Respiratory failure, ARDS and sepsis

Pathophysiology of Acute Respiratory Failure

Respiratory failure occurs when the respiratory system cannot adequately perform gas exchange, resulting in arterial hypoxaemia, carbon dioxide retention, or both. Categorisation into Type 1 and Type 2 guides diagnostic investigation and determines ventilatory support modalities.

Type 1: Hypoxaemic Respiratory Failure

Type 1 respiratory failure is defined by arterial hypoxaemia with a $\text{PaO}_2 < 60\text{ mmHg}$ ($8.0\text{ kPa}$) while breathing room air, accompanied by a normal or low arterial $\text{PaCO}_2$ ($< 45\text{ mmHg}$). Hyperventilation in response to hypoxia frequently lowers the $\text{PaCO}_2$.

• Mechanisms:
  • Ventilation-Perfusion (V/Q) Mismatch: The most common clinical mechanism. Areas of low ventilation relative to perfusion (e.g., bronchospasm, mucous plugging, mild pulmonary oedema) result in desaturated blood leaving pulmonary capillaries. Hypoxaemia from V/Q mismatch responds readily to modest increases in inspired oxygen concentration ($\text{FiO}_2$).
  • Right-to-Left Intrapulmonary Shunt: Blood traverses non-ventilated alveolar units without participating in gas exchange (e.g., severe ARDS, dense lobar consolidation, complete lung atelectasis). Shunt fractions exceeding 20% to 30% are refractory to high $\text{FiO}_2$ alone and require positive end-expiratory pressure (PEEP) to recruit collapsed alveoli.
  • Diffusion Impairment: Thickened alveolar-capillary membrane (e.g., pulmonary fibrosis) impairs oxygen transit during states of high cardiac output.

Type 2: Hypercapnic Respiratory Failure

• Hypercapnic respiratory failure: PaCO2 above the normal range (commonly above 45 mmHg) signifies inadequate alveolar ventilation. Interpret pH and bicarbonate to distinguish acute from chronic disease. Hypoxaemia can coexist, but may be masked by supplemental oxygen.

$$\text{P}_A\text{O}_2 = \text{FiO}_2 \times (\text{P}_{\text{atm}} - \text{P}_{\text{H}_2\text{O}}) - \frac{\text{PaCO}_2}{\text{R}}$$

• Mechanisms: The fundamental defect is alveolar hypoventilation, reflecting failure of the respiratory 'pump' rather than alveolar parenchymal exchange.

  • Depressed Central Respiratory Drive: Drug overdoses (opioids, benzodiazepines), brainstem infarcts, severe hypothyroidism, obesity hypoventilation syndrome.
  • Neuromuscular Weakness: Guillain-Barré syndrome, myasthenia gravis crisis, motor neurone disease, cervical cord injury, severe hypophosphataemia.
  • Chest Wall & Pleural Deformities: Flail chest, severe kyphoscoliosis, massive ascites, circumferential thoracic burns.
  • Increased Work of Breathing & Fatigued Muscles: Advanced COPD, status asthmaticus, severe upper airway obstruction.

• Arterial $\text{PaO}_2$: Type 1 (Hypoxaemic): $< 60\text{ mmHg}$ ($< 8.0\text{ kPa}$); Type 2 (Hypercapnic): Decreased (unless supplemental $\text{O}_2$ given)

• Arterial $\text{PaCO}_2$: Type 1 (Hypoxaemic): Normal or low ($< 45\text{ mmHg}$); Type 2 (Hypercapnic): $> 50\text{ mmHg}$ ($> 6.7\text{ kPa}$)

• Alveolar-Arterial (A-a) Gradient: Type 1 (Hypoxaemic): Elevated ($> 15-20\text{ mmHg}$); Type 2 (Hypercapnic): Normal if pure hypoventilation; elevated if combined lung disease

• Primary Pathology: Type 1 (Hypoxaemic): Alveolar filling, collapse, or vascular occlusion; Type 2 (Hypercapnic): Failure of neuromuscular pump or severe ventilatory dead space

• Initial Ventilatory Strategy: Type 1 (Hypoxaemic): High-flow nasal cannula (HFNC) or CPAP; Type 2 (Hypercapnic): Non-invasive ventilation (BiPAP) or mechanical ventilation

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Acute Respiratory Distress Syndrome (ARDS)

ARDS is a devastating inflammatory syndrome characterized by diffuse alveolar-capillary endothelial and epithelial barrier disruption, accumulation of proteinaceous alveolar exudate, loss of surfactant, alveolar flooding, and microvascular thrombosis.

The Berlin Definition (a widely used classification; newer global criteria also recognise additional settings) of ARDS

The Berlin criteria mandate four core clinical components:

1. Timing: Acute onset within 1 week of a known clinical insult (e.g., sepsis, pneumonia, aspiration, major trauma, pancreatitis) or new/worsening respiratory symptoms.
2. Chest Radiography: Bilateral opacities on chest X-ray or CT scan not fully explained by pleural effusions, lobar/lung collapse, or nodules.
3. Origin of Oedema: Respiratory failure not fully explained by cardiac failure or hydrostatic fluid overload. Objective assessment (such as echocardiography) is required to exclude hydrostatic pulmonary oedema if no clear risk factor is present.
4. Oxygenation Impairment: Assessed with a minimum PEEP of $\ge 5\text{ cmH}_2\text{O}$:
   • Mild ARDS: $200 < \text{PaO}_2/\text{FiO}_2 \le 300\text{ mmHg}$
   • Moderate ARDS: $100 < \text{PaO}_2/\text{FiO}_2 \le 200\text{ mmHg}$
   • Severe ARDS: $\text{PaO}_2/\text{FiO}_2 \le 100\text{ mmHg}$

Evidence-Based Mechanical Ventilation Strategy

• Low Tidal Volume Ventilation: Set tidal volumes at $6\text{ mL/kg}$ of Predicted Body Weight (PBW) (calculated from sex and height, never actual weight). Ventilating with standard $10-12\text{ mL/kg}$ tidal volumes causes severe volutrauma and biotrauma in non-aerated 'baby lungs'.
• Plateau Pressure Limitation: Keep end-inspiratory plateau pressure ($P_{\text{plat}}$) $\le 30\text{ cmH}_2\text{O}$.
• Prone Positioning: For patients with $\text{PaO}_2/\text{FiO}_2 < 150\text{ mmHg}$, early prone positioning for at least 16 consecutive hours per day significantly reduces 28-day and 90-day mortality. Proning redistributes transpulmonary pressures, unloads the heart, recruits dorsal dependent lung units, and dramatically improves V/Q matching.

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Sepsis-3 Definitions & Shock Syndromes

Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection.

Sepsis-3 Clinical Diagnostic Criteria

• Organ Dysfunction: An acute change in total Sequential Organ Failure Assessment (SOFA) score of $\ge 2$ points attributable to the infection. A SOFA increase of 2 reflects an overall in-hospital mortality excess of $> 10\%$.
• qSOFA: A bedside prognostic prompt using respiratory rate, systolic pressure and mental state. It must not be the only sepsis screen; infection plus organ dysfunction, early-warning systems and the overall clinical course guide recognition. Its three components are:
  • Respiratory rate $\ge 22\text{ breaths/min}$
  • Altered mentation (Glasgow Coma Scale $< 15$)
  • Systolic blood pressure $\le 100\text{ mmHg}$
• Septic Shock Definition: A subset of sepsis in which underlying circulatory and cellular/metabolic abnormalities are profound enough to substantially increase mortality ($> 40\%$). Clinically identified by:
  1. Persistent arterial hypotension requiring vasopressors to maintain a Mean Arterial Pressure (MAP) $\ge 65\text{ mmHg}$, AND
  2. Serum lactate $> 2.0\text{ mmol/L}$ ($18\text{ mg/dL}$) despite adequate intravenous fluid resuscitation.

Differentiating Shock Etiologies

• Distributive (Septic / Anaphylactic): Primary Mechanism: Vasoplegia, peripheral pooling, capillary leak; CVP / PCWP: Decreased or Normal; Cardiac Output: Increased (Early hyperdynamic); Systemic Vascular Resistance (SVR): Markedly Decreased; Mixed Venous $S\text{vO}_2$: Increased ($> 70\%$)
• Cardiogenic (MI / Arrhythmia): Primary Mechanism: Primary myocardial pump failure; CVP / PCWP: Increased; Cardiac Output: Markedly Decreased; Systemic Vascular Resistance (SVR): Increased (Compensatory); Mixed Venous $S\text{vO}_2$: Decreased ($< 60\%$)
• Hypovolaemic (Haemorrhage): Primary Mechanism: Loss of intravascular volume; CVP / PCWP: Markedly Decreased; Cardiac Output: Decreased; Systemic Vascular Resistance (SVR): Increased (Compensatory); Mixed Venous $S\text{vO}_2$: Decreased ($< 60\%$)
• Obstructive (Massive PE / Tamponade): Primary Mechanism: Extracardiac outflow obstruction; CVP / PCWP: Increased; Cardiac Output: Markedly Decreased; Systemic Vascular Resistance (SVR): Increased (Compensatory); Mixed Venous $S\text{vO}_2$: Decreased ($< 60\%$)

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Septic Shock Resuscitation Bundle

Septic shock requires immediate resuscitation, antibiotics and source control. Possible sepsis without shock warrants rapid assessment rather than treating every infection with an identical compulsory bundle.

• Lactate: Follow trends together with capillary refill, mental state, urine output and haemodynamics. Lactate has causes beyond hypoperfusion; a fixed 20% reduction every two hours is not a universal treatment endpoint.

1. Blood Cultures Prior to Antibiotics: Draw at least two sets of blood cultures (aerobic and anaerobic) before initiating antimicrobials, provided this does not cause significant delay ($> 45\text{ minutes}$).
2. Antibiotics: Give immediately, ideally within one hour, in shock or high-likelihood sepsis. Possible sepsis without shock permits rapid assessment, with treatment within three hours if concern persists. Obtain cultures first only if this does not meaningfully delay urgent treatment.

• Sepsis fluids: Give isotonic crystalloid for hypoperfusion in measured boluses with repeated assessment of circulation and fluid responsiveness. The international suggestion of at least 30 mL/kg in the first 3 hours is weak guidance for sepsis-induced hypoperfusion or shock, not a compulsory dose for every infection. Heart failure, renal disease and respiratory deterioration demand adjustment and early vasopressor assessment.

1. First-Line Vasopressor - Noradrenaline: If mean arterial pressure remains $< 65\text{ mmHg}$ despite fluid loading, or if the patient presents with profound hypotension, initiate noradrenaline (norepinephrine) immediately via central line (or temporarily via dedicated large-bore peripheral line). Noradrenaline provides potent alpha-1 vasoconstriction with modest beta-1 chronotropy, restoring perfusion pressure without inducing excessive tachycardia.
2. Second-Line / Refractory Vasopressors: Add vasopressin ($0.03\text{ units/min}$) to reduce noradrenaline dosage. For patients with refractory septic shock despite escalating vasopressors, administer intravenous hydrocortisone ($200\text{ mg/day}$ continuous infusion or $50\text{ mg}$ 6-hourly).

Primary references (checked 7 October 2026): Surviving Sepsis Campaign.