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High Altitude Pulmonary Edema (HAPE)

Definition

Pathophysiology

1. Overperfusion of some capillary beds
2. Elevated pulmonary capillary pressure (>18 mmHg)
3. Capillary "stress failure" and fluid leakage into alveoli

• Reduced nitric oxide (endothelium-derived vasodilator) due to endothelial dysfunction
• Elevated endothelin-1 (potent vasoconstrictor) in HAPE-susceptible individuals
• Increased sympathetic drive from hypoxia causing pulmonary venoconstriction
• Impaired alveolar fluid clearance (transepithelial sodium/water transport)
• Inflammation is an epiphenomenon, not the primary cause (though infections predispose)

Risk Factors

• Rapid ascent
• Prior history of HAPE
• Respiratory tract infections
• Cold environmental temperatures
• Male sex
• Cardiopulmonary abnormalities causing pulmonary hypertension (mitral stenosis, primary pulmonary hypertension, absent pulmonary artery)
• Patent foramen ovale (4x more common in HAPE-susceptible individuals)

Clinical Features

• Develops within 2-4 days of arriving at altitude
• Reduced exercise tolerance (earliest sign)
• Dry persistent cough, progressing to blood-tinged sputum
• Tachycardia and tachypnea at rest (important markers)
• Crackles on auscultation
• May be accompanied by signs of HACE

Investigations

• CXR: Patchy/localized opacities or streaky interstitial edema (not Kerley B lines or bat-wing pattern; the appearance can mimic pneumonia)
• ECG: Right ventricular strain or hypertrophy
• ABG/Pulse oximetry: Hypoxemia + respiratory alkalosis (metabolic acidosis if on acetazolamide)
• Echocardiography recommended if HAPE occurs at <3000 m or cardiopulmonary disease is suspected

Treatment

1. Descent - definitive treatment; even 300-1000 m can be life-saving
2. Supplemental oxygen - corrects hypoxemia rapidly
3. Gamow bag (portable hyperbaric chamber) - useful when descent is impossible
4. Nifedipine - 30 mg sustained-release, reduces pulmonary artery pressure
5. Phosphodiesterase-5 inhibitors (sildenafil/tadalafil) - reduce altitude-induced pulmonary hypertension
6. Dexamethasone - reduces HAPE incidence by ~78%; also useful in field treatment

Prevention

• Gradual ascent (best method)
• Nifedipine SR 30 mg twice daily for those who must ascend rapidly or have a prior HAPE history
• Tadalafil - reduces risk by ~65%
• Dexamethasone - reduces risk by ~78%
• Salmeterol inhaled (125 µg twice daily) - reduces incidence by ~50% (high dose; caution)

Source: Harrison's Principles of Internal Medicine, 22nd Edition (2025)

HAPE vs HACE - Comparison Table

• HAPE = Pulmonary - think breathlessness, crackles, pink frothy sputum - treat with Nifedipine
• HACE = Cerebral - think confusion, ataxia, coma - treat with Dexamethasone

NYHA Functional Classification of Dyspnoea

Introduction

• Assessing severity of functional impairment
• Prognostication
• Evaluating response to treatment

Classification

Types of Dyspnoea in Heart Failure (Spectrum of Severity)

Mechanism of Dyspnoea in Heart Failure

• Pulmonary venous congestion → fluid transudation into interstitium/alveoli
• Decreased lung compliance
• Increased airway resistance
• Hypoxemia and V/Q mismatch
• Stimulation of juxtacapillary J receptors → increased ventilatory drive
• Reduced blood flow to respiratory muscles → lactic acidosis

Important Notes

• NYHA class does not correlate well with objective measures like LV size or ejection fraction
• Unlike ACC/AHA staging (A → D), NYHA class is reversible - a Class IV patient can revert to Class II with appropriate guideline-directed medical therapy (GDMT)
• Limitations: subjective, affected by non-cardiac conditions (obesity, anaemia, emphysema, neuromuscular disease)

ACC/AHA Staging vs NYHA Classification (Quick Comparison)

Note: ACC/AHA stages are irreversible (cannot go backward); NYHA classes are reversible.

Treatment of Dioxin Toxicity

What is Dioxin?

• Contamination of Agent Orange (Vietnam War)
• Industrial accident in Seveso, Italy
• Assassination attempt on Viktor Yushchenko (Ukraine, 2004)

Mechanism of Toxicity

• TCDD binds the Aryl Hydrocarbon Receptor (AhR) - a ligand-activated transcription factor
• Activates CYP1A1, CYP1A2, CYP1B1 enzymes
• T-cell immunosuppression - promotes regulatory T-cell differentiation; depletes CD4+ T-helper cells; induces tolerogenic dendritic cells; inhibits B-cell antibody production
• Thymic involution/atrophy
• Half-life in humans: 7 to 11 years (due to resistance to metabolism)
• Elimination: primarily via feces
• Bioaccumulates in liver and adipose tissue (lipophilic)

Clinical Features of Dioxin Toxicity

Acute

• Chemical burn (skin)
• GI irritation

Chronic

Chloracne is the most characteristic and reliable clinical marker of dioxin toxicity. It may persist for long periods because dioxin is stored in the liver and released slowly into circulation.

Treatment

1. Remove from Exposure

• Immediate removal from the contaminated source
• Decontamination: remove and discard clothing, thorough skin washing

2. Decontamination / Reduce Absorption

• Activated charcoal - may reduce enteral absorption if ingestion is recent
• Cholestyramine - an anion exchange resin that interrupts enterohepatic recirculation of TCDD and increases fecal elimination (given the long half-life, this is a key long-term strategy)
• Olestra (fat substitute) - experimental; increases fecal elimination of lipophilic dioxins by acting as a non-absorbable fat carrier

3. Treatment of Chloracne

• Isotretinoin (13-cis-retinoic acid) - drug of choice for chloracne; same medications used in acne vulgaris apply
• Topical retinoids, antibiotics as needed

4. Treatment of Porphyria Cutanea Tarda

• Phlebotomy (venesection)
• Chloroquine (low-dose)
• Sun protection

5. Supportive Care

• Monitor and treat organ-specific complications (hepatotoxicity, immunosuppression)
• Surveillance for long-term cancer risk (lymphoma, GI malignancies)
• Psychological support

6. Long-Term Follow-up

• Regular monitoring of liver function, CBC, immune status
• Cancer screening

Key Points to Remember

• No antidote - treatment is supportive
• Chlorestyramine reduces body burden by interrupting enterohepatic recirculation
• Isotretinoin is used for chloracne
• Half-life is 7-11 years - chronic effects dominate
• Dioxin is a persistent organic pollutant (POP) - bioaccumulates up the food chain (primarily via fatty foods: dairy, meat, fish)

Management of Hypertriglyceridemia

Definition and Classification

Causes (Secondary - must be addressed)

• Metabolic: Obesity, diabetes mellitus, insulin resistance, metabolic syndrome, hypothyroidism
• Renal: Renal insufficiency, nephrotic syndrome
• Drugs: Oral estrogens, glucocorticoids, beta-blockers, tamoxifen, cyclosporine, antiretrovirals (protease inhibitors), retinoids, thiazides, atypical antipsychotics, sirolimus
• Dietary: Excess alcohol, high saturated fat diet, high carbohydrate diet
• Genetic: Familial hypertriglyceridemia, LPL deficiency, Apo C-II deficiency, Apo A-V deficiency

Goals of Treatment

• TG ≥ 500 mg/dL - primary goal is to prevent acute pancreatitis via TG reduction
• TG 200-499 mg/dL - primary goal is LDL-C reduction for cardiovascular risk; lifestyle changes first

A. Non-Pharmacological (Lifestyle / Dietary Measures)

1. Diet modification:
   • Very-low-fat diet (≤15% of calories from fat) for very high TG
   • Reduce simple carbohydrates and sugars
   • Avoid alcohol (increases VLDL production markedly)
   • Reduce saturated fat intake
2. Weight loss - especially important in central obesity/insulin resistance
3. Regular aerobic exercise
4. Glycemic control in diabetics
5. Treat underlying causes - hypothyroidism, renal disease, etc.
6. Stop offending drugs where possible (estrogens, thiazides, beta-blockers)

B. Pharmacological Management

1. Fibrates (First-line drug for high TG)

• Drugs: Fenofibrate, Gemfibrozil, Bezafibrate
• Mechanism: Activate PPAR-α → increase LPL activity → enhanced TG clearance; reduce VLDL synthesis
• TG reduction: 30-50%
• Use: TG ≥ 500 mg/dL or high CV risk with high TG
• Caution: Avoid gemfibrozil with statins (myopathy risk); if combined with statin, prefer pravastatin or rosuvastatin with fenofibrate (neither metabolized by CYP3A4)

2. Omega-3 Fatty Acids (Fish oil / Icosapentaenoic acid - EPA)

• Drugs: Omega-3 ethyl esters, Icosapentaenoic acid (EPA only - Vascepa/Icosapent ethyl)
• Mechanism: Reduce hepatic VLDL synthesis and secretion
• TG reduction: 20-50%
• Evidence: EPA only (not DHA) shown to reduce cardiovascular events in patients with elevated TG and established CV disease (REDUCE-IT trial)
• Use: High TG; especially in CAD patients or high CV risk

3. Niacin (Nicotinic acid)

• Mechanism: Inhibits hepatic VLDL synthesis and secretion; reduces free fatty acid mobilization from adipose tissue
• TG reduction: Immediate-release: 20-50%; extended-release: 10-30%
• Also: Raises HDL (most potent agent for raising HDL)
• Use: When insulin resistance is NOT present; less commonly used now due to side effects (flushing, hepatotoxicity, worsening glucose control)

4. Statins

• TG reduction: 10-30%
• Use: When LDL is also elevated alongside TG; not primarily for TG lowering
• Note: Useful in familial combined hyperlipoproteinemia; if combined with fibrate, choose pravastatin or rosuvastatin

5. Metformin

• Useful specifically in patients with insulin resistance causing hypertriglyceridemia

6. Emerging/Specialist Therapies

• Volanesorsen (Apo C-III antisense oligonucleotide) - available in Europe; reduces TG in familial chylomicronemia syndrome
• Plasmapheresis - for rapid TG reduction in acute pancreatitis setting with extremely high TG levels

Drug TG Reduction Summary

Special Situations

P2Y12 Receptor Blockers

Introduction

Mechanism of Action

• ADP released from damaged tissue binds platelet P2Y12 receptors
• This activates GP IIb/IIIa receptors, which bind fibrinogen and cause platelet aggregation
• P2Y12 blockers inhibit ADP binding to P2Y12 → prevent GP IIb/IIIa activation → block platelet aggregation and adhesion

Classification

Individual Drug Profiles

1. Clopidogrel

• Type: Thienopyridine; prodrug (requires hepatic activation via CYP2C19)
• Dose: 75 mg OD (maintenance); 300-600 mg loading dose
• Onset: 3-5 days (slow)
• Binding: Irreversible
• Key issue: CYP2C19 polymorphism - "poor metabolizers" have reduced response; PPIs (especially omeprazole) inhibit CYP2C19 and reduce efficacy
• Uses: ACS, recent MI or stroke, PAD, post-PCI stenting
• Preferred in: High bleeding risk patients (less potent = less bleeding)

2. Prasugrel

• Type: Thienopyridine; prodrug (single CYP-dependent step - faster, more reliable activation)
• Dose: 10 mg OD; 60 mg loading dose
• Onset: 2-4 hours (faster than clopidogrel)
• Binding: Irreversible
• Key issue: More potent than clopidogrel → higher bleeding risk
• Uses: ACS managed with PCI (STEMI, NSTEMI, UA)
• Contraindicated in: History of TIA or stroke; age >75 years; weight <60 kg (relative)
• Boxed warning: Bleeding

3. Ticagrelor

• Type: Cyclopentyl-triazolo-pyrimidine; not a prodrug (direct acting, no hepatic activation needed)
• Dose: 90 mg BD; 180 mg loading dose
• Onset: 2-4 hours; plasma half-life 6-13 hours → requires twice daily dosing
• Binding: Reversible
• Advantages: Faster onset, more consistent effect (no CYP2C19 variability), also blocks adenosine reuptake
• Unique side effects: Dyspnoea (due to adenosine accumulation), ventricular pauses, bradycardia
• Uses: ACS (UA, NSTEMI, STEMI); post-PCI; ischemic stroke/TIA
• Boxed warning: Bleeding; aspirin dose >100 mg reduces efficacy (use low-dose aspirin ≤100 mg only)

4. Ticlopidine

• Type: Thienopyridine; first-generation prodrug
• Binding: Irreversible
• Onset: 3-4 days
• Now rarely used due to severe adverse effects
• Serious ADRs: Agranulocytosis, Thrombotic Thrombocytopenic Purpura (TTP), aplastic anemia
• Use: TIA/stroke prevention in aspirin-intolerant patients (last resort)

5. Cangrelor

• Type: IV ATP analogue; direct-acting
• Dose: IV infusion
• Onset: Within 2 minutes (fastest)
• Half-life: 3-6 minutes (very short)
• Binding: Reversible
• Note: Cangrelor blocks clopidogrel and prasugrel binding to P2Y12 (competitive displacement) but not ticagrelor binding
• Use: Adjunct during PCI in patients not pre-treated with oral P2Y12 inhibitors

Comparison Table

Adverse Effects (Class-wide)

• Bleeding - most important; no antidote (platelet transfusion used if life-threatening)
• TTP - rare but possible with all agents; most common with ticlopidine
• Thrombocytopenia

Clinical Uses Summary

Important Drug Interaction

• Omeprazole + Clopidogrel - omeprazole inhibits CYP2C19, reducing clopidogrel activation; use pantoprazole instead if a PPI is needed
• Aspirin >100 mg + Ticagrelor - high-dose aspirin reduces ticagrelor efficacy (boxed warning)

Non-Cardiogenic Pulmonary Edema (NCPE)

Definition

Pathophysiology

• Direct or indirect lung injury → diffuse alveolar damage (DAD)
• Injury to alveolar epithelium and vascular endothelium → increased permeability
• Protein-rich fluid floods alveoli → impaired surfactant → alveolar collapse
• V/Q mismatch and intrapulmonary shunting → refractory hypoxemia
• Inflammatory mediators (cytokines, neutrophils, reactive oxygen species) amplify injury

Causes / Aetiology

Berlin Definition of ARDS (2012)

Severity Classification (Berlin)

Clinical Features

• Acute onset severe dyspnoea and tachypnoea
• Refractory hypoxemia (does not correct well with supplemental O₂)
• Bilateral crepitations on auscultation
• No signs of heart failure (no raised JVP, no S3, no cardiomegaly)
• Cyanosis in severe cases

Investigations

• CXR: Bilateral diffuse alveolar opacities; no cardiomegaly, no Kerley B lines, no upper lobe diversion (in contrast to cardiogenic edema)
• CT chest: Bilateral ground-glass opacities, consolidation (predominantly dependent zones)
• ABG: Hypoxemia + respiratory alkalosis (early); hypercapnia (late/severe)
• PaO₂/FiO₂ ratio - key diagnostic marker
• Echocardiography / PCWP: Normal (to exclude cardiogenic cause)
• BNP/NT-proBNP: Normal or mildly elevated (helpful in differentiation)
• Investigations to identify underlying cause (blood cultures, BAL, etc.)

Cardiogenic vs Non-Cardiogenic PE (Key Differences)

Management

1. Treat Underlying Cause

• Antibiotics for sepsis/pneumonia
• Lavage/decontamination for aspiration
• Stop offending drug; symptoms often resolve within days of drug discontinuation
• Source control for sepsis

2. Respiratory Support

• Low tidal volume: 6 mL/kg of predicted body weight (reduces volutrauma)
• Plateau pressure: ≤ 30 cmH₂O (reduces barotrauma)
• PEEP: Titrated upward to prevent alveolar collapse (atelectrauma); maintain adequate PaO₂ while minimizing FiO₂
• Target: PaO₂ 55-80 mmHg or SpO₂ 88-95%
• This strategy reduced mortality from 40% → 31% (NIH ARDSNet trial)

• Accepting elevated PaCO₂ as a consequence of low tidal volumes
• Avoid in raised intracranial pressure

3. Prone Positioning (Proning)

• For severe ARDS (PaO₂/FiO₂ < 150 mmHg)
• At least 16 hours/day
• Mechanism: Equalizes chest wall compliance; reduces lung compression by heart; improves V/Q matching
• Reduces 28-day mortality: 32.8% → 16.0% (PROSEVA trial, 2013)

4. Fluid Management

• Conservative fluid strategy - avoid excess IV fluids (reduces days on ventilator)
• No mortality benefit of liberal vs conservative fluids, but conservative strategy shortens ICU stay

5. High-Flow Nasal Oxygen (HFNO) / Non-Invasive Ventilation (NIV)

• Increasingly used in mild-moderate ARDS to avoid intubation
• HFNO provides CPAP-like effect and delivers high FiO₂

6. Pharmacological Adjuncts (limited evidence)

• Neuromuscular blocking agents (NMBAs): Cisatracurium - used to facilitate proning in moderate-severe ARDS; reduces ventilator dyssynchrony
• Corticosteroids: Used in specific causes (e.g., drug-induced ARDS, refractory ARDS); no universal benefit
• Inhaled nitric oxide / Prostacyclin: Improve oxygenation but no mortality benefit; used as bridge
• Surfactant: Benefit not demonstrated in adult ARDS (unlike neonates)

7. ECMO (Extracorporeal Membrane Oxygenation)

• For severe ARDS failing conventional ventilation
• Veno-venous (VV) ECMO provides oxygenation and CO₂ removal while allowing "lung rest"

8. General ICU Bundle Care

• VTE prophylaxis
• GI stress ulcer prophylaxis
• Head-of-bed elevation (30-45°) to prevent aspiration
• Enteral nutrition (preferred over parenteral)
• Prompt treatment of nosocomial infections

Prognosis

• Overall mortality: 27-45% depending on severity
• Survivors may have long-term pulmonary impairment, cognitive dysfunction, and PTSD

ECG Findings in Atrial Fibrillation (AF)

Definition

Classic ECG Features (The 5 Key Findings)

1. Absent P Waves

• No discrete, organized P waves visible
• In some patients, f waves are so small they are not perceptible - diagnosis is then based on the irregularly irregular rhythm alone

2. Fibrillatory (f) Waves

• Replace normal P waves
• Atrial rate: 350-600 beats/min
• Appear as rapid, irregular, low-amplitude baseline oscillations of varying morphology, amplitude, and timing
• Can be:
  • Coarse (amplitude >1 mm) - better seen, often in valvular AF (e.g., mitral stenosis)
  • Fine (amplitude <1 mm) - difficult to see, may appear as flat baseline
• Best seen in: Lead V1 and inferior leads (II, III, aVF)
• Important distinction: In lead V1, f waves can occasionally appear uniform and mimic atrial flutter waves

3. Irregularly Irregular Ventricular (QRS) Rhythm

• The hallmark and most reliable feature of AF
• R-R intervals vary constantly with no repeating pattern
• This is the defining feature even when f waves are not clearly visible

4. Normal QRS Complexes (Usually)

• QRS is typically narrow (≤0.12 sec) because ventricular conduction is normal
• Exceptions causing wide QRS in AF:
  • Pre-existing or rate-related bundle branch block (Ashman phenomenon)
  • Wolff-Parkinson-White (WPW) syndrome - conduction via accessory pathway → wide, bizarre QRS; ventricular rate may exceed 250 beats/min (dangerous - can degenerate to VF)
  • Ventricular pacing

5. Ventricular Rate

• Untreated AF: typically 100-160 beats/min
• Usually does not exceed 150-170 beats/min in adults with intact AV node
• AF + ventricular rate >200 beats/min → strongly suggests accessory pathway (WPW)
• Regularized AF (slow, regular ventricular rate): Suggests complete AV block with junctional/ventricular escape rhythm - classically associated with digoxin toxicity

Summary Table: AF ECG Features

AF vs Atrial Flutter (Quick ECG Comparison)

Classification of AF (for clinical context)

Special ECG Situations in AF

• Ashman phenomenon: Aberrant ventricular conduction of a beat following a long-short R-R cycle; the beat after the pause conducts with RBBB pattern - can mimic PVC
• AF + WPW: Wide, bizarre QRS at very fast rate (>200/min) - medical emergency; avoid AV nodal blocking agents (digoxin, verapamil, adenosine) as they accelerate conduction down the accessory pathway
• AF + complete heart block: Slow, regular ventricular rate with f waves visible - digoxin toxicity until proven otherwise

Ortner's Syndrome (Cardiovocal Syndrome)

Definition

Note: "Ortner's syndrome II" is an entirely different condition referring to abdominal angina - do not confuse the two.

Anatomical Basis (Why the LEFT nerve?)

• Branches from the left vagus nerve at the level of the transverse aortic arch
• Hooks under the arch of the aorta, posterior to the ligamentum arteriosum
• Ascends between the trachea and oesophagus to reach the larynx

Causes

Classic Cause

• Mitral stenosis (original description by Ortner) - enlarged left atrium compresses the LRLN

Expanded Causes (Cardiovascular)

Clinical Features

• Murmur of the underlying cardiac condition (most common PE finding)
• Signs of the causative disease (e.g., signs of mitral stenosis, pulmonary hypertension)

Investigations

Diagnosis

1. Hoarseness (dysphonia)
2. Confirmed LRLN palsy on laryngoscopy
3. Identified cardiovascular cause on imaging
4. Exclusion of other causes (malignancy, iatrogenic, etc.)

Management

1. Treat the Underlying Cause (Primary)

• This is the mainstay of treatment
• Mitral stenosis: Balloon mitral valvotomy (PTMC), surgical valvotomy, or valve replacement
• Aortic aneurysm: Endovascular or surgical repair
• Pulmonary hypertension: Pulmonary vasodilators (sildenafil, bosentan, prostacyclins), treat underlying cause

2. Voice/Laryngeal Management

• Vocal cord medialization (injection laryngoplasty or thyroplasty) for persistent hoarseness if nerve recovery is incomplete
• Voice therapy/speech therapy

3. Conservative Management

• ~27% of patients opt for non-surgical/conservative management
• Appropriate when surgical risk is high or patient declines intervention

4. Prognosis

• Potentially reversible syndrome - 85% of surgically treated patients had symptom improvement
• Prognosis of hoarseness depends on duration and severity of nerve compression
• Early recognition and treatment improves outcome
• Untreated: risk of recurrent aspiration pneumonia → significant morbidity/mortality

Summary Box