Page of

Hypoxaemia in the critically ill 

Hypoxaemia in the critically ill
Hypoxaemia in the critically ill
Oxford Textbook of Critical Care (2 ed.)

Susannah Leaver

and Timothy Evans


Key points

  • Hypoxaemia is reduced arterial oxygen tension (usually below 8 kPa). Hypoxia is an inadequate oxygen supply to the tissues.

  • Hypoxaemia can result from a ventilation (V)/perfusion (Q) mismatch, anatomical (intrapulmonary, intracardiac) shunt, diffusion limitation, and/or hypoventilation. In clinical practice, a combination of these factors is usually responsible.

  • Diagnosis is based on a clinical history and examination, with appropriate blood tests, imaging and physiological tests.

  • Management involves securing the airway (if required), correcting hypoxaemia by increasing inspired oxygen concentration (FiO2) and where necessary instituting respiratory support (mechanical, extracorporeal, non-invasive/invasive).

  • The precipitating cause should be identified and treated.


The term hypoxaemia is defined by a reduction in the partial pressure of oxygen in the blood below 8 kPa/60 mmHg (normal range 10–13.3 kPa/75–100 mmHg). Hypoxia has no precise or quantitative definition, but describes inadequate oxygen supply to the tissues.

Acute respiratory failure (ARF) has conventionally been divided into hypoxaemic (type I) and hypoxaemic/hypercapnic (type II) subgroups. Type I is the principle focus of this chapter. Ventilatory/hypercapnic (type II) respiratory failure is the presence of hypoxaemia with hypercapnia (PaCO2 >6.5 kPa/50 mmHg, normal range 4.5–6.2 kPa/35–45 mmHg). In clinical practice, type II can occur following type I if the underlying cause is not corrected.

Pathophysiology of hypoxaemia

Different causes of hypoxaemia are discussed below as separate entities [1]‌, but in the critically ill a combination of these is usual.

  • Ventilation/perfusion mismatch: In the perfect lung, each alveolus would be ventilated by a volume of gas equal to that of the blood perfusing it. However, even in normal physiological circumstances ventilation/perfusion (V/Q) mismatch exists. Both V and Q are greater in the anatomically dependent parts of the lung, which vary with posture (i.e. erect supine and prone), although while ventilation diminishes slowly across the relevant gradient (bases to apices when upright) perfusion decreases faster. V/Q mismatch is therefore greater in the lung apices. V/Q mismatch is responsible for the normal alveolar–arterial (A–a) gradient. In the diseased lung, V/Q mismatch increases as both become more heterogeneous resulting in hypoxaemia. If alveoli are ventilated and not perfused, such as occurs following pulmonary thromboembolism, a proportion of ventilation is wasted and behaves as dead space. By contrast, if alveoli are perfused and not ventilated, for example, in pneumonia, oxygenation of the blood is impaired through intrapulmonary shunt. Increased V/Q mismatch increases A–a gradient and is the commonest cause of hypoxaemia.

  • Right-to-left shunt occurs when blood bypasses ventilated areas of lung. There are two types:

    • Anatomical: alveoli are bypassed, for example, via intracardiac shunts or pulmonary arteriovenous malformations.

    • Physiological (intra-pulmonary) shunt: blood passes through non-ventilated areas, for example, when alveoli are collapsed (atelectasis), consolidated (pneumonia), or fluid-filled (pulmonary oedema).

  • Diffusion limitation: transfer of oxygen across the alveolar-capillary membrane is impaired due to alveolar and/or interstitial inflammation or fibrosis.

  • Hypoventilation: causing low alveolar oxygen tension (PaO2). PAO2 is determined by the rate of oxygen extraction from the blood by the tissues, and is therefore dependent on the metabolic demands of tissues (oxygen consumption); and the supply of oxygen to the alveoli, which reflects alveolar ventilation. Low PaO2 thereby reduces the rate of diffusion of oxygen from the alveoli to the pulmonary capillaries and hypoxaemia ensues. Carbon dioxide is retained, and arterial and alveolar PCO2 rise. In accordance with the simplified alveolar gas equation (eqn 1) alveolar oxygen concentration falls further, but will rise if supplementary oxygen is administered.

    [eqn 1] where PaO2 is the alveolar partial pressure of oxygen, PiO2 is the inspired partial pressure of oxygen, PaCO2 is the arterial tension of carbon dioxide, R is the respiratory quotient.

Other causes of hypoxaemia include decreased inspired oxygen tension, such as occurs at high altitude, decreased mixed venous oxygen saturations (e.g. in anaemia or low cardiac outputs states) and changes in affinity of haemoglobin for oxygen due to a shift in the oxygen dissociation curve.


History and examination

Hypoxaemia can manifest clinically in a number of ways (Box 85.1). The history and physical examination must be comprehensive as ARF may result from pulmonary or extrapulmonary causes. Recording observations and calculating a clinical (early warning) score may facilitate recognition of impending or actual hypoxaemia. By contrast, delays adversely affect outcome. ARF is a dynamic process and frequent reassessment is required. A differential diagnosis of acute type I hypoxaemia is displayed in Box 85.2.


Blood tests and infection screen

Abnormalities in common haematological and biochemical indices aid diagnosis (raised C-reactive protein indicating infection, raised B-type natri-uretic peptide indicating pulmonary oedema) and the identification of other organ system failures (e.g. acute kidney injury, disseminated intravascular coagulopathy) and/or previously unknown premorbid conditions. Furthermore, anaemia contributes to tissue hypoxaemia and polycythaemia might be secondary to chronic hypoxaemia.

Sepsis is commonly associated with acute respiratory insufficiency and a full infection screen should be sent. In immunosuppressed or immunocompromised patients evidence of fungal infection and tuberculosis should be sought. Pneumocystis jirovecii can induce type 1 respiratory failure.

Arterial blood gas

Arterial blood gas measurement quantifies the severity of hypoxaemia, identifies the type of respiratory failure and can provide information regarding metabolic status, haemoglobin, electrolytes, and lactate.

The defining criteria for respiratory failure are most applicable to patients breathing room air. When oxygen supplements are administered, calculating the A–a gradient or PaO2:FiO2 ratio is more useful in determining the severity of hypoxaemia.

The alveolar–arterial (A–a) gradient

The A–a gradient is the difference between the amount of oxygen in the alveoli (PaO2) and the amount of oxygen in the blood (PaO2) (eqn 2). Therefore:

[eqn 2]

PaO2 is measured by arterial blood gas analysis and PaO2 derived from the alveolar gas equation (eqn 1). Normal A–a gradient is age-dependent and in healthy adults is <3.5 kPa (26 mmHg). Hypoxaemia with a normal A–a gradient is secondary to alveolar hypoventilation (raised PaCO2), low PiO2 or low barometric pressure <760 mmHg, whereas hypoxaemia associated with an elevated A–a gradient is secondary to V/Q mismatch, right–left shunt, a diffusion defect or increased oxygen extraction.

The Pao2:Fio2 (P:F) ratio

The ratio of partial pressure of oxygen in the blood to inspired oxygen concentration also defines the severity of hypoxaemia (normal value of > 40 kPa, >300 mmHg). P:F ratio is used to define acute respiratory distress syndrome (ARDS) with mild moderate and severe ARDS defined as values of <40 kPa, <300 mmHg; <26.6 kPa, 200 mmHg, and <13.3 kPa, <100 mmHg, respectively.


Chest radiography is mandatory in any patient with respiratory failure and may reveal abnormalities suggestive of pneumonia, lobar collapse, pulmonary oedema, or pneumothorax. Conversely, in asthma or chronic obstructive pulmonary disease (COPD) it might be normal.

Bedside ultrasound is an increasingly recognized useful diagnostic adjunct, which can assist in revealing pleural effusions, and facilitates safe diagnostic aspiration or therapeutic drainage. Removal of fluid can improve hypoxaemia through enhanced ventilation and increased pulmonary compliance. In experienced hands, ultrasound can aid the diagnosis of a pneumothorax when suspected clinically.

Transporting critically-ill patients is not without risk, but thoracic computed tomography (CT) can identify pathologies such as pulmonary emboli, pneumothoraces, small pleural effusions, parenchymal infiltrates, and abscess cavities that are not apparent on plain chest radiography.

Electrocardiogram and echocardiography

Electrocardiogram (ECG) and echocardiography can help to exclude a cardiac cause of hypoxaemia, and differentiate between acute pulmonary oedema and ALI/ARDS, as well as identify right heart strain secondary to massive pulmonary embolism.

Fibre optic bronchoscopy

Fibre optic bronchoscopy can be used for therapeutic reasons such as to alleviate endobronchial obstruction or for diagnostic purposes to obtain samples for microbiology or cytology, or to identify the source or bleeding in patients with haemoptysis.

Principles of management

Clearly, if the patient is ‘in extremis’ or in cardiopulmonary arrest the airway breathing circulation disability exposure (ABCDE) algorithm advocated by advanced life support guidelines should be adopted [2]‌.

Once identified, the principles of management of hypoxaemia are:

  • Securing the airway if required.

  • Correcting hypoxaemia by increasing inspired oxygen.

  • Identifying and treating the precipitating cause.

  • Control of secretions.

  • Instituting respiratory support (invasive/non-invasive) if necessary.

Airway management

In assessing a critically-ill patient ensuring a patent airway and adequate oxygenation takes priority even in the absence of a specific diagnosis. Simple procedures, such as head positioning (head tilt, chin lift, jaw thrust), removal of obstructions, such as vomitus or dentures, and airway adjuncts, such as nasopharyngeal or oropharyngeal airways may be sufficient. However, application of positive pressure using bag-mask supplementation, escalating to non-invasive intermittent positive pressure ventilation (NIV) administered by mask or other interface, or to endotracheal intubation and invasive ventilatory support might be required. Common indications for endotracheal intubation are displayed in Box 85.3.

Correcting hypoxaemia

Supplementary oxygen is always indicated in patients with acute hypoxaemia and should improve oxygenation in all cases except those with true right to left shunt. Oxygen can be delivered via a number of devices. However, in the initial management of a critically-ill hypoxaemic patient, who does not require immediate intubation, high dose oxygen therapy should be administered via reservoir mask at 10–15 L/min. Following stabilization this can be titrated to achieve arterial oxygen saturations estimated by oximetry of 94–98%, or escalated to supportive ventilation should the patient deteriorate. In patients at risk of hypercapnic respiratory failure controlled oxygen therapy administered via a venturi mask aiming for saturations of 88–92% should be given. Concerns regarding the provocation of hypercapnia through suppression of respiratory drive should not take precedence over the need for oxygenation.

Identify and treat the precipitating cause

Hypoxaemia is the final common pathway of a number of conditions. It may not be possible to identify the cause of the deterioration immediately, in which circumstances general respiratory and haemodynamic support should be applied. However, if the cause is identified immediate specific treatment should be instituted (see Table 85.1).

Table 85.1 Identification and treatment of common causes of acute hypoxaemia


Aids to diagnosis

Specific management

Obstructive airways disease

  • Previous history and lung function.

  • Wheeze on examination.

  • Hyperexpanded chest X-ray.

  • Nebulised B2 agonists and ipatropium bromide.

  • Steroids.

  • Consider:

    • Theophyllines.

    • Magnesium.

    • NIV.

    • Volatile anaesthetic agents.

    • Ketamine.

    • Heliox.


  • History of cough and sputum.

  • Signs of sepsis +/– septic shock.

  • Raised inflammatory markers.

  • Consolidation on chest X-ray.

  • Positive microbiology.

  • Early antibiotic therapy according to local hospital policy.

  • Control of secretions:

    • Mucolytic agents.

    • Physiotherapy.

Pulmonary oedema

  • History of cardiac disease.

  • Clinical examination.

  • ECG and chest X-ray.

  • Raised troponin/BNP.

  • Diuretics.

  • iv nitrates.

  • CPAP.

  • Treat acute coronary syndrome if indicated.


Clinical examination:Chest X-ray.

  • Decompression/intercostal drainage.

  • Oxygen therapy.


  • Presence of risk factors for ARDS.

  • P:F ratio.

  • Chest X-ray and ECHO.

  • Treat underlying cause.

  • Conservative fluid balance [9]‌.

  • Low tidal volume ventilation [8].‌

Pulmonary embolism

  • History and examination: presence of risk factors.


  • CTPA.

  • Thrombolysis if massive PE.

  • Anti-coagulation.

Pleural effusion

  • History and examination.

  • CXR.

Drainage and search for underlying cause.

NIV, Non-invasive ventilation; CPAP, continuous positive airway pressure; ECG, electrocardiogram; BNP, B-type natri-uretic peptide; ECHO, echocardiogram; PE pulmonary embolism; CTPA, CT pulmonary angiogram.

Control of secretions

Patients with ARF may produce copious secretions, for which physiotherapy and mucolytics can be helpful. Ultimately, if these cannot be controlled, endotracheal intubation can alleviate sputum retention and airway obstruction.

Non-invasive ventilation (niv)

NIV is the delivery of a mechanically-ventilated breath, either via a portable or standard intensive care unit (ICU) ventilator, through an appropriate interface (e.g. nasal mask, full face mask, or nasal pillows), rather than an endotracheal tube or tracheostomy. The term NIV incorporates systems that deliver bi-level positive pressure ventilation (BiPAP), in which inspiratory and expiratory pressures are set at required levels, and continuous positive airway pressure ventilation (CPAP), where one pressure is maintained throughout inspiration and expiration. The rationale for NIV is to support the patient during respiratory failure, but avoiding the need for intubation and its associated complications. While there is evidence for the benefits of NIV in patients with hypercapnic respiratory failure, especially secondary to COPD, its use in hypoxaemic respiratory failure remains less evident. However, a trial of NIV in patients who do not require immediate endotracheal intubation and who have no contraindications is recommended (Box 85.4), instituted in the high dependency unit or ICU setting, and monitored over a preset time (e.g. 1–2 hours).

Acute pulmonary oedema

NIV improves pulmonary compliance in cardiogenic pulmonary oedema through alveolar recruitment and redistribution of intra-alveolar fluid. A Cochrane review comprising 21 studies found NIV to be safe and effective in reducing hospital mortality, and the need for intubation compared with standard treatment [3]‌. However, more recent randomized controlled trials showed that, despite rapid improvement in physiological parameters and dyspnoea scores, NIV does not confer a mortality benefit [4,5]. Furthermore, in these patients no significant difference in the combined endpoint of death or intubation within 7 days was found between CPAP and BiPAP. Despite this, it is usual to treat hypoxic patients with acute pulmonary oedema who do not require immediate intubation with CPAP as it is easier to implement.

Severe community-acquired pneumonia

If secretions are controlled, NIV can be applied successfully in community-acquired pneumonia (CAP) [6]‌. In those with successful NIV, ICU stay was shorter and mortality was lower. Variables independently associated with failure of NIV were maximum sepsis-related organ failure assessment (SOFA) score during NIV, worsening infiltrates on chest X-ray at 24 hours, and higher heart rate, lower PaO2:FiO2 ratio and bicarbonate after 1 hour of NIV. The increased duration of NIV prior to intubation was associated with increased mortality. Thus, emphasizing the importance of a short trial of NIV with early endotracheal intubation and mechanical ventilation if no improvement is seen after a preset time.


While small studies have shown improved oxygenation and reduced intubation rates compared with oxygen therapy alone, the majority of patients with ARDS require ventilation.


One small trial in severe asthma found NIV improved rates of hospitalization and simple indices of lung function [7]‌. However, until larger randomized controlled trials are performed NIV is not routinely recommended in asthmatic patients and should only be considered in an ICU setting.


The use of NIV in hypercapnic respiratory failure is well established.

Invasive ventilation

In patients unresponsive or unsuitable for other forms of support, endotracheal intubation should be instituted in those with reversible pathology. The decision to intubate is based on clinical grounds, with the assistance of arterial blood gases and the investigations mentioned previously. Indications are outlined in Box 85.3. Ventilation is applied as support to facilitate treatment of the underlying condition while minimizing side effects. The optimal mode depends on the nature of the underlying disease process. Ventilator strategies should include first, titration of PEEP to maximize alveolar recruitment, increase FRC, and minimize intrapulmonary shunt, and secondly, lung protective ventilation using low tidal volumes to minimize alveolar damage secondary to cyclical opening and closing of damaged lung units [8]‌. These approaches can result in reduced CO2 clearance and, therefore, a respiratory acidosis. While evidence is lacking regarding the safe level of acidosis, ‘permissive hypercapnia’ is accepted as long as oxygenation is not compromised. In patients with refractory hypoxaemia, despite conventional ventilation prone positioning, nitric oxide, high frequency oscillation ventilation, and extracorporeal membrane oxygenation can be considered but are beyond the scope of this chapter.


1. West JB (ed.) (2000). Respiratory Physiology The Essentials, 6th edn. Baltimore, MD: Lippincott Williams & Wilkins.Find this resource:

2. UK RC (ed.) (2011). Advanced Life Support, 6th edn. London: Resuscitation Council UK.Find this resource:

3. Vital FM, Saconato H, Ladeira MT, et al. (2008). Non-invasive positive pressure ventilation (CPAP or bilevel NPPV) for cardiogenic pulmonary edema. Cochrane Database Systematic Reviews, 3, CD005351.Find this resource:

4. Gray A, Goodacre S, Newby DE, Masson M, Sampson F, and Nicholl J. (2008). Noninvasive ventilation in acute cardiogenic pulmonary edema. New England Journal of Medicine, 359(2), 142–51.Find this resource:

5. Moritz F, Brousse B, Gellee B, et al. (2007). Continuous positive airway pressure versus bilevel noninvasive ventilation in acute cardiogenic pulmonary edema: a randomized multicenter trial. Annals of Emergency Medicine, 50(6), 666–75.Find this resource:

6. Carrillo A, Gonzalez-Diaz G, Ferrer M, et al. (2012). Non-invasive ventilation in community-acquired pneumonia and severe acute respiratory failure. Intensive Care Medicine, 38(3), 458–66.Find this resource:

7. Soroksky A, Stav D, and Shpirer I. (2003). A pilot prospective, randomized, placebo-controlled trial of bilevel positive airway pressure in acute asthmatic attack. Chest, 123(4), 1018–25.Find this resource:

8. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. New England Journal of Medicine, 342(18), 1301–8.Find this resource:

9. Wiedemann HP, Wheeler AP, Bernard GR, et al. (2006). Comparison of two fluid-management strategies in acute lung injury. New England Journal of Medicine, 354(24), 2564–75.Find this resource:

Copyright © 2022. All rights reserved.