When to intubate in GCS?

GCS ≤ 8 requires intubation for airway protection. The patient cannot protect their own airway at this level of consciousness. Motor score is the most prognostically important component.

What is the best initial fluid for sepsis resuscitation?

Lactated Ringer's (LR) is the preferred resuscitation fluid. The SMART trial (2018) showed balanced crystalloids reduced death, new renal failure, and persistent renal dysfunction compared to normal saline.

When to start vasopressors in septic shock?

Start norepinephrine (first-line vasopressor) if MAP remains < 65 mmHg after initial 30 mL/kg crystalloid resuscitation, or earlier if patient is profoundly hypotensive. Do not delay pressors to complete full fluid resuscitation.

Why can serum uric acid be normal during acute gout?

During acute inflammation, IL-6 increases renal urate excretion and redistributes urate from plasma to tissues. Up to 40% of acute gout flares have normal serum uric acid. Joint aspiration with polarized microscopy is needed for definitive diagnosis.

How do you distinguish lupus flare from infection in SLE?

Key clues: CRP is low/normal in flare but elevated in infection. Complement (C3/C4) drops in flare but is normal/elevated in infection. Procalcitonin is elevated in bacterial infection but normal in flare. Anti-dsDNA rises in flare, stable in infection.

What is the difference between DKA and HHS?

DKA features acidosis (pH 600), hyperosmolality (> 320), and minimal ketosis -typically in Type 2 DM. DKA requires insulin drip; HHS requires aggressive fluid resuscitation first.

When to give tPA in acute ischemic stroke?

IV alteplase (tPA) can be given within 4.5 hours of last known well time in eligible patients. CT head must rule out hemorrhage first. For large vessel occlusion, mechanical thrombectomy can be performed up to 24 hours with favorable imaging.

What antibiotics for community-acquired pneumonia?

Inpatient non-ICU: ceftriaxone + azithromycin. ICU: ceftriaxone + azithromycin (add vancomycin if MRSA risk). Outpatient healthy: amoxicillin. Outpatient with comorbidities: augmentin + azithromycin or respiratory fluoroquinolone. Duration: 5 days if clinically stable for 48 hours.

How to interpret iron studies?

Iron deficiency: low ferritin (< 30), high TIBC, low iron, low transferrin saturation (< 20%). Anemia of chronic disease: normal/high ferritin (acute phase reactant), low TIBC, low iron. A ferritin of 50-100 in an inflamed patient may still represent iron deficiency.

What is the correction rate for hyponatremia?

Correct sodium no more than 8 mEq/L in 24 hours to avoid osmotic demyelination syndrome (ODS). For symptomatic severe hyponatremia with seizures, give 3% hypertonic saline 100-150 mL bolus over 10-20 minutes. If overcorrected, use D5W + DDAVP rescue protocol.

When to start antibiotics in meningitis?

Within 30-60 minutes. Do NOT delay antibiotics for LP or CT. Draw blood cultures, start empiric antibiotics (vancomycin + ceftriaxone ± ampicillin if > 50 or immunocompromised), then perform LP when possible. Dexamethasone should be given before or with the first antibiotic dose.

DOACs vs warfarin in antiphospholipid syndrome?

DOACs are contraindicated in APS. The TRAPS trial (2018) showed rivaroxaban was inferior to warfarin with more thrombotic events in triple-positive APS patients. Warfarin with INR target 2-3 is the standard for APS, indefinitely.

How to manage scleroderma renal crisis?

ACE inhibitors (captopril) are life-saving -start immediately and titrate aggressively. Do NOT hold for rising creatinine. Steroids > 15 mg prednisone per day precipitate scleroderma renal crisis. ARBs are NOT a substitute -evidence is only for ACEi.

What are the 4 pillars of heart failure treatment?

Guideline-directed medical therapy (GDMT) for HFrEF: (1) ARNI or ACEi/ARB, (2) beta-blocker (carvedilol, metoprolol succinate, or bisoprolol), (3) MRA (spironolactone or eplerenone), (4) SGLT2 inhibitor (dapagliflozin or empagliflozin). All four should be initiated and titrated to target doses.

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Endocrine

Cushing's Syndrome

Chronic cortisol excess. Most common cause: exogenous steroids. Most common endogenous cause: pituitary adenoma (Cushing's disease). Systematic biochemical → localization approach.

🔍 Overview

Overview

Cushing's syndrome = clinical manifestations of chronic cortisol excess. Exogenous (iatrogenic steroids) is by far the most common cause overall. Among endogenous causes: Cushing's disease (ACTH-secreting pituitary adenoma, ~70%), ectopic ACTH (small cell lung cancer, carcinoid, ~15%), adrenal adenoma/carcinoma (~15%). Classic features: central obesity, moon facies, dorsal fat pad (buffalo hump), violaceous striae (> 1 cm wide), proximal muscle weakness, easy bruising, hyperglycemia, HTN, osteoporosis, hirsutism, menstrual irregularity, depression/psychosis. Key teaching point: the workup is a 3-step process -(1) confirm hypercortisolism, (2) determine ACTH dependence, (3) localize the source.

🧪 Workup

Workup

Step 1 -Confirm hypercortisolism (need 2 of 3 tests positive):
- 24-hour urine free cortisol (× 2) -elevated > 3× ULN is virtually diagnostic. Mild elevations can be false positive (pseudo-Cushing: alcoholism, depression, obesity).
- Late-night salivary cortisol (× 2) -loss of diurnal cortisol rhythm. Cortisol should nadir at 11 PM. Elevated = abnormal. Convenient outpatient test.
- 1 mg overnight dexamethasone suppression test (DST) -give dex 1 mg PO at 11 PM → check 8 AM cortisol. Normal: cortisol < 1.8 mcg/dL (suppressed). Cushing's: cortisol fails to suppress (> 1.8). Nieman, 2008
Step 2 -ACTH level (determine dependence):
- ACTH elevated (> 20 pg/mL) → ACTH-dependent: pituitary (Cushing's disease) vs ectopic ACTH
- ACTH suppressed (< 5 pg/mL) → ACTH-independent: adrenal source (adenoma, carcinoma, bilateral hyperplasia)
Step 3 -Localize:
- ACTH-dependent: MRI pituitary (60% show adenoma). If MRI negative or equivocal → inferior petrosal sinus sampling (IPSS) with CRH stimulation (gold standard to confirm pituitary vs ectopic).
- ACTH-independent: CT adrenals (adenoma vs carcinoma vs bilateral hyperplasia)
- Ectopic ACTH: CT chest/abdomen (small cell, carcinoid, thymic tumors). Octreotide scan. PET/CT.

Exogenous Cushing's: Taper steroids as disease allows. Never stop abruptly (adrenal suppression → adrenal crisis). Taper over weeks-months depending on duration.

Cushing's disease (pituitary): Transsphenoidal surgery (TSS) -first-line. Cure rate 65-90% for microadenomas. Post-op: patients develop adrenal insufficiency (need hydrocortisone replacement until HPA axis recovers -months to years). If surgery fails: repeat TSS, radiation, bilateral adrenalectomy, or medical therapy.

Adrenal adenoma: Laparoscopic adrenalectomy -curative. Post-op AI (contralateral adrenal suppressed).

Adrenal carcinoma: Surgical resection + mitotane (adrenolytic agent). Poor prognosis.

Ectopic ACTH: Treat underlying tumor. Medical cortisol reduction while awaiting definitive therapy.

Medical therapy (cortisol-lowering agents): ketoconazole (steroidogenesis inhibitor), metyrapone (11β-hydroxylase inhibitor), osilodrostat [LINC-3, 2022], mifepristone (glucocorticoid receptor antagonist -for hyperglycemia), pasireotide (somatostatin analog for Cushing's disease). SEISMIC, 2012

Monitoring

💊 Medications

Medications

Drug	Dose	Route	Notes
Ketoconazole	200-400 mg BID-TID	PO	Steroidogenesis inhibitor. Most commonly used medical therapy. Monitor LFTs (hepatotoxicity). QTc prolongation. Drug interactions (CYP3A4).
Metyrapone	250-750 mg TID-QID	PO	11β-hydroxylase inhibitor. Blocks cortisol synthesis. Can cause hyperandrogenism (hirsutism, acne). Monitor cortisol + ACTH.
Osilodrostat	2-7 mg BID	PO	11β-hydroxylase inhibitor. Newer. LINC-3, 2022. QTc monitoring. Adrenal insufficiency risk.
Mifepristone	300-1200 mg daily	PO	GR antagonist. FDA-approved for Cushing's-associated hyperglycemia. Cannot monitor cortisol (blocked receptor). Monitor clinically. SEISMIC, 2012
Pasireotide	0.6-0.9 mg SQ BID	SQ	Somatostatin analog for Cushing's disease. Hyperglycemia is major side effect (up to 70%).
Mitotane	2-6 g/day (titrate)	PO	Adrenolytic -for adrenal carcinoma. Causes AI (needs replacement). Monitor levels (target 14-20 mcg/mL). Teratogenic.

🏥 Rounds

Pimp Questions

❓ What are the 3 steps in the Cushing's workup?

Step 1: Confirm hypercortisolism -2 of 3 positive: 24h UFC, late-night salivary cortisol, 1 mg DST. Step 2: ACTH level -high = ACTH-dependent (pituitary or ectopic), low = ACTH-independent (adrenal). Step 3: Localize -MRI pituitary (if ACTH-dependent) or CT adrenals (if ACTH-independent). IPSS if pituitary MRI equivocal. Nieman, 2008

❓ What is inferior petrosal sinus sampling (IPSS)?

Gold standard to differentiate pituitary vs ectopic ACTH. Catheters placed in bilateral inferior petrosal sinuses (drain the pituitary). Compare petrosal ACTH to peripheral ACTH before and after CRH stimulation. Central-to-peripheral ACTH ratio ≥ 2 (basal) or ≥ 3 (post-CRH) = pituitary source. If ratio < 2 → ectopic ACTH. Indicated when MRI is negative or equivocal.

❓ Why do patients develop adrenal insufficiency after successful pituitary surgery?

Chronic ACTH excess from the pituitary adenoma → chronic cortisol excess → suppresses CRH and the normal corticotrophs (negative feedback). When the adenoma is removed, the remaining normal pituitary tissue is atrophied and cannot produce adequate ACTH → secondary adrenal insufficiency. HPA axis recovery takes 6-18 months. Patients need hydrocortisone replacement until the axis recovers.

❓ What features help distinguish Cushing's from simple obesity?

Cushing's-specific features: (1) Proximal muscle weakness (can't rise from chair without arms -obesity alone doesn't cause this), (2) wide (> 1 cm) violaceous striae (obesity has narrow, pink striae), (3) easy bruising + skin thinning, (4) new-onset diabetes + HTN + osteoporosis in a young person, (5) facial plethora. Weight gain in Cushing's is classically central with thin extremities (muscle wasting). Obese patients have more generalized fat distribution.

❓ Why can't you monitor cortisol levels on mifepristone?

Mifepristone is a glucocorticoid receptor antagonist -it blocks the receptor, not cortisol production. In fact, cortisol levels rise on mifepristone (loss of negative feedback → ACTH increases → cortisol increases). You must monitor clinical response (glucose, weight, striae, weakness) and urinary cortisol will be misleadingly HIGH. This makes dose titration challenging.

Clinical Examples

📋 Case 1, Cushing's Disease (Pituitary Adenoma)

Patient: 36F with 25 lb central weight gain, new T2DM, HTN, wide purple striae, easy bruising, and proximal weakness × 10 months. Moon facies, dorsocervical fat pad. No exogenous steroids.

Key findings: 24h UFC 420 mcg (4× ULN), late-night salivary cortisol elevated, 1 mg DST cortisol 14.2 (failed suppression). ACTH 72 pg/mL (elevated → ACTH-dependent). MRI pituitary: 7 mm adenoma.

Management:

Confirm ACTH-dependent Cushing's: high-dose DST (8 mg) → > 50% suppression supports pituitary source
Referral for transsphenoidal surgery (TSS), first-line, cure rate 70-90% for microadenomas
Pre-op: insulin for hyperglycemia, VTE prophylaxis (Cushing's is hypercoagulable), PCP prophylaxis with TMP-SMX
Post-op: expect adrenal insufficiency (start hydrocortisone 15-20 mg/day, taper over months)
If TSS fails or recurrence: repeat surgery, radiation, bilateral adrenalectomy, or medical therapy (ketoconazole, osilodrostat)

Teaching point: After successful TSS, cortisol should be undetectable (< 2 mcg/dL), this confirms cure. Patients will need glucocorticoid replacement for 6-18 months until the suppressed HPA axis recovers.

📋 Case 2, Ectopic ACTH (Small Cell Lung Cancer)

Patient: 58M smoker with rapid-onset HTN, hypokalemia (K⁺ 2.4), hyperglycemia (glucose 380), and proximal weakness over 6 weeks. Hyperpigmented. No classic Cushingoid body habitus (too rapid for fat redistribution).

Key findings: ACTH 280 pg/mL (markedly elevated), UFC > 1000 mcg. High-dose DST: no suppression. CT chest: 3 cm RLL mass with hilar lymphadenopathy. Consistent with ectopic ACTH from SCLC.

Management:

Aggressive K⁺ replacement + spironolactone (mineralocorticoid excess from cortisol overwhelming 11β-HSD2)
Ketoconazole 200 mg TID or metyrapone to rapidly lower cortisol (medical adrenalectomy)
Oncology: staging and treatment of SCLC (chemo ± radiation)
If refractory hypercortisolism: bilateral adrenalectomy (definitive but causes permanent AI)
VTE prophylaxis, extreme hypercortisolism is profoundly prothrombotic

Teaching point: Ectopic ACTH presents differently from pituitary Cushing's: rapid onset, severe hypokalemia, very high ACTH (> 200), and hyperpigmentation. The patient often looks sick, not Cushingoid, because fat redistribution takes months.

📋 Case 3, Iatrogenic Cushing's (Exogenous Steroids)

Patient: 65F with RA on prednisone 20 mg daily × 2 years. Moon facies, central obesity, osteoporosis (T-score -3.2), T2DM, recurrent oral candidiasis. Rheumatologist requests steroid taper advice.

Key findings: Iatrogenic Cushing syndrome, the #1 cause of Cushing's overall. Chronic exogenous steroids have suppressed the HPA axis. Abrupt discontinuation → adrenal crisis.

Management:

Slow taper: reduce by 2.5 mg q2-4 weeks until physiologic dose (5 mg prednisone ≈ 20 mg hydrocortisone)
Below physiologic dose: switch to hydrocortisone 10-15 mg/day and taper by 2.5 mg q2-4 weeks
ACTH stimulation test before final discontinuation, if cortisol > 18 mcg/dL, axis has recovered
DMARD optimization for RA (methotrexate, biologics) to enable steroid discontinuation
Address complications: DEXA + bisphosphonate for osteoporosis, diabetes management, PCP prophylaxis if > 20 mg/day

Teaching point: Exogenous steroids at any dose for > 3 weeks can suppress the HPA axis. Always taper, never stop abruptly. Patients on chronic steroids need stress-dose steroids for surgery or acute illness until axis recovery is confirmed.

Sample Presentation

Ms. Rivera is a 38-year-old woman with new-onset diabetes, HTN, 30 lb weight gain (central), wide purple striae on abdomen, and proximal weakness × 8 months. No exogenous steroid use. Labs: 24h UFC 380 mcg (3× ULN), late-night salivary cortisol 0.85 mcg/dL (elevated), 1 mg DST cortisol 12.4 (failed suppression). ACTH 68 pg/mL (elevated). MRI pituitary: 8 mm left-sided adenoma.

Key Points: Classic Cushing's disease -confirmed hypercortisolism (2/3 tests positive), ACTH-dependent, pituitary adenoma on MRI. Refer for TSS. Pre-op: control hyperglycemia (insulin), VTE prophylaxis (hypercoagulable), PCP prophylaxis if severely Cushingoid, address osteoporosis. Post-op: expect AI (start hydrocortisone replacement).

24h urine free cortisol -to monitor treatment response. Target: normalization.
AM cortisol + ACTH -post-TSS: check day 1-3. Undetectable cortisol (< 2) = successful surgery. Patient needs hydrocortisone replacement.
Morning cortisol off replacement -periodically to assess HPA axis recovery (may take 6-18 months post-surgery). Cosyntropin stim test when cortisol approaches normal.
LFTs q2-4 weeks on ketoconazole
ECG (QTc) on ketoconazole, osilodrostat
Blood glucose -Cushing's causes insulin resistance. May need insulin during active disease. Hyperglycemia also a major side effect of pasireotide.
DEXA scan -osteoporosis screening (cortisol excess → bone loss)
MRI pituitary annually × 5 years post-TSS (recurrence monitoring)

Monitoring

📋 Summary

Summary

Step 1

Confirm: 24h UFC + salivary cortisol + 1mg DST (need 2/3 positive)

Step 2

ACTH: High → pituitary or ectopic. Low → adrenal.

Step 3

Localize: MRI pituitary (high ACTH) or CT adrenals (low ACTH). IPSS if equivocal.

Treatment

TSS for Cushing's disease (cure 65-90%). Adrenalectomy for adrenal tumors. Medical if inoperable.

Post-Op

Expect AI → hydrocortisone until HPA recovery (6-18 months). Check AM cortisol periodically.

Pearl

Wide purple striae + proximal weakness = Cushing's, not obesity. #1 cause overall = exogenous steroids.

📄 One Pager

One-Pager

Cushing's Syndrome

Confirm → ACTH → Localize

3-Step Workup

1. Confirm: 24h UFC, late-night salivary cortisol, 1mg DST (2/3 positive). 2. ACTH: high = pituitary/ectopic, low = adrenal. 3. Localize: MRI pituitary or CT adrenals. IPSS if MRI equivocal.

Trials

Nieman 2008 (Endocrine Society Guidelines) · LINC-3 2022 (osilodrostat) · SEISMIC 2012 (mifepristone)