Critical illness-related corticosteroid insufficiency (CIRCI) · ICU Topics

Cinematic ICU scene of a vasopressor-dependent septic shock patient with a cortisol level and a delta cortisol after cosyntropin on the screen, a hydrocortisone infusion on the trolley, clinical-blue lighting, medical educational, no faces, no text — FigureThe CIRCI — the critical illness-related corticosteroid insufficiency. The vasopressor-dependent septic shock that does not clear the lactate, the rising ventilatory requirement. The 250 mcg cosyntropin with the delta cortisol under 250 nmol per litre supports the diagnosis; the hydrocortisone 200 mg per day is the treatment, tapered as the shock resolves.

CIRCI versus absolute adrenal failure and high-dose steroid eras — FigureDistinguish CIRCI (relative, shock-context) from Addisonian crisis; modern stress-dose replacement replaced harmful high-dose regimens.

Key corticosteroid trials in septic shock

Trial	Year	Intervention	Key finding
Annane 2002	JAMA	Hydrocortisone + fludrocortisone vs placebo (ACTH non-responders)	REDUCED mortality in ACTH non-responders (29% vs 63%)
CORTICUS	NEJM 2008	Hydrocortisone vs placebo (all septic shock)	NO mortality benefit. Faster shock reversal. No rebound on stopping.
ADRENAL	NEJM 2018	Hydrocortisone vs placebo (3658 patients)	NO mortality benefit (27.9% vs 28.8%). Faster shock reversal, more infections.
APROCCHSS	NEJM 2018	Hydrocortisone + fludrocortisone vs placebo	REDUCED 90-day mortality (43% vs 49%). Benefit in severe septic shock.

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Management of suspected CIRCI in septic shock

Ensure adequate resuscitation FIRST — fluids (30 mL/kg), vasopressors (noradrenaline titrated to MAP ≥65), source control, antibiotics
If shock REFRACTORY (ongoing vasopressor requirement despite adequate fluid + max vasopressor dose) → consider CIRCI
DON'T do ACTH stimulation test routinely — SSC 2021: suggests against routine testing. Just give empirically
Start hydrocortisone — 200 mg/day: continuous infusion OR 50 mg IV QDS. Add fludrocortisone 50 mcg PO/NG daily (APROCCHSS)
Assess response — vasopressor dose decreasing, improving haemodynamics, lactate clearing within 24-48h
Continue until vasopressors weaned — then STOP (CORTICUS: no taper needed, no rebound)
Monitor — hyperglycaemia (corticosteroids increase glucose), infection (immunosuppression), neuromuscular weakness, GI bleeding (add PPI)

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Exam practice

SAQ — Vasopressor-refractory septic shock and the role of hydrocortisone

10 minutes · 10 marks

A 62-year-old man is admitted to ICU with pyelonephritis and septic shock from an ESBL-producing E. coli. Within the first hour he received broad-spectrum antibiotics and a percutaneous nephrostomy, plus 30 mL/kg crystalloid. Eight hours later he requires noradrenaline 0.5 mcg/kg/min AND vasopressin 0.03 U/min to hold MAP at 62; lactate is 5.2 mmol/L, he is oliguric and peripherally cool. A baseline cortisol drawn at intubation is 410 nmol/L. Sodium 134, potassium 4.4, glucose 8.1.

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SAQ — Interpreting a baseline cortisol in the critically ill

10 minutes · 10 marks

A 48-year-old woman is in ICU on day 2 of septic shock from a perforated viscus. She is on noradrenaline 0.4 mcg/kg/min after adequate fluid resuscitation, source control and antibiotics. A registrar orders a random cortisol to exclude adrenal insufficiency; the result is 480 nmol/L. A 250 mcg ACTH (cosyntropin) stimulation test is then planned to guide the decision on hydrocortisone.

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Clinical pearls

High-yield CIRCI points for CICM/FFICM exam

CIRCI is NOT classic adrenal insufficiency. It's RELATIVE — cortisol production may be normal or even high, but INSUFFICIENT for the severity of critical illness (inflammatory demand exceeds supply). Mechanisms: HPA axis suppression (cytokines), cortisol resistance (tissue level), altered cortisol metabolism. Don't think 'low cortisol' — think 'inadequate for demand'.[5] }
Don't do ACTH stimulation test routinely. SSC 2021: suggests AGAINST routine testing. The test (250 mcg cosyntropin, measure cortisol at 0 and 60 min) is INCONCLUSIVE in critical illness (protein binding, assay variability, stress confounders). Just GIVE hydrocortisone empirically if septic shock is refractory.[6] }
ADRENAL trial (2018): hydrocortisone did NOT improve survival overall. 3,658 patients with septic shock. Hydrocortisone 200 mg/day vs placebo. Mortality: 27.9% vs 28.8% (not significant). BUT: faster shock reversal (1.5 days faster off vasopressors). More superinfections (with hydrocortisone). CONCLUSION: hydrocortisone for shock reversal, not mortality.[1] }
APROCCHSS trial (2018): hydrocortisone + FLUDROCORTISONE reduced mortality. 1,241 patients with SEVERE septic shock (SOFA ≥8 or shock index >0.8). Hydrocortisone 200 mg/day + fludrocortisone 50 mcg/day vs placebo. 90-day mortality: 43% vs 49% (significant). APROCCHSS included sicker patients and used FLUDROCORTISONE (mineralocorticoid — may add benefit).[4] }
Hydrocortisone dose: 200 mg/day (NOT high-dose). 200 mg/day = physiological replacement (not pharmacological). Old studies used 'stress dose' methylprednisolone (HIGH dose — harmful, increased infection). Modern: LOW-dose hydrocortisone (equivalent to normal daily cortisol production under stress). Continuous infusion preferred (avoids peaks/troughs — more stable haemodynamics).[5] }
Annane 2002: benefit in ACTH non-responders — but CORTICUS didn't confirm. Annane (JAMA 2002): hydrocortisone + fludrocortisone reduced mortality in vasopressor-unresponsive septic shock with ACTH non-response (cortisol rise <250 nmol/L after 250 mcg ACTH). Mortality: 29% vs 63%. BUT: CORTICUS (2008) did NOT confirm — no benefit in ACTH non-responders. CONFLICT: Annane enrolled SICKER patients (vasopressor-dependent, within 8h). CORTICUS enrolled broader (including milder).[3] }
CORTICUS: no rebound on stopping (no taper needed). Old practice: taper steroids gradually (fear of rebound). CORTICUS: hydrocortisone STOPPED abruptly at day 11 — NO rebound (no increased vasopressor need, no new shock). CONCLUSION: stop when vasopressors weaned — don't taper (CORTICUS). APROCCHSS: tapered over 7 days (more conservative — may be safer).[2] }
Indication: SEPTIC SHOCK refractory to fluids + vasopressors. NOT all septic shock (most respond to fluids + noradrenaline). ONLY if: (1) Persistent hypotension despite adequate fluid (30 mL/kg) + vasopressor (noradrenaline ≥0.25 mcg/kg/min, or multiple vasopressors). (2) Ongoing lactate elevation. (3) Not responding within 4-6h of resuscitation. THIS is when CIRCI may be contributing.[6] }
Hydrocortisone improves SHOCK REVERSAL (even if not mortality). Across trials (ADRENAL, CORTICUS, APROCCHSS): hydrocortisone consistently reduces time on vasopressors (by 1-2 days). This is useful: shorter vasopressor time → fewer complications (peripheral ischaemia, arrhythmia), shorter ICU stay. Even without survival benefit, shock reversal is clinically meaningful.[1] }
Add fludrocortisone (APROCCHSS approach). Fludrocortisone: mineralocorticoid (aldosterone analogue) → sodium retention, potassium excretion → fluid retention + vascular tone. APROCCHSS: hydrocortisone + fludrocortisone reduced mortality (where hydrocortisone alone in ADRENAL did not). Possible: fludrocortisone adds mineralocorticoid benefit (vascular tone). DOSE: fludrocortisone 50 mcg PO/NG daily (add to hydrocortisone).[4] }
CIRCI diagnosis criteria (if testing). SSC/CIRCI guidelines (2017): (1) Random TOTAL cortisol <276 nmol/L (10 mcg/dL). OR (2) Delta cortisol (after 250 mcg ACTH) <250 nmol/L (9 mcg/dL). EITHER suggests CIRCI. BUT: guidelines also say DON'T test routinely (just treat empirically). Test only if: diagnostic uncertainty, research, borderline case.[5] }
Adverse effects of hydrocortisone. (1) HYPERGLYCAEMIA (steroid-induced — monitor glucose, insulin). (2) INFECTION (immunosuppression — more superinfections in ADRENAL). (3) NEUROMUSCULAR WEAKNESS (especially with prolonged use + paralysis — critical illness myopathy). (4) GI BLEEDING (stress ulcer — add PPI). (5) WOUND HEALING (impaired — surgical patients). (6) PSYCHIATRIC (agitation, delirium — common in ICU). MONITOR: glucose, WBC, GI symptoms.[1] }
CIRCI vs classic adrenal insufficiency. Classic Addison's (primary adrenal insufficiency): autoimmune, TB, bilateral adrenal haemorrhage. PERMANENT deficiency. Treatment: lifelong hydrocortisone + fludrocortisone. CIRCI: TRANSIENT (critical illness only). Resolves when illness resolves. Treatment: temporary (while in ICU). DISTINGUISH: history (Addison's — known), examination (hyperpigmentation — Addison's), cortisol (very low in Addison's).[5] }
Other ICU indications for corticosteroids (beyond CIRCI). (1) SEVERE CAP (prednisolone 50 mg — CAPE COVID, meta-analysis: reduces mortality). (2) ARDS (dexamethasone — DExa-ARDS: reduces mortality in moderate-severe). (3) Severe ASTHMA/COPD. (4) ANAPHYLAXIS (not first-line — adrenaline first). (5) Pneumocystis pneumonia (adjunctive if hypoxic). (6) Thyroid storm. (7) Bacterial meningitis (dexamethasone before/with first antibiotic).[6] }

Red flags

Prognosis

APROCCHSS trial (Annane 2018, NEJM) — hydrocortisone + fludrocortisone in severe septic shock

RCT: 1,241 patients with SEVERE septic shock (SOFA ≥8 or shock index >0.8 for >6h). Hydrocortisone 200 mg/day + fludrocortisone 50 mcg/day vs placebo.

90-day mortality: 43.0% vs 48.8% (RR 0.89, p=0.03) — REDUCED mortality
28-day mortality: 33.7% vs 38.9%
Vasopressor-free days: more with treatment
Adverse events: similar (no excess infection)
CONCLUSION: Hydrocortisone + fludrocortisone REDUCES mortality in SEVERE septic shock. (ADRENAL — hydrocortisone alone — did not. Difference: APROCCHSS used fludrocortisone + enrolled sicker patients.) [1]

ADRENAL (2018, NEJM): 3,658 patients. Hydrocortisone alone. NO mortality benefit. Faster shock reversal. More infections. CORTICUS (2008, NEJM): 499 patients. Hydrocortisone alone. NO mortality benefit. Faster shock reversal. No rebound on stopping. Annane 2002 (JAMA): 299 patients. Hydrocortisone + fludrocortisone in ACTH non-responders. REDUCED mortality (29% vs 63%).

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Definition and pathophysiology

Relative cortisol insufficiency and catecholamine resistance in septic shock — FigureCIRCI is relative insufficiency for demand — cytokine-suppressed HPA axis and tissue resistance produce vasopressor-refractory shock.

Critical illness-related corticosteroid insufficiency (CIRCI) is a syndrome — not a single disease — defined by the 2017 SCCM/ESICM multispecialty task force as "inadequate cellular corticosteroid activity for the severity of the patient's illness."[8] The emphasis on cellular activity (not plasma cortisol) is deliberate: the problem is one of tissue-level glucocorticoid action relative to inflammatory demand, not simply a low blood level. This reframing explains why the term "relative adrenal insufficiency" has been abandoned — the adrenal is often secreting at or above basal rate, yet the patient is still functionally steroid-deficient.[5][7]

The hypothalamic–pituitary–adrenal (HPA) axis in health

Hypothalamic corticotropin-releasing hormone (CRH) → anterior pituitary adrenocorticotropic hormone (ACTH) → zona fasciculata of adrenal cortex → cortisol. Cortisol exerts negative feedback on hypothalamus and pituitary. Basal cortisol secretion is ~10 mg/day (≈275 nmol/day), rising to 200–350 mg/day (≈5500–9700 nmol/day) under maximal surgical/anaesthetic stress. In the circulation ~90 % of cortisol is bound to cortisol-binding globulin (CBG, transcortin) and ~5–7 % to albumin; only the free fraction is biologically active. CBG falls during critical illness (and oestrogen therapy raises it), which is one reason a measured total cortisol can mislead.[8]

Three mechanisms producing CIRCI in critical illness

HPA-axis suppression / inadequate drive. Pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) and circulating toxins depress hypothalamic and pituitary function, blunt the ACTH response, and impair adrenal steroidogenesis. Drugs compound this: etomidate (inhibits 11β-hydroxylase — even a single induction dose suppresses cortisol for 24–48 h), ketoconazole/posaconazole (inhibit CYP-dependent steroidogenesis), high-dose opioids, and chronic exogenous steroids (suppression of CRH → adrenal atrophy, the commonest cause in the ward patient admitted to ICU).[7]
Tissue glucocorticoid resistance. Inflammation upregulates the inactive β-isoform of the glucocorticoid receptor (GRβ) at the expense of the active α-isoform, and activates p38 MAPK and JNK pathways that phosphorylate and inactivate the receptor. The net effect: even normal intracellular cortisol concentrations fail to transactivate anti-inflammatory genes. This is why "normal" plasma cortisol does not exclude CIRCI.[8]
Altered cortisol metabolism and distribution. Critical illness lowers CBG (more free cortisol cleared) and, in prolonged illness, the 2-oxo-reductase pathway accelerates cortisol inactivation. Adrenal infarction or bilateral adrenal haemorrhage (classically in meningococcaemia/Waterhouse–Friderichsen, heparin-induced thrombocytopenia, or antiphospholipid syndrome) produces absolute deficiency — a distinct entity, but lumped with CIRCI when the trigger is sepsis.[5]

Normal HPA axis vs CIRCI in septic shock

Feature	Healthy, unstressed	Healthy, stressed	CIRCI (septic shock)
Cortisol production	~10 mg/day	200–350 mg/day	May be raised but inadequate for demand
Plasma total cortisol	140–700 nmol/L	Often >1000 nmol/L	Variable; can be "normal"
Cortisol-binding globulin	Normal	Falls slightly	Markedly reduced (free fraction ↑ but total misleading)
Tissue glucocorticoid action	Normal	Augmented	Impaired (GRβ upregulation, receptor resistance)
ACTH response	Brisk	Augmented	Blunted by cytokines
Response to exogenous hydrocortisone	—	—	Often dramatic vasopressor wean

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Why it matters clinically: cortisol maintains vascular tone (permissive action on catecholamines — α1-receptor expression and Ca²⁺ signalling), suppresses NF-κB-driven inflammation, stabilises lysosomal membranes, and supports gluconeogenesis. In CIRCI the cardinal sign is vasopressor-refractory vasodilatory shock; the cardinal therapeutic principle is give the steroid, do not chase the number.[6]

Diagnosis of CIRCI

The two proposed (but contentious) thresholds

The 2008 task force (Marik, Pastores & Annane) offered a biochemical definition that the 2017 update largely retained for completeness while downgrading its clinical role:[7][5]

CIRCI is suggested if random total cortisol < 276 nmol/L (10 µg/dL) OR delta cortisol < 248 nmol/L (9 µg/dL) after 250 µg ACTH (cosyntropin) stimulation. [1]

The "delta" (increment) is the 30- or 60-minute value minus baseline. Note the units: 276 nmol/L ≈ 10 µg/dL and 248 nmol/L ≈ 9 µg/dL (cortitol: 1 µg/dL = 27.6 nmol/L).[5]

Why the test is NOT recommended for routine decisions

Why the ACTH stimulation test is unreliable in critical illness (and what to do instead)

CBG shifts — total cortisol falls when CBG falls even if the free (active) fraction is normal, generating false-positives.
Assay variability — immunoassays cross-react with prednisolone, methylprednisolone and cortisone; LC-MS/MS is not universally available.
No validated outcome threshold — neither baseline nor delta cortisol predicts response to hydrocortisone or mortality in CORTICUS or ADRENAL.
Confounding by illness phase — early (hyperdynamic) vs late (hypodynamic) sepsis give different cortisol kinetics.
Does not change management — SSC 2021 recommends AGAINST using the ACTH test to decide who gets hydrocortisone.[6]
DO INSTEAD — make the decision on clinical grounds: vasopressor-refractory septic shock (ongoing noradrenaline requirement after adequate fluids and source control). Treat empirically; reserve the test for diagnostic uncertainty (suspected Addison's, prior chronic steroids, bilateral adrenal lesions).[5]

Diagnostic thresholds and units (know both, exams ask for nmol/L OR µg/dL)

Test	Cutoff suggesting CIRCI	Units
Random total cortisol	< 276 nmol/L	= < 10 µg/dL
Delta cortisol after 250 µg cosyntropin (30 or 60 min − baseline)	< 248 nmol/L	= < 9 µg/dL
Random free cortisol (research)	< 55 nmol/L	not standardised
Low-dose 1 µg ACTH test	Not validated in ICU	research only

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Caveat on the high-dose 250 µg test: it supra-physiologically stimulates a gland that may be maximally driven already, so a normal response does not exclude CIRCI; conversely a blunted response does not predict steroid responsiveness. Base-7 / delta-9 is a useful mnemonic for the two numbers (276 nmol/L baseline; 248 nmol/L delta) but should not drive the decision.[7]

The four pivotal trials — deep dive

These are the studies every examiner expects you to compare. The single most important teaching point is the apparent contradiction between CORTICUS/ADRENAL (no mortality benefit) and APROCCHSS (mortality benefit), explained by patient severity and the addition of fludrocortisone.[1][2][4]

ADRENAL — Venkatesh 2018 (NEJM 378:797)

Design: Multicentre, randomised, double-blind, placebo-controlled; 3,658 adults with septic shock within 24 h of onset.
Intervention: Hydrocortisone 200 mg/day (continuous infusion) vs placebo, until shock reversal or 7 days, then tapered over 3 days.
Primary outcome — 90-day mortality: 27.9 % vs 28.8 % (OR 0.95, 95 % CI 0.82–1.10, p = 0.50) — NO significant difference.
Secondary outcomes: faster shock resolution (median 3 days vs 4 days, p<0.001); faster wean from mechanical ventilation; no difference in recurrence of shock.
Safety: more new bacteraemia/fungaemia and superinfections with hydrocortisone (but not significantly more serious adverse events); no excess bleeding, ICU-acquired weakness, or gastroduodenal bleeding.
Take-home: hydrocortisone in unselected septic shock does not save lives but speeds shock reversal. Reserve for those not weaning from vasopressors.[1]

CORTICUS — Sprung 2008 (NEJM 358:111)

Design: Multicentre RCT, 499 patients with septic shock (within 72 h), including all septic shock (less sick than Annane 2002).
Intervention: Hydrocortisone 50 mg IV q6h for 5 days, then tapered over 6 days, vs placebo.
Primary outcome — 28-day mortality in ACTH non-responders: 29 % vs 31 % (no difference) — failed to confirm Annane 2002.
Key finding: faster shock reversal (hazard ratio 1.32, p<0.001) in both responders and non-responders.
Critical safety finding: hydrocortisone could be stopped abruptly without rebound shock (cited ever since as the reason not to taper); more superinfections (notably Gram-positive).
Why it changed practice: removed the requirement for an ACTH test and removed the mandate to taper — but the unselected population (and delayed randomisation up to 72 h) diluted any mortality signal.[2]

APROCCHSS — Annane 2018 (NEJM 378:809)

Design: Multicentre RCT, 1,241 adults with severe septic shock (SOFA ≥ 8 or shock index > 0.8 for > 6 h) within 24 h.
Intervention: Hydrocortisone 200 mg/day + fludrocortisone 50 µg/day enterally for 7 days, tapered over 3 days, vs placebo. No ACTH testing.
Primary outcome — 90-day mortality: 43.0 % vs 48.8 % (RR 0.89, p = 0.03) — SIGNIFICANT mortality reduction.
Secondary outcomes: lower 28-day mortality (33.7 % vs 38.9 %), more vasopressor-free days by day 28, fewer Gram-negative infections; no excess serious adverse events.
Why it worked when ADRENAL did not: (1) sicker patients (the patients most likely to have CIRCI); (2) fludrocortisone added mineralocorticoid effect — hydrocortisone at 200 mg/day provides sub-replacement mineralocorticoid activity; (3) earlier enrolment and stricter shock criteria.
Caveat: fludrocortisone in adrenal-sufficient patients raises risk of fluid/sodium retention and hypokalaemia — monitor electrolytes.[4]

Annane 2002 (JAMA 288:862) — the original positive trial

Design: Multicentre RCT, 299 patients with vasopressor-unresponsive septic shock (SBP < 90 mmHg despite fluids + vasopressors for > 1 h) within 8 h of onset.
Pre-stratified by ACTH response, then randomised to hydrocortisone 50 mg IV q6h + fludrocortisone 50 µg/day for 7 days vs placebo.
Primary outcome — 28-day survival in ACTH non-responders: 29 % vs 63 % (RR for death 0.67) — dramatic benefit.
No benefit in ACTH responders; benefit only in non-responders.
Why later trials differed: enrolled the sickest patients very early; used fludrocortisone; unblinded; smaller, single-country. CORTICUS (2008) attempted to confirm in a broader population and failed.[3]

Reconciling the four trials — what determines benefit

Determinant	Annane 2002 / APROCCHSS (positive)	CORTICUS / ADRENAL (negative)
Shock severity	Vasopressor-refractory / SOFA ≥ 8	Unselected septic shock
Timing	Within 8 h / within 24 h	Up to 72 h (CORTICUS)
Fludrocortisone added	YES	NO
ACTH-test guided	Annane: yes; APROCCHSS: no	CORTICUS: explored; ADRENAL: no
Practical reading	Steroids save lives in severe refractory septic shock	Steroids speed shock reversal but not survival in unselected shock

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Management

Empiric hydrocortisone pathway for refractory septic shock CIRCI — FigureIf shock persists after fluids + noradrenaline ± vasopressin: hydrocortisone 200 mg/day (± fludrocortisone per APROCCHSS); no routine cosyntropin; wean when off vasopressors.

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Indication (Surviving Sepsis Campaign 2021)

Suggest IV hydrocortisone 200 mg/day for adults with septic shock on ongoing vasopressor support (weak recommendation, low-quality evidence).[6]

Do not start steroids for sepsis without shock, or for shock that is responding to fluids and a single low-dose vasopressor. The trigger is persistent vasopressor dependence.[5]

Hydrocortisone dosing regimens for septic shock (all deliver ~200 mg/day)

Regimen	Dose	Pros	Cons
Continuous infusion	200 mg (10 mg/h) over 24 h	Smooth plasma levels, fewer glycaemic excursions, easiest to titrate down	Needs a dedicated line / pump
Intermittent bolus	50 mg IV q6h	Simple, cheap	Peaks/troughs — fluctuations in MAP and glucose
Bolus + infusion	100 mg loading then 10 mg/h	Rapid onset	Two preparations
Add fludrocortisone (APROCCHSS)	50 µg PO/NG once daily	Mineralocorticoid effect; adds mortality signal	Hypokalaemia, sodium/fluid retention — monitor

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Starting, tapering and stopping hydrocortisone in septic shock (CIRCI)

Confirm the trigger — ongoing noradrenaline (or multiple vasopressors) after adequate fluids (≥ 30 mL/kg crystalloid), source control and broad-spectrum antibiotics within 1 h.
Baseline bloods — glucose, Na⁺/K⁺ (fludrocortisone lowers K⁺), WBC; consider a baseline cortisol only if the patient is chronically steroid-treated or has known adrenal disease.
Start hydrocortisone 200 mg/day (continuous infusion preferred; or 50 mg IV q6h). Add fludrocortisone 50 µg/day enteral if shock is severe (APROCCHSS regimen).
Re-assess at 24–48 h — expected response: falling vasopressor dose, rising MAP, improving lactate, warming peripheries. No response by 72 h suggests steroid-refractory shock (revisit diagnosis: cardiogenic component, source control, adequacy of antibiotics).
Taper as vasopressors wean — halve the infusion as noradrenaline falls below 0.1 µg/kg/min; stop when vasopressors cease.
Tapering vs abrupt stop — CORTICUS showed no rebound with abrupt cessation; APROCCHSS tapered over 3 days. Many units taper over 2–4 days as a pragmatic compromise. In patients on pre-existing long-term steroids, do NOT abruptly stop — convert to their chronic dose and plan a slow outpatient wean.
Add GI prophylaxis (PPI) and glucose monitoring (steroid-induced hyperglycaemia — usually an insulin infusion).
Watch for superinfection (ADRENAL signal): repeat cultures if fever/persistent leucocytosis; consider opportunistic infection (Candida) in prolonged use.

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Special situations and confounders

CIRCI vs confounders — drugs and conditions that alter cortisol/steroid need

Situation	Effect	Action
Etomidate induction	11β-hydroxylase inhibition; cortisol ↓ 24–48 h	Avoid if possible in sepsis; if used, anticipate CIRCI — do not need a test, give hydrocortisone if shock refractory
Ketoconazole / posaconazole	Steroidogenesis inhibition	Consider empiric hydrocortisone in shock
Chronic exogenous steroids (prednisolone ≥ 5 mg > 4 wk)	HPA suppression, adrenal atrophy	Stress-dose hydrocortisone perioperatively/peri-illness; never stop abruptly; total daily dose ≥ usual steroid
Bilateral adrenal haemorrhage (Waterhouse–Friderichsen, anticoagulation, APS)	Absolute deficiency	Treat as adrenal crisis — hydrocortisone 100 mg IV stat then 200 mg/day; fludrocortisone; investigate with CT abdomen
Critical illness in pregnancy / peripartum	Higher CBG → misleading high total cortisol	Treat clinically; hydrocortisone safe in pregnancy

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Beyond septic shock — other ICU corticosteroid indications (know the evidence)

Non-sepsis ICU corticosteroid indications (high-yield for vivas)

Severe community-acquired pneumonia — prednisolone 50 mg/day for 5–7 days reduces mortality and time to clinical stability (CAPE-COVID; CAPE-SARI; 2023 meta-analyses).[6]
Moderate–severe ARDS (PaO₂/FiO₂ < 200) — dexamethasone 20 mg/day × 5 d → 10 mg/day × 5 d (DExa-ARDS) reduced ventilator days and mortality; not for mild ARDS or undrained infection.
Early severe ARDS (within 14 d, P/F < 200) — methylprednisolone per Meduri protocol considered; evidence weaker than dexamethasone.
Severe asthma / COPD exacerbation — prednisolone 40–50 mg; for life-threatening asthma, magnesium + hydrocortisone 100 mg q6h.
Anaphylaxis — adrenaline first; hydrocortisone 200 mg and chlorphenamine are adjuncts that prevent biphasic reactions, not first-line.
Bacterial meningitis — dexamethasone 10 mg IV before or with the first antibiotic dose (especially pneumococcal); benefit maximal if given early.
Pneumocystis jirovecii pneumonia with PaO₂ < 70 mmHg — prednisolone 40 mg BD before antibiotics and taper.
Thyroid storm — hydrocortisone 100 mg IV q8h blocks T4→T3 conversion and treats coexistent adrenal insufficiency.
Cardiac arrest post-ROSC — adrenal insufficiency debated; not routine.

Monitoring and adverse effects

Steroid adverse effects in ICU and how to mitigate

Effect	Mechanism / signal	Mitigation
Hyperglycaemia	Gluconeogenesis ↑, insulin resistance	Q1–2 h glucose; insulin infusion; adjust feed
Superinfection	Immunosuppression (ADRENAL showed ↑)	Surveillance cultures; treat source; shortest effective course
ICU-acquired weakness	Critical-illness myopathy, additive with paralysis	Minimise neuromuscular blockade; early mobilisation; glycaemic control
GI bleeding	Mucosal protection lost	Stress-ulcer prophylaxis (PPI) if > 48 h ventilated/coagulopathic
Neuropsychiatric	Agitation, delirium, steroid psychosis	Delirium screening (CAM-ICU); haloperidol if severe; dose relates to severity
Fluid/sodium retention, hypokalaemia	Mineralocorticoid effect (esp. fludrocortisone)	Daily weights, K⁺ replacement, restrict Na⁺ if needed
Wound healing	Collagen deposition ↓	Surgical review; delayed closure; nutritional support
Reactivation of latent infection	HBV, strongyloides, TB	Screen if from endemic region / long course; antiviral prophylaxis for HBV if long steroids

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Additional clinical pearls (advanced / viva-level)

CIRCI — beyond the basics (15–28)

"CIRCI" replaced "relative adrenal insufficiency" for a reason. The 2008 task force (Marik, Pastores, Annane) deliberately renamed the syndrome to shift focus from a number (plasma cortisol) to a state (inadequate cellular glucocorticoid activity). If you say "relative adrenal insufficiency" in a viva, expect the examiner to correct you to CIRCI.[7]
The two diagnostic numbers every fellow must know (and their limits). Baseline total cortisol < 276 nmol/L (10 µg/dL) or delta cortisol < 248 nmol/L (9 µg/dL) after 250 µg ACTH. Mnemonic 276 / 248 nmol/L (= 10 / 9 µg/dL). Critically: these are consensus, not evidence-graded against outcome — SSC 2021 says do not use them to decide treatment.[5][6]
Free cortisol, not total, is what matters — and assays don't measure it. CBG falls in inflammation, so total cortisol under-represents the active free fraction. A measured total cortisol of 400 nmol/L in florid sepsis is low for the stress. This is the physiological basis for treating empirically.[8]
Tissue glucocorticoid resistance is mediated by GRβ. Inflammation (TNF-α, IL-2) splices the glucocorticoid receptor toward the β-isoform that cannot activate anti-inflammatory genes and competitively inhibits GRα. A patient can have a high cortisol and still be functionally steroid-resistant — exogenous hydrocortisone overcomes this by mass action.[8]
Etomidate is the classic drug-induced CIRCI. A single intubating dose inhibits 11β-hydroxylase for 24–48 h. The ESETT/Ketamine-vs-Etomidate debate showed increased adrenal suppression but no mortality difference; nonetheless, avoid etomidate in known septic shock if ketamine is available, and anticipate refractory hypotension.[7]
Fludrocortisone is the missing piece explaining APROCCHSS. Hydrocortisone at 200 mg/day supplies only ~20 % of mineralocorticoid replacement. Fludrocortisone 50 µg/day restores mineralocorticoid tone → Na⁺ retention, vascular smooth-muscle responsiveness, and may explain the mortality signal where ADRENAL (hydrocortisone alone) was neutral. Add it in severe shock.[4]
Refractory shock on day 3 of hydrocortisone is NOT "just CIRCI". If vasopressors are still climbing, revisit: undrained source (abscess, infected line), inadequate antibiotics / resistant organism, cardiogenic component (bedside echo — low EF, RV failure), profound acidosis, hypocalcaemia, adrenal haemorrhage. Steroids are adjunctive, not a substitute for definitive resuscitation.[6]
Don't confuse CIRCI with absolute adrenal insufficiency / Addisonian crisis. Adrenal crisis presents with hyponatraemia, hyperkalaemia, hypoglycaemia, hypotension, abdominal pain, and (in primary disease) hyperpigmentation — and needs lifelong replacement after the acute episode. CIRCI is transient and resolves with the critical illness. Test for Addison's if: known autoimmune disease, prior steroids, characteristic electrolytes, or CT showing bilateral adrenal abnormalities.[5]
The "stress dose" concept applies to chronic-steroid patients. Any patient on prednisolone ≥ 5 mg/day for > 4 weeks (or recent high-dose course) has a suppressed HPA axis. For surgery or sepsis, double their usual dose or give IV hydrocortisone 100 mg stat then 50 mg q6h for the acute illness, then taper back to baseline over days. Never stop chronic steroids abruptly in ICU.[7]
Bilateral adrenal haemorrhage = absolute deficiency, not CIRCI. Suspect in: anticoagulated patient, postoperative, meningococcaemia (Waterhouse–Friderichsen), heparin-induced thrombocytopenia, severe DIC. CT abdomen shows enlarged non-enhancing adrenals. Treat with hydrocortisone 100 mg IV stat + 200 mg/day (the dose is higher than CIRCI), fluid resuscitation, and investigate/treat the cause. Mineralocorticoid not needed acutely (high hydrocortisone dose provides mineralocorticoid activity).[5]
Corticosteroids interact with vasopressors, not replace them. Cortisol is permissive — it upregulates α1-adrenergic receptors and restores catecholamine sensitivity. Expect to wean noradrenaline over 24–72 h, not switch it off. Conversely, in absolute Addisonian crisis, hydrocortisone alone may restore BP enough to stop catecholamines within hours.[8]
CORTICUS changed two pieces of practice. (a) No ACTH test needed before starting steroids — contradicted the Annane 2002 strategy. (b) No taper needed on stopping — no rebound shock. Both have stood the test of time and are embedded in SSC 2021.[2]
ADRENAL changed none of the indications but tightened safety expectations. Hydrocortisone did not reduce 90-day mortality in 3,658 patients, so it is not a default treatment for all septic shock — reserve it for ongoing vasopressor need. Watch for superinfection, especially bacteraemia/fungaemia, after a week of therapy.[1]
Steroid-induced hyperglycaemia is itself harmful. Intensive insulin to maintain glucose 6–10 mmol/L was net-harmful overall (NICE-SUGAR), but uncontrolled steroid hyperglycaemia drives infection and weakness. Practical approach: correction insulin with meals/feeds, or a sliding-scale infusion matched to the dexamethasone/hydrocortisone peak.[6]

Additional red flags

Don't-miss CIRCI red flags

Noradrenaline dose escalating despite fluids + source control → start hydrocortisone 200 mg/day empirically.[6] }
Shock plus unexplained hyperkalaemia, hyponatraemia, hypoglycaemia → think absolute adrenal insufficiency, not just CIRCI — give hydrocortisone 100 mg IV and investigate.[5] }
Patient intubated with etomidate now in refractory shock → drug-induced 11β-hydroxylase block — treat as CIRCI.[7] }
Septic patient on long-term steroids → do NOT stop their steroids; give stress-dose hydrocortisone.[7] }
No vasopressor wean by 72 h of hydrocortisone → the diagnosis is wrong/incomplete — bedside echo, repeat cultures, CT for source, exclude adrenal haemorrhage.[6] }
Skin hyperpigmentation, postural drop, salt-craving history → underlying primary adrenal insufficiency — different management (lifelong replacement).[5] }
Persistent hypotension after bilateral adrenalectomy / on ketoconazole → iatrogenic adrenal suppression — empiric steroids.[8] }

Approach to the viva / written question

How to answer "corticosteroids in septic shock" in a structured viva

Define the entity — CIRCI: inadequate cellular corticosteroid activity for the severity of illness; not absolute deficiency.
State the mechanism — HPA suppression (cytokines, drugs), tissue resistance (GRβ), altered metabolism/CBG.
State the diagnosis — clinical, not biochemical; random/delta cortisol cutoffs (276 / 248 nmol/L) are consensus only; SSC 2021 recommends AGAINST routine ACTH testing.
State the indication — septic shock with ongoing vasopressor requirement despite adequate fluids, source control and antibiotics within 1 h.
State the regimen — hydrocortisone 200 mg/day (continuous or 50 mg q6h); add fludrocortisone 50 µg/day in severe shock (APROCCHSS).
Justify with evidence — cite ADRENAL (no mortality, faster shock reversal), CORTICUS (no mortality, no taper needed), APROCCHSS (mortality benefit with fludrocortisone in severe shock).
Address safety — hyperglycaemia, superinfection, ICU-acquired weakness, GI bleeding; add PPI and glucose control.
Address stopping — taper as vasopressors wean; abrupt stop acceptable (CORTICUS); chronic-steroid patients must transition to their usual dose.

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Prognosis and bottom line

Untreated refractory septic shock with CIRCI carries mortality > 60 %; early empiric hydrocortisone typically weans vasopressors within 24–48 h and, in the sickest subgroup (APROCCHSS), reduces 90-day mortality to ~43 % vs ~49 %.[4]
No long-term steroid dependence is created by a 5–7 day septic-shock course of hydrocortisone — the HPA axis recovers within days to weeks (unlike chronic steroid therapy).
The single defensible position for a fellow: "I start hydrocortisone 200 mg/day, with fludrocortisone 50 µg/day if shock is severe, in vasopressor-dependent septic shock, after adequate resuscitation, source control and antibiotics. I do not use an ACTH test. I taper as vasopressors wean and stop when off vasopressors. I monitor glucose, electrolytes, infection and weakness."[6][4]

References

[1]Venkatesh B, Finfer S, Myburgh J, et al. Adjunctive Glucocorticoid Therapy in Patients with Septic Shock N Engl J Med, 2018.PMID 29347874
[2]Sprung CL, Annane D, Keh D, et al. Hydrocortisone therapy for patients with septic shock N Engl J Med, 2008.PMID 18184957
[3]Annane D, Sébille V, Charpentier C, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock JAMA, 2002.PMID 12186604
[4]Annane D, Renault A, Brun-Buisson C, et al. Hydrocortisone plus Fludrocortisone for Adults with Septic Shock N Engl J Med, 2018.PMID 29490185
[5]Annane D, Pastores SM, Rochwerg B, et al. Guidelines for the Diagnosis and Management of Critical Illness-Related Corticosteroid Insufficiency (CIRCI) in Critically Ill Patients (Part I): Society of Critical Care Medicine (SCCM) and European Society of Intensive Care Medicine (ESICM) 2017 Crit Care Med, 2017.PMID 28938253
[6]Evans L, Rhodes A, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021 Crit Care Med, 2021.PMID 34605781
[7]Marik PE, Pastores SM, Annane D, et al. Recommendations for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients: consensus statements from an international task force by the American College of Critical Care Medicine Crit Care Med, 2008.PMID 18496365
[8]Annane D, Pastores SM, Arlt W, et al. Critical Illness-Related Corticosteroid Insufficiency (CIRCI): A Narrative Review from a Multispecialty Task Force of the Society of Critical Care Medicine (SCCM) and the European Society of Intensive Care Medicine (ESICM) Crit Care Med, 2017.PMID 28938251

[1]

Key corticosteroid trials in septic shock

Trial	Year	Intervention	Key finding
Annane 2002	JAMA	Hydrocortisone + fludrocortisone vs placebo (ACTH non-responders)	REDUCED mortality in ACTH non-responders (29% vs 63%)
CORTICUS	NEJM 2008	Hydrocortisone vs placebo (all septic shock)	NO mortality benefit. Faster shock reversal. No rebound on stopping.
ADRENAL	NEJM 2018	Hydrocortisone vs placebo (3658 patients)	NO mortality benefit (27.9% vs 28.8%). Faster shock reversal, more infections.
APROCCHSS	NEJM 2018	Hydrocortisone + fludrocortisone vs placebo	REDUCED 90-day mortality (43% vs 49%). Benefit in severe septic shock.

[1]

Management of suspected CIRCI in septic shock

Ensure adequate resuscitation FIRST — fluids (30 mL/kg), vasopressors (noradrenaline titrated to MAP ≥65), source control, antibiotics
If shock REFRACTORY (ongoing vasopressor requirement despite adequate fluid + max vasopressor dose) → consider CIRCI
DON'T do ACTH stimulation test routinely — SSC 2021: suggests against routine testing. Just give empirically
Start hydrocortisone — 200 mg/day: continuous infusion OR 50 mg IV QDS. Add fludrocortisone 50 mcg PO/NG daily (APROCCHSS)
Assess response — vasopressor dose decreasing, improving haemodynamics, lactate clearing within 24-48h
Continue until vasopressors weaned — then STOP (CORTICUS: no taper needed, no rebound)
Monitor — hyperglycaemia (corticosteroids increase glucose), infection (immunosuppression), neuromuscular weakness, GI bleeding (add PPI)

[1]

Exam practice

SAQ — Vasopressor-refractory septic shock and the role of hydrocortisone

10 minutes · 10 marks

[1]

SAQ — Interpreting a baseline cortisol in the critically ill

10 minutes · 10 marks

[1]

Clinical pearls

High-yield CIRCI points for CICM/FFICM exam

CIRCI is NOT classic adrenal insufficiency. It's RELATIVE — cortisol production may be normal or even high, but INSUFFICIENT for the severity of critical illness (inflammatory demand exceeds supply). Mechanisms: HPA axis suppression (cytokines), cortisol resistance (tissue level), altered cortisol metabolism. Don't think 'low cortisol' — think 'inadequate for demand'.[5] }
Don't do ACTH stimulation test routinely. SSC 2021: suggests AGAINST routine testing. The test (250 mcg cosyntropin, measure cortisol at 0 and 60 min) is INCONCLUSIVE in critical illness (protein binding, assay variability, stress confounders). Just GIVE hydrocortisone empirically if septic shock is refractory.[6] }
ADRENAL trial (2018): hydrocortisone did NOT improve survival overall. 3,658 patients with septic shock. Hydrocortisone 200 mg/day vs placebo. Mortality: 27.9% vs 28.8% (not significant). BUT: faster shock reversal (1.5 days faster off vasopressors). More superinfections (with hydrocortisone). CONCLUSION: hydrocortisone for shock reversal, not mortality.[1] }
APROCCHSS trial (2018): hydrocortisone + FLUDROCORTISONE reduced mortality. 1,241 patients with SEVERE septic shock (SOFA ≥8 or shock index >0.8). Hydrocortisone 200 mg/day + fludrocortisone 50 mcg/day vs placebo. 90-day mortality: 43% vs 49% (significant). APROCCHSS included sicker patients and used FLUDROCORTISONE (mineralocorticoid — may add benefit).[4] }
Hydrocortisone dose: 200 mg/day (NOT high-dose). 200 mg/day = physiological replacement (not pharmacological). Old studies used 'stress dose' methylprednisolone (HIGH dose — harmful, increased infection). Modern: LOW-dose hydrocortisone (equivalent to normal daily cortisol production under stress). Continuous infusion preferred (avoids peaks/troughs — more stable haemodynamics).[5] }
Annane 2002: benefit in ACTH non-responders — but CORTICUS didn't confirm. Annane (JAMA 2002): hydrocortisone + fludrocortisone reduced mortality in vasopressor-unresponsive septic shock with ACTH non-response (cortisol rise <250 nmol/L after 250 mcg ACTH). Mortality: 29% vs 63%. BUT: CORTICUS (2008) did NOT confirm — no benefit in ACTH non-responders. CONFLICT: Annane enrolled SICKER patients (vasopressor-dependent, within 8h). CORTICUS enrolled broader (including milder).[3] }
CORTICUS: no rebound on stopping (no taper needed). Old practice: taper steroids gradually (fear of rebound). CORTICUS: hydrocortisone STOPPED abruptly at day 11 — NO rebound (no increased vasopressor need, no new shock). CONCLUSION: stop when vasopressors weaned — don't taper (CORTICUS). APROCCHSS: tapered over 7 days (more conservative — may be safer).[2] }
Indication: SEPTIC SHOCK refractory to fluids + vasopressors. NOT all septic shock (most respond to fluids + noradrenaline). ONLY if: (1) Persistent hypotension despite adequate fluid (30 mL/kg) + vasopressor (noradrenaline ≥0.25 mcg/kg/min, or multiple vasopressors). (2) Ongoing lactate elevation. (3) Not responding within 4-6h of resuscitation. THIS is when CIRCI may be contributing.[6] }
Hydrocortisone improves SHOCK REVERSAL (even if not mortality). Across trials (ADRENAL, CORTICUS, APROCCHSS): hydrocortisone consistently reduces time on vasopressors (by 1-2 days). This is useful: shorter vasopressor time → fewer complications (peripheral ischaemia, arrhythmia), shorter ICU stay. Even without survival benefit, shock reversal is clinically meaningful.[1] }
Add fludrocortisone (APROCCHSS approach). Fludrocortisone: mineralocorticoid (aldosterone analogue) → sodium retention, potassium excretion → fluid retention + vascular tone. APROCCHSS: hydrocortisone + fludrocortisone reduced mortality (where hydrocortisone alone in ADRENAL did not). Possible: fludrocortisone adds mineralocorticoid benefit (vascular tone). DOSE: fludrocortisone 50 mcg PO/NG daily (add to hydrocortisone).[4] }
CIRCI diagnosis criteria (if testing). SSC/CIRCI guidelines (2017): (1) Random TOTAL cortisol <276 nmol/L (10 mcg/dL). OR (2) Delta cortisol (after 250 mcg ACTH) <250 nmol/L (9 mcg/dL). EITHER suggests CIRCI. BUT: guidelines also say DON'T test routinely (just treat empirically). Test only if: diagnostic uncertainty, research, borderline case.[5] }
Adverse effects of hydrocortisone. (1) HYPERGLYCAEMIA (steroid-induced — monitor glucose, insulin). (2) INFECTION (immunosuppression — more superinfections in ADRENAL). (3) NEUROMUSCULAR WEAKNESS (especially with prolonged use + paralysis — critical illness myopathy). (4) GI BLEEDING (stress ulcer — add PPI). (5) WOUND HEALING (impaired — surgical patients). (6) PSYCHIATRIC (agitation, delirium — common in ICU). MONITOR: glucose, WBC, GI symptoms.[1] }
CIRCI vs classic adrenal insufficiency. Classic Addison's (primary adrenal insufficiency): autoimmune, TB, bilateral adrenal haemorrhage. PERMANENT deficiency. Treatment: lifelong hydrocortisone + fludrocortisone. CIRCI: TRANSIENT (critical illness only). Resolves when illness resolves. Treatment: temporary (while in ICU). DISTINGUISH: history (Addison's — known), examination (hyperpigmentation — Addison's), cortisol (very low in Addison's).[5] }
Other ICU indications for corticosteroids (beyond CIRCI). (1) SEVERE CAP (prednisolone 50 mg — CAPE COVID, meta-analysis: reduces mortality). (2) ARDS (dexamethasone — DExa-ARDS: reduces mortality in moderate-severe). (3) Severe ASTHMA/COPD. (4) ANAPHYLAXIS (not first-line — adrenaline first). (5) Pneumocystis pneumonia (adjunctive if hypoxic). (6) Thyroid storm. (7) Bacterial meningitis (dexamethasone before/with first antibiotic).[6] }

Red flags

Prognosis

APROCCHSS trial (Annane 2018, NEJM) — hydrocortisone + fludrocortisone in severe septic shock

RCT: 1,241 patients with SEVERE septic shock (SOFA ≥8 or shock index >0.8 for >6h). Hydrocortisone 200 mg/day + fludrocortisone 50 mcg/day vs placebo.

90-day mortality: 43.0% vs 48.8% (RR 0.89, p=0.03) — REDUCED mortality
28-day mortality: 33.7% vs 38.9%
Vasopressor-free days: more with treatment
Adverse events: similar (no excess infection)
CONCLUSION: Hydrocortisone + fludrocortisone REDUCES mortality in SEVERE septic shock. (ADRENAL — hydrocortisone alone — did not. Difference: APROCCHSS used fludrocortisone + enrolled sicker patients.) [1]

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Definition and pathophysiology

The hypothalamic–pituitary–adrenal (HPA) axis in health

Three mechanisms producing CIRCI in critical illness

HPA-axis suppression / inadequate drive. Pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) and circulating toxins depress hypothalamic and pituitary function, blunt the ACTH response, and impair adrenal steroidogenesis. Drugs compound this: etomidate (inhibits 11β-hydroxylase — even a single induction dose suppresses cortisol for 24–48 h), ketoconazole/posaconazole (inhibit CYP-dependent steroidogenesis), high-dose opioids, and chronic exogenous steroids (suppression of CRH → adrenal atrophy, the commonest cause in the ward patient admitted to ICU).[7]
Tissue glucocorticoid resistance. Inflammation upregulates the inactive β-isoform of the glucocorticoid receptor (GRβ) at the expense of the active α-isoform, and activates p38 MAPK and JNK pathways that phosphorylate and inactivate the receptor. The net effect: even normal intracellular cortisol concentrations fail to transactivate anti-inflammatory genes. This is why "normal" plasma cortisol does not exclude CIRCI.[8]
Altered cortisol metabolism and distribution. Critical illness lowers CBG (more free cortisol cleared) and, in prolonged illness, the 2-oxo-reductase pathway accelerates cortisol inactivation. Adrenal infarction or bilateral adrenal haemorrhage (classically in meningococcaemia/Waterhouse–Friderichsen, heparin-induced thrombocytopenia, or antiphospholipid syndrome) produces absolute deficiency — a distinct entity, but lumped with CIRCI when the trigger is sepsis.[5]

Normal HPA axis vs CIRCI in septic shock

Feature	Healthy, unstressed	Healthy, stressed	CIRCI (septic shock)
Cortisol production	~10 mg/day	200–350 mg/day	May be raised but inadequate for demand
Plasma total cortisol	140–700 nmol/L	Often >1000 nmol/L	Variable; can be "normal"
Cortisol-binding globulin	Normal	Falls slightly	Markedly reduced (free fraction ↑ but total misleading)
Tissue glucocorticoid action	Normal	Augmented	Impaired (GRβ upregulation, receptor resistance)
ACTH response	Brisk	Augmented	Blunted by cytokines
Response to exogenous hydrocortisone	—	—	Often dramatic vasopressor wean

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Diagnosis of CIRCI

The two proposed (but contentious) thresholds

The 2008 task force (Marik, Pastores & Annane) offered a biochemical definition that the 2017 update largely retained for completeness while downgrading its clinical role:[7][5]

CIRCI is suggested if random total cortisol < 276 nmol/L (10 µg/dL) OR delta cortisol < 248 nmol/L (9 µg/dL) after 250 µg ACTH (cosyntropin) stimulation. [1]

The "delta" (increment) is the 30- or 60-minute value minus baseline. Note the units: 276 nmol/L ≈ 10 µg/dL and 248 nmol/L ≈ 9 µg/dL (cortitol: 1 µg/dL = 27.6 nmol/L).[5]

Why the test is NOT recommended for routine decisions

Why the ACTH stimulation test is unreliable in critical illness (and what to do instead)

CBG shifts — total cortisol falls when CBG falls even if the free (active) fraction is normal, generating false-positives.
Assay variability — immunoassays cross-react with prednisolone, methylprednisolone and cortisone; LC-MS/MS is not universally available.
No validated outcome threshold — neither baseline nor delta cortisol predicts response to hydrocortisone or mortality in CORTICUS or ADRENAL.
Confounding by illness phase — early (hyperdynamic) vs late (hypodynamic) sepsis give different cortisol kinetics.
Does not change management — SSC 2021 recommends AGAINST using the ACTH test to decide who gets hydrocortisone.[6]
DO INSTEAD — make the decision on clinical grounds: vasopressor-refractory septic shock (ongoing noradrenaline requirement after adequate fluids and source control). Treat empirically; reserve the test for diagnostic uncertainty (suspected Addison's, prior chronic steroids, bilateral adrenal lesions).[5]

Diagnostic thresholds and units (know both, exams ask for nmol/L OR µg/dL)

Test	Cutoff suggesting CIRCI	Units
Random total cortisol	< 276 nmol/L	= < 10 µg/dL
Delta cortisol after 250 µg cosyntropin (30 or 60 min − baseline)	< 248 nmol/L	= < 9 µg/dL
Random free cortisol (research)	< 55 nmol/L	not standardised
Low-dose 1 µg ACTH test	Not validated in ICU	research only

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The four pivotal trials — deep dive

ADRENAL — Venkatesh 2018 (NEJM 378:797)

Design: Multicentre, randomised, double-blind, placebo-controlled; 3,658 adults with septic shock within 24 h of onset.
Intervention: Hydrocortisone 200 mg/day (continuous infusion) vs placebo, until shock reversal or 7 days, then tapered over 3 days.
Primary outcome — 90-day mortality: 27.9 % vs 28.8 % (OR 0.95, 95 % CI 0.82–1.10, p = 0.50) — NO significant difference.
Secondary outcomes: faster shock resolution (median 3 days vs 4 days, p<0.001); faster wean from mechanical ventilation; no difference in recurrence of shock.
Safety: more new bacteraemia/fungaemia and superinfections with hydrocortisone (but not significantly more serious adverse events); no excess bleeding, ICU-acquired weakness, or gastroduodenal bleeding.
Take-home: hydrocortisone in unselected septic shock does not save lives but speeds shock reversal. Reserve for those not weaning from vasopressors.[1]

CORTICUS — Sprung 2008 (NEJM 358:111)

Design: Multicentre RCT, 499 patients with septic shock (within 72 h), including all septic shock (less sick than Annane 2002).
Intervention: Hydrocortisone 50 mg IV q6h for 5 days, then tapered over 6 days, vs placebo.
Primary outcome — 28-day mortality in ACTH non-responders: 29 % vs 31 % (no difference) — failed to confirm Annane 2002.
Key finding: faster shock reversal (hazard ratio 1.32, p<0.001) in both responders and non-responders.
Critical safety finding: hydrocortisone could be stopped abruptly without rebound shock (cited ever since as the reason not to taper); more superinfections (notably Gram-positive).
Why it changed practice: removed the requirement for an ACTH test and removed the mandate to taper — but the unselected population (and delayed randomisation up to 72 h) diluted any mortality signal.[2]

APROCCHSS — Annane 2018 (NEJM 378:809)

Design: Multicentre RCT, 1,241 adults with severe septic shock (SOFA ≥ 8 or shock index > 0.8 for > 6 h) within 24 h.
Intervention: Hydrocortisone 200 mg/day + fludrocortisone 50 µg/day enterally for 7 days, tapered over 3 days, vs placebo. No ACTH testing.
Primary outcome — 90-day mortality: 43.0 % vs 48.8 % (RR 0.89, p = 0.03) — SIGNIFICANT mortality reduction.
Secondary outcomes: lower 28-day mortality (33.7 % vs 38.9 %), more vasopressor-free days by day 28, fewer Gram-negative infections; no excess serious adverse events.
Why it worked when ADRENAL did not: (1) sicker patients (the patients most likely to have CIRCI); (2) fludrocortisone added mineralocorticoid effect — hydrocortisone at 200 mg/day provides sub-replacement mineralocorticoid activity; (3) earlier enrolment and stricter shock criteria.
Caveat: fludrocortisone in adrenal-sufficient patients raises risk of fluid/sodium retention and hypokalaemia — monitor electrolytes.[4]

Annane 2002 (JAMA 288:862) — the original positive trial

Design: Multicentre RCT, 299 patients with vasopressor-unresponsive septic shock (SBP < 90 mmHg despite fluids + vasopressors for > 1 h) within 8 h of onset.
Pre-stratified by ACTH response, then randomised to hydrocortisone 50 mg IV q6h + fludrocortisone 50 µg/day for 7 days vs placebo.
Primary outcome — 28-day survival in ACTH non-responders: 29 % vs 63 % (RR for death 0.67) — dramatic benefit.
No benefit in ACTH responders; benefit only in non-responders.
Why later trials differed: enrolled the sickest patients very early; used fludrocortisone; unblinded; smaller, single-country. CORTICUS (2008) attempted to confirm in a broader population and failed.[3]

Reconciling the four trials — what determines benefit

Determinant	Annane 2002 / APROCCHSS (positive)	CORTICUS / ADRENAL (negative)
Shock severity	Vasopressor-refractory / SOFA ≥ 8	Unselected septic shock
Timing	Within 8 h / within 24 h	Up to 72 h (CORTICUS)
Fludrocortisone added	YES	NO
ACTH-test guided	Annane: yes; APROCCHSS: no	CORTICUS: explored; ADRENAL: no
Practical reading	Steroids save lives in severe refractory septic shock	Steroids speed shock reversal but not survival in unselected shock

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Management

[1]

Indication (Surviving Sepsis Campaign 2021)

Suggest IV hydrocortisone 200 mg/day for adults with septic shock on ongoing vasopressor support (weak recommendation, low-quality evidence).[6]

Do not start steroids for sepsis without shock, or for shock that is responding to fluids and a single low-dose vasopressor. The trigger is persistent vasopressor dependence.[5]

Hydrocortisone dosing regimens for septic shock (all deliver ~200 mg/day)

Regimen	Dose	Pros	Cons
Continuous infusion	200 mg (10 mg/h) over 24 h	Smooth plasma levels, fewer glycaemic excursions, easiest to titrate down	Needs a dedicated line / pump
Intermittent bolus	50 mg IV q6h	Simple, cheap	Peaks/troughs — fluctuations in MAP and glucose
Bolus + infusion	100 mg loading then 10 mg/h	Rapid onset	Two preparations
Add fludrocortisone (APROCCHSS)	50 µg PO/NG once daily	Mineralocorticoid effect; adds mortality signal	Hypokalaemia, sodium/fluid retention — monitor

[1]

Starting, tapering and stopping hydrocortisone in septic shock (CIRCI)

Confirm the trigger — ongoing noradrenaline (or multiple vasopressors) after adequate fluids (≥ 30 mL/kg crystalloid), source control and broad-spectrum antibiotics within 1 h.
Baseline bloods — glucose, Na⁺/K⁺ (fludrocortisone lowers K⁺), WBC; consider a baseline cortisol only if the patient is chronically steroid-treated or has known adrenal disease.
Start hydrocortisone 200 mg/day (continuous infusion preferred; or 50 mg IV q6h). Add fludrocortisone 50 µg/day enteral if shock is severe (APROCCHSS regimen).
Re-assess at 24–48 h — expected response: falling vasopressor dose, rising MAP, improving lactate, warming peripheries. No response by 72 h suggests steroid-refractory shock (revisit diagnosis: cardiogenic component, source control, adequacy of antibiotics).
Taper as vasopressors wean — halve the infusion as noradrenaline falls below 0.1 µg/kg/min; stop when vasopressors cease.
Tapering vs abrupt stop — CORTICUS showed no rebound with abrupt cessation; APROCCHSS tapered over 3 days. Many units taper over 2–4 days as a pragmatic compromise. In patients on pre-existing long-term steroids, do NOT abruptly stop — convert to their chronic dose and plan a slow outpatient wean.
Add GI prophylaxis (PPI) and glucose monitoring (steroid-induced hyperglycaemia — usually an insulin infusion).
Watch for superinfection (ADRENAL signal): repeat cultures if fever/persistent leucocytosis; consider opportunistic infection (Candida) in prolonged use.

[1]

Special situations and confounders

CIRCI vs confounders — drugs and conditions that alter cortisol/steroid need

Situation	Effect	Action
Etomidate induction	11β-hydroxylase inhibition; cortisol ↓ 24–48 h	Avoid if possible in sepsis; if used, anticipate CIRCI — do not need a test, give hydrocortisone if shock refractory
Ketoconazole / posaconazole	Steroidogenesis inhibition	Consider empiric hydrocortisone in shock
Chronic exogenous steroids (prednisolone ≥ 5 mg > 4 wk)	HPA suppression, adrenal atrophy	Stress-dose hydrocortisone perioperatively/peri-illness; never stop abruptly; total daily dose ≥ usual steroid
Bilateral adrenal haemorrhage (Waterhouse–Friderichsen, anticoagulation, APS)	Absolute deficiency	Treat as adrenal crisis — hydrocortisone 100 mg IV stat then 200 mg/day; fludrocortisone; investigate with CT abdomen
Critical illness in pregnancy / peripartum	Higher CBG → misleading high total cortisol	Treat clinically; hydrocortisone safe in pregnancy

[1]

Beyond septic shock — other ICU corticosteroid indications (know the evidence)

Non-sepsis ICU corticosteroid indications (high-yield for vivas)

Severe community-acquired pneumonia — prednisolone 50 mg/day for 5–7 days reduces mortality and time to clinical stability (CAPE-COVID; CAPE-SARI; 2023 meta-analyses).[6]
Moderate–severe ARDS (PaO₂/FiO₂ < 200) — dexamethasone 20 mg/day × 5 d → 10 mg/day × 5 d (DExa-ARDS) reduced ventilator days and mortality; not for mild ARDS or undrained infection.
Early severe ARDS (within 14 d, P/F < 200) — methylprednisolone per Meduri protocol considered; evidence weaker than dexamethasone.
Severe asthma / COPD exacerbation — prednisolone 40–50 mg; for life-threatening asthma, magnesium + hydrocortisone 100 mg q6h.
Anaphylaxis — adrenaline first; hydrocortisone 200 mg and chlorphenamine are adjuncts that prevent biphasic reactions, not first-line.
Bacterial meningitis — dexamethasone 10 mg IV before or with the first antibiotic dose (especially pneumococcal); benefit maximal if given early.
Pneumocystis jirovecii pneumonia with PaO₂ < 70 mmHg — prednisolone 40 mg BD before antibiotics and taper.
Thyroid storm — hydrocortisone 100 mg IV q8h blocks T4→T3 conversion and treats coexistent adrenal insufficiency.
Cardiac arrest post-ROSC — adrenal insufficiency debated; not routine.

Monitoring and adverse effects

Steroid adverse effects in ICU and how to mitigate

Effect	Mechanism / signal	Mitigation
Hyperglycaemia	Gluconeogenesis ↑, insulin resistance	Q1–2 h glucose; insulin infusion; adjust feed
Superinfection	Immunosuppression (ADRENAL showed ↑)	Surveillance cultures; treat source; shortest effective course
ICU-acquired weakness	Critical-illness myopathy, additive with paralysis	Minimise neuromuscular blockade; early mobilisation; glycaemic control
GI bleeding	Mucosal protection lost	Stress-ulcer prophylaxis (PPI) if > 48 h ventilated/coagulopathic
Neuropsychiatric	Agitation, delirium, steroid psychosis	Delirium screening (CAM-ICU); haloperidol if severe; dose relates to severity
Fluid/sodium retention, hypokalaemia	Mineralocorticoid effect (esp. fludrocortisone)	Daily weights, K⁺ replacement, restrict Na⁺ if needed
Wound healing	Collagen deposition ↓	Surgical review; delayed closure; nutritional support
Reactivation of latent infection	HBV, strongyloides, TB	Screen if from endemic region / long course; antiviral prophylaxis for HBV if long steroids

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Additional clinical pearls (advanced / viva-level)

CIRCI — beyond the basics (15–28)

"CIRCI" replaced "relative adrenal insufficiency" for a reason. The 2008 task force (Marik, Pastores, Annane) deliberately renamed the syndrome to shift focus from a number (plasma cortisol) to a state (inadequate cellular glucocorticoid activity). If you say "relative adrenal insufficiency" in a viva, expect the examiner to correct you to CIRCI.[7]
The two diagnostic numbers every fellow must know (and their limits). Baseline total cortisol < 276 nmol/L (10 µg/dL) or delta cortisol < 248 nmol/L (9 µg/dL) after 250 µg ACTH. Mnemonic 276 / 248 nmol/L (= 10 / 9 µg/dL). Critically: these are consensus, not evidence-graded against outcome — SSC 2021 says do not use them to decide treatment.[5][6]
Free cortisol, not total, is what matters — and assays don't measure it. CBG falls in inflammation, so total cortisol under-represents the active free fraction. A measured total cortisol of 400 nmol/L in florid sepsis is low for the stress. This is the physiological basis for treating empirically.[8]
Tissue glucocorticoid resistance is mediated by GRβ. Inflammation (TNF-α, IL-2) splices the glucocorticoid receptor toward the β-isoform that cannot activate anti-inflammatory genes and competitively inhibits GRα. A patient can have a high cortisol and still be functionally steroid-resistant — exogenous hydrocortisone overcomes this by mass action.[8]
Etomidate is the classic drug-induced CIRCI. A single intubating dose inhibits 11β-hydroxylase for 24–48 h. The ESETT/Ketamine-vs-Etomidate debate showed increased adrenal suppression but no mortality difference; nonetheless, avoid etomidate in known septic shock if ketamine is available, and anticipate refractory hypotension.[7]
Fludrocortisone is the missing piece explaining APROCCHSS. Hydrocortisone at 200 mg/day supplies only ~20 % of mineralocorticoid replacement. Fludrocortisone 50 µg/day restores mineralocorticoid tone → Na⁺ retention, vascular smooth-muscle responsiveness, and may explain the mortality signal where ADRENAL (hydrocortisone alone) was neutral. Add it in severe shock.[4]
Refractory shock on day 3 of hydrocortisone is NOT "just CIRCI". If vasopressors are still climbing, revisit: undrained source (abscess, infected line), inadequate antibiotics / resistant organism, cardiogenic component (bedside echo — low EF, RV failure), profound acidosis, hypocalcaemia, adrenal haemorrhage. Steroids are adjunctive, not a substitute for definitive resuscitation.[6]
Don't confuse CIRCI with absolute adrenal insufficiency / Addisonian crisis. Adrenal crisis presents with hyponatraemia, hyperkalaemia, hypoglycaemia, hypotension, abdominal pain, and (in primary disease) hyperpigmentation — and needs lifelong replacement after the acute episode. CIRCI is transient and resolves with the critical illness. Test for Addison's if: known autoimmune disease, prior steroids, characteristic electrolytes, or CT showing bilateral adrenal abnormalities.[5]
The "stress dose" concept applies to chronic-steroid patients. Any patient on prednisolone ≥ 5 mg/day for > 4 weeks (or recent high-dose course) has a suppressed HPA axis. For surgery or sepsis, double their usual dose or give IV hydrocortisone 100 mg stat then 50 mg q6h for the acute illness, then taper back to baseline over days. Never stop chronic steroids abruptly in ICU.[7]
Bilateral adrenal haemorrhage = absolute deficiency, not CIRCI. Suspect in: anticoagulated patient, postoperative, meningococcaemia (Waterhouse–Friderichsen), heparin-induced thrombocytopenia, severe DIC. CT abdomen shows enlarged non-enhancing adrenals. Treat with hydrocortisone 100 mg IV stat + 200 mg/day (the dose is higher than CIRCI), fluid resuscitation, and investigate/treat the cause. Mineralocorticoid not needed acutely (high hydrocortisone dose provides mineralocorticoid activity).[5]
Corticosteroids interact with vasopressors, not replace them. Cortisol is permissive — it upregulates α1-adrenergic receptors and restores catecholamine sensitivity. Expect to wean noradrenaline over 24–72 h, not switch it off. Conversely, in absolute Addisonian crisis, hydrocortisone alone may restore BP enough to stop catecholamines within hours.[8]
CORTICUS changed two pieces of practice. (a) No ACTH test needed before starting steroids — contradicted the Annane 2002 strategy. (b) No taper needed on stopping — no rebound shock. Both have stood the test of time and are embedded in SSC 2021.[2]
ADRENAL changed none of the indications but tightened safety expectations. Hydrocortisone did not reduce 90-day mortality in 3,658 patients, so it is not a default treatment for all septic shock — reserve it for ongoing vasopressor need. Watch for superinfection, especially bacteraemia/fungaemia, after a week of therapy.[1]
Steroid-induced hyperglycaemia is itself harmful. Intensive insulin to maintain glucose 6–10 mmol/L was net-harmful overall (NICE-SUGAR), but uncontrolled steroid hyperglycaemia drives infection and weakness. Practical approach: correction insulin with meals/feeds, or a sliding-scale infusion matched to the dexamethasone/hydrocortisone peak.[6]

Additional red flags

Don't-miss CIRCI red flags

Noradrenaline dose escalating despite fluids + source control → start hydrocortisone 200 mg/day empirically.[6] }
Shock plus unexplained hyperkalaemia, hyponatraemia, hypoglycaemia → think absolute adrenal insufficiency, not just CIRCI — give hydrocortisone 100 mg IV and investigate.[5] }
Patient intubated with etomidate now in refractory shock → drug-induced 11β-hydroxylase block — treat as CIRCI.[7] }
Septic patient on long-term steroids → do NOT stop their steroids; give stress-dose hydrocortisone.[7] }
No vasopressor wean by 72 h of hydrocortisone → the diagnosis is wrong/incomplete — bedside echo, repeat cultures, CT for source, exclude adrenal haemorrhage.[6] }
Skin hyperpigmentation, postural drop, salt-craving history → underlying primary adrenal insufficiency — different management (lifelong replacement).[5] }
Persistent hypotension after bilateral adrenalectomy / on ketoconazole → iatrogenic adrenal suppression — empiric steroids.[8] }

Approach to the viva / written question

How to answer "corticosteroids in septic shock" in a structured viva

Define the entity — CIRCI: inadequate cellular corticosteroid activity for the severity of illness; not absolute deficiency.
State the mechanism — HPA suppression (cytokines, drugs), tissue resistance (GRβ), altered metabolism/CBG.
State the diagnosis — clinical, not biochemical; random/delta cortisol cutoffs (276 / 248 nmol/L) are consensus only; SSC 2021 recommends AGAINST routine ACTH testing.
State the indication — septic shock with ongoing vasopressor requirement despite adequate fluids, source control and antibiotics within 1 h.
State the regimen — hydrocortisone 200 mg/day (continuous or 50 mg q6h); add fludrocortisone 50 µg/day in severe shock (APROCCHSS).
Justify with evidence — cite ADRENAL (no mortality, faster shock reversal), CORTICUS (no mortality, no taper needed), APROCCHSS (mortality benefit with fludrocortisone in severe shock).
Address safety — hyperglycaemia, superinfection, ICU-acquired weakness, GI bleeding; add PPI and glucose control.
Address stopping — taper as vasopressors wean; abrupt stop acceptable (CORTICUS); chronic-steroid patients must transition to their usual dose.

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Prognosis and bottom line

Untreated refractory septic shock with CIRCI carries mortality > 60 %; early empiric hydrocortisone typically weans vasopressors within 24–48 h and, in the sickest subgroup (APROCCHSS), reduces 90-day mortality to ~43 % vs ~49 %.[4]
No long-term steroid dependence is created by a 5–7 day septic-shock course of hydrocortisone — the HPA axis recovers within days to weeks (unlike chronic steroid therapy).
The single defensible position for a fellow: "I start hydrocortisone 200 mg/day, with fludrocortisone 50 µg/day if shock is severe, in vasopressor-dependent septic shock, after adequate resuscitation, source control and antibiotics. I do not use an ACTH test. I taper as vasopressors wean and stop when off vasopressors. I monitor glucose, electrolytes, infection and weakness."[6][4]

References

[1]Venkatesh B, Finfer S, Myburgh J, et al. Adjunctive Glucocorticoid Therapy in Patients with Septic Shock N Engl J Med, 2018.PMID 29347874
[2]Sprung CL, Annane D, Keh D, et al. Hydrocortisone therapy for patients with septic shock N Engl J Med, 2008.PMID 18184957
[3]Annane D, Sébille V, Charpentier C, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock JAMA, 2002.PMID 12186604
[4]Annane D, Renault A, Brun-Buisson C, et al. Hydrocortisone plus Fludrocortisone for Adults with Septic Shock N Engl J Med, 2018.PMID 29490185
[5]Annane D, Pastores SM, Rochwerg B, et al. Guidelines for the Diagnosis and Management of Critical Illness-Related Corticosteroid Insufficiency (CIRCI) in Critically Ill Patients (Part I): Society of Critical Care Medicine (SCCM) and European Society of Intensive Care Medicine (ESICM) 2017 Crit Care Med, 2017.PMID 28938253
[6]Evans L, Rhodes A, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021 Crit Care Med, 2021.PMID 34605781
[7]Marik PE, Pastores SM, Annane D, et al. Recommendations for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients: consensus statements from an international task force by the American College of Critical Care Medicine Crit Care Med, 2008.PMID 18496365
[8]Annane D, Pastores SM, Arlt W, et al. Critical Illness-Related Corticosteroid Insufficiency (CIRCI): A Narrative Review from a Multispecialty Task Force of the Society of Critical Care Medicine (SCCM) and the European Society of Intensive Care Medicine (ESICM) Crit Care Med, 2017.PMID 28938251