Hypoadrenalism

Addison’s

Hypoadrenalism is relatively straightforward once considered; the trick is thinking about it in the first place. In a healthcare environment where AIDS is common, it is particularly easy to overlook. Think of it in any hypotensive, thin, or hypoglycaemic patient. It is not rare for patients to have been admitted several times previously for unexpectedly severe gastroenteritis or ‘sepsis’ which seems to settle promptly with a little intravenous saline. As the test is relatively cheap and the consequences of missing the diagnosis can be quite severe, screening for hypoadrenalism should be considered in all such patients. Note that the absence of hyponatraemia is not sufficiently sensitive to rule out the diagnosis.

Testing for hypoadrenalism:

If the patient is hypotensive or stressed by a severe intercurrent illness, a random cortisol greater than 550 nmol/l is adequate to exclude the diagnosis. In a less stressed patient do a morning cortisol before 9 am. If this is greater than 550 nmol/l, the diagnosis is unlikely. If it is less than 100 nmol/L the diagnosis is highly likely.¹. Another cohort study used the same rule-in level of 100 nmol/L and found a PPV of 93%, but used a rule-out level of 450 nmol/L for a negative predictive value (rule out) of 98.7%.² A higher cut-off of 140 nmol/L has also been recommended³ – this will increase sensitivity and is appropriate if combined with a serum ACTH. In primary adrenal insufficiency (adrenal rather than pituitary disease) the serum ACTH is usually > 22pmol/L.⁴ Patients with values between cortisol levels 100 and 550 nmol/L should be subjected to an ACTH stimulation test – if hypoadrenalism is present, the cortisol will fail to double. Intravenous ACTH is difficult to access; using I mg IM depot ACTH and looking for at least doubling at 2 hours is probably adequate.⁵

Testing for secondary adrenal insufficiency.

Testing is somewhat different in patients who are thought to have secondary adrenal insufficiency, i.e. where adrenal reserve is thought to be reduced secondary to chronic use of corticosteroid medication or pituitary disease. Using a cut-off of 500-600 nmol/l yields a range of sensitivities from 33% to 100%, and specificities from 60% to 100% using 250 mcg of ACTH IV. The low-dose (1 mcg) test probably doesn’t perform better. A synthesis of 20 studies⁶ found that a cortisol of more than 550 had a sensitivity of only 57% (specificity was however 95%, LR+ 11.5, LR- 0.45.)

Pre-test probability	0.01	0.05	0.1	0.25	0.5	0.75	0.9	0.95	0.99
Revised probability
< 550 nmol/l	0.10	0.38	0.56	0.79	0.92	0.97	0.99	1.00	1.00
>550 nmol/l	0.01	0.03	0.05	0.14	0.33	0.60	0.82	0.90	0.98

The same authors looked at pooled results of ACTH stimulation tests in primary adrenal insufficiency and felt that ascertainment bias probably led to the test being flattered, but managed to generate a ROC for 4 studies, yielding a sensitivity of 0.975 when specificity was set at 0.95: hence LR+ 19.5 and LR- 0.03, using a cut-off of 415 nmol/l.

Treatment of hypoadrenalism.

Drugs – hydrocortisone 20 mg mane and 10 mg nocte is a ‘classical’ replacement dose, which should obviously be adjusted according to symptoms. Dosing 10 mg mane, 5 mg at lunch time and 5 mg in the evening is gaining popularity, although unequivocal advantages are still to be demonstrated.

An alternative that causes less variation in levels is prednisone 5 – 7.5 mg daily. It is also cheaper and easier to access. Although its sodium retaining activity is listed as 0.8 of that of hydrocortisone, its biological half-life is 2-3 times as long.

Fludrocortisone 0.05 – 0.2 mg per day with salt supplementation is recommended for the mineralocorticoid effect not fully provided by prednisone or hydrocortisone. If the drug is difficult to access and the patient is normokalaemic with an adequate BP and no postural symptoms, it may be appropriate to just give the hydrocortisone or prednisone, although there may be biochemical evidence of hypoaldosteronism (elevated renin).

Management of hypoadrenalism during intercurrent illnesses or surgery.

In the absence of clear guidelines there is often a tendency to err on the side of over-treatment, which is probably not a terribly bad state of affairs. However, as a general guide, less extensive surgery needs less hydrocortisone. One review suggested the use of a once off dose of 25 mg of hydrocortisone on the day of surgery for minor procedures, and only 100 mg daily for two days (then taper off over a few days) for major surgery, with 100 mg four times per day being reserved for critical illness, and being supplemented by fludrocortisone 0.05 mg/day.⁷

Perspective – hypocortisolism in acutely ill patients

Very ill patients with septic shock or other reasons to require ICU admission may develop hypocortisolism. In patients with low albumin, cortisol measurements on their own can be difficult to interpret, but there are suggestions⁸ that a random cortisol of greater than 950 nmol/l makes the diagnosis unlikely in this context, whereas a figure of less than 400 nmol/l makes it very likely. The exact derivation of these figures was not provided.

There was some evidence⁹ that low dose hydrocortisone replacement in such patients may be of benefit (e.g. hydrocortisone 50 mg 6 hourly IV). However the raw data from that trial actually didn’t show a mortality benefit – it was only found after an (unnecessary?) adjusted analysis using a model from a previous study. A subsequent somewhat underpowered trial¹⁰ of 499 less ill patients failed to demonstrate a survival advantage, which is where things rested until the publication of the large, well conducted ADRENAL study which failed to demonstrate a mortality advantage in 3658 patients – 28% in both arms¹¹ , even when followed to 6 months (unusual in previous trials of this nature) The trial gave a hydrocortisone infusion rather than boluses, and there is probably still evidence that some steroid use may reduce time on vasopressors (median time to resolution of shock 3 versus 4 days).

The Cochrane review incorporating ADRENAL but done by Annanne et al¹² focused on the modest 2% reduction in 28 day mortality (RR 0.91, 95% CI 0.84 to 0.99) although noting no difference in long-term mortality. So depending on one’s perspective, a single large high quality trial showing lack of benefit has been ‘diluted’ , or the single large trial now provided robust additive evidence (despite being negative!) that there is something there when pooled for a total of about 10 000 patients…

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9. Annanne D, Sebille V, Charpentier C, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA. 2002;288:862-71 ↩

10. Sprung CL, Annane D, Keh D, et al. Hydrocortisone therapy for patients with septic shock. N Engl J Med. 2008;358:111-24 ↩

11. Venkatesh B, Finfer S, Cohen J, Rajbhandari D, Arabi Y, Bellomo R, Billot L, Correa M, Glass P, Harward M, Joyce C, Li Q, McArthur C, Perner A, Rhodes A, Thompson K, Webb S, Myburgh J; ADRENAL Trial Investigators and the Australian–New Zealand Intensive Care Society Clinical Trials Group. Adjunctive Glucocorticoid Therapy in Patients with Septic Shock. N Engl J Med. 2018 Mar 1;378(9):797-808. doi: 10.1056/NEJMoa1705835. Epub 2018 Jan 19. PMID: 29347874 ↩

12. Annane D, Bellissant E, Bollaert PE, Briegel J, Keh D, Kupfer Y, Pirracchio R, Rochwerg B.Corticosteroids for treating sepsis in children and adults.
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