Real world evidence supports waking salivary cortisone as a screening test for adrenal insufficiency.

OBJECTIVE: Worldwide, adults and children are at risk of adrenal insufficiency largely due to infectious diseases and adrenal suppression from use of anti-inflammatory glucocorticoids. Home waking salivary cortisone is an accurate screening test for adrenal insufficiency, it has potential to reduce costs, and patients prefer it to the adrenocorticotropin (ACTH) (synacthen) stimulation test. We carried out a service evaluation of home waking salivary cortisone in clinical care to identify implementation barriers. DESIGN, PATIENTS AND MEASUREMENTS: Service evaluation in a centre where 212 patients referred for adrenal insufficiency had a waking salivary cortisone. Problems encountered during testing were recorded and patient feedback, via focus groups, collected. RESULTS: From all patients providing a waking salivary cortisone 55% had a normal test, 23% adrenal suppression, and 22% an equivocal result requiring a clinical centre ACTH stimulation test. The median (interquartile range [IQR]) for the time of the saliva sample was 07:40 (07:00-08:40). The median (IQR) days between collection and (i) delivery to local laboratory was 1 (0.25-2) day; (ii) reporting by local laboratory was 13 (11-18) days. Patients considered the test is "easy to do" and preferred it to the inpatient ACTH stimulation test. The principal challenge to clinical implementation was results reporting to clinicians due to delays at the local laboratory. CONCLUSIONS: This service evaluation provides real-world evidence that home waking salivary cortisone is an effective, practical screening test for adrenal insufficiency. It identified key barriers to testing implementation that need to be addressed when introducing the test to a health service.

Use of salivary cortisol and cortisone in the high- and low-dose synacthen test.

CONTEXT: Salivary cortisone reflects serum cortisol levels, is more sensitive than salivary cortisol at lower values of serum cortisol and is noninvasive. OBJECTIVE: To investigate the relationship between serum cortisol and salivary cortisol and cortisone following low- and high-dose synacthen. DESIGN AND SETTING: Prospective pharmacodynamic studies in clinical research facilities. PARTICIPANTS AND INTERVENTION: Thirty-five dexamethasone-suppressed, healthy adult males underwent an intravenous synacthen test: N = 23 low-dose (1 mcg), N = 12 high-dose (250 mcg). Paired serum and salivary samples were taken at 15 sampling points over 120 minutes. MAIN OUTCOME MEASURE: Serum cortisol and salivary cortisol and cortisone were analysed for correlations and by a mixed-effects model. RESULTS: At baseline, the correlation between serum cortisol and salivary cortisol was weak with many samples undetectable (r = .45, NS), but there was a strong correlation with salivary cortisone (r = .94, P < .001). Up to 50 minutes following synacthen, the correlation coefficient between serum cortisol and salivary cortisol and cortisone was <0.8, but both had a stronger correlation at 60 minutes (salivary cortisol r = .89, P < .001, salivary cortisone r = .85, P < .001). The relationship was examined excluding samples in the dynamic phase (baseline to 60 minutes). Salivary cortisol and cortisone showed a close relationship to serum cortisol. Salivary cortisone showed the stronger correlation: salivary cortisol r = .82, P < .001, salivary cortisone r = .96, P < .001. CONCLUSION: Following synacthen, both salivary cortisol and cortisone reflect serum cortisol levels, but there is a lag in their rise up to 60 minutes. The results support further research for possible future use of a 60-minute salivary cortisone measurement during the synacthen test.

Home Waking Salivary Cortisone to Screen for Adrenal Insufficiency.

BACKGROUND: Worldwide, adults and children are at risk of adrenal insufficiency as a result of adrenal suppression from use of anti-inflammatory glucocorticoids and opiates, as well as infectious diseases. The adrenocorticotropin (ACTH) stimulation test is the reference standard for diagnosis of adrenal insufficiency but requires clinic attendance and venesection. Salivary cortisone reflects free serum cortisol, and samples can be collected at home and posted to a laboratory. We tested whether home waking salivary cortisone level could be used to screen for adrenal insufficiency. METHODS: A prospective, diagnostic accuracy study was performed in patients at high risk of adrenal insufficiency. Patients collected a home salivary sample on waking and then attended the clinical facility for an ACTH stimulation test. Salivary cortisone was measured by liquid chromatography­tandem mass spectrometry. Receiver-operating characteristic curves were computed, and positive and negative predictive values were calculated. RESULTS: Two hundred twenty patients were recruited. As measured by an ACTH stimulation test, the prevalence of adrenal insufficiency was 44%. The area under the receiver-operating characteristic curve for waking salivary cortisone as a predictor of adrenal insufficiency was 0.95 (95% confidence interval [CI], 0.92 to 0.97). Cutoffs to ensure a minimum of 95% sensitivity and specificity gave a negative predictive value of 96% (95% CI, 90 to 99) and a positive predictive value of 95% (95% CI, 87 to 99) to exclude and confirm adrenal insufficiency, respectively. Waking salivary cortisone data provided information similar to that of an ACTH stimulation test in 70% of participants. Eighty-three percent of patients preferred home salivary collection to clinic attendance. CONCLUSIONS: Home waking salivary cortisone sampling has accuracy for the diagnosis of adrenal insufficiency similar to that of a standard ACTH stimulation test. Patients found the at-home test to be more convenient than the hospital-based test. (Funded by the National Institute for Health Research.)

Emergency and perioperative management of adrenal insufficiency in children and young people: British Society for Paediatric Endocrinology and Diabetes consensus guidance.

Adrenal insufficiency (AI) is characterised by lack of cortisol production from the adrenal glands. This can be a primary adrenal disorder or secondary to adrenocorticotropic hormone deficiency or suppression from exogenous glucocorticoids. Symptoms of AI in children may initially be non-specific and include growth faltering, lethargy, poor feeding, weight loss, abdominal pain, vomiting and lingering illnesses. AI is treated with replacement doses of hydrocortisone. At times of physiological stress such as illness, trauma or surgery, there is an increased requirement for exogenous glucocorticoids, which if untreated can lead to an adrenal crisis and death. There are no unified guidelines for those <18 years old in the UK, leading to substantial variation in the management of AI. This paper sets out guidance for intercurrent illness, medical, dental and surgical procedures to allow timely and appropriate recognition and treatment of AI and adrenal crisis for children and young people.

Salivary Steroid Collection in Children Under Conditions Replicating Home Sampling.

CONTEXT: Measurement of salivary glucocorticoids is an accepted method for testing adrenal function but there are few data on stability during home collection. Current salivary collection techniques require active participation or present a choking hazard and are unsuitable for young children. OBJECTIVE: We sought to compare different salivary collection methods; assess the stability of salivary glucocorticoids under conditions replicating home collection; and assess patient tolerability and caregiver acceptability of a salivary collection device for young children, a swab encased in an infant pacifier (SaliPac). METHODS: Six healthy adults collected salivary samples using a Salivette Cortisol, passive drool, and SalivaBio at night, waking, and 3 Pm for five days. Time to collect 1-mL saliva using the SalivaBio and SaliPac and caregiver acceptability were assessed in 30 children younger than 6 years. Saliva was stored at 4 °C, room temperature (RT), and 50 °C for 24, 48, 72 hours and 1 week to replicate potential postage conditions. Salivary cortisol and cortisone concentrations were measured by mass spectrometry. RESULTS: There was no difference in salivary glucocorticoid concentrations using the 3 collection methods. Salivary cortisol and cortisone were stable for 72 hours at RT and 4 °C, and repeated freeze-thaw cycles did not cause significant degradation. In children younger than 6 years the SalivaBio and SaliPac were well tolerated and collected sufficient saliva for salivary steroid analysis in less than 4 minutes. CONCLUSION: Salivette, passive drool, and SalivaBio collect samples with comparable salivary cortisol and cortisone concentrations, which are stable under conditions replicating home collection. SaliPac is an acceptable device for salivary sampling in young children.

Pharmacodynamic studies of nasal tetracosactide with salivary glucocorticoids for a noninvasive Short Synacthen Test.

CONTEXT: The Short Synacthen Test (SST) is the gold standard for diagnosing adrenal insufficiency. It requires invasive administration of Synacthen, venous sampling, and is resource-intensive. OBJECTIVE: To develop a nasally administered SST, with salivary glucocorticoids measurement, to assess the adrenal response. DESIGN: We conducted 5 studies: 4 open-label, sequence-randomized, crossover, pharmacodynamic studies testing 6 doses/formulations and a repeatability study. Additionally, pharmacokinetic analysis was undertaken using our chosen formulation, 500 µg tetracosactide with mucoadhesive chitosan, Nasacthin003, in our pediatric study. SETTING: Adult and children's clinical research facilities. PARTICIPANTS: A total of 36 healthy adult males and 24 healthy children. INTERVENTION: We administered all 6 nasal formulations using an European regulator endorsed atomization device. The IV comparators were 250 µg or 1 µg SST. MAIN OUTCOME MEASURES: We analyzed paired blood and saliva samples for plasma cortisol and salivary cortisol and cortisone. RESULTS: The addition of chitosan to tetracosactide and dose escalation increased peak cortisol response (P = 0.01 and 0.001, respectively). The bioavailability of Nasacthin003 was 14.3%. There was no significant difference in plasma cortisol at 60 minutes between 500 µg Nasacthin003 and 250 µg IV Synacthen (P = 0.17). The repeatability coefficient at 60 minutes was 105 nmol/L for IV Synacthen and salivary cortisol and cortisone was 10.3 and 21.1 nmol/L, respectively. The glucocorticoid response in children was indistinguishable from that of adults. CONCLUSIONS: Nasal administration of Nasacthin003 generates equivalent plasma cortisol values to the 250-µg IV SST and, with measurement at 60 minutes of salivary cortisol or cortisone, provides a noninvasive test for adrenal insufficiency.