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Summary Table

Feature	Detail
Risk Factors	COPD, neuromuscular disease (e.g., Guillain-Barr syndrome, myasthenia gravis), morbid obesity, drug overdose (opioids, benzodiazepines), ARDS triggers (sepsis, aspiration, pancreatitis, trauma), interstitial lung disease, chest wall deformities (kyphoscoliosis)
Etiology	Failure of oxygenation (Type 1) or failure of ventilation (Type 2), or both. Underlying mechanisms include V/Q mismatch, intrapulmonary shunt, diffusion impairment, and alveolar hypoventilation
Patient Presentation	Dyspnea, tachypnea, accessory muscle use, altered mental status (especially in hypercapnia), cyanosis, diaphoresis. In chronic cases: morning headaches, daytime somnolence, polycythemia
Classic Physical Exam	Tachypnea (RR > 20), paradoxical abdominal breathing (diaphragm fatigue), accessory muscle recruitment, cyanosis, asterixis and somnolence (CO2 narcosis in Type 2), diffuse crackles (if ARDS/pneumonia), diminished breath sounds (if COPD/pneumothorax)
Key Diagnostic Results	ABG: PaO2 < 60 mmHg (Type 1) or PaCO2 > 50 mmHg (Type 2); elevated A-a gradient (V/Q mismatch, shunt, diffusion defect) vs. normal A-a gradient (pure hypoventilation); CXR findings vary by etiology; PaO2/FiO2 ratio < 300 in ARDS
Management	Supplemental O2 (target SpO2 92-96%, or 88-92% in COPD); non-invasive positive pressure ventilation (BiPAP for acute hypercapnic failure); intubation and mechanical ventilation for refractory cases; lung-protective ventilation (6 mL/kg IBW, Pplat < 30 cmH2O) in ARDS; treat the underlying cause
Keywords	"Hypoxemia refractory to supplemental oxygen" (shunt), "CO2 narcosis," "A-a gradient," "bilateral opacities not explained by effusion," "PaO2/FiO2 ratio," "paradoxical abdominal breathing," "acute-on-chronic"

1. Pathophysiology

Respiratory failure occurs when the respiratory system fails to maintain adequate gas exchange. It is defined by arterial blood gas (ABG) criteria, not by clinical appearance alone. The two primary functions of the lung that can fail are oxygenation (getting oxygen into the blood) and ventilation (removing carbon dioxide from the blood). Understanding which function has failed, and why, is the foundation for every exam question on this topic.

Type 1 (hypoxemic) respiratory failure is defined as $PaO_2 < 60\ mmHg$ with a normal or low $PaCO_2$. The underlying problem is a failure of oxygen transfer across the alveolar-capillary membrane. Four mechanisms can cause this. V/Q mismatch is the most common cause overall: blood perfuses alveoli that are poorly ventilated (e.g., pneumonia filling alveoli with exudate, or asthma causing bronchoconstriction), resulting in venous admixture and decreased PaO2. Intrapulmonary shunt is the extreme form of V/Q mismatch where perfusion continues through completely non-ventilated alveoli (e.g., ARDS, complete lobar consolidation, or atelectasis). The hallmark of true shunt is that hypoxemia does not correct with supplemental oxygen, because the shunted blood never contacts ventilated alveoli. Diffusion impairment occurs when the alveolar-capillary membrane is thickened (e.g., interstitial lung disease, pulmonary fibrosis), reducing oxygen transfer, although CO2 diffuses 20 times more readily and is usually unaffected. Low inspired oxygen (high altitude) is a less common but testable cause.

Type 2 (hypercapnic) respiratory failure is defined as $PaCO_2 > 50\ mmHg$. The fundamental problem is alveolar hypoventilation: the patient cannot move enough air to clear CO2. The relationship is governed by the equation:

$$PaCO_2 = \frac{VCO_2 \times k}{V_A}$$

Where $VCO_2$ is CO2 production, $k$ is a constant, and $V_A$ is alveolar ventilation. Anything that reduces alveolar ventilation (reduced respiratory drive, neuromuscular weakness, chest wall restriction, or severe airflow obstruction) raises PaCO2. Importantly, hypoventilation causes hypoxemia as well, because as PaCO2 rises, PAO2 must fall (as described by the alveolar gas equation). This is why Type 2 failure often involves both hypercapnia and hypoxemia simultaneously.

The alveolar gas equation and the A-a gradient are the conceptual tools that connect pathophysiology to diagnosis:

$$PAO_2 = FiO_2 \times (P_{atm} - P_{H_2O}) - \frac{PaCO_2}{R}$$

Where $P_{atm} = 760\ mmHg$, $P_{H_2O} = 47\ mmHg$, $FiO_2 = 0.21$ on room air, and $R = 0.8$ (respiratory quotient).

$$A\text{-}a\ gradient = PAO_2 - PaO_2$$

A normal A-a gradient (approximately $< \frac{Age}{4} + 4$) means the lungs themselves are functioning normally and the problem is purely hypoventilation (CNS depression, neuromuscular weakness). An elevated A-a gradient points to intrinsic lung pathology: V/Q mismatch, shunt, or diffusion impairment. This distinction is one of the most frequently tested concepts in respiratory physiology.

When interpreting the ABG in respiratory failure, the pH and bicarbonate tell you whether the process is acute or chronic. In acute respiratory acidosis, renal compensation has not yet occurred: for every 10 mmHg rise in PaCO2, bicarbonate rises only by ~1 mEq/L and pH drops by ~0.08. In chronic respiratory acidosis (over 3 to 5 days), the kidneys retain bicarbonate: for every 10 mmHg rise in PaCO2, bicarbonate rises by ~3.5 mEq/L, partially normalizing the pH. A patient with a PaCO2 of 70 mmHg and a near-normal pH has chronic hypercapnic failure; a patient with PaCO2 of 70 and pH of 7.15 has acute failure and needs urgent intervention.

2. Classification and Clinical Manifestation

By Type

Type	Definition	A-a Gradient	Key Mechanism	Classic Causes
Type 1 (Hypoxemic)	$PaO_2 < 60\ mmHg$, $PaCO_2$ normal or low	Elevated	V/Q mismatch, shunt, diffusion impairment	Pneumonia, ARDS, pulmonary embolism, pulmonary edema, ILD
Type 2 (Hypercapnic)	$PaCO_2 > 50\ mmHg$	Normal (pure hypoventilation) or elevated (if concurrent lung disease)	Alveolar hypoventilation	COPD exacerbation, opioid overdose, neuromuscular disease (GBS, MG), obesity hypoventilation, kyphoscoliosis
Type 3 (Perioperative)	Subtype of Type 1	Elevated	Atelectasis from anesthesia, splinting	Post-surgical patients (upper abdominal/thoracic surgery)
Type 4 (Shock)	Hypoperfusion-related	Elevated	Respiratory muscle hypoperfusion, increased O2 extraction	Cardiogenic shock, septic shock, hemorrhagic shock

By Acuity

Feature	Acute	Chronic	Acute-on-Chronic
Onset	Minutes to hours	Weeks to months	Acute deterioration superimposed on chronic baseline
pH	Significantly abnormal (uncompensated)	Near-normal (compensated)	pH drops from a compensated baseline
Bicarbonate	Minimally elevated (if hypercapnic)	Significantly elevated (renal compensation)	Elevated baseline with acute drop in pH
Clinical Clue	Acute distress, tachypnea, confusion	Polycythemia, cor pulmonale, elevated bicarbonate on BMP	COPD patient with infection triggering acute decompensation
Classic Example	Massive PE, acute pneumonia, ARDS	End-stage COPD, severe ILD, chronic NMD	COPD patient with baseline PaCO2 55 who develops pneumonia with PaCO2 rising to 80

By Type

Feature	Hypoxemia (Type 1)	Hypercapnia (Type 2)
Respiratory	Tachypnea, dyspnea, accessory muscle use, cyanosis	Shallow or slow respirations (if CNS depression), paradoxical abdominal movement
Cardiovascular	Tachycardia, hypertension (sympathetic response), arrhythmias if severe	Bounding pulse, peripheral vasodilation, warm extremities
Neurologic	Restlessness, agitation, confusion (late)	Somnolence, confusion, headache (especially morning), asterixis, coma (CO2 narcosis)
Other	Diaphoresis	Papilledema (raised ICP from cerebral vasodilation), tremor

3. Diagnostic Workup

Test	Role	Key Findings
Pulse Oximetry	Screening/triage	SpO2 < 90% suggests PaO2 < 60 mmHg (based on oxyhemoglobin dissociation curve); does NOT detect hypercapnia
Arterial Blood Gas (ABG)	Gold standard for diagnosis	Defines Type 1 ($PaO_2 < 60$) vs. Type 2 ($PaCO_2 > 50$); allows A-a gradient calculation; determines acid-base status and acuity
A-a Gradient (calculated)	Differentiates mechanism	Normal: pure hypoventilation (extrapulmonary). Elevated: intrinsic lung disease (V/Q mismatch, shunt, diffusion defect)
Chest X-Ray	First-line imaging	Identifies etiology: consolidation (pneumonia), bilateral opacities (ARDS/edema), hyperinflation (COPD), clear lungs (PE, NMD)
PaO2/FiO2 Ratio	Severity grading in ARDS	Mild: 200-300; Moderate: 100-200; Severe: < 100 (all with PEEP $\geq$ 5 cmH2O)
CT Pulmonary Angiography	If PE suspected	Filling defect in pulmonary arteries
Echocardiography	If cardiogenic cause suspected	LV dysfunction, elevated filling pressures, valvular pathology
Pulmonary Function Tests	Chronic/stable settings	Obstructive pattern (COPD), restrictive pattern (ILD, NMD), reduced DLCO (diffusion impairment)

The best initial test in any patient with respiratory distress is pulse oximetry combined with clinical assessment. Pulse oximetry provides a continuous, non-invasive estimate of oxygen saturation. However, it has important limitations: it cannot detect elevated CO2, it becomes unreliable in the setting of poor perfusion, carbon monoxide poisoning (falsely normal SpO2), or methemoglobinemia (reads ~85% regardless of true saturation), and it only reflects hypoxemia after PaO2 drops below ~60 mmHg due to the sigmoid shape of the oxyhemoglobin dissociation curve.

The gold standard and confirmatory test for respiratory failure is the arterial blood gas. The ABG provides PaO2, PaCO2, pH, and bicarbonate, which together allow you to: (1) confirm respiratory failure and classify it as Type 1 or Type 2, (2) calculate the A-a gradient to identify the mechanism, and (3) determine whether the process is acute or chronic by examining the degree of metabolic compensation. On a licensing exam, if a vignette describes respiratory distress and asks for the next best step in diagnosis, the answer is almost always ABG (unless the clinical picture already demands immediate intervention such as intubation).

Calculating the A-a gradient is a high-yield exam skill. On room air:

$$PAO_2 = 0.21 \times (760 - 47) - \frac{PaCO_2}{0.8} = 150 - 1.25 \times PaCO_2$$

Then:

$$A\text{-}a\ gradient = PAO_2 - PaO_2$$

A normal value is roughly $\frac{Age}{4} + 4$ (or generally < 10 to 15 mmHg in a young adult). If the gradient is normal, the lungs are intrinsically healthy and the hypoxemia is from hypoventilation alone (think: opioid overdose, GBS, myasthenia crisis). If the gradient is elevated, intrinsic lung pathology exists.

To further distinguish among the causes of elevated A-a gradient, the response to supplemental oxygen is the key test. V/Q mismatch and diffusion impairment will improve with supplemental O2. True shunt (ARDS, complete consolidation) will not correct with 100% FiO2 because shunted blood bypasses ventilated alveoli entirely. This is why vignettes describing "hypoxemia refractory to supplemental oxygen" are classic for shunt physiology and ARDS.

Chest X-ray is ordered alongside or immediately after the ABG to identify the etiology. Bilateral diffuse opacities suggest ARDS or pulmonary edema. Lobar consolidation points to pneumonia. Hyperinflated lungs with flattened diaphragms suggest COPD. A clear chest X-ray with hypoxemia is a classic vignette for pulmonary embolism or early ARDS.

For ARDS, the Berlin Criteria (2012) are the diagnostic framework:

Criterion	Requirement
Timing	Within 1 week of known insult or new/worsening respiratory symptoms
Imaging	Bilateral opacities not fully explained by effusions, atelectasis, or nodules
Origin	Respiratory failure not fully explained by cardiac failure or fluid overload (objective assessment needed if no risk factor)
Oxygenation	PaO2/FiO2 $\leq$ 300 with PEEP $\geq$ 5 cmH2O

4. Management and Treatment

Setting	Intervention	Details
Oxygen Therapy	Supplemental O2 (nasal cannula, face mask, non-rebreather)	Target SpO2 92-96% generally; 88-92% in COPD to avoid oxygen-induced hypercapnia
High-Flow Nasal Cannula (HFNC)	Heated, humidified O2 at high flow rates (up to 60 L/min)	Provides modest PEEP effect; useful in Type 1 failure not yet requiring positive pressure ventilation
Non-Invasive Ventilation (NIV)	BiPAP (IPAP + EPAP) or CPAP	First-line for acute hypercapnic failure in COPD exacerbation (pH < 7.35, PaCO2 > 45). Also used in acute cardiogenic pulmonary edema. Reduces intubation rates and mortality
Intubation + Mechanical Ventilation	Endotracheal intubation	For failure of NIV, severe hypoxemia (PaO2 < 60 on high FiO2), inability to protect airway, hemodynamic instability, respiratory arrest
Lung-Protective Ventilation (ARDS)	Low tidal volume strategy	TV 6 mL/kg IBW, plateau pressure < 30 cmH2O, PEEP titrated by FiO2-PEEP table, permissive hypercapnia if needed
Prone Positioning (ARDS)	Turning patient face-down for $\geq$ 16 hours/day	Indicated in moderate-to-severe ARDS (PaO2/FiO2 < 150); improves V/Q matching and survival
Treat Underlying Cause	Antibiotics, anticoagulation, bronchodilators, diuretics, naloxone, etc.	Respiratory failure is a syndrome, not a diagnosis; identifying and treating the trigger is essential

Acute Stabilization is the first priority. Regardless of type, establish monitoring (continuous pulse oximetry, cardiac monitor) and secure IV access. Administer supplemental oxygen to achieve the target saturation range. In a patient without known COPD or chronic hypercapnia, target SpO2 of 92-96%. In patients with known COPD or those at risk for chronic CO2 retention, target SpO2 of 88-92% using controlled oxygen delivery (Venturi mask at 24-28% FiO2 is ideal for precision). The rationale is that in chronic hypercapnic patients, the respiratory drive partially depends on hypoxic drive; giving excessive oxygen can suppress ventilation and worsen hypercapnia (oxygen-induced hypercapnia). However, never withhold oxygen from a dying patient because of theoretical concern for CO2 retention.

For acute hypercapnic respiratory failure (most classically in COPD exacerbation with pH < 7.35 and PaCO2 > 45 mmHg), BiPAP is the first-line treatment. Typical initial settings are IPAP 10-12 cmH2O and EPAP 4-5 cmH2O, titrated based on clinical response, tidal volume, and repeat ABG. BiPAP reduces work of breathing, improves alveolar ventilation, and has been shown to reduce intubation rates and mortality compared to standard oxygen therapy alone. Reassess within 1 to 2 hours with a repeat ABG. If pH fails to improve or the patient deteriorates (worsening mental status, hemodynamic instability, inability to clear secretions), proceed to intubation.

Contraindications to NIV include: facial trauma or surgery (cannot seal the mask), inability to protect the airway (decreased consciousness with GCS < 8, absent gag reflex), uncontrolled vomiting, hemodynamic instability, undrained pneumothorax, and copious secretions.

For acute hypoxemic respiratory failure, the approach depends on severity. Mild cases may respond to nasal cannula or face mask. HFNC (heated humidified O2 at flows up to 60 L/min, FiO2 up to 1.0) is increasingly used as a bridge, providing some PEEP effect and improved comfort. For patients who fail these measures or meet ARDS criteria, intubation and mechanical ventilation are necessary.

In ARDS, the ventilator strategy is critical and highly testable. The ARDSNet low tidal volume protocol is the standard of care:

Parameter	Target
Tidal Volume	6 mL/kg of ideal body weight (not actual weight)
Plateau Pressure	< 30 cmH2O
PEEP	Titrated using FiO2-PEEP table (higher PEEP for higher FiO2 requirement)
FiO2	Lowest needed to maintain PaO2 55-80 mmHg or SpO2 88-95%
Respiratory Rate	Up to 35/min to maintain pH > 7.25 (permissive hypercapnia is acceptable)

Ideal body weight (IBW) is calculated based on height, not actual body weight:

$$IBW_{male} = 50 + 2.3 \times (height\ in\ inches - 60)$$ $$IBW_{female} = 45.5 + 2.3 \times (height\ in\ inches - 60)$$

This distinction is a classic exam trap: an obese patient with ARDS should receive tidal volumes based on IBW, not actual weight. Using actual weight results in dangerously high tidal volumes and volutrauma.

Prone positioning for $\geq$ 16 hours per day is indicated in moderate-to-severe ARDS (PaO2/FiO2 < 150 despite optimized ventilator settings). The PROSEVA trial demonstrated a survival benefit. Proning improves V/Q matching by redistributing perfusion and reducing dorsal atelectasis.

Neuromuscular blockade (cisatracurium) may be considered in the first 48 hours for severe ARDS with refractory hypoxemia, though recent trials have yielded mixed results. Conservative fluid strategy (targeting even to negative fluid balance) improves oxygenation and ventilator-free days in ARDS patients who are not in shock.

Treatment of the underlying cause cannot be overstated. Antibiotics for pneumonia/sepsis, anticoagulation for PE, bronchodilators and systemic corticosteroids for COPD exacerbation, diuretics for cardiogenic pulmonary edema, naloxone for opioid overdose. Respiratory failure is a physiologic endpoint, not a primary disease. Fixing the gas exchange problem without addressing the trigger will lead to treatment failure.

Long-term management in chronic respiratory failure includes optimizing the underlying disease (inhaler therapy for COPD, immunosuppression for ILD), pulmonary rehabilitation, nocturnal NIV for patients with chronic hypercapnic failure (obesity hypoventilation syndrome, stable neuromuscular disease), and long-term oxygen therapy (LTOT) for patients with chronic resting PaO2 $\leq$ 55 mmHg or PaO2 $\leq$ 59 mmHg with evidence of cor pulmonale or polycythemia. LTOT used for $\geq$ 15 hours/day has been shown to improve survival in chronic hypoxemic COPD.

5. Differential Diagnosis and Distractors

Differential	Why It Is Similar	Key Discriminator
Pulmonary embolism vs. Pneumonia	Both cause Type 1 respiratory failure with dyspnea, tachycardia, and hypoxemia	PE: clear CXR with hypoxemia, pleuritic chest pain, risk factors for DVT (immobilization, surgery, malignancy); pneumonia: fever, productive cough, consolidation on CXR
ARDS vs. Cardiogenic pulmonary edema	Both present with bilateral opacities on CXR and severe hypoxemia	ARDS: identified risk factor (sepsis, aspiration, pancreatitis), no cardiomegaly, low BNP, no response to diuretics, non-cardiogenic wedge pressure ($\leq$ 18 mmHg). Cardiogenic edema: elevated BNP, cardiomegaly, S3 gallop, jugular venous distension, responds to diuretics
COPD exacerbation vs. Opioid overdose	Both cause hypercapnic (Type 2) respiratory failure	COPD: history of smoking, wheezing, prolonged expiratory phase, elevated A-a gradient (lungs are diseased). Opioid overdose: pinpoint pupils, decreased respiratory rate, normal A-a gradient (lungs are healthy, the problem is central drive), responds to naloxone
Neuromuscular respiratory failure (GBS, MG) vs. Asthma exacerbation	Both can cause acute respiratory distress and hypercapnia	NMD: ascending weakness, areflexia (GBS) or fluctuating weakness worse with exertion (MG), normal A-a gradient, no wheezing. Asthma: wheezing, history of atopy, elevated A-a gradient, responds to bronchodilators
Anxiety/hyperventilation vs. Early Type 1 respiratory failure	Both present with tachypnea, dyspnea, and respiratory alkalosis	Anxiety: low PaCO2, normal PaO2, normal A-a gradient, perioral/digital paresthesias. Early Type 1 failure: low PaCO2 (compensatory hyperventilation) but PaO2 is low or borderline with elevated A-a gradient
Metabolic acidosis (e.g., DKA) vs. Primary respiratory failure	Kussmaul breathing in DKA can mimic tachypnea of respiratory failure	DKA: low PaCO2 is compensatory (appropriate for the metabolic acidosis), anion gap elevated, glucose elevated. Primary respiratory failure: ABG shows a primary respiratory process, not compensatory hyperventilation

6. Traps and High-Yield Pearls

The most common way students get questions on respiratory failure wrong is by failing to calculate or interpret the A-a gradient. A vignette will present a hypoxemic, hypercapnic patient and ask for the most likely cause. Students who skip the A-a gradient calculation may not distinguish between a pure hypoventilation problem (normal A-a gradient, extrapulmonary cause such as opioid overdose or neuromuscular disease) and a combined hypoventilation-plus-lung-disease problem (elevated A-a gradient, such as COPD exacerbation). The A-a gradient is the single most discriminating calculation in respiratory failure questions.

The second major trap involves oxygen therapy in COPD patients. A common vignette presents a COPD patient in exacerbation who is initially placed on high-flow oxygen; a repeat ABG then shows worsening hypercapnia and somnolence. Students must recognize oxygen-induced hypercapnia and know that the solution is to reduce FiO2 to target SpO2 88-92% and initiate BiPAP, not to discontinue oxygen entirely.

The third classic trap is ARDS tidal volume calculation using actual body weight instead of ideal body weight. This is tested explicitly. An obese patient with ARDS should have tidal volume set at 6 mL/kg of IBW (based on height). Using actual body weight in an obese patient leads to injurious tidal volumes.

Students also confuse ARDS with cardiogenic pulmonary edema because both present with bilateral white-out on CXR and severe hypoxemia. The key discriminators are the clinical context (a risk factor for ARDS such as sepsis or aspiration), the absence of signs of volume overload (no elevated JVP, no S3, no elevated BNP), and the PCWP $\leq$ 18 mmHg if a Swan-Ganz catheter is used.

Finally, remember that a normal or rising PaCO2 in a patient with an asthma exacerbation is an ominous sign. In acute asthma, patients should be hyperventilating (low PaCO2). A "normalizing" PaCO2 in severe asthma means respiratory muscle fatigue and impending respiratory arrest. This patient needs immediate preparation for intubation, not reassurance.

The core competency tested across all respiratory failure questions is the ability to integrate ABG interpretation (type, mechanism, acuity) with the clinical context to determine both the diagnosis and the correct next step in management.

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