resulting in upregulation of gluconeogenesis and dyslipidemia. In addition, stress, either psychological from managing diabetes or lifestyle related, further activates the HPA axis causing an exaggerated stress response. This study investigated the activity of the HPA axis in selected markers of glucose handling, and the stress response relative to components of the HPA axis in a diet-induced pre-diabetic rat model. Methods: Sprague Dawley Rats were randomly divided into non-prediabetic group (NPD) and pre-diabetic group (PD) (n=6, per group) over a 20-week induction period and a further 12-week experimental period to get 32 weeks. At the end of the 20 and 32-week periods, glucose handling using the Homeostasis Model Assessment indices, adrenocorticotropic (ACTH) and corticosterone (CORT) concentrations were measured. Stress was induced and the forced swim test (FST) were performed in the 12-week experimental week. At the end of 32 weeks glucocorticoid and mineralocorticoid hippocampal receptors were measured too. Results: Impaired glucose handling in the PD group as well as increase in corticosterone (CORT) was observed at the end of both 20 and 32-week periods by comparison to NPD groups. No changes were observed in ACTH concentration at week 20 while, at week 32, a decrease in plasma ACTH concentration was observed in the PD group by comparison to the NPD group. The stressed-induced animals were stressed underwent the forced swim test: the behaviour observed showed an increase in immobility time in the PD stressed group by comparison to the NPD group. This was followed by the observation of a decrease in ACTH and CORT concentration in the PD stressed group by comparison to the NPD stressed group. Mineralocorticoid and glucocorticoid receptors gene expression were elevated in the stressed PD group relative to the stressed NPD group. Conclusion: These observations, together, suggest that diet-induced pre-diabetes is associated with impaired HPA axis activity and deteriorating response to stress.

The dysregulation of the hypothalamic–pituitary–adrenal axis in diet-induced prediabetic male Sprague Dawley rats

Background Altered function of the hypothalamic–pituitary–adrenal (HPA) axis in type 2 diabetic patients, a condition preceded by pre-diabetes, has been shown to increase the risk of depression as well as cause downstream effects resulting in upregulation of gluconeogenesis and dyslipidemia. In addition, stress, either psychological from managing diabetes or lifestyle related, further activates the HPA axis causing an exaggerated stress response. This study investigated the activity of the HPA axis in selected markers of glucose handling, and the stress response relative to components of the HPA axis in a diet-induced pre-diabetic rat model. Methods Sprague Dawley Rats were randomly divided into non-pre-diabetic group (NPD) and pre-diabetic group (PD) (n = 6, per group) over a 20-week induction period and a further 12-week experimental period to get 32 weeks. At the end of the 20 and 32-week periods, glucose handling using the Homeostasis Model Assessment indices, adrenocorticotropic (ACTH) and corticosterone (CORT) concentrations were measured. Stress was induced and the forced swim test were performed in the 12-week experimental week. At the end of 32 weeks glucocorticoid and mineralocorticoid hippocampal receptors were also measured. Results Impaired glucose handling in the PD group as well as increase in corticosterone was observed at the end of both 20 and 32-week periods by comparison to NPD groups. No changes were observed in ACTH concentration at week 20 while, at week 32, a decrease in plasma ACTH concentration was observed in the PD group by comparison to the NPD group. The stressed-induced animals were stressed using the forced swim test: the behaviour observed showed an increase in immobility time in the PD stressed group by comparison to the NPD group. This was followed by the observation of a decrease in ACTH and CORT concentration in the PD stressed group by comparison to the NPD stressed group. Mineralocorticoid and glucocorticoid receptors gene expression were elevated in the stressed PD group relative to the stressed NPD group. Conclusion These observations, together, suggest that diet-induced pre-diabetes is associated with impaired HPA axis activity and deteriorating response to stress.

Can Endocrine Dysfunction Be Reliably Tested in Aged Horses That Are Experiencing Pain?

The aim of the present study was to evaluate (i) the effects of different intensities and types of treated pain on the basal concentrations of adrenocorticotropic hormone (ACTH) and cortisol, and (ii) the thyrotropin-releasing hormone (TRH) stimulation test, to determine whether treated pain caused a marked increase of ACTH, which would lead to a false positive result in the diagnosis of pituitary pars intermedia dysfunction (PPID). Methods: Fifteen horses with treated low to moderate pain intensities were part of the study. They served as their own controls as soon as they were pain-free again. The horses were divided into three disease groups, depending on their underlying disease (disease group 1 = colic, disease group 2 = laminitis, disease group 3 = orthopedic problems). A composite pain scale was used to evaluate the intensity of the pain. This pain scale contained a general part and specific criteria for every disease. Subsequently, ACTH and cortisol were measured before and after the intravenous application of 1 mg of TRH. Results: There was no significant difference in the basal or stimulated ACTH concentration in horses with pain and controls, between different pain intensities or between disease groups. Descriptive statistics, however, revealed that pain might decrease the effect of TRH on the secretion of ACTH. There was an increase of ACTH 30 min after TRH application (p = 0.007) in the treated pain group, but this difference could not be statistically confirmed. Measuring the basal ACTH concentration and performing the TRH stimulation test for the diagnosis of PPID seem to be possible in horses with low to moderate pain.

The Dysregulation of the Hypothalamic-pituitary-adrenal Axis in Diet-induced Prediabetic Male Sprague Dawley Rats

Background: Altered function of the hypothalamic-pituitary-adrenal (HPA) axis in type 2 diabetic patients, a condition preceded by pre-diabetes, has been shown to increase the risk of depression as well as cause downstream effects resulting in upregulation of gluconeogenesis and dyslipidemia. In addition, stress, either psychological from managing diabetes or lifestyle related, further activates the HPA axis causing an exaggerated stress response. This study investigated the activity of the HPA axis in selected markers of glucose handling, and the stress response relative to components of the HPA axis in a diet-induced pre-diabetic rat model. Methods: Sprague Dawley Rats were randomly divided into non-prediabetic group (NPD) and pre-diabetic group (PD) (n=6, per group) over a 20-week induction period and a further 12-week experimental period to get 32 weeks. At the end of the 20 and 32-week periods, insulin resistance using the HOMA-IR index, adrenocorticotropic (ACTH) and corticosterone (CORT) concentrations were measured. Stress was induced and the forced swim test (FST) were performed in the 12-week experimental week. At the end of 32 weeks glucocorticoid and mineralocorticoid hippocampal receptors were measured too. Results: Impaired glucose handling in the PD group as well as increase in corticosterone (CORT) was observed at the end of both 20 and 32-week periods by comparison to NPD groups. No changes were observed in ACTH concentration at week 20 while, at week 32, a decrease in plasma ACTH concentration was observed in the PD group by comparison to the NPD group. The stressed-induced animals were stressed underwent the forced swim test: the behaviour observed showed an increase in immobility time in the PD stressed group by comparison to the NPD group. This was followed by the observation of a decrease in ACTH and CORT concentration in the PD stressed group by comparison to the NPD stressed group. Mineralocorticoid and glucocorticoid receptors gene expression were elevated in the stressed PD group relative to the stressed NPD group. Conclusion: These observations, together, suggest that diet-induced pre-diabetes is associated with impaired HPA axis activity and deteriorating response to stress.

Influence of Concentration on Release and Permeation Process of Model Peptide Substance-Corticotropin-From Semisolid Formulations

The transdermal route of administration of drug substances allows clinicians to obtain a therapeutic effect bypassing the gastrointestinal tract, where the active substance could be inactivated. The hormonal substance used in the study-corticotropin (ACTH)-shows systemic effects. Therefore, the study of the effect of the type of ointment base and drug concentration on the release rate and also permeation rate in in vivo simulated conditions may be a valuable source of information for clinical trials to effectively optimize corticotropin treatment. This goal was achieved by preparation ointment formulation selecting the appropriate ointment base and determining the effect of ACTH concentration on the release and permeation studies of the ACTH. Semi-solid preparations containing ACTH were prepared using Unguator CITO e/s. The release study of ACTH was tested using a modified USP apparatus 2 with Enhancer cells. The permeation study was conducted with vertical Franz cells. Rheograms of hydrogels were made with the use of a universal rotational rheometer. The dependence of the amount of released and permeated hormone on the ointment concentration was found. Based on the test of ACTH release from semi-solid formulations and evaluation of rheological parameters, it was found that glycerol ointment is the most favourable base for ACTH. The ACTH release and permeation process depends on both viscosity and ACTH concentration. The higher the hormone concentration, the higher the amount of released ACTH but it reduces the amount of ACTH penetrating through porcine skin.

SUN-162 Isolated Primary Pigmented Micronodular Adrenal Disease. Unilateral or Bilateral Adrenalectomy? Two Cases Report

Background: Isolated primary pigmented nodular adrenal disease (i-PPNAD) is a particular case of micronodular bilateral hyperplasia (MiBAH) leading to Cushing syndrome (CS). We present two patients with i-PPNAD who undergone unilateral adrenalectomy with different disease outcomes. Case 1: A 56 yo man presented with typical signs and symptoms of CS, including central weight gain, proximal muscle weakness, hypertension and marked osteoporosis. A biochemical investigation showed an assessment of late-night salivary cortisol - 23 nmol/l (n &lt;9), 24h urinary free cortisol (UFC)- 1206 nmol/24h (n-60–413). The 1 mg DST showed post-DST cortisol 617 nmol/l (n&lt;50). ACTH concentration was suppressed at 1.1 pg/ml (n-7–66). Adrenal CT-scan was normal. PPNAD was assumed and the screening for Carney complex components was negative. After left adrenalectomy, histological examination confirmed the diagnosis of PPNAD. However, biochemical remission wasn’t achieved: postoperative UFC-860 nmol/24h. Thus, the right adrenalectomy was conducted. Case 2: A 40 yo female presented with long term drug-corrected (beta-blockers, ACE inhibitor) arterial hypertension, menstrual dysfunction and clinical features of CS (central obesity, proximal muscle weakness, hirsutism), without osteoporosis. Baseline hormonal evaluation documented slightly increased level of salivary cortisol- 9,8 nmol/l (n &lt;9), post 1 mg DST cortisol - 470 nmol/l (n&lt;50) and ACTH-concentration below detection &lt;1 pg/ml (n-7–66). However, UFC was normal – 215 nmol/l (n-60–413). Abdominal CT-scan revealed micronodular hyperplasia of the left adrenal and was suggestive of possible right adrenal gland hyperplasia. We performed left adrenalectomy. In the early postoperative period, adrenal insufficiency was diagnosed and thus it required hydrocortisone replacement. Discussion: We obtained two opposite results: in case 1, an expected remission after unilateral adrenalectomy was not achieved, while patient No.2 developed adrenal insufficiency, which was a more favourable prognostic sign and attested to the successful outcome of surgical treatment. A possible explanation of the ineffectiveness of surgical intervention in patient No.1 was primary more severe hypercortisolism. It is also necessary to take into account that according to the CT data of the patient No.1, both adrenal glands were within normal ranges and did not differ from one another, while in the patient No.2, the lesion was more prominent on the right side. Conclusion: Diagnostic of i-PPNAD and choice of intervention can be precarious, consequently more studies are needed to define to which patients unilateral adrenalectomy could be an efficient treatment modality. It is possible to perform unilateral adrenalectomy with subsequent assessment of cortisol levels, in case of lack of remission the contralateral adrenalectomy is required.

SUN-911 Immunotherapy Use in Adrenocortical Carcinoma with Encouraging Results- a Case Report

Adrenocortical carcinoma (ACC) is a rare cancer with a very poor prognosis with median survival of around 17 months. We present a patient with metastatic ACC in whom the response to PD1 inhibitor pembrolizumab has been promising. Case report: A Caucasian female patient presented at the age of 19 y with weight gain, hypertension, moon facies, supraclavicular fullness and increased hair growth on her upper back. Serum potassium concentration was 2.6 mmol/l, cortisol was 46 mcg/dL (nl = 3-12mcg/dL), and plasma ACTH concentration was &lt; 5 pg/ml (nl = 6-58pg/ml). CT abdomen revealed a 5.4 cm right adrenal mass. For ACTH-independent Cushing’s Syndrome, she underwent right adrenalectomy within 1 week of presentation. Pathology revealed a 6.5 cm ACC with negative margins, with sinusoidal invasion, but no vascular or capsular invasion. Mitosis rate was 15-20/HPF with atypical mitotic figures. Immunohistochemistry showed no loss of expression of mismatch repair gene products associated with microsatellite instability. She was unable to tolerate mitotane. Genetic analysis was negative for TP53 mutation, and she underwent radiation to the adrenal bed within 6 months following adrenalectomy. She remained without biochemical or structural evidence of disease recurrence until 2.5 years following adrenalectomy, when AM cortisol was 6 mcg/dL (nl &lt; 1.8) after 1 mg and after 2 mg of dexamethasone the previous evening. CT scan of the pelvis, abdomen, and chest revealed 5 solid masses scattered within the lungs. The largest of these being 2.3 cm and 2 cm, and the other 3 being approximately 1 cm. Fine needle aspiration biopsy of the lung lesion revealed ACC metastases. Immunotherapy with pembrolizumab 200 mg every 3 weeks was initiated and continued for 2 years, with a side effect being grade 1 diarrhea. At 1 year after initiating pembrolizumab, she developed primary adrenal insufficiency that is being treated with 0.1 mg/d of fludrocortisone and low dose glucocorticoid replacement (hydrocortisone: 10mg in the morning and 5 mg in the evening), to avoid immune suppression. Pulmonary nodules decreased in size to 6 mm over the 2 years of pembrolizumab therapy and remained stable in size 1 year following completion of pembrolizumab therapy at which time the early morning serum cortisol concentration remained undetectable with a plasma ACTH concentration of 1177 pg/ml (nl = 6-50 pg/ml). In summary, this patient with ACC with normal mismatch repair gene expression demonstrated both structural and biochemical responses to 2 years of pembrolizumab therapy. The major side effect has been primary adrenal insufficiency. The biochemical and structural responses have been durable for 1 year after completion of pembrolizumab therapy. Conclusion: This patient with microsatellite stable ACC has had a 36-month response to pembrolizumab.

Reversible megaoesophagus in a dog with isolated glucocorticoid-deficient hypoadrenocorticism

An eight-year-old, female, neutered labradoodle was presented for investigation of a three-week history of lethargy and regurgitation. Two sets of conscious thoracic radiographs, performed approximately two weeks apart, revealed the presence of megaoesophagus. Serum cortisol concentration (pre-adrenocorticotrophic hormone (ACTH) and post-ACTH stimulation), serum aldosterone concentration post-ACTH stimulation and plasma endogenous ACTH concentration confirmed the diagnosis of isolated glucocorticoid-deficient hypoadrenocorticism. Following glucocorticoid supplementation, rapid resolution of the clinical signs was reported, and repeated conscious thoracic radiographs one week later showed complete resolution of the megaoesophagus.