12-phase flow (10)

1. 1FRAME
   Cushing syndrome HTN crisis = supraphysiologic cortisol → mineralocorticoid receptor activation (saturates 11β-HSD2) + RAAS + α-adrenergic upregulation → severe HTN + hypokalemia + metabolic alkalosis + hyperglycemia. Pharmacology pivot: MR-blockade FIRST (spironolactone or eplerenone) + K replacement; nicardipine for acute crisis; AVOID isolated ACEi acutely (often borderline K + RAAS-driven); cortisol-lowering medical bridge (ketoconazole, metyrapone, osilodrostat, mifepristone, mitotane) if surgery delayed. Definitive: transsphenoidal pituitary adenectomy for Cushing disease (most common ACTH-dependent); adrenalectomy for adrenal source; ectopic resection for ectopic ACTH (most often SCLC / bronchial carcinoid). Route to parent engine for shared HTN-emergency arc; this dossier owns cortisol-specific pharmacology + biochemical dx + perioperative pathway.
   inputs: sbp, dbp, potassium
   advance: Cushing phenotype identified (clinical + biochemical screen positive)
2. 2ENTRY
   Recognize Cushingoid phenotype + severe HTN + hypokalemia; rapid biochemical screen (24h UFC + midnight salivary + 1 mg DST); assess for opportunistic infection (cortisol-induced immunosuppression); BG check for hyperglycemic emergency
   inputs: age, sbp, potassium
   advance: IV access + cardiac monitor + biochemistry sent + K replacement initiated
3. 3CONTEXT
   Glucocorticoid exposure history (exogenous Cushing iatrogenic — most common cause overall); rate of onset (rapid + cachexia + hypoK = ectopic ACTH suggesting SCLC); known malignancy hx; family hx (MEN1, Carney complex, McCune-Albright); medications (high-dose inhaled fluticasone, intra-articular triamcinolone, megestrol can all cause)
   inputs: age
   advance: context complete
4. 4RED_FLAGS
   Concurrent severe hyperglycemia/HHS (cortisol → insulin resistance → DKA/HHS), opportunistic infection (PJP, CMV, fungal — cortisol immunosuppression, treat empirically if febrile), DVT/PE (cortisol prothrombotic), psychosis/suicide risk (hypercortisolism mood symptoms), severe hypokalemia <2.5 with arrhythmia (Wellens-like ECG, U waves, Torsades), osteoporotic fracture (vertebral compression), pituitary apoplexy if known macroadenoma
   inputs: sbp, glucose, potassium
   actions: htn_emergency
   advance: RED flags screened + K replaced to ≥3.5 + MR-blockade started
5. 5INITIAL_WORKUP
   24h UFC × 2 + midnight salivary cortisol + 1 mg overnight DST (Endocrine Society 2008 PMID 18334580 — at least 2 of 3 abnormal); plasma ACTH; BMP + Mg + glucose + bicarbonate; ECG (LV strain, hypokalemia U waves, Torsades risk); CBC (cortisol → leukocytosis with neutrophilia + eosinopenia); echo for LV strain
   inputs: urine_free_cortisol_24h, midnight_salivary_cortisol, low_dose_dexamethasone_suppression, potassium, creatinine, glucose
   actions: panel.cardiac, panel.renal, panel.hormone
   advance: biochemistry + ACTH sent + crisis stabilized acutely + K ≥3.5
6. 6BRANCHING_WORKUP
   Plasma ACTH stratifies — ACTH suppressed (<5 pg/mL): CT/MRI adrenals → adenoma vs carcinoma vs bilateral hyperplasia; ACTH normal/elevated (>20 pg/mL): MRI pituitary → if microadenoma >6 mm with consistent biochemistry → Cushing disease; if equivocal → INFERIOR PETROSAL SINUS SAMPLING (IPSS — gold standard for pituitary vs ectopic differentiation, central:peripheral ratio >2 baseline or >3 post-CRH = pituitary); if IPSS confirms ectopic → CT chest/abd/pelvis + 68Ga-DOTATATE for SCLC/carcinoid/MTC localization
   inputs: plasma_acth, mri_pituitary_or_ct_adrenal
   advance: source localized + endocrine surgery referral booked
7. 7TREATMENT
   ACUTE CRISIS: nicardipine 5 mg/h IV titrate (predictable, safe in cortisol HTN with renal involvement) + spironolactone 25-100 mg PO (or eplerenone 25-50 mg PO if gynecomastia concern) + aggressive K replacement (KCl IV 10-20 mEq/h via central line if K <3, oral KCl 40-80 mEq for milder); IV magnesium (Mg almost always low coexisting); AVOID isolated ACEi/ARB acutely (often borderline K — start once K stable). MEDICAL CORTISOL-LOWERING BRIDGE if surgery delayed: ketoconazole 400-1200 mg/d (CYP17/CYP11B inhibitor, hepatotoxic monitor LFTs); metyrapone 250-1000 mg q6h (11β-hydroxylase inhibitor); osilodrostat 2-30 mg BID (newer 11β-hydroxylase inhibitor, LINC-3 PMID 31523029); mifepristone 300-1200 mg/d (GR antagonist, FDA-approved Korlym for Cushing-induced hyperglycemia); mitotane 0.5-8 g/d (adrenolytic, for adrenal carcinoma). DEFINITIVE: transsphenoidal pituitary adenectomy for Cushing disease (≥80% remission high-volume center); laparoscopic unilateral adrenalectomy for adenoma; bilateral adrenalectomy for refractory ACTH-dependent or ectopic without source; ectopic source resection for SCLC/carcinoid.
   inputs: sbp, dbp, potassium, creatinine
   advance: BP at target (<160/100) + K ≥3.5 + MR-blockade established + surgical/medical pathway initiated
8. 8DISPOSITION
   ICU for severe crisis with hypokalemic arrhythmia, HHS, or pituitary apoplexy; step-down for stable on PO MR-blockade; endocrine + endocrine surgery + neurosurgery (if pituitary) consults; medical oncology if ectopic ACTH from SCLC/carcinoid
   advance: Unit assigned + endocrine + surgical consults booked + glucocorticoid replacement plan documented for postop
9. 9MONITORING
   Continuous ECG (hypokalemia Torsades risk); q4-6h K, Mg, glucose during acute crisis; daily LFTs if on ketoconazole; q6-12h cortisol if on metyrapone or osilodrostat (titrate to mid-normal); daily weight + BP; postop monitoring for ADRENAL INSUFFICIENCY (after pituitary or unilateral adrenal surgery — contralateral often suppressed) → IV hydrocortisone 100 mg IV → 50 mg q6h taper; monitor glucose normalization
   inputs: potassium, glucose, creatinine
   actions: panel.cardiac
   advance: BP stable + electrolytes stable + postop adrenal axis recovery monitored
10. 10FOLLOWUP
    Postop morning cortisol day 1-3 (suppression to <1.8 mcg/dL = remission); if <5 — physiologic hydrocortisone replacement 15-25 mg/d divided BID (or 10/5 split); follow ACTH stim test annually until HPA recovery (usually 6-18 mo); annual UFC + ACTH for recurrence (10-15% recurrence at 10 years for Cushing disease); cardiovascular risk reassessment (cardiometabolic legacy effect persists years after cure); bone density DEXA + osteoporosis treatment; psychiatric follow-up (mood symptoms slow recovery); diabetes management (often resolves but chronic GI insulin resistance may persist)
    advance: biochemical remission confirmed + glucocorticoid replacement plan + lifelong endocrine surveillance booked