---

Harrison's Chapters 39-46: Complete Study Guide

Section 5 - Cardinal Manifestations of Cardiopulmonary Disease

---

CHAPTER 39 - DYSPNEA

Definition

Key clinical distinction: Dyspnea is a symptom (self-reported only). Signs of increased work of breathing - tachypnea, accessory muscle use, intercostal retraction - are objective findings.

Epidemiology

• Up to 1/2 of inpatients and 1/4 of ambulatory patients experience dyspnea
• Community prevalence: 9-13%, rising to 37% in adults ≥70 years
• Accounts for 3-4 million ER visits/year in the US
• Dyspnea severity may predict outcomes in COPD better than FEV1 - incorporated into GOLD guidelines
• Post-COVID persistent dyspnea has increased focus on this symptom

Mechanisms of Dyspnea

1. Afferent Signals (Receptors → CNS)

• Peripheral: carotid body and aortic arch
• Central: medulla (respond to hypercapnia)
• Activated by: hypoxemia, hypercapnia, acidemia
• Produce sensation of "air hunger"

• Upper airways, lungs (stretch receptors, irritant receptors, J receptors), chest wall (muscle spindles, Golgi tendon organs)
• Activated when increased airway resistance occurs (asthma, COPD) → chest tightness
• J receptors (juxtacapillary) in alveolar walls activated by pulmonary edema → rapid, shallow breathing

2. Efferent Signals (CNS → Respiratory Muscles)

• Corollary discharge signals sent to sensory cortex simultaneously with motor commands

3. Efferent-Reafferent Mismatch (Most Important Concept)

• When the CNS motor command does not match the sensory feedback from the chest/lungs, dyspnea is intensified
• Example: in neuromuscular disease, the motor command is large but chest wall movement is small - major mismatch

Qualitative Descriptors (Clinically Useful)

Differential Diagnosis of Dyspnea

Cardiac Causes

• Heart failure (left-sided: orthopnea, PND; right-sided: dependent edema, ascites)
• Pericardial effusion/tamponade
• Cardiomyopathy
• Ischemic heart disease (angina equivalent)
• Valvular disease (AS, MR, MS)

Pulmonary Causes

• COPD (most common in smokers)
• Asthma (episodic, reversible)
• Interstitial lung disease (progressive exertional)
• Pulmonary hypertension
• Pneumonia, pleural effusion
• Pneumothorax (acute onset)
• Pulmonary embolism

Non-Cardiopulmonary Causes

• Severe anemia (reduced O2 carrying capacity)
• Neuromuscular disease (ALS, Guillain-Barré)
• Obesity hypoventilation
• Metabolic acidosis (Kussmaul breathing)
• Anxiety/panic disorder
• Severe deconditioning

Distinguishing Cardiac from Pulmonary Dyspnea

Assessment Tools

• MRC Dyspnea Scale: grades 1-5 by exertion level that produces dyspnea
• Borg Scale: 0-10 rating of perceived exertion/dyspnea
• Modified Borg Scale: used during exercise testing
• SOBQ (Shortness of Breath Questionnaire): validated tool

Diagnostic Approach

1. History: onset, timing, triggers, qualitative description, associated symptoms
2. Physical exam: JVP, S3 gallop, crackles, wheezes, accessory muscle use
3. Pulse oximetry and ABG
4. Chest X-ray: cardiomegaly, pulmonary edema, effusions, hyperinflation
5. ECG: ischemia, arrhythmia, RV strain pattern
6. BNP/NT-proBNP: elevated in heart failure
7. Pulmonary function tests (PFTs): obstruction vs. restriction
8. Echocardiography
9. HRCT chest: ILD, emphysema
10. V/Q scan or CT pulmonary angiography: PE
11. Cardiopulmonary exercise testing (CPET): integrative assessment

Treatment

• Opioids (low-dose morphine): effective for refractory dyspnea in advanced disease - reduces air hunger sensation
• Anxiolytics (benzodiazepines): for anxiety-related dyspnea
• Supplemental O2: only beneficial if hypoxic (SpO2 <88-90%)
• Pulmonary rehabilitation for COPD
• Diuretics/vasodilators for heart failure

---

CHAPTER 40 - COUGH AND HEMOPTYSIS

COUGH

Definition and Mechanism

1. Afferent limb: Rapidly-adapting irritant receptors (RARs) and C-fibers in the larynx, trachea, and bronchi → via vagus nerve → cough center in medulla
2. Efferent limb: Vagus (larynx), phrenic and spinal motor nerves (diaphragm, intercostal, abdominal muscles)

Phases of Cough

1. Deep inspiration
2. Glottic closure (compressive phase) - intrathoracic pressure rises to 300 mmHg
3. Explosive expiration - air velocity up to 500 miles/hour achieved
4. Dynamic airway compression aiding mucus clearance

Causes of Chronic Cough (>8 weeks) - "The Usual Suspects"

1. Upper airway cough syndrome (UACS) - formerly "postnasal drip" - most common cause
2. Asthma - especially cough-variant asthma (no wheeze)
3. GERD - acid reflux triggering cough reflex
4. ACE inhibitor-induced cough - bradykinin/substance P accumulation; occurs in 5-20% of patients; class effect; resolves 1-4 weeks after stopping; switch to ARB
5. Non-asthmatic eosinophilic bronchitis (NAEB)

Other Causes by Timing

Impaired Cough - Clinical Consequences

• Aspiration pneumonia
• Atelectasis
• Inability to clear secretions (mucus plugging)

Evaluation

• Duration, character (dry vs. productive), hemoptysis, associated symptoms
• CXR first; if normal and patient is non-smoker, non-ACEi, stop smoking/ACEi then trial therapy
• If persistent: sinus CT, 24-hr pH monitor (GERD), spirometry, methacholine challenge (cough-variant asthma), HRCT chest

---

HEMOPTYSIS

Definition

• Hematemesis: vomiting blood (gastrointestinal) - typically with nausea, dark/brown color, low pH
• Nasopharyngeal bleeding: blood drips posteriorly, not coughed up

Classification

• Nonmassive (minor) hemoptysis: <100-200 mL/24h - most common; focus on diagnosis
• Massive hemoptysis: >100-600 mL/24h (definitions vary; >150 mL/24h commonly used) - life-threatening; death from asphyxiation (airway flooding), not blood loss

Anatomy - Why Hemoptysis is Mostly from Bronchial Arteries

• Bronchial arteries (systemic circulation, high pressure ~120 mmHg) supply the bronchi and are the source of 90% of hemoptysis
• Pulmonary arteries (low pressure ~25 mmHg) supply alveoli - less commonly the source

Causes of Hemoptysis

• Tuberculosis: cavitary disease; Rasmussen's aneurysm (pulmonary artery erosion into TB cavity) - massive hemoptysis
• Bronchitis/bronchiectasis: most common in industrialized countries
• Aspergilloma (fungus ball in pre-existing cavity - neovascularization → bleeding)
• Other endemic fungi, Nocardia, NTM
• Paragonimiasis - mimics TB; common in Southeast Asia/China; raw crayfish ingestion; consider in immigrants
• Lung abscess, necrotizing pneumonia (S. aureus, Klebsiella, oral anaerobes)

• Pulmonary edema (pink, frothy sputum from elevated LVEDP)
• Pulmonary embolism with infarction (uncommon, but possible)
• AVM (pulmonary arteriovenous malformation)
• Diffuse alveolar hemorrhage (DAH): ground-glass opacities on CT; NOT always associated with hemoptysis; causes include:
  • SLE, GPA (granulomatosis with polyangiitis), anti-GBM disease
  • Cocaine, vaping injury
  • Stem cell transplantation
• "Pulmonary-renal syndromes": GPA (anti-PR3/ANCA) and anti-GBM disease
• Aortobronchial fistula: rare; aortic aneurysm/pseudoaneurysm eroding into bronchus → herald bleeds before massive hemoptysis

• Bronchogenic carcinoma (any histology)
• Squamous cell and small cell: central, more likely to erode into major vessels
• Carcinoid tumors: arise in proximal airways, vascular

• Coagulopathy, anticoagulants, antiplatelet drugs
• Mitral stenosis (elevated pulmonary venous pressure)

Management of Hemoptysis

• History, exam, CXR, CT chest, bronchoscopy for diagnosis
• Treat underlying cause

1. Protect the airway - intubate with large-bore ETT; place bleeding lung DOWN (decubitus position with bleeding side dependent) to protect contralateral lung
2. Rigid bronchoscopy - gold standard for visualization and intervention in massive hemoptysis
3. Flexible bronchoscopy - useful for diagnosis and endobronchial tamponade
4. Bronchial artery embolization (BAE) - most effective immediate intervention; high success rate
5. Surgery - resection as last resort for localized, uncontrolled bleeding

---

CHAPTER 41 - HYPOXIA AND CYANOSIS

HYPOXIA

Definition

Causes of Hypoxemia (Low PaO2) - 5 Mechanisms

1. Hypoventilation - Low alveolar ventilation → CO2 rises, O2 falls. A-a gradient is normal. Response: A-a gradient = PAO2 - PaO2.
   • Examples: narcotic overdose, neuromuscular disease, obesity hypoventilation
2. V/Q Mismatch - Most common cause of hypoxemia clinically. Blood flows through poorly ventilated areas. A-a gradient is elevated. Corrects with supplemental O2.
   • Examples: COPD, asthma, pulmonary embolism
3. Shunt (R→L) - Blood bypasses ventilated alveoli. A-a gradient elevated. Does NOT correct with 100% O2 (hallmark feature).
   • Intracardiac: ASD, VSD, PFO with R→L shunting, tetralogy of Fallot
   • Intrapulmonary: AVM, hepatopulmonary syndrome, complete lobar consolidation/atelectasis
4. Diffusion impairment - Thickened alveolar-capillary membrane reduces O2 transfer. More pronounced with exercise. A-a gradient elevated.
   • Example: ILD, emphysema (reduced surface area)
5. Low inspired O2 (FiO2) - High altitude; A-a gradient is normal
   • Example: altitude, FiO2 <21% (rare clinical scenarios)

Response to Hypoxia

• Carotid body chemoreceptors → increased ventilation (hyperventilation → respiratory alkalosis)
• Sympathetic activation: tachycardia, peripheral vasoconstriction
• CNS effects: impaired judgment, confusion, unconsciousness at PaO2 <40 mmHg

• Erythropoiesis: hypoxia-inducible factor (HIF) → EPO production → polycythemia
• Right heart strain/cor pulmonale from chronic pulmonary hypertension
• Clubbing of fingers

Alveolar Gas Equation (Must Know)

---

CYANOSIS

Definition

• Cyanosis in anemia is rare (not enough absolute Hgb to have 5 g/dL deoxy-Hgb)
• Cyanosis in polycythemia is common at higher SpO2 levels

Central vs. Peripheral Cyanosis

Special Cases

• Upper body pink + lower body cyanotic: preductal coarctation with patent ductus arteriosus
• Right hand pink + left hand + lower body cyanotic: PDA with Eisenmenger physiology
• Lower body cyanotic only: PDA with large R→L shunt

• Ferrous Fe2+ → oxidized to ferric Fe3+ → cannot carry O2
• Causes: dapsone, nitrates, benzocaine, nitrites (recreational)
• Blood appears chocolate-brown
• SpO2 reads ~85% regardless of true MetHgb%
• Treatment: Methylene blue 1-2 mg/kg IV
• If G6PD deficient: use ascorbic acid instead

• Bright cherry-red skin (classic) but often not seen
• SpO2 falsely normal (pulse ox cannot distinguish COHgb from OxyHgb)
• Diagnose with co-oximetry (ABG machine measures actual COHgb%)

---

CHAPTER 42 - EDEMA

Pathophysiology - Starling Forces

• Pc = capillary hydrostatic pressure (pushes fluid OUT)
• Pi = interstitial hydrostatic pressure (pushes fluid IN)
• πp = plasma oncotic pressure (pulls fluid IN)
• πi = interstitial oncotic pressure (pulls fluid OUT)
• Kf = filtration coefficient
• σ = reflection coefficient

Causes of Edema - Mechanisms

• Right heart failure → elevated systemic venous pressure
• Deep vein thrombosis → elevated limb venous pressure
• Hypoalbuminemia → splanchnic vasodilatation → secondary renal sodium retention
• Cirrhosis with portal hypertension

• Nephrotic syndrome (massive proteinuria)
• Cirrhosis (reduced albumin synthesis)
• Severe malnutrition / kwashiorkor
• Protein-losing enteropathy

• Inflammation (cellulitis, burns)
• Allergic reactions (angioedema)
• Sepsis (leaky capillaries)
• ARDS

• Milroy's disease (congenital lymphedema)
• Filariasis (Wuchereria bancrofti) - tropical cause of elephantiasis
• Post-surgical lymph node dissection (e.g., post-mastectomy lymphedema)
• Malignant lymphatic obstruction

Neurohumoral Mediators of Edema in Heart Failure

• Secreted by posterior pituitary in response to increased osmolality
• In heart failure: non-osmotic AVP release due to reduced effective arterial volume and reduced LA compliance
• Binds V2 receptors in collecting duct → free water reabsorption → hyponatremia + edema

• Released by endothelial cells
• Elevated in severe heart failure
• Contributes to renal vasoconstriction and sodium retention

• ANP: released from atrial myocytes when stretched → natriuresis, diuresis, vasodilation
• BNP: released from ventricular myocytes when ventricular diastolic pressure rises → same effects
• Both oppose sodium retention, but in established heart failure they are insufficient to prevent edema
• Resistance to natriuretic peptides develops in edematous states

Clinical Causes of Edema

• Pitting edema of lower extremities
• Worse in evening, better in morning (positional)
• In bedridden patients: presacral edema
• Associated: JVP elevated, S3, hepatomegaly

• Periorbital, facial edema - most prominent in morning (recumbent overnight)
• Generalized, soft tissue
• Massive proteinuria >3.5 g/day, hypoalbuminemia, hyperlipidemia

• Ascites disproportionately prominent
• Peripheral edema often coexists
• Portal hypertension → splanchnic vasodilation → reduced effective arterial volume → RAAS activation
• SAAG ≥1.1 g/dL confirms portal hypertension as cause of ascites

• Kwashiorkor: protein deficiency → edema despite adequate calories
• Anasarca in severe malnutrition

• Non-pitting facial edema (especially periorbital)
• Caused by glycosaminoglycan deposition, not fluid

• Primarily women of reproductive age
• Cyclical pattern; worsens in heat and premenstrually
• May be related to abnormal capillary permeability

• CCBs (particularly dihydropyridines): peripheral vasodilation → increased capillary pressure
• NSAIDs: sodium retention
• Corticosteroids: mineralocorticoid effects
• Thiazolidinediones (TZDs): renal tubular sodium retention
• Estrogens

Distribution of Edema - Key Clinical Guide

Approach to Patient with Edema

1. Localized or generalized?

• Localized → look for local cause (DVT, lymphedema, cellulitis, trauma)

1. If generalized: hypoalbuminemia present (albumin <3.0 g/dL)?

• Yes → cirrhosis, nephrotic syndrome, malnutrition, PLE

1. If albumin normal: signs of heart failure?

• Elevated JVP, S3, cardiomegaly, BNP elevated → cardiac cause

1. Check urine output: oliguria/anuria → renal cause

---

CHAPTER 43 - CHEST PAIN

Overview

Dangerous "Must-Not-Miss" Causes (The ACUTE Chest Pain Differentials)

1. Acute coronary syndrome (ACS) - STEMI, NSTEMI, unstable angina
2. Aortic dissection - tearing, ripping, radiates to back
3. Pulmonary embolism - pleuritic, sudden onset, with dyspnea and hypoxia
4. Tension pneumothorax - sudden, tracheal deviation, hypotension
5. Esophageal rupture (Boerhaave's) - sudden after vomiting, Hamman's sign (mediastinal crunch)
6. Cardiac tamponade - Beck's triad (hypotension, muffled heart sounds, JVD)

Causes by Character and Location

Ischemic/Cardiac

• Substernal pressure/squeezing, radiates to left arm/jaw/shoulder
• Triggered by exertion or emotional stress
• Relieved by rest or nitroglycerin within 5 minutes
• Canadian Cardiovascular Society (CCS) grading I-IV

• Same quality as above but at rest, prolonged (>20 min), or new-onset severe
• ST depression, T-wave changes; troponin elevated (NSTEMI) or normal (UA)

• ST elevation in ≥2 contiguous leads
• New LBBB with symptoms is STEMI-equivalent
• Time is muscle: door-to-balloon <90 min

• Sharp, pleuritic chest pain (worse with inspiration, better leaning forward)
• Friction rub (best heard with patient leaning forward)
• ECG: diffuse ST elevation with PR depression (PR depression pathognomonic)
• Saddle-shaped ST elevation (in contrast to STEMI's localized changes)
• Treatment: NSAIDs + colchicine (prevents recurrence)

• Chest pain + troponin elevation in young patients
• No obstructive CAD on cath
• Post-viral (Coxsackie B, parvovirus B19, SARS-CoV-2, COVID vaccine-related)

Aortic Causes

• Tearing/ripping pain, maximal at onset, radiates to the back
• Type A (ascending aorta involved): surgical emergency
• Type B (descending only): often managed medically
• BP differential between arms (>20 mmHg)
• CXR: widened mediastinum
• CT angiography: diagnostic gold standard
• Risk factors: hypertension, Marfan syndrome, bicuspid aortic valve, cocaine

Pulmonary Causes

• Pleuritic chest pain (sharp, worse with breathing), sudden onset
• Associated dyspnea, tachycardia, hypoxia
• Risk factors: Virchow's triad (stasis, hypercoagulability, endothelial injury)
• ECG: sinus tachycardia most common; S1Q3T3 pattern; new right bundle branch block
• CT pulmonary angiography: diagnostic gold standard
• D-dimer: high sensitivity, low specificity (useful to rule OUT if pre-test probability low)

• Sharp, well-localized, worse with inspiration and movement
• Causes: pneumonia, viral pleuritis, PE, autoimmune (SLE, RA)

• Sudden sharp chest pain, ipsilateral, with dyspnea
• Spontaneous: young, tall, thin males; Marfan syndrome
• Secondary: COPD (emphysema bullae), CF, mechanical ventilation
• Tension: requires immediate needle decompression (2nd ICS, MCL) then chest tube

Esophageal/GI Causes

• GERD: burning, substernal, worse after meals and lying down, relieved by antacids
• Esophageal spasm: can exactly mimic angina - substernal squeezing, may be relieved by nitroglycerin
• Mallory-Weiss tear: hematemesis after retching, without perforation
• Boerhaave syndrome: transmural esophageal rupture after forceful vomiting - severe pain, Hamman's sign, mediastinitis (surgical emergency)
• Peptic ulcer disease: epigastric, food-related pattern
• Biliary colic: right upper quadrant, after fatty meals, colicky

Musculoskeletal Causes

• Costochondritis (Tietze syndrome): reproducible tenderness on palpation of costochondral junctions
• Chest wall strain: history of trauma, exertion
• Rib fracture: focal bony tenderness, history of trauma or osteoporosis

Anxiety/Psychogenic

• Panic attacks: tachycardia, hyperventilation, diaphoresis, sense of doom
• Associated with paraesthesias (from hyperventilation-induced respiratory alkalosis → hypocalcemia)
• Diagnosis of exclusion

ECG Changes Summary (Must Know)

---

CHAPTER 44 - APPROACH TO THE PATIENT WITH A HEART MURMUR

Overview

Mechanisms of Heart Murmurs

1. Accelerated flow through normal or abnormal orifice
2. Flow through a narrowed/irregular orifice into a dilated vessel or chamber
3. Backward (regurgitant) flow through incompetent valve, VSD, or PDA

Classification by Timing

Systolic Murmurs

• Begin with or after S1, end at or before S2

• Crescendo-decrescendo pattern
• Arise from flow through the aortic or pulmonic valve
• Causes: AS, aortic sclerosis (benign), HCM, PS, increased flow states (anemia, pregnancy, fever, thyrotoxicosis - "innocent" flow murmur)
• Aortic stenosis (AS): harsh, midsystolic, right 2nd ICS, radiates to carotids; parvus et tardus pulse; S4 gallop; single S2 (A2 soft/absent)
• Severity: mild (<20 mmHg gradient), moderate (20-40 mmHg), severe (>40 mmHg mean or AVA <1.0 cm2)

• Begin with S1 and continue to S2 - occurs when pressure gradient exists throughout systole
• Causes: MR, TR, VSD
• Mitral regurgitation (MR): blowing, pansystolic, apex, radiates to axilla; S3 (due to rapid ventricular filling)
• Tricuspid regurgitation (TR): pansystolic at LLSB; increases with inspiration (Carvallo's sign)
• VSD: harsh, pansystolic, LLSB

• Mitral valve prolapse (MVP): mid-systolic click followed by late systolic murmur
• Click and murmur move EARLIER with maneuvers that decrease LV volume (standing, Valsalva)
• Click and murmur move LATER with maneuvers that increase LV volume (squatting, lying supine)

Diastolic Murmurs (Always Pathological)

• Early diastolic (decrescendo): AR, PR
• Mid-diastolic (rumble): MS, TS (tricuspid stenosis), Austin Flint murmur (severe AR)
• Late diastolic (presystolic): MS in sinus rhythm (augmented by atrial contraction)

• High-pitched, blowing, decrescendo
• Best heard at aortic or Erb's point (3rd LICS) with patient leaning forward, breath held in expiration
• Chronic severe AR: wide pulse pressure, water-hammer (Corrigan's) pulse, Quincke's pulsations, de Musset's sign (head bobbing), Duroziez's sign (femoral artery to-and-fro murmur), pistol-shot sounds
• Austin Flint murmur: apical mid-diastolic rumble in severe AR (AR jet impinges on mitral valve leaflet, causing functional MS)

• Low-pitched rumble (use bell of stethoscope), best at apex
• Opening snap (OS): high-pitched, shortly after S2 → A2-OS interval inversely related to severity (shorter = more severe; LA pressure higher, valve opens earlier)
• Loud S1 (pliable valve in early/mild disease)
• In severe MS: secondary pulmonary hypertension → loud P2, Graham Steell murmur (PR from pHTN)
• Rheumatic fever is the most common worldwide cause of MS

• Decrescendo, early-mid diastolic murmur
• Begins after P2, best at 2nd LICS
• Usually due to pulmonary hypertension causing annular dilation
• Increases with inspiration

Continuous Murmurs

• Heard in both systole and diastole (not to be confused with "to-and-fro" = separate systolic + diastolic murmurs)
• Causes: PDA (most common), AV fistula, Blalock-Taussig shunt, coronary artery fistula
• PDA: machinery murmur, best at left infraclavicular area, peaks at S2

Bedside Maneuvers (Critical for Exams)

Grading of Murmur Intensity (Levine Scale)

Innocent (Benign) Murmurs

• Grade I-II/VI midsystolic murmur
• Normal S1, S2
• No other abnormal signs
• Still flow (changed with position)
• Common in children, pregnancy, fever, anemia, athletes
• Still's murmur: musical/vibratory quality, 2nd-4th LICS in children

Indications for Echo

• Any diastolic murmur (always pathological)
• Systolic murmur grade ≥III/VI
• Any murmur with symptoms (dyspnea, syncope, chest pain)
• Late systolic murmur (MVP)
• Continuous murmurs
• Any murmur in a patient with a relevant clinical history (valve disease, endocarditis risk, etc.)

---

CHAPTER 45 - PALPITATIONS

Definition

Causes

Cardiac Arrhythmias

• SVT (AVNRT most common): sudden onset and offset, regular fast rate 150-250 bpm, "neck pulsations" (cannon A waves from RA contracting against closed TV)
• Atrial fibrillation: irregularly irregular, common in older patients, thyrotoxicosis, alcohol
• Atrial flutter: regular, rate ~150 bpm (2:1 block of flutter at 300 bpm); sawtooth P waves in II, III, aVF
• PACs: "flip-flop" or "skipped beat" sensation - actually the compensatory pause after the PAC that is felt

• PVCs: "skipped beat," "thump" - the pause and then the stronger post-PVC beat
• PVCs are benign in structurally normal heart
• Bigeminy (every other beat), trigeminy (every third beat)
• PVC burden >10-15% on Holter may cause tachycardia-induced cardiomyopathy
• VT: rapid, life-threatening; structural heart disease (post-MI, cardiomyopathy)
• Torsades de pointes: polymorphic VT; long QT syndrome (congenital or drug-induced)

Non-Cardiac Causes

• Anxiety/panic attacks: tachycardia + awareness of heartbeat; often associated with hyperventilation
• Anemia: increased cardiac output
• Thyrotoxicosis: sinus tachycardia or AF; tremor, weight loss, heat intolerance
• Pheochromocytoma: episodic hypertension + palpitations + diaphoresis (the triad)
• Hypoglycemia: sympathetic surge
• Fever
• Caffeine, stimulants, cocaine, amphetamines
• Beta-agonists (albuterol, theophylline)

Diagnostic Approach

History (Most Important)

• Regularity: regular vs. irregular
• Onset/offset: sudden (arrhythmia) vs. gradual (sinus tachycardia)
• Rate: fast (tachyarrhythmia) vs. slow (bradyarrhythmia)
• Associated symptoms: presyncope, syncope, chest pain, dyspnea (suggest serious arrhythmia)
• Triggers: exercise (VT, RVOT tachycardia, catecholaminergic PVT), caffeine, alcohol, stress
• Neck pulsations with SVT: cannon A waves

Physical Exam

• Thyroid examination
• BP both arms
• Cardiac exam: murmurs suggesting structural disease
• Signs of HF

Investigations

• ECG (12-lead): first test always
• Delta wave: WPW (pre-excitation)
• Prolonged QTc: >440 ms in men, >460 ms in women (risk for torsades)
• Short PR + delta wave: WPW
• Epsilon wave + RBBB: ARVC
• Holter monitor (24-48h): for frequent palpitations
• Event recorder (30 days): for infrequent palpitations
• Implantable loop recorder: for very infrequent, unexplained episodes
• Exercise stress test: for exercise-induced arrhythmias
• Echo: structural heart disease
• Electrophysiology (EP) study: for sustained VT, WPW with syncope

Prolonged QT - Key Drug Causes (Must Know)

• Antibiotics: quinolones, macrolides (azithromycin, clarithromycin)
• Antifungals: fluconazole
• Antipsychotics: haloperidol, droperidol, ziprasidone, quetiapine
• Antidepressants: TCAs, citalopram at high doses
• Antiarrhythmics: sotalol, amiodarone, quinidine (class Ia and III)
• Methadone
• Electrolyte abnormalities: hypokalemia, hypomagnesemia, hypocalcemia (can extend QTc)

---

CHAPTER 46 - SYNCOPE AND PRESYNCOPE

Definition

Mechanisms

1. Reduced cardiac output (arrhythmia, structural obstruction)
2. Systemic vasodilation with inadequate compensation
3. Both simultaneously

Classification and Causes

1. Neurally Mediated (Reflex) Syncope - Most Common Overall

• Vasovagal syncope (common faint): most common type
• Triggered by: prolonged standing, emotional stress, pain, fear, phlebotomy, heat
• Prodrome: nausea, diaphoresis, pallor, yawning, lightheadedness
• Mechanism: Bezold-Jarisch reflex - vigorous LV contraction in volume-depleted state → C-fiber activation → paradoxical vagal activation → bradycardia + vasodilation
• Benign prognosis; upright tilt-table test can confirm
• Situational reflex syncope: cough syncope, micturition syncope, defecation syncope, deglutition syncope, post-exercise syncope, post-prandial
• Carotid sinus syndrome: exaggerated response to carotid sinus pressure; occurs in elderly men; triggered by head-turning, shaving neck, tight collar

2. Orthostatic Hypotension Syncope

• Defined as drop in SBP ≥20 mmHg or DBP ≥10 mmHg within 3 minutes of standing
• Causes:
• Hypovolemia (dehydration, hemorrhage, diarrhea)
• Autonomic failure: Parkinson's disease, MSA (multiple system atrophy), pure autonomic failure, diabetic autonomic neuropathy
• Medications: antihypertensives, diuretics, alpha-blockers, TCAs, levodopa
• Post-prandial hypotension: common in elderly; splanchnic pooling after meals

3. Cardiac Syncope (Most Dangerous Type)

• Bradyarrhythmias: Sick sinus syndrome, high-degree AV block (Mobitz II or 3rd degree), pacemaker malfunction
• Tachyarrhythmias: VT (especially in structural heart disease), SVT with rapid ventricular response, torsades de pointes
• Onset is abrupt (no prodrome), recovery is rapid - classic feature of arrhythmic syncope

• Aortic stenosis: syncope on exertion (inability to increase CO with exertion) - classic triad: angina, syncope, dyspnea; worst prognosis
• HCM: dynamic LVOT obstruction; exercise-induced syncope in young athletes
• Massive PE: acute right heart failure → reduced LV preload → syncope
• Cardiac tamponade: pulsus paradoxus, Beck's triad
• Pulmonary hypertension: exertional syncope from inability to increase CO
• Left atrial myxoma: ball-valve obstruction of mitral valve; positional syncope

Features Distinguishing Syncope from Seizure

Convulsive syncope: brief myoclonic jerks CAN occur during syncope (from cerebral hypoperfusion), which can be mistaken for seizure - key distinction is the cardiac origin.

High-Risk Features in Syncope (Require Urgent Workup/Admission)

• Syncope during exertion (aortic stenosis, HCM, pulmonary HTN, RVOT obstruction)
• Syncope with chest pain, palpitations preceding event
• Sudden onset without prodrome
• Known structural heart disease or CAD
• Family history of sudden cardiac death
• Abnormal ECG (QTc prolongation, Brugada pattern, pre-excitation, LBBB, Q waves)
• Age >60 with unexplained syncope

Diagnostic Workup

Initial (All Patients)

1. History and physical (highest diagnostic yield - identifies cause in 50-60% of cases)
2. 12-lead ECG
3. Orthostatic BP measurements

Targeted (Based on Suspicion)

• Echo: suspected structural heart disease, exertional syncope
• Tilt-table test: vasovagal (sensitivity 60-80%); patient tilted 60-80° for 20-45 minutes; may add sublingual nitroglycerine for pharmacologic provocation
• Holter/event monitor: suspected arrhythmic syncope
• Implantable loop recorder (ILR): unexplained syncope with high clinical suspicion; records for up to 3 years
• EP study: suspected VT, bundle branch block with syncope
• Carotid sinus massage: suspected carotid sinus syndrome (performed with ECG and BP monitoring)
• Neuroimaging (MRI/CT): only if neurological cause suspected (NOT routine for syncope)
• Tilt-table test, EEG: for distinguishing seizure from syncope when needed

Management

• Education and reassurance (benign)
• Physical counter-pressure maneuvers (leg crossing, squatting, tensing muscles during prodrome)
• Increased salt and fluid intake
• Avoid triggers
• Compression stockings
• Medications if recurrent: fludrocortisone, midodrine, beta-blockers (limited evidence), SSRIs, pyridostigmine
• Permanent pacing only in rare cases of cardioinhibitory (asystole-dominant) vasovagal syncope in older patients (ISSUE-3 trial)

• Remove offending medications
• Increased salt, fluids
• Compression stockings, abdominal binder
• Medications: midodrine (alpha-1 agonist), fludrocortisone (mineralocorticoid)
• Droxidopa for neurogenic OH

• Pacemaker: for symptomatic bradycardia, high-degree AV block, sick sinus
• ICD: for VT/VF syncope, especially with reduced EF
• Ablation: for SVT, VT, WPW

• Treat the underlying condition (AVR for AS, septal reduction for HCM, etc.)

---

HIGH-YIELD SUMMARY TABLE - Chapters 39-46

---