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Heart Block (Atrioventricular Block)

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Anatomy of the Conduction System

• The AV node
• The His bundle itself
• The bundle branches (intraventricular/infranodal block)

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Classification

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First-Degree AV Block

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Second-Degree AV Block

Type I - Mobitz I (Wenckebach)

• Progressive lengthening of the PR interval until a P wave is blocked (dropped beat), then the cycle resets
• The R-R interval actually shortens before the dropped beat (increment in PR gets smaller each cycle)
• Reflects progressive fatigue of conduction within the AV node
• Often associated with increased vagal tone, inferior MI, or drug effects (digoxin, beta-blockers)
• Generally benign; rarely progresses to complete block

Type II - Mobitz II

• Fixed PR interval with sudden, unexpected failure of a P wave to conduct
• Located below the AV node (His bundle or bundle branches)
• QRS is often wide (bundle branch block pattern) indicating extensive infranodal disease
• Associated with anterior MI; carries a high risk of progressing to complete heart block
• Requires pacemaker implantation

2:1 AV Block

• A special case where every other P wave is blocked - cannot be classified as Mobitz I or II on ECG alone
• Narrow QRS with slower atrial rate suggests nodal (Mobitz I); wide QRS suggests infranodal (Mobitz II)

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Third-Degree (Complete) AV Block

• Junctional escape (AV node/His bundle origin): rate 40-60 bpm, narrow QRS - more stable
• Ventricular escape (below the His): rate 20-40 bpm, wide QRS - less reliable, high risk of asystole

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Etiology

1. Fibrosis/degeneration of the conduction system (most common in the elderly - Lenegre's disease and Lev's disease)
2. Ischemic heart disease - coronary insufficiency causing ischemia of the AV node or bundle
3. Medications - beta-blockers, calcium channel blockers (verapamil, diltiazem), digoxin, adenosine, amiodarone
4. Sarcoidosis - accounts for ~34% of unexplained 2nd/3rd degree AV block in patients under 60; 27% of these later develop VT or heart failure
5. Inflammatory/infectious - rheumatic fever, Lyme disease, viral myocarditis, diphtheria, endocarditis
6. Compression by scar tissue or calcified cardiac structures
7. Hyperkalemia and other electrolyte disturbances
8. Valvular heart disease - calcification extending into the conduction system
9. Cardiac procedures - transcatheter aortic valve implantation (TAVI), cardiac surgery
10. Vagal stimulation - carotid sinus hypersensitivity, increased vagal tone
11. Neuromuscular diseases - myotonic dystrophy, Kearns-Sayre syndrome, Erb dystrophy
12. Hypothyroidism, amyloidosis

Note: Most patients with AV block attributed to verapamil, diltiazem, or beta-blockers have underlying conduction disease - >80% will experience AV block even off the medications.

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Clinical Features

• 1st degree: Asymptomatic; incidental ECG finding
• 2nd degree Mobitz I: Usually asymptomatic; may feel palpitations from "dropped beats"
• 2nd degree Mobitz II / 3rd degree: Symptomatic bradycardia - fatigue, dyspnea, presyncope, syncope (Stokes-Adams attacks), hypotension, angina, or sudden death

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Diagnosis

• Third-degree AV block on any monitoring
• Advanced second-degree AV block (≥2 consecutively blocked P waves) with: symptoms, ventricular arrhythmias, asystole ≥3 seconds, escape rate <40 bpm, or infranodal escape rhythm
• Symptomatic second-degree AV block (regardless of type)

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Management

Acute / Transient

• Atropine (0.5-1 mg IV) for symptomatic nodal block (1st or 2nd degree Mobitz I)
• Temporary transvenous pacing for hemodynamically unstable complete heart block or Mobitz II
• Treat reversible causes: withdraw offending drugs, correct hyperkalemia, treat ischemia/infection

Permanent Pacemaker - Class I Indications (pacemaker required)

Permanent Pacemaker - Class IIa Indications (reasonable)

• Persistent 3rd-degree AV block with escape rate >40 bpm in asymptomatic adults without cardiomegaly
• Asymptomatic 2nd-degree infranodal AV block
• Asymptomatic Mobitz II with narrow QRS
• 1st or 2nd degree AV block with pacemaker-syndrome-like symptoms
• Bifascicular block with syncope (other causes excluded) or HV interval ≥100 ms

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Key Distinguishing Points

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Atrial Fibrillation (AF)

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Definition and ECG Features

• No discernible P waves - replaced by a chaotic, irregular fibrillatory baseline (best seen in V1 and inferior leads)
• Irregularly irregular QRS complexes - the hallmark finding
• Ventricular rate in adults is typically 150-170 bpm (rarely exceeds this unless an accessory pathway is present)

Important differential: AF can mimic a regular rhythm when complete AV block or VT coexists. A ventricular rate >200 bpm strongly suggests an accessory pathway (e.g., WPW) - do NOT use nodal blocking agents in that situation, as they can paradoxically accelerate ventricular response and precipitate VF.

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Classification

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Pathophysiology

1. Triggers

2. Substrate

• Multiple-wavelet reentry (Moe's hypothesis) - multiple simultaneous reentrant circuits
• Rotor/focal driver activity - a small number of high-frequency rotating circuits or focal sources that drive the rest of the atrium into fibrillation
• Atrial remodeling - prolonged AF causes electrical remodeling (shortened atrial action potential due to downregulation of L-type Ca²+ current) and structural remodeling (fibrosis, gap junction remodeling), both of which perpetuate AF ("AF begets AF")

Ion Channel Abnormalities

• Gain-of-function mutations in IK (delayed rectifier K+ channels) shorten APD and atrial refractoriness, facilitating fibrillatory activity
• Mutations in KCNJ2, KCNA5, and the connexin-40 gene (GJA5) are linked to familial AF
• Genome-wide association studies have identified variants in HCN4, PRRX1, and CAV1

Hemodynamic Consequences

• Loss of atrial kick: In normal individuals, atrial contraction contributes ~15% of ventricular filling - this is usually well tolerated. In patients with stiff, non-compliant ventricles (aortic stenosis, hypertrophic cardiomyopathy, long-standing hypertension), up to 40% of filling depends on atrial contraction - these patients may develop acute pulmonary edema when AF starts
• Tachycardia-induced cardiomyopathy: Sustained rapid ventricular rates (>120 bpm for weeks) can cause biventricular dysfunction, which is often reversible with rate/rhythm control

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Causes and Risk Factors

• Hypertensive heart disease (most common)
• Ischemic heart disease / CAD
• Valvular disease (especially mitral)
• Cardiomyopathy (dilated, hypertrophic, restrictive)
• Heart failure (~one-third of HF patients have AF)
• Pericarditis
• Sick sinus syndrome
• WPW / accessory pathway
• Myocardial contusion / cardiac surgery

• Hyperthyroidism
• Obstructive sleep apnea
• Obesity
• Diabetes mellitus
• Pulmonary embolism
• Catecholamine excess

• Acute alcohol intoxication ("holiday heart")
• Long-term significant alcohol use
• Vagally-mediated AF (post-exercise, after large meals)
• Excessive caffeine (rare)
• About 20% of patients have no identifiable comorbidity ("lone AF")

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Clinical Manifestations

• Palpitations (most common in young patients; less prominent with chronic AF)
• Dyspnea, chest pain/discomfort
• Fatigue, reduced exercise tolerance
• Lightheadedness / presyncope
• Syncope - usually due to a conversion pause when AF terminates

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Complications

1. Thromboembolism / Stroke

• Non-valvular AF is associated with a 5-fold increase in stroke risk
• Primary mechanism: thrombus formation in the left atrial appendage (LAA) during stasis, followed by embolization
• Even subclinical ("silent") AF carries a 2.5-fold increased risk of ischemic stroke
• Risk is independent of AF pattern (paroxysmal = persistent in stroke risk)
• ~12% of embolic events are extracranial (~70% to limbs, remainder to mesenteric circulation)
• AF is associated with a 1.4-fold higher risk of cognitive impairment and dementia

2. Heart Failure

• Tachycardia-induced cardiomyopathy with ventricular rates >120 bpm

3. Increased Mortality

• AF in older adults associated with decreased physical performance, shorter disability-free survival, and increased mortality

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Stroke Risk Assessment: CHA₂DS₂-VASc Score

• Score ≥2: Anticoagulation indicated (DOAC preferred over warfarin)
• Score 1: Anticoagulation or no therapy (shared decision with patient)
• Score 0: No therapy required
• All patients ≥75 years automatically score ≥2 and are candidates for anticoagulation regardless of AF pattern

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Diagnosis and Initial Workup

• ECG: Irregularly irregular rhythm, absent P waves, fibrillatory baseline - minimum 2 minutes required for diagnosis by convention
• Blood work: CBC, electrolytes, creatinine, TSH (thyroid-stimulating hormone), glucose
• Echocardiogram: Assess for ventricular dysfunction, valvular disease, left atrial size
• Stress test: Only if clinical suspicion of ischemia; not required routinely
• Transesophageal echocardiogram (TEE): Required before cardioversion if AF duration >48 hours without adequate anticoagulation - to exclude LAA thrombus

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Management

Step 1 - Assess and Treat Reversible Causes

Step 2 - Anticoagulation (guided by CHA₂DS₂-VASc)

• Dabigatran (direct thrombin inhibitor)
• Rivaroxaban, apixaban, edoxaban (factor Xa inhibitors)
• Dose adjustment required based on age, weight, renal function (especially for dabigatran and edoxaban)
• Warfarin (INR 2-3): reserved for mechanical valves; bioprosthetic valve patients may use rivaroxaban

• Patients with AF + stable CAD: DOAC monotherapy preferred; if stented, DOAC + P2Y12 inhibitor (clopidogrel) without aspirin has lower bleeding risk
• Mechanical valves: warfarin required (DOACs contraindicated)
• Patients unable to take anticoagulation: LAA occlusion (WATCHMAN device) is a non-inferior alternative

Step 3 - Rate Control vs. Rhythm Control

• Lenient control (<110 bpm at rest) is acceptable for asymptomatic patients with preserved LV function
• Strict control (<80 bpm at rest) is a Class IIa recommendation when symptoms persist

• Rate control fails to relieve symptoms
• Patient is hemodynamically unstable (cardiovert immediately)
• First episode with reasonable chance of success
• Patient preference

• Flecainide (300 mg PO - "pill-in-the-pocket") or propafenone (600 mg PO) - for paroxysmal AF without structural heart disease
• Amiodarone - preferred in structural heart disease or HF
• Ibutilide IV - for acute cardioversion in hospital setting

• Synchronized DC shock (typically 100-360 J biphasic)
• If AF duration >48 hours: TEE to exclude LAA thrombus first, OR anticoagulate for ≥3 weeks before cardioversion (and continue for ≥4 weeks after, regardless of CHA₂DS₂-VASc - due to "stunning" of atrial mechanical function)
• For AF ≤48 hours or patient on therapeutic anticoagulation: cardioversion can proceed without TEE

• About 50% of acute-onset AF converts spontaneously within 48-96 hours; a brief period of rate control with delayed cardioversion (if no spontaneous conversion by 48 hours) is as effective as early cardioversion at 1 month

Step 4 - Long-Term Rhythm Control Strategy

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Catheter Ablation

• Success rates: 75-85% at 1 year for paroxysmal AF; 60-75% for persistent AF
• Reduces AF recurrence by 50-70% compared with antiarrhythmic drugs alone in symptomatic paroxysmal AF
• First-line ablation (without prior antiarrhythmic drug failure) results in similar or better outcomes and may be preferred
• For AF with heart failure: catheter ablation (but NOT antiarrhythmic drugs) is associated with reduced all-cause mortality and is the preferred initial therapy
• Early intervention may reduce progression from paroxysmal to permanent AF and reduce stroke/death

• Atrial perforation / cardiac tamponade
• Thromboembolism
• Atrioesophageal fistula (rare but life-threatening)
• Phrenic nerve injury
• Pulmonary vein stenosis
• Left atrial macro-reentrant tachycardia (requiring repeat ablation)

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Ashman Phenomenon

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AF in Special Contexts

• AF with anterograde accessory pathway conduction can produce rapid, irregularly irregular wide-complex tachycardia at >200 bpm
• AV nodal blocking agents (beta-blockers, calcium channel blockers, digoxin, adenosine) are contraindicated - they block the AV node but spare the accessory pathway, potentially accelerating ventricular response → VF
• Treatment: IV procainamide or ibutilide; electrical cardioversion if unstable

• Very common (~30-50% of CABG patients)
• Usually transient; beta-blockers and amiodarone are used for prophylaxis

• AF is poorly tolerated due to heavy dependence on atrial kick
• Disopyramide and amiodarone are preferred antiarrhythmic agents; ablation considered for refractory cases

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Prognosis

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• The 2024 ESC Guidelines for AF management are the most current practice guidelines [PMID: 39210723]
• A meta-analysis of RCTs ([PMID: 38727662], JACC Clin Electrophysiol 2024) compared rhythm vs. rate control strategies
• For AF + stable coronary disease: anticoagulation alone (without antiplatelet) is supported by recent meta-analysis data [PMID: 39918465]

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1. JVP Waves (Jugular Venous Pulse)

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Normal JVP Waveform Components

In normal persons, the a wave is larger than the v wave.

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Abnormalities of Each Component

A Wave Abnormalities

Key clinical pearl: Variable cannon a waves in bradycardia = complete heart block. Regular cannon a waves in narrow tachycardia = AVNRT. Cannon a waves in wide-complex tachycardia = ventricular tachycardia (not aberrancy).

X Descent Abnormalities

V Wave Abnormalities

Y Descent Abnormalities

Special Signs

• Kussmaul's sign: Rise (or failure to fall) in JVP with inspiration. Classic in constrictive pericarditis; also in restrictive cardiomyopathy, massive PE, RV infarction, advanced LV systolic HF
• Abdominojugular reflux: Sustained rise >3 cm in JVP with firm RUQ pressure for >15 sec = positive; predicts pulmonary artery wedge pressure >15 mmHg in HF
• Normal response: JVP falls ≥3 mmHg within 15 seconds

Disease-Specific JVP Patterns Summary

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2. NT-proBNP (N-Terminal Pro-Brain Natriuretic Peptide)

Biochemistry

• BNP (32 aa) - the biologically active peptide
• NT-proBNP (76 aa) - the inactive N-terminal fragment

Clinical Actions of BNP

• Promotes natriuresis and diuresis
• Vasodilation
• Inhibits the renin-angiotensin-aldosterone system
• Anti-fibrotic, anti-hypertrophic effects

Diagnostic Use

Diagnosing Acute Heart Failure in the ED (Acute Dyspnea)

Age-Stratified NT-proBNP Cutoffs (ICON study)

Outpatient Setting

• NT-proBNP values are considerably lower in stable outpatients
• ED cutoffs should NOT be applied; use lower thresholds optimized for negative predictive value (ruling out HF)

Prognostic Use

• BNP/NT-proBNP levels provide prognostic information across all ACC/AHA stages of HF, even after adjusting for history, physical exam, echo, and exercise testing
• Serial measurements add incremental prognostic value
• Failure to decrease BNP/NT-proBNP by ≥30% at hospital discharge predicts higher morbidity/mortality
• Chronically elevated or rising natriuretic peptide levels = high-risk patient
• HF therapies that lower natriuretic peptides are associated with improved prognosis

Factors Affecting Levels

BNP is sensitive (~95-99%) but less specific (~50-60%) for HF. Always interpret in clinical context - natriuretic peptides supplement but do not replace clinical judgment.

Key Distinction: BNP vs. NT-proBNP

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3. PSVT (Paroxysmal Supraventricular Tachycardia)

Definition

Mechanisms and Types

AVNRT (most common)

• Slow pathway: slower conduction, shorter refractory period
• Fast pathway: faster conduction, longer refractory period

ECG Features

A pseudo-R' in V1 or pseudo-S in inferior leads (retrograde P distorting the QRS end) is a classic ECG sign of AVNRT.

Clinical Features

• More common in females
• Peak incidence in late teens and young adults
• Majority without structural heart disease
• Symptoms: palpitations (prominent, often "pounding in throat" due to cannon a waves), lightheadedness, dyspnea, chest discomfort, anxiety, near-syncope
• Patients can often describe exact onset and self-termination

Management

Acute Management

• Valsalva maneuver - patient bears down; modified supine Valsalva (legs elevated after straining) has higher success (~43% vs ~17%)
• Carotid sinus massage - only if no carotid bruits, no prior stroke history
• Success is often related to how early in the episode they are applied

• Dose: 6 mg rapid IV bolus; repeat with 12 mg if no effect
• Mechanism: transiently blocks AV node conduction, terminating AV-node-dependent tachycardias
• Onset: within seconds; half-life: ~10 sec
• Side effects: chest pain, dyspnea, anxiety, flushing (transient, ~10-15 sec)
• Contraindications: cardiac transplant (hypersensitivity), severe asthma (relative), WPW with anterograde pre-excitation (may precipitate AF → VF)
• Precipitates AF in ~15% of cases - use cautiously in WPW
• Diagnostic use: if adenosine produces AV block but tachycardia continues (ongoing P waves exposed), the mechanism is AT or atrial flutter - not AV-dependent reentry

• Verapamil 5-10 mg IV, or diltiazem IV
• Metoprolol IV
• May cause hypotension; have longer duration of action than adenosine
• Can also be given orally as "pill-in-the-pocket" for out-of-hospital self-treatment

Chronic/Long-Term Management

• Catheter ablation (preferred for recurrent symptomatic PSVT):
  • AVNRT: slow pathway ablation - success rate ~95-98%; risk of complete AV block ~0.5-1%
  • AVRT: accessory pathway ablation
  • First-line for patients who prefer cure over ongoing drug therapy
• Antiarrhythmic drugs for those who decline ablation or as a bridge:
  • Flecainide, propafenone (no structural heart disease)
  • Diltiazem, verapamil, beta-blockers (rate-control + prevention)
  • Amiodarone (structural heart disease, last resort due to toxicity)

Wide-Complex PSVT

• Treat as VT until proven otherwise
• If clearly PSVT with aberrancy (prior documented episodes): vagal maneuvers + adenosine reasonable
• If irregular wide-complex: likely preexcited AF/flutter → cardioversion, IV procainamide, or ibutilide
• Never use adenosine, verapamil, or diltiazem in preexcited AF (anterograde accessory pathway conduction - risk of VF)

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1. Insulin Classification

Classification Table

Combination Insulins

• 70/30 - 70% NPH + 30% regular
• 50/50 - 50% NPH + 50% regular
• 75/25 - 75% NPH protamine lispro + 25% lispro
• Degludec/aspart (Ryzodeg) - ultra-long + rapid

Combination insulins are convenient (2 injections/day) but cannot independently adjust short and long components - not appropriate for Type 1 DM management.

Key Clinical Points

• Rapid-acting analogues should be injected <10 min before meals (regular: 30-45 min before)
• Basal insulin (glargine, degludec) provides ~50% of daily insulin requirements; prandial provides the other 50%
• Type 1 DM: typically 0.4-1.0 units/kg/day total, split between basal and prandial
• Glargine vs. degludec: Both peakless; degludec has longer duration and is more flexible in dosing time
• Exogenous insulin enters the systemic (not portal) circulation → subphysiologic hepatic insulin levels; higher peripheral levels needed → no current regimen perfectly mimics pancreatic secretion
• Inhaled insulin: faster onset than SC; requires FEV1 screening; can cause bronchospasm/cough

Basal-Bolus (MDI) Regimen

• Basal: once-daily glargine or degludec (dose adjusted to fasting glucose)
• Prandial bolus: rapid-acting (aspart/lispro/glulisine) before each meal, dosed by an insulin-to-carbohydrate ratio (commonly 1 unit per 10-15 g carbohydrate in Type 1 DM) plus correction dose for premeal hyperglycemia

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2. Miliary Tuberculosis

Definition and Origin of the Term

Pathogenesis

• During primary TB: early hematogenous seeding occurs in ~95% of cases but is controlled by cell-mediated immunity. When immunity is overwhelmed, widespread disseminated disease results
• During secondary (reactivation) TB: miliary pulmonary disease occurs when organisms draining through lymphatics enter the venous blood and circulate back to the lung - often in the setting of immunosuppression
• Histology: caseating or non-caseating granulomas with Langhans giant cells at multiple sites; immunocompromised patients may fail to form characteristic granulomas

Who Is at Risk

• Children (especially <5 years)
• Elderly
• Immunocompromised: HIV/AIDS (CD4 <200), organ transplant, anti-TNF therapy
• Malnutrition, diabetes, chronic kidney disease, hematologic malignancies
• Post-primary immunosuppression (steroids, biologics)

Clinical Features

• Prolonged fever, night sweats, anorexia, weight loss
• Dry cough, progressive dyspnea
• Splenomegaly, lymphadenopathy
• Hepatomegaly (hepatic involvement)
• Signs of multisystem illness

• Can present with multiorgan failure, septic shock, ARDS
• Higher mortality than reactivation miliary TB

• Choroidal tubercles (on fundoscopy) - pathognomonic for miliary TB; present in ~13% of cases
• Cutaneous involvement: papules or vesiculopapules (tuberculosis cutis miliaris disseminata) - more common in HIV patients
• Meningitis may coexist (miliary TB frequently seeds the meninges)
• Adrenal involvement → Addison's disease

Investigations

The classic radiographic miliary pattern may not appear on CXR until disease has progressed; CT detects it earlier. A miliary pattern is not specific to TB - also seen in histoplasmosis, malignancy (e.g., miliary carcinomatosis), sarcoidosis, and siderosis.

Treatment

• Intensive phase (2 months): Rifampicin + Isoniazid + Pyrazinamide + Ethambutol (RIPE)
• Continuation phase (4-7 months): Rifampicin + Isoniazid (extending to 9-12 months total for CNS/bone disease)
• Adjunctive corticosteroids: indicated for TB meningitis and TB pericarditis; may be used in severe miliary disease with ARDS or adrenal insufficiency

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3. Pyrexia of Unknown Origin (PUO / FUO)

Definition

• Fever >101°F (38.3°C) on several occasions
• Duration >3 weeks
• Diagnostic uncertainty despite appropriate evaluation including:
  • At least 3 outpatient visits, OR
  • At least 3 days in hospital

The key principle: atypical presentations of common diseases (e.g., TB, lymphoma, SLE) are far more likely than classic presentations of rare diseases.

Classification (Durack and Street, 1991 categories)

Causes (Goldman-Cecil - by domain)

Infectious (most common overall, ~30-40%)

• Occult abscess (abdominal, pelvic, dental)
• Cytomegalovirus (CMV)
• Culture-negative endocarditis
• Epstein-Barr virus (EBV/infectious mononucleosis)
• M. tuberculosis (especially extrapulmonary)
• Osteomyelitis

• Bartonella spp., Brucella spp.
• Hepatitis A, B, or E
• Acute HIV
• Salmonella spp., Toxoplasma

Malignant (~20-30%)

• Lymphoma (Hodgkin's and non-Hodgkin's) - most common malignant cause
• Leukemia
• Renal cell carcinoma ("internist's tumor")
• Hepatocellular carcinoma
• Atrial myxoma
• Castleman disease
• Myelodysplastic syndrome

Inflammatory / Rheumatologic (~20-30%)

• Adult-onset Still disease (classic triad: quotidian fever, evanescent salmon-pink rash, arthritis)
• Temporal (giant cell) arteritis - especially in elderly; ESR markedly elevated
• Polymyalgia rheumatica
• Systemic lupus erythematosus (SLE)
• Granulomatosis with polyangiitis (Wegener's)
• Inflammatory bowel disease
• Rheumatoid arthritis
• Sarcoidosis
• Polyarteritis nodosa, Takayasu arteritis

Miscellaneous

• Drug fever (common, often overlooked)
• Factitious fever
• Hyperthyroidism / subacute thyroiditis (de Quervain)
• Pheochromocytoma
• Chronic pulmonary embolism
• Hemophagocytic lymphohistiocytosis (HLH)
• Periodic fever syndromes (e.g., FMF, PFAPA)
• Hematoma
• Adrenal insufficiency (hypoadrenalism)

Undiagnosed (~10-15%)

Diagnostic Approach (Goldman-Cecil)

• FDG-PET/CT scan: identifies a cause in 30-60% of cases; can detect large-vessel vasculitis, metabolically active tumor, occult infection, or guide biopsy site
• Echocardiography: endocarditis, atrial myxoma
• CT chest/abdomen/pelvis: lymphoma, abscess, malignancy
• Tissue biopsy (lymph node, liver, bone marrow, temporal artery): guided by imaging or clinical clues

• Treat reversible causes; avoid empiric antibiotics/steroids unless patient is critically ill (they mask the diagnosis)
• If no diagnosis after full workup: watchful waiting or shared-decision trial of NSAIDs/corticosteroids for presumed inflammatory etiology
• Periodically reassess (new symptoms, new findings)

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4. Irregular Pulse

Types of Irregular Pulse

A. Irregularly Irregular

Clinical clue: In AF, the peripheral pulse rate is less than the apical rate (pulse deficit) because short R-R intervals don't allow sufficient LV filling to produce a palpable radial pulse.

B. Regularly Irregular

Examination Tips

• Feel the radial pulse for rhythm and rate
• Confirm with apical auscultation - count apical rate vs. radial rate (pulse deficit = AF)
• JVP inspection: absent a waves = AF; cannon a waves = complete heart block or VT
• Always confirm with ECG - history and exam narrow the differential, but rhythm diagnosis requires ECG

Key Clinical Associations

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5. Myxedema Coma

Definition

• Altered mental status (ranging from confusion/obtundation to frank coma)
• Hypothermia (a hallmark; temperature often 32-35°C)
• A precipitating event (almost always present)

Precipitating Factors (Rosen's Box 117.6)

Clinical Features

• Hypothermia (core temperature often <35°C; severe hypothermia <30°C)
• Bradycardia
• Hypotension
• Hypoventilation (respiratory failure is a major cause of death)

• Confusion, obtundation, stupor, coma
• Seizures
• Delayed relaxation of deep tendon reflexes ("hung-up" reflexes)
• Cerebellar ataxia

• Sinus bradycardia
• Long QT interval → ventricular arrhythmias
• Cardiomegaly, pericardial effusion
• Diastolic heart failure

• Hypoventilation → hypercapnia → respiratory acidosis
• Pleural effusions
• Obstructive sleep apnea history

• Hyponatremia (dilutional; impaired free water excretion) - associated with increased mortality; correct carefully to avoid osmotic demyelination
• Hypoglycemia (esp. in children)
• Elevated CPK
• Anemia

• Dry, coarse, cool, pale-yellow skin
• Periorbital and facial puffiness (non-pitting myxedema)
• Macroglossia
• Lateral eyebrow thinning (Queen Anne's sign)
• Husky, deep voice
• Goiter (if Hashimoto's) or absent thyroid (post-thyroidectomy/RAI)

Investigations

• TSH: markedly elevated (primary hypothyroidism); may be low/normal in central hypothyroidism
• Free T4: very low
• Free T3: low
• Cortisol: measure before steroids; adrenal insufficiency may coexist
• ABG: hypoxia, hypercapnia, respiratory acidosis
• Electrolytes: hyponatremia
• Glucose: hypoglycemia
• ECG: bradycardia, long QT, low-voltage complexes, T-wave changes
• CXR: cardiomegaly, pleural/pericardial effusion
• CBC: normocytic anemia

Treatment (ICU Setting)

1. Thyroid Hormone Replacement (cornerstone)

• Loading dose: 200-400 µg IV (lower end for elderly, small body habitus, known CAD, or arrhythmias)
• Maintenance: 1.6 µg/kg/day IV (reduce to 75% of IV dose when switching to oral)

• Considered in severely ill patients for faster effect (T4→T3 conversion is impaired in critical illness)
• Use with extreme caution - elevated serum T3 is associated with increased mortality; lower doses (5-10 µg IV q8h)

2. Glucocorticoids (stress dose)

• Hydrocortisone 100 mg IV q8h (covers possible concurrent adrenal insufficiency - up to 10% of myxedema coma cases)
• Taper as the patient recovers; can discontinue once adrenal function is confirmed normal

3. Supportive Care

Disposition

• All myxedema coma patients: ICU admission
• Regular hypothyroidism: outpatient management

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1. Polycystic Kidney Disease (PKD)

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A. Autosomal Dominant PKD (ADPKD)

Genetics

Risk Factors for ESRD Progression

• Early age of presentation
• Male sex
• PKD1 mutation (worse than PKD2)
• Hypertension (present in >75% by age 20-30)
• African ethnicity
• Larger total kidney volume (TKV) - measured by MRI/CT

Clinical Features

• Abdominal/flank pain (distension, cyst hemorrhage, infection, nephrolithiasis)
• Hematuria (gross or microscopic; cyst rupture)
• Palpable bilateral flank/abdominal masses
• Hypertension (early, due to intrarenal RAAS activation - often before any decline in GFR)
• Recurrent UTIs and cyst infections
• Progressive decline in GFR → ESRD (median age ~58 years for PKD1, ~79 years for PKD2)
• Nephrolithiasis (uric acid and calcium oxalate stones, in ~20%)

Key exam pearl: Intracranial aneurysms (10-30%) can cause sudden death from SAH in young adults with ADPKD. Screen patients with family history of SAH or aneurysm with MR angiography.

Diagnosis

• Ultrasound: most practical; age-specific criteria - in PKD1 family: ≥3 cysts (one kidney) in patients 15-39 years; ≥2 per kidney age 40-59; ≥4 per kidney ≥60
• CT/MRI: more sensitive; MRI used for TKV measurement (prognostic tool)
• Genetic testing: useful if atypical presentation or for living donor screening of family members before cysts develop

Treatment

• Target: 110/75 mmHg in young patients (HALT-PKD trial showed rigorous BP control with ACEi slowed TKV growth and preserved GFR)
• ACE inhibitors or ARBs (first-line; RAAS blockade)

• FDA-approved for patients ≥18 years at risk of rapidly progressing ADPKD
• Reduces cAMP in collecting duct cells → inhibits cyst epithelial cell proliferation and fluid secretion
• TEMPO 3:4 trial: slowed TKV growth and rate of GFR decline
• Side effects: polyuria, polydipsia, nocturia; hepatotoxicity (monitor LFTs)
• Not for all patients - reserve for those with evidence of rapid progression (TKV >750 mL, age-adjusted mayo imaging class 1C/1D/1E)

• Somatostatin analogues (octreotide-LAR): reduce cAMP; slowed renal function decline (ALADIN trial)
• mTOR inhibitors (sirolimus, everolimus): trialed but significant side effects; not standard care
• Pain management: simple analgesics; nerve block for refractory chronic pain (DIPAK trial)
• Cyst infection: fluoroquinolones (penetrate cysts); occasionally drainage

• Peritoneal dialysis and hemodialysis both used; PD may be challenging in very large kidneys
• Renal transplantation is preferred ESRD treatment

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B. Autosomal Recessive PKD (ARPKD)

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2. Irritable Bowel Syndrome (IBS)

Definition (Rome IV Criteria)

1. Related to defecation
2. Associated with a change in stool frequency
3. Associated with a change in stool form (appearance)

IBS is a disorder of gut-brain interaction (not a structural or inflammatory disease). No organic cause is identified on investigation.

Subtypes (by predominant stool pattern)

Epidemiology

• Global prevalence: 4.1% (Rome IV); higher with older criteria
• More common in women (5.2% vs 2.9% in men)
• Incidence: ~38 per 10,000 person-years
• Up to 50% of affected individuals never seek healthcare
• Generates ~4.4 million physician visits annually in the US alone

Pathophysiology

1. Visceral hypersensitivity - abnormally increased pain perception in response to normal gut distension (lowered visceral pain threshold); strongest pathophysiologic mechanism
2. Altered gut motility - slower transit in IBS-C, faster in IBS-D; no consistent specific pattern
3. Gut microbiota dysbiosis - altered composition; post-infectious IBS develops in ~10% after gastroenteritis
4. Mucosal immune activation - increased mast cells, inflammatory mediators, increased intestinal permeability
5. Enteroendocrine dysfunction - abnormal serotonin (5-HT) signaling; serotonin plays a key role in gut motility and visceral sensation
6. Autonomic nervous system dysregulation
7. CNS modulation - altered central processing of visceral input; comorbid anxiety/depression in >50%

• Genetic predisposition (familial clustering, 1.75-2.75x odds)
• Adverse childhood experiences
• Post-infectious gastroenteritis (bacterial, viral, or parasitic)
• Food (FODMAPs, fat, caffeine)
• Psychological stress

Clinical Features

• Abdominal pain/discomfort: crampy, variable location; relieved (partially) by defecation
• Altered bowel habits: diarrhea, constipation, or both; urgency; incomplete evacuation; mucus in stool
• Bloating/distension: very common, especially post-meal
• Absence of alarm features: no weight loss, no blood in stool, no nocturnal symptoms, no fever

• Fibromyalgia, chronic fatigue syndrome
• Dyspareunia, urinary urgency
• Anxiety, depression (>50% comorbidity)
• Headache

Diagnosis

• Age >50 at onset (or family history of colorectal cancer → colonoscopy)
• Unexplained weight loss
• Blood in stool / iron-deficiency anemia
• Fever
• Nocturnal symptoms waking from sleep
• Recent antibiotic use (Clostridioides difficile)
• Inflammatory markers elevated (ESR, CRP, fecal calprotectin)

• CBC (anemia)
• CRP, fecal calprotectin (rule out IBD)
• TSH (thyroid disease)
• Celiac serology (anti-tTG IgA) - important as celiac disease mimics IBS-D
• Consider stool culture/O&P if infectious etiology suspected

Treatment

Lifestyle and Dietary

• Low-FODMAP diet (Fermentable Oligosaccharides, Disaccharides, Monosaccharides And Polyols): strongest evidence; reduces symptoms in ~50-70% of IBS patients; guided by dietitian
• Regular exercise; adequate sleep
• Identify and avoid trigger foods

Pharmacological (symptom-directed)

• Antispasmodics: dicyclomine, hyoscine (anticholinergics); mebeverine; peppermint oil
• Low-dose TCAs (amitriptyline, desipramine): for pain; especially IBS-D (slow transit)
• SSRIs: for pain + comorbid depression; better for IBS-C (faster transit)
• Gabapentin/pregabalin: visceral hypersensitivity

• Cognitive behavioral therapy (CBT): strong evidence
• Gut-directed hypnotherapy
• Mindfulness-based therapy

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3. Ulcerative Colitis (UC)

Definition and Pathology

Gross and Histologic Features

Comparison: UC vs Crohn's Disease

Clinical Features

• Bloody diarrhea (hallmark - mucus and blood)
• Rectal urgency, tenesmus
• Abdominal cramping (before defecation)
• Constitutional symptoms in severe disease: fever, weight loss, anemia, hypoalbuminemia

• Proctitis: rectum only (~30%)
• Left-sided colitis: rectum to splenic flexure (~30%)
• Extensive/pancolitis: beyond splenic flexure (~40%)

Severity Classification (Truelove & Witts)

Extraintestinal Manifestations

Cancer Risk

• Colorectal cancer (CRC) risk increases with: extent of disease, duration (significant after 8-10 years), severity, concomitant PSC
• Surveillance colonoscopy recommended starting 8-10 years after diagnosis; every 1-3 years

Medical Treatment

Step 1 - Mild to Moderate UC

• Mesalamine (oral + rectal enema/suppository) - mainstay; induction and maintenance of remission
• Sulfasalazine (5-ASA + sulfapyridine carrier) - less preferred due to side effects
• Olsalazine, balsalazide - prodrugs released by bacterial cleavage in colon
• Rectal preparations (suppositories, enemas) for proctitis/left-sided disease

Step 2 - Moderate to Severe UC

• Oral prednisone 40-60 mg/day, tapered over 8-12 weeks
• IV methylprednisolone 40-60 mg/day for severe disease
• Budesonide MMX (colonic release) for mild-moderate UC; lower systemic bioavailability

Step 3 - Immunomodulators

• Azathioprine / 6-mercaptopurine (6-MP): steroid-sparing maintenance therapy; slow onset (3-6 months); risk of lymphoma, pancreatitis, myelosuppression
• Methotrexate: mainly Crohn's; less used in UC
• Ozanimod (S1P receptor modulator): new oral agent for moderately-severely active UC

Step 4 - Biologics (moderate-severe, or steroid-refractory)

Surgical Treatment

• Indications: medically refractory disease, fulminant/toxic megacolon, hemorrhage, perforation, high-grade dysplasia, or colorectal cancer
• Total proctocolectomy with ileal pouch-anal anastomosis (IPAA / J-pouch) - procedure of choice; curative
• Complications: pouchitis (up to 50%), pelvic sepsis, infertility (females)

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4. Pneumothorax

Definition

Classification

By Cause

By Size

• Small: <20% of hemithorax or <3 cm from lung apex to chest wall
• Large: >20% or >3 cm

Pathophysiology

• Compresses ipsilateral lung (complete collapse)
• Shifts mediastinum contralaterally (tracheal deviation away from affected side)
• Compresses vena cava → reduces venous return → obstructive shock
• Compresses heart

Clinical Features

Simple/Spontaneous

• Sudden onset pleuritic chest pain (sharp, worse with breathing)
• Dyspnea (severity proportional to size and underlying lung reserve)
• Dry cough
• Most occur at rest (not with exertion)

Tension Pneumothorax (Emergency)

• Tachycardia
• Hypotension (obstructive shock)
• JVD (elevated JVP due to impaired venous return)
• Tracheal deviation away from affected side
• Absent breath sounds + hyperresonance on affected side
• Progressive respiratory failure and cardiac arrest if untreated
• Elevated peak airway pressure (if mechanically ventilated)

In tension pneumothorax: Do NOT wait for imaging - treat immediately based on clinical findings.

Investigations

• CXR (PA/erect): absent lung markings peripheral to the visceral pleural line; collapsed lung; mediastinal shift in tension
• Ultrasound (POCUS): absence of "lung sliding" sign at point of care - fast and sensitive
• CT chest: most sensitive; identifies blebs, underlying lung disease, exact size

Treatment

Tension Pneumothorax - IMMEDIATE

1. Needle decompression: 14-16G needle, 2nd intercostal space, midclavicular line → converts to simple pneumothorax
2. Follow with chest tube (tube thoracostomy)

Primary Spontaneous Pneumothorax

• Small (<20% or <3 cm) + asymptomatic + no underlying lung disease: Observation; supplemental O₂ (accelerates reabsorption by ~4x); repeat CXR in 4-6 hours
• Large (>20% or >3 cm) or symptomatic:
  • 1st episode: needle aspiration (85% success rate) OR small-bore chest tube (24Fr or pigtail catheter via Seldinger technique) connected to water-seal drainage ± suction (-20 cm H₂O)
  • Chest tube removed when lung re-expanded and air leak has stopped (4-hour clamp test before removal)

Secondary Spontaneous Pneumothorax

• Observation has NO role - even small SSP requires intervention (poor reserve, high risk of tension)
• Chest tube + consider early surgical/thoracoscopic intervention even on first episode
• VATS (video-assisted thoracoscopic surgery) with bleb resection + pleurodesis

Recurrence Prevention (2nd episode or persistent air leak)

• Chemical pleurodesis: talc instilled via chest tube
• Surgical pleurodesis: VATS with mechanical pleurodesis + bleb/bullae resection (preferred when patient can tolerate surgery)
• Recurrence rate: ~30% within 2 years without pleurodesis; VATS reduces recurrence to <5%

Iatrogenic Pneumothorax

• Manage same as spontaneous
• Small + asymptomatic + not on PPV: observation acceptable
• On any form of positive pressure ventilation: drain immediately (risk of tension)

Practical Notes

• Persistent air leak initially: suction at -20 cm H₂O to promote visceral-parietal pleural apposition
• Switch to water seal only after air leak resolves, then confirm with CXR before tube removal
• Loculated pneumothoraces: drain under US or CT guidance

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Acute Respiratory Distress Syndrome (ARDS)

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Definition - The Berlin Definition (2012)

Severity Classification

The PaO₂/FiO₂ (P/F ratio) is the key diagnostic and severity marker. Normal P/F ratio ≈ 400-500 mmHg. ARDS was formerly called acute lung injury (ALI) when P/F was 200-300; the Berlin definition eliminates this term.

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Causes and Risk Factors

Direct (Pulmonary)

Indirect (Extrapulmonary)

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Pathophysiology

Phases of ARDS (Diffuse Alveolar Damage - DAD)

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Phase 1: Exudative (Days 0-7) - the "wet lung"

1. Injury to alveolar-capillary membrane: damage to type I pneumocytes (alveolar epithelium) and pulmonary microvascular endothelial cells disrupts the normally tight barrier
2. Protein-rich edema fluid floods the interstitium and alveolar spaces (non-cardiogenic pulmonary edema)
3. Cytokine storm: proinflammatory mediators (IL-1, IL-6, IL-8, TNF-α, leukotriene B₂) recruit and activate neutrophils into alveoli and interstitium
4. Hyaline membrane formation: condensed plasma proteins + cellular debris + dysfunctional surfactant aggregate in air spaces
5. Surfactant dysfunction: reduced and qualitatively abnormal surfactant → alveolar collapse (atelectasis)
6. Microvascular occlusion: microthrombi + fibrocellular proliferation in pulmonary vasculature → increased dead space + pulmonary hypertension
7. Result: severe V/Q mismatch, intrapulmonary shunting, refractory hypoxemia, reduced compliance, increased work of breathing

Only ~50% of patients meeting clinical ARDS criteria show histologic DAD on biopsy/autopsy. Patients with confirmed DAD are younger, more severely ill, have lower P/F ratios, and are ~5× more likely to die of hypoxemic respiratory failure.

Phase 2: Proliferative (Days 7-14)

• Hyaline membranes are reorganized
• Type II pneumocyte proliferation to replace damaged type I cells (attempted repair)
• Interstitial inflammation; early fibroproliferation begins (collagen synthesis detectable in BAL as early as 24 hours)
• Decreased neutrophils; reduced pulmonary edema
• Many patients begin to recover; others progress

Phase 3: Fibrotic (Day 14+, weeks)

• Occurs in a subset with persistent ARDS (>2 weeks)
• Pulmonary fibrosis - obliteration of alveolar architecture
• Obliteration of pulmonary capillaries; interstitial and alveolar collagen deposition; bulla formation
• Markedly decreased compliance
• Sustained oxygen dependence; risk of barotrauma

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Pathophysiologic Consequences

• Dependent zones: consolidated/fluid-filled or recruitable atelectatic (posterior/inferior)
• Non-dependent zones: relatively normal (anterior/superior) - this is the "baby lung" that receives all the tidal volume if standard Vt used → overdistention
• Intermediate zones: poorly aerated but recruitable

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Clinical Features and Diagnosis

Symptoms

• Acute onset dyspnea (usually within 12-36 hours of insult; occasionally up to 5-7 days)
• Rapid, shallow breathing; sensation of inability to get enough air
• Tachypnea; increased work of breathing → respiratory fatigue → respiratory failure

Signs

• Tachycardia, tachypnea
• Accessory muscle use, nasal flaring
• Widespread bilateral crackles on auscultation
• Cyanosis (refractory hypoxemia)
• Low SpO₂ despite supplemental O₂

Investigations

• ABG: hypoxemia (low PaO₂/FiO₂ <300), often hypocapnia early (respiratory alkalosis); hypercapnia develops as dead space increases and patient tires
• CXR: bilateral opacities involving ≥75% of lung fields; no cardiomegaly, no pleural effusions (unlike cardiogenic edema) - though difficult to distinguish clinically
• CT chest: bilateral infiltrates; demonstrates extensive heterogeneity; dependent consolidation; non-dependent relatively preserved areas
• Echocardiography: needed if no risk factor identified, to exclude cardiogenic edema; also evaluates RV function
• BAL: neutrophilia (>60% of cells); elevated protein (>0.5 total:serum protein ratio); elevated cytokines - not routinely done but supports diagnosis

Differential Diagnosis of Bilateral Infiltrates + Hypoxemia

• Cardiogenic pulmonary edema (most common mimic) - wedge pressure >18 mmHg
• Diffuse alveolar hemorrhage
• Bilateral pneumonia
• Acute eosinophilic pneumonia
• Cryptogenic organizing pneumonia
• Acute interstitial pneumonia (Hamman-Rich syndrome)

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Management

Principle: No specific therapy reverses DAD. Management is supportive - protect the lungs while the underlying insult is treated.

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1. Treat the Underlying Cause

• Antibiotics for sepsis/pneumonia
• Source control for sepsis
• Treat pancreatitis, reverse drug overdose, etc.

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2. Lung-Protective Mechanical Ventilation (ARDSNet Protocol)

• Male: PBW (kg) = 50 + 2.3 × (height [inches] - 60)
• Female: PBW (kg) = 45.5 + 2.3 × (height [inches] - 60)

• Required to reduce atelectasis, keep alveoli open, reduce shunting
• Higher PEEP (~12-13 cm H₂O) may benefit moderate-severe ARDS (P/F <200) but not mild ARDS
• Guided by FiO₂/PEEP table (see ARDSNet algorithm) or esophageal pressure monitoring in obese/chest wall stiff patients
• Very high PEEP + aggressive recruitment maneuvers can be harmful (ART trial - increased mortality)

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3. Prone Positioning

• Prone positioning for ≥16 hours/day in patients with P/F <150 mmHg
• Reduced 28-day mortality: 32.8% vs. 16% (absolute risk reduction ~17%)
• Mechanism: more uniform distribution of pleural pressure and ventilation; recruits dependent lung; reduces VILI; improves V/Q matching

• Indicated for severe ARDS (P/F <150 mmHg) refractory to conventional ventilation
• Should be initiated early (within 12-24h of intubation)
• Used irrespective of its effect on oxygenation in individual patients (mortality benefit is the goal)
• Requires experienced personnel; careful coordination with nursing; risk of accidental extubation, line dislodgement

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4. Neuromuscular Blockade (NMB)

• ACURASYS trial (2010): 48h cisatracurium infusion in moderate-severe ARDS improved 90-day mortality
• ROSE trial (2019): routine NMB showed no benefit over light sedation with deep sedation as needed
• Current recommendation: not routinely recommended in all moderate-severe ARDS; judicious use for patient-ventilator asynchrony, breath stacking, or very large patient-driven tidal volumes
• Facilitates lung-protective ventilation when patients strongly override ventilator settings

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5. Fluid Management

• Conservative fluid strategy (FACTT trial): compared liberal vs. conservative fluid management
  • Conservative strategy: improved oxygenation (higher P/F, more ventilator-free days, more ICU-free days)
  • No mortality difference, but the conservative group had shorter duration of mechanical ventilation
• Goal: euvolemia to mild negative fluid balance; use diuretics to reduce extrapulmonary edema; avoid aggressive fluid resuscitation unless hemodynamically unstable
• Optimize fluid status before increasing FiO₂ or PEEP

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6. Corticosteroids

• Rationale: reduce inflammation; may limit fibroproliferative phase
• Evidence: mixed and controversial
  • Low-to-moderate dose methylprednisolone (1-2 mg/kg/day) in early ARDS: may improve oxygenation and reduce ventilator days in some trials
  • DEXA-ARDS trial (2020): dexamethasone 20 mg/day × 5 days then 10 mg/day × 5 days significantly reduced ventilator days and 60-day mortality in moderate-severe ARDS
  • Steroids given late (>2 weeks after onset) may increase mortality - avoid in late fibrotic phase
• Current use: considered in moderate-severe ARDS not improving with standard measures; avoid in septic shock unless already indicated; do not use routinely

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7. Rescue/Salvage Therapies (Refractory Hypoxemia)

Key principle: inhaled NO, prostacyclin, and HFOV improve oxygenation but have not been shown to reduce mortality - use only as bridging strategies.

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8. Supportive ICU Care

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9. Liberation from Mechanical Ventilation

• Underlying cause improving/resolved
• P/F ratio >150-200 on FiO₂ ≤0.4 and PEEP ≤8 cm H₂O
• Hemodynamically stable (minimal/no vasopressors)
• Able to initiate respiratory effort
• Adequate secretion management

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Prognosis and Outcomes

• Overall ICU mortality: 30-45% (varies by severity and cause)
  • Mild ARDS: ~27%
  • Moderate ARDS: ~32%
  • Severe ARDS: ~45%
• Most deaths in ARDS are from multi-organ failure (not hypoxemic respiratory failure per se)
• Survivors: commonly experience long-term impairments:
  • Reduced exercise tolerance and lung function (restrictive pattern)
  • Cognitive impairment, PTSD, depression (post-intensive care syndrome - PICS)
  • Muscle weakness and fatigue (ICU-acquired weakness)
  • Quality of life frequently impaired for months to years

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Summary: Key Evidence-Based Interventions That Reduce Mortality

NOT proven to reduce mortality: HFOV, inhaled NO, inhaled prostacyclin, recruitment maneuvers. ECMO remains uncertain (EOLIA).

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Topic 1: Sarcoidosis

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Epidemiology

• Incidence highest in Scandinavian countries and African Americans (3-5× more common than in whites)
• Peak incidence: ages 25-45; second peak in women >50 years
• African Americans tend to have more severe, multisystem, and chronic disease
• Women more commonly affected than men

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Pathophysiology

1. An unknown antigen (possibly mycobacterial, propionibacterial, or environmental trigger) activates alveolar macrophages → present antigen to CD4+ T helper cells
2. Th1-predominant immune response: IL-2, IFN-γ, TNF-α, IL-12 are released
3. Macrophages fuse to form multinucleated giant cells (Langhans or foreign-body type)
4. Epithelioid histiocytes surround a central core - this is the granuloma
5. No central necrosis distinguishes from TB (which has caseating granulomas)
6. Granulomas either resolve (spontaneous in 50-70%) or progress to fibrosis (irreversible organ damage)

Key pearl: Caseation = TB. Non-caseation = sarcoidosis. Asteroid bodies and Schaumann bodies (calcified inclusions) are seen inside giant cells in sarcoidosis but are non-specific.

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Clinical Features by Organ

Pulmonary (most important - 90%)

Cutaneous

• Lupus pernio: violaceous plaques on nose, cheeks, ears - highly specific for sarcoidosis; strongly associated with chronic pulmonary and upper airway granulomatous infiltration
• Erythema nodosum (tender red nodules on shins) - seen in Lofgren syndrome; represents a reactive (not granulomatous) response
• Maculopapular plaques: red-brown, non-scaly papules around nose/mouth
• Scar sarcoidosis: old scars become infiltrated with granulomas

Ocular (25%)

• Anterior uveitis most common (photophobia, floaters, red eye) - can cause blindness
• Posterior uveitis, keratoconjunctivitis sicca
• Optic nerve involvement
• Regular slit-lamp ophthalmologic examination required

Cardiac (5-10% clinical; up to 25% on autopsy)

• Potentially fatal - accounts for ~13-25% of sarcoidosis deaths in the USA
• Granulomatous infiltration of myocardium → conduction defects, arrhythmias, heart block, VT, sudden cardiac death
• Cardiomyopathy
• Requires cardiac MRI (late gadolinium enhancement) and PET-CT for diagnosis

Neurologic (5-15%)

• Cranial nerve palsies (VII most common = Bell's palsy-like) - frequently bilateral
• Aseptic meningitis
• Hypothalamic/pituitary dysfunction (diabetes insipidus)
• Peripheral neuropathy
• Seizures

Hepatic and Splenic

• Hepatic granulomas in 50-80% (usually asymptomatic; elevated ALP)
• Splenomegaly
• Rarely: portal hypertension, cirrhosis

Renal

• Hypercalciuria and hypercalcemia (most important): activated macrophages in granulomas produce 1-alpha-hydroxylase, converting 25-OH vitamin D to 1,25-(OH)₂ vitamin D (calcitriol) → increased intestinal calcium absorption + increased bone resorption → hypercalcemia + nephrocalcinosis + nephrolithiasis
• Interstitial nephritis from granulomatous infiltration

Hematologic

• Lymphopenia (CD4+ cells redistributed to lungs), anemia, thrombocytopenia
• Hypersplenism

Other

• Lofgren syndrome: acute presentation with BHL + erythema nodosum + fever + polyarthritis - excellent prognosis (80-90% spontaneous resolution)
• Heerfordt syndrome (uveoparotid fever): uveitis + parotid enlargement + facial nerve palsy + fever
• Peripheral lymphadenopathy, salivary gland enlargement

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Laboratory Findings

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Diagnosis

1. Compatible clinical picture
2. Histologic evidence of non-caseating granulomas (biopsy)
3. Exclusion of other causes (TB, fungal infection, foreign body, lymphoma, berylliosis)

• Most accessible lesion first: skin, peripheral lymph node, conjunctiva
• Endobronchial/transbronchial biopsy: yield ~50-80% with BAL showing lymphocytosis with elevated CD4:CD8 ratio (>3.5:1) - highly suggestive
• EBUS-guided transbronchial needle aspiration (TBNA): high yield for hilar/mediastinal nodes
• Mediastinoscopy/VATS: if bronchoscopic biopsy non-diagnostic
• BAL lymphocytosis >15% with CD4:CD8 >3.5:1 - highly specific (if present) but poorly sensitive
• Biopsy can be avoided in classic Lofgren syndrome and Heerfordt syndrome

• CXR: BHL - the most characteristic finding
• HRCT: peribronchial nodules with "galaxy sign"; upper-lobe predominant; mediastinal LAD; beaded fissures
• FDG-PET: identifies occult lesions for biopsy; monitors treatment response; evaluates cardiac sarcoidosis

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Management

When to Treat

• Stage I (BHL only): usually observed; >70% spontaneous resolution
• Asymptomatic Stage II: close observation acceptable

• Symptomatic pulmonary disease with declining lung function
• Cardiac sarcoidosis (always treat)
• Ocular disease (posterior uveitis, optic nerve)
• Neurologic sarcoidosis
• Hypercalcemia/hypercalciuria
• Severe extrapulmonary involvement (hepatic, renal, CNS)
• Cutaneous disease causing functional impairment or disfigurement

Pharmacological Treatment

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Prognosis

• 50-70% spontaneous resolution (especially Stage I-II, Lofgren syndrome)
• 20-30% chronic course with significant morbidity
• <5% mortality in Western countries; main causes: pulmonary fibrosis, cardiac arrhythmia/sudden death, hemorrhage from aspergilloma in fibrotic cavities
• Poor prognostic factors: African American race, lupus pernio, Stage III/IV, cardiac/neurological involvement, multiple extrapulmonary organs

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Topic 2: Lupus Nephritis

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Pathogenesis

1. Loss of tolerance to self-antigens (especially nuclear antigens: dsDNA, histones, ribonucleoprotein)
2. Autoantibody formation: anti-dsDNA, anti-Sm, anti-C1q are most closely associated with nephritis
3. Immune complex deposition in the glomerulus:
   • Circulating immune complexes trapped in mesangium/capillary walls
   • In-situ complex formation (anti-dsDNA binding glomerular heparan sulfate or cross-reacting with alpha-actinin)
4. Complement activation: C1q → C3/C4 consumption → "full house" immunofluorescence
5. Neutrophil and macrophage infiltration → cytokine release → glomerular damage
6. NET formation (neutrophil extracellular traps): release chromatin → stimulate type I interferon → perpetuate autoimmunity

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ISN/RPS Classification (2003, revised 2018)

Key pearls:

• Class III and IV are proliferative lupus nephritis - require aggressive immunosuppression
• Class IV is most common severe form; "wire loop" lesions = massive subendothelial immune deposits
• "Full house" immunofluorescence: IgG, IgA, IgM, C3, C4, C1q all positive - highly specific for lupus nephritis
• Class V + IV (mixed membranous + proliferative): treat as Class IV
• Classes I and II: usually no immunosuppression for kidneys

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Clinical Features and Presentation

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Investigation

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Treatment

General Principles

• Kidney biopsy is essential before starting induction therapy (Class determines treatment)
• Induction phase: 3-6 months to achieve remission
• Maintenance phase: at least 2-3 years to prevent relapse
• Hydroxychloroquine (200-400 mg/day): given to all SLE patients regardless of activity - reduces flares, thrombosis risk, and improves long-term survival

Treatment by Class

• No specific immunosuppression for the kidney
• Treat extrarenal SLE manifestations; hydroxychloroquine

• MMF 1-2 g/day OR azathioprine 2 mg/kg/day + low-dose prednisone + hydroxychloroquine
• MMF superior to azathioprine (MAINTAIN Nephritis Trial)
• Duration: minimum 2-3 years; many experts recommend indefinite low-dose maintenance

• MMF + prednisone (preferred)
• If not responding: IV CYC or calcineurin inhibitors (tacrolimus, cyclosporine)
• Voclosporin + MMF (FDA-approved 2021): newer calcineurin inhibitor with lower nephrotoxicity

• Immunosuppression generally unhelpful (sclerosed glomeruli)
• Prepare for renal replacement therapy (dialysis/transplant)

Novel/Biologic Therapies

Supportive Measures

• ACE inhibitors / ARBs: reduce proteinuria and slow CKD progression (all LN patients with proteinuria)
• Blood pressure target: <130/80 mmHg
• Statins: dyslipidemia common (nephrotic syndrome + steroids)
• Antithrombotic therapy: if antiphospholipid antibodies + thrombosis
• Calcium + vitamin D supplementation with steroids (osteoporosis prophylaxis)
• PCP prophylaxis (cotrimoxazole) during high-dose immunosuppression
• Vaccinations (avoid live vaccines during active immunosuppression)
• Sunscreen (UV triggers SLE flares)

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Monitoring and Response Assessment

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Prognosis

• Without treatment: ~50% progress to ESKD within 10 years (Class IV)
• With modern treatment: 10-year renal survival >80-90% for most classes
• Poor prognostic factors: serum creatinine >2 mg/dL at diagnosis, nephrotic syndrome, histological features (crescents, fibrous crescents, interstitial fibrosis, tubular atrophy), African/Black race (2-3× higher ESKD risk), non-compliance, delayed diagnosis

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Topic 3: Approach to a Patient with Diarrhoea

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Definitions

• Diarrhea (symptom): decreased stool consistency, increased urgency, or increased frequency
• Diarrhea (sign): stool weight >200 g/day (adult)
• Acute diarrhea: <2-3 weeks duration (most commonly infectious)
• Persistent diarrhea: 2-4 weeks
• Chronic diarrhea: ≥4 weeks

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Mechanisms of Diarrhea

Stool osmotic gap = 290 - 2 × (stool Na⁺ + stool K⁺)

• 125 mOsm/kg = osmotic diarrhea

• <50 mOsm/kg = secretory diarrhea

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Step 1: Clinical History

Duration and Onset

• Acute (<2 weeks): infectious most likely
• Chronic (>4 weeks): inflammatory, malabsorptive, functional, or secretory

Stool Characteristics

Associated Symptoms (Alarm Features - warrant urgent investigation)

• Unintentional weight loss
• Rectal bleeding / melena
• Nocturnal diarrhea
• Fever
• Severe abdominal pain
• Age >45 years with new-onset diarrhea
• Family history of colorectal cancer or IBD
• Signs of malabsorption (anemia, edema, glossitis)
• Immunosuppression

Epidemiological History

• Recent travel (traveler's diarrhea: E. coli, Giardia, Cryptosporidium, norovirus)
• Food history (poultry → Salmonella/Campylobacter; beef → E. coli O157; shellfish → Vibrio; rice → Bacillus cereus; precooked foods → Staphylococcus)
• Antibiotic use (C. difficile)
• Hospital/institutional exposure
• Sexual history (HIV, MSM - Shigella, LGV proctitis, CMV)
• Daycare exposure

Medication History

• 700 medications cause diarrhea: antibiotics, metformin, SSRIs, PPIs, NSAIDs, colchicine, magnesium-containing antacids, lactulose, immune checkpoint inhibitors (colitis), mycophenolate mofetil

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Step 2: Physical Examination

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Step 3: Initial Investigation

Stool Studies

Blood Tests

Imaging

• Plain AXR: rule out toxic megacolon, obstruction
• CT abdomen/pelvis with enterography: IBD, malignancy, diverticular disease, small bowel pathology
• MR enterography: IBD (preferred - no radiation, better soft tissue)
• Somatostatin receptor scintigraphy/PET with ⁶⁸Ga-DOTATATE: neuroendocrine tumors

Endoscopy

• Colonoscopy with biopsies: inflammatory bowel disease, colorectal cancer, microscopic colitis (requires biopsy - normal gross appearance), ischemic colitis
• EGD with duodenal biopsies: celiac disease (villous atrophy), tropical sprue, Whipple's disease
• Sigmoidoscopy: if predominant rectal symptoms

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Step 4: Treatment Principles

Rehydration (always first)

• Mild-moderate: oral rehydration solution (ORS) - glucose-sodium cotransport intact even in secretory diarrhea
• Severe/elderly: IV crystalloid

Antimotility Agents

• Loperamide (2 mg after each loose stool; max 16 mg/day): safe in non-inflammatory, non-febrile diarrhea; NOT in dysentery (fever + blood in stool) - can worsen invasive infection
• Bismuth subsalicylate: effective in bacterial diarrhea
• Racecadotril (enkephalinase inhibitor): antisecretory without paralysing motility

Antibiotics (selective use)

• Most acute infectious diarrhea is self-limiting (3-7 days) and does not require antibiotics
• Indications: fever + bloody diarrhea (dysentery), immunosuppressed, severe traveler's diarrhea, suspected cholera
• C. difficile: oral vancomycin 125 mg QID × 10 days (preferred over metronidazole); fidaxomicin for recurrent CDI; fecal microbiota transplant (FMT) for recurrent/severe CDI

Do NOT give antimotility agents in dysentery (Shigella, E. coli O157) - risk of HUS, toxic megacolon, prolonged excretion.

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Topic 4: Portal Hypertension

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Pathophysiology

1. Cirrhosis → progressive hepatic fibrosis → distortion of sinusoidal architecture → increased intrahepatic resistance to portal flow
2. Intrahepatic component: structural (fibrosis, regenerative nodules) + dynamic (contracted hepatic stellate cells, reduced intrahepatic NO from eNOS → vasoconstriction)
3. Raised portal pressure → splanchnic vasodilator release (NO, prostacyclin, substance P, glucagon) → splanchnic arterial vasodilatation
4. Reduced effective arterial blood volume → baroreceptors triggered → activation of RAAS, SNS, and vasopressin (ADH)
5. These compensatory responses cause:
   • Na+ retention → ascites
   • Free water retention → dilutional hyponatremia
   • Renal vasoconstriction → hepatorenal syndrome
6. Bacterial translocation: increased gut permeability → PAMPs (bacterial LPS, DNA) enter mesenteric lymph → activate innate immunity → systemic inflammation → worsen circulatory dysfunction → ACLF (acute-on-chronic liver failure)

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Classification by Location

HVPG (hepatic venous pressure gradient = wedged - free hepatic vein pressure) reflects sinusoidal portal pressure; elevated in intrahepatic (sinusoidal) and post-hepatic causes; NORMAL in pre-hepatic and presinusoidal causes.

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Causes of Cirrhosis (most common cause of portal hypertension)

• Alcohol-related liver disease (most common in Western countries)
• Chronic viral hepatitis (HBV, HCV)
• NAFLD/MASLD (metabolic-associated steatotic liver disease)
• Autoimmune hepatitis
• Primary biliary cholangitis (PBC)
• Primary sclerosing cholangitis (PSC)
• Wilson's disease, hemochromatosis, alpha-1 antitrypsin deficiency

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Complications and Management

1. Esophageal/Gastric Varices

• Non-selective beta-blockers (NSBB): propranolol 20-40 mg BD or nadolol; or carvedilol (also reduces HVPG more than propranolol) - first-line for medium/large varices; target: resting HR 55-60 bpm or max tolerated dose
• Endoscopic variceal ligation (EVL): for patients intolerant to NSBB; equally effective

• EVL + NSBB (combination better than either alone)
• TIPS for Child-Pugh A/B patients with re-bleeding despite EVL + NSBB

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2. Ascites

• SAAG ≥1.1 g/dL = portal hypertension (cirrhosis, cardiac ascites, Budd-Chiari)
• SAAG <1.1 g/dL = non-portal hypertension cause (malignancy, TB, pancreatitis, nephrotic syndrome)

• Ascitic fluid PMN count ≥250 cells/mm³
• Most common organism: E. coli, Klebsiella, S. pneumoniae
• Treatment: IV cefotaxime 2g TDS × 5 days; albumin 1.5 g/kg day 1 + 1 g/kg day 3 (reduces HRS, reduces mortality)
• Prophylaxis: norfloxacin 400 mg/day indefinitely in high-risk (prior SBP, low-protein ascites <15 g/L)

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3. Hepatic Encephalopathy (HE)

• Grade I: subtle confusion, altered mood, sleep disturbance
• Grade II: obvious disorientation, asterixis (flapping tremor), inappropriate behavior
• Grade III: somnolence, gross disorientation, asterixis
• Grade IV: coma

• Identify and treat precipitant
• Lactulose (15-30 mL TDS; target 2-3 soft stools/day): reduces colonic pH → traps NH₄⁺; reduces ammonia absorption; first-line
• Rifaximin 550 mg BD: non-absorbable antibiotic; reduces gut ammonia-producing bacteria; adjunct to lactulose; reduces recurrent HE by 58% (RFHE trial)
• IV fluids if dehydrated; protein restriction is no longer recommended (may worsen sarcopenia)

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4. Hepatorenal Syndrome (HRS)

• Terlipressin + albumin (first-line; CONFIRM trial): terlipressin 1 mg IV every 4-6h + albumin 20-40 g/day; reversal in ~30-40%
• Noradrenaline + albumin: effective alternative in ICU setting
• TIPS: limited role in HRS; may improve renal function
• Liver transplant: definitive treatment

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5. Other Complications

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6. TIPS (Transjugular Intrahepatic Portosystemic Shunt)

• Refractory variceal bleeding
• Pre-emptive TIPS in high-risk acute variceal bleeding (Child B + active bleeding or Child C <14)
• Refractory/recurrent ascites
• Refractory hepatic hydrothorax
• Budd-Chiari syndrome

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Topic 5: Acute Exacerbation of COPD (AECOPD)

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Definition

• Increased dyspnea
• Increased cough
• Increased sputum production and/or purulence
• Wheezing, chest tightness

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Triggers / Causes

• Respiratory infections (most common, ~70-80%):
  • Viral: rhinovirus, influenza, RSV, parainfluenza, adenovirus - account for ~50%
  • Bacterial: H. influenzae (most common), S. pneumoniae, M. catarrhalis; Pseudomonas aeruginosa in severe/frequent exacerbators
• Air pollution: particulates, ozone, SO₂, NO₂
• Unknown (~30% of exacerbations have no identifiable cause)

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Pathophysiology

• Viral/bacterial infection → mucosal inflammation → increased mucus secretion → bronchoconstriction → worsening airflow obstruction
• Air trapping → dynamic hyperinflation → increased intrinsic PEEP → increased work of breathing
• V/Q mismatch worsens → hypoxemia
• Respiratory muscle fatigue → hypercapnia → respiratory acidosis
• Hypoxic vasoconstriction → acute-on-chronic pulmonary hypertension → acute right heart strain

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Assessment and Severity Grading

History

• Baseline FEV₁ and functional status (important context)
• Number of prior exacerbations (≥2/year = "frequent exacerbator" phenotype)
• Home oxygen/NIV use
• Vaccination status
• Current medications

Physical Examination

• Use of accessory muscles, paradoxical breathing
• Cyanosis, asterixis (CO₂ narcosis)
• Tachycardia, tachypnea, diaphoresis
• Auscultation: wheeze, reduced air entry, crackles
• Signs of right heart failure (elevated JVP, peripheral edema, hepatomegaly)
• Sputum color: purulent = more likely bacterial

Investigations

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Differential Diagnosis

• Pneumothorax (can be catastrophic in severe COPD; check CXR urgently)
• Pneumonia (consolidation on CXR; higher fever, purulent sputum)
• Acute left ventricular failure (orthopnea, bilateral crackles, elevated BNP, cardiomegaly on CXR)
• Pulmonary embolism (pleuritic chest pain, elevated D-dimer; COPD patients have 3× increased PE risk)
• Cardiac ischaemia / arrhythmia (ECG)
• Upper airway obstruction

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Hospital Admission Criteria

• Severe dyspnea not responding to emergency treatment
• Severe underlying COPD (GOLD Stage III/IV; FEV₁ <30%)
• Hypoxemia (SpO₂ <90% on room air) or worsening hypercapnia
• Significant comorbidities (cardiac, renal, hepatic)
• New arrhythmia
• Diagnostic uncertainty
• Failure to respond to initial outpatient therapy
• Insufficient home support

• Respiratory arrest / hemodynamic instability
• Severe dyspnea not responding to therapy
• pH <7.25 with hypercapnia despite NIV
• Persistent/worsening hypoxemia despite O₂ and NIV
• Mental status changes (confusion, somnolence)
• Need for invasive mechanical ventilation

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Treatment

Step 1: Controlled Oxygen Therapy

• Target SpO₂: 88-92% (NOT 94-98%)
• Rationale: COPD patients may rely on hypoxic drive; over-oxygenation → CO₂ retention via Haldane effect, worsening V/Q mismatch, absorptive atelectasis
• Use Venturi mask (24% or 28%) or nasal cannulae at 1-2 L/min for precise O₂ delivery
• Titrate by ABG monitoring

Step 2: Bronchodilators

Methylxanthines (theophylline): not recommended for acute exacerbations due to risk of arrhythmias and narrow therapeutic window; if patient takes chronically, do NOT abruptly stop.

Step 3: Systemic Corticosteroids

• Prednisone 40 mg orally × 5 days (or IV methylprednisolone if unable to take orally)
• Benefits: improved FEV₁, shorter hospital stay, reduced treatment failure, reduced re-admission
• 5 days = as effective as 14 days (REDUCE trial) with fewer side effects
• Eosinophilic exacerbation (blood eosinophils ≥300 cells/µL) responds best to steroids

Step 4: Antibiotics

• All three major symptoms (dyspnea + sputum volume increase + sputum purulence) - Anthonisen Type I
• Two major symptoms if one is sputum purulence - Anthonisen Type II
• Requiring mechanical ventilation (invasive or non-invasive)

Step 5: Noninvasive Ventilation (NIV/BiPAP)

• Respiratory/cardiac arrest
• Hemodynamic instability
• Unable to cooperate (confusion, agitation)
• High aspiration risk
• Excessive/viscous secretions
• Recent facial or esophageal surgery
• Craniofacial trauma

Step 6: Invasive Mechanical Ventilation

• Failure of or contraindication to NIV
• pH <7.25 with rising PaCO₂ despite NIV
• PaO₂ <40 mmHg (5.3 kPa)
• RR >35/min
• Hemodynamic instability or cardiac arrest
• Altered consciousness

• Set respiratory rate to ALLOW adequate expiratory time (low RR, prolonged I:E ratio 1:3 or 1:4)
• Low tidal volume (6-8 mL/kg PBW)
• Minimize auto-PEEP (intrinsic PEEP from air trapping)
• Add external PEEP to match ~80% of intrinsic PEEP to reduce patient's inspiratory effort
• Target pH normalization rather than normal PaCO₂ (permissive hypercapnia)

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Additional Supportive Measures

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Discharge Criteria and Follow-up

• SABA required no more often than every 4h
• Patient can walk across room; able to eat and sleep without dyspnoea
• SpO₂ ≥90% on room air (or home O₂ level)
• Stable for 12-24h

• Switch to long-acting bronchodilators (LAMA ± LABA ± ICS based on GOLD group)
• Prescribe rescue inhaler; review inhaler technique
• Arrange follow-up within 4-6 weeks
• Pulmonary rehabilitation referral (reduces re-exacerbation by 25-50%)
• Smoking cessation counseling
• Influenza and pneumococcal vaccination
• Assess home oxygen need (reassess 8 weeks after exacerbation; acute hypoxia does not indicate long-term O₂ need)

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GOLD Severity Assessment (for stable COPD context)

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Summary of All 5 Topics

1. Sarcoidosis

2. Lupus Nephritis

3. Approach to Diarrhoea

4. Portal Hypertension

5. Acute Exacerbation of COPD