Short Synacthen test

The test measures the ability of the adrenal cortex to respond to maximal ACTH stimulation, and it is rarely the injection itself that determines whether the result can be interpreted. What decides that is whether the patient is taking a steroid that cross-reacts in the cortisol assay, whether the samples were taken at the right times, and whether you know which decision threshold your own laboratory's method uses. In a suspected Addisonian crisis, hydrocortisone must be given immediately — the test must never delay treatment.

Indications

• Suspected primary adrenal insufficiency (Addison's disease): fatigue, weight loss, hyperpigmentation, hyponatraemia, hyperkalaemia, postural symptoms.
• Suspected secondary adrenal insufficiency in pituitary disease, after pituitary surgery or radiotherapy, or with suspected suppression of the HPA axis after long-term glucocorticoid treatment.
• A basal morning cortisol in the grey zone. A morning value below about 100 nmol/L strongly suggests insufficiency, and a value above about 350–400 nmol/L makes it unlikely; in between, a stimulation test is needed. These thresholds are also assay-dependent.
• Follow-up of known HPA suppression to determine whether replacement can be stopped.

The test is not the first-line investigation in a suspected acute crisis. There, cortisol and ACTH are taken immediately, treatment is given, and the test is performed later.

Contraindications

• Known hypersensitivity to tetracosactide or ACTH.
• Marked atopic disease, particularly severe asthma and a history of anaphylaxis — a relative contraindication; the test is then performed with preparedness for anaphylaxis.
• An untreated Addisonian crisis in progress: treat first, test later.

Preparation and equipment

• Tetracosactide (Synacthen) 0.25 mg/mL, one ampoule.
• A peripheral venous cannula and a saline flush.
• A tube for serum or plasma cortisol according to local instructions, and a chilled EDTA tube for plasma ACTH, which must be centrifuged and frozen promptly — ACTH is unstable at room temperature.
• Emergency preparedness: adrenaline, an antihistamine, oxygen.

Drugs that must be dealt with before the test

A patient who needs steroid cover simply to get through the day of the test can therefore be given dexamethasone. That is the practical key: the patient does not have to be left unprotected for the test to be interpretable.

Procedure

1. Schedule the test in the morning, preferably starting between 08:00 and 09:00, with the patient fasting or having had a light breakfast according to local practice. Let the patient rest lying down or sitting for at least 15 minutes.
2. Insert a venous cannula. Wait a few minutes — the venepuncture itself can cause a stress-related rise in cortisol.
3. Take the baseline sample: cortisol and plasma ACTH. The ACTH sample is taken before the injection and handled chilled.
4. Inject 0.25 mg of tetracosactide intravenously, slowly. Intramuscular administration is an equivalent alternative where there is no venous access.
5. Flush the cannula. Discard the first few millilitres at the subsequent samplings so that residual drug does not contaminate the sample.
6. Take cortisol at 30 minutes and at 60 minutes. Some laboratories accept one of these time points — follow the local instructions, but where the response is equivocal both are valuable.
7. Observe the patient throughout the test and for 15 minutes after the last sample.

flowchart TD
  A[Suspected adrenal insufficiency] --> B{A suspected acute crisis?}
  B -- Yes --> C[Take cortisol and ACTH, give hydrocortisone 100 mg IV immediately]
  C --> D[Investigate with a Synacthen test later]
  B -- No --> E[Adjust the steroids: pause hydrocortisone, change to dexamethasone if needed]
  E --> F[Time 0 min: cortisol and plasma ACTH, give tetracosactide 0.25 mg IV]
  F --> G[Time 30 min: cortisol]
  G --> H[Time 60 min: cortisol]
  H --> I{Is the peak cortisol above the laboratory's decision threshold?}
  I -- Yes --> J[A normal response: primary insufficiency excluded]
  I -- No --> K{The plasma ACTH in the baseline sample}
  K -- High --> L[Primary adrenal insufficiency]
  K -- Low or normal --> M[Secondary adrenal insufficiency: investigate the pituitary]

The low-dose 1 µg test

A low-dose test with 1 µg of tetracosactide is used in some units for the question of mild secondary insufficiency, on the argument that 250 µg is a markedly supraphysiological dose. Practice differs between regions, the dose must be diluted on site, and the decision thresholds are different. Use the local instructions or the 250 µg test.

Interpretation

Assess the peak value at 30 or 60 minutes, not the increment from baseline.

• A peak cortisol above the laboratory's decision threshold argues against adrenal insufficiency.
• The classical threshold is 550 nmol/L with older polyclonal assays and 450 nmol/L in several Swedish instructions, but modern monoclonal immunoassays and LC-MS/MS give systematically 20–30 % lower values, with proposed thresholds of around 420–430 nmol/L. Telephone the laboratory and use their threshold — otherwise you risk over-diagnosing insufficiency.
• The plasma ACTH in the baseline sample distinguishes the levels: high ACTH in primary insufficiency, low or inappropriately normal in secondary.
• A normal response does not exclude recent-onset secondary insufficiency. The adrenal cortex atrophies only after weeks, so immediately after pituitary surgery or with newly acquired pituitary damage the response can be normal despite insufficiency. Wait 4–6 weeks or use another method.

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  "description": "Schematic cortisol response during a Synacthen test",
  "data": {"values": [
    {"tid": 0, "kortisol": 400, "svar": "Normal response"},
    {"tid": 30, "kortisol": 620, "svar": "Normal response"},
    {"tid": 60, "kortisol": 700, "svar": "Normal response"},
    {"tid": 0, "kortisol": 120, "svar": "Adrenal insufficiency"},
    {"tid": 30, "kortisol": 180, "svar": "Adrenal insufficiency"},
    {"tid": 60, "kortisol": 200, "svar": "Adrenal insufficiency"}
  ]},
  "layer": [
    {"mark": {"type": "line", "point": true},
     "encoding": {
       "x": {"field": "tid", "type": "quantitative", "title": "Time after injection (minutes)", "axis": {"values": [0, 30, 60]}},
       "y": {"field": "kortisol", "type": "quantitative", "title": "Serum cortisol (nmol/L)", "scale": {"domain": [0, 800]}},
       "color": {"field": "svar", "type": "nominal", "title": "Response"}
     }},
    {"mark": {"type": "rule", "strokeDash": [6, 4]},
     "data": {"values": [{"grans": 450}]},
     "encoding": {"y": {"field": "grans", "type": "quantitative"}}}
  ],
  "title": "Schematic cortisol response in the Synacthen test"
}

The figure shows the pattern in principle: with a normal response the cortisol rises above the decision threshold (dashed line) as early as 30 minutes, while in adrenal insufficiency the response stays flat and low. The curves are schematic — the threshold that applies to your patient is the laboratory's.

Complications

• A hypersensitivity reaction, rarely anaphylaxis. The risk is highest in patients with marked atopic disease.
• Transient flushing, a sensation of warmth or mild nausea at the injection.
• A local reaction at the injection site.
• The test itself does not precipitate a crisis, but the time that passes while the patient is left without a steroid does.

Aftercare and follow-up

The patient returns to their usual steroid dose immediately after the last sample. With an abnormal response, replacement must be started without awaiting further investigation: hydrocortisone in divided doses, with the addition of fludrocortisone in primary insufficiency.

In primary insufficiency the work-up is completed with 21-hydroxylase antibodies and, if these are negative, with imaging of the adrenal glands. In secondary insufficiency, pituitary investigation is performed with the other axes and MRI of the pituitary.

Everyone with confirmed insufficiency must have written stress-dosing instructions, a steroid card and hydrocortisone for injection at home, together with training for the patient and their relatives in when it is to be used.

Common pitfalls

• Testing instead of treating in a suspected crisis. Give hydrocortisone; the samples can be taken at the same moment.
• Not pausing the hydrocortisone — the morning dose is measured as cortisol and makes the response falsely normal.
• Stopping all steroid in a patient who needs cover, when dexamethasone would have done the same job without interfering with the assay.
• Using 550 or 500 nmol/L as the threshold in a laboratory that has changed to a modern assay with a lower threshold.
• Assessing the increment instead of the peak value.
• Trusting a normal response shortly after pituitary surgery — the adrenal glands do not have time to atrophy in a few days.
• Forgetting the ACTH in the baseline sample. Without it, primary and secondary insufficiency cannot be distinguished retrospectively, and the sample cannot be repeated once the stimulation has been given.
• A mishandled ACTH sample — an uncentrifuged tube at room temperature gives a worthless result.