RESPIRATORY FAILURE
Respiratory failure
Ben Creagh-Brown
Abstract
Respiratory failure is a common complication of acute cardiorespira-
tory disease and exacerbations of chronic respiratory disease. It can
be a feature of advanced chronic cardiac, respiratory and neurological
diseases. Respiratory failure can manifest as hypoxaemia, hypercap-
nia or both. This article reviews the pathophysiology of these perturba-
tions in respiratory homeostasis, the clinical features of acute and
chronic respiratory failure and a brief discussion of the management.
Keywords Acidaemia; acidosis; dyspnoea; hypercapnia; hypo-
xaemia; non-invasive ventilation; oxygen therapy; respiratory failure
Incidence
In the UK, approximately one-third of medical patients admitted
to hospital have a respiratory problem, the most important of
which is respiratory failure. In the USA, the number of hospital
admissions for acute respiratory failure (ARF), and the associated
costs, are increasing. The mortality associated with admission to
hospital with ARF varies according to the cause, but overall US
data suggest a 20% risk of death.1 Pneumonia accounts for
approximately 60% of all hypoxaemic ARF. By contrast, the most
common cause of hypercapnic ARF is chronic obstructive pul-
monary disease (COPD), with 44% of patients admitted with
acute exacerbations showing a degree of hypercapnia.
Normal physiological functions of the respiratory system
The primary function of the respiratory system is gas exchange e
the maintenance of oxygenation and the removal of carbon di-
oxide from the blood. The respiratory system consist of the
substance of the lung e the parenchyma (including the alveoli)
e the associated circulation (pulmonary vasculature) and the
airways (trachea, bronchi, bronchioles). The lungs are only able
to adequately perform their function with the assistance of the
respiratory muscles, which themselves rely on intact neuronal
connections to a functioning brain. Impaired function of any of
these four major constituents can manifest as respiratory failure.
Measuring gas exchange
The most common method of measuring adequacy of gas ex-
change is by measuring arterial oxygen saturation using pulse
oximetry. Arterial oxygen saturation (the percentage of haemo-
globin that is oxygenated) provides information on the partial
pressure of oxygen in the arterial system; the relationship be-
tween these variables is illustrated by the oxygen dissociation
Ben Creagh-Brown BM MRCP PhD DICM FFICM is Consultant Physician
in Intensive Care and Respiratory Medicine at Royal Surrey County
Hospital, Guildford, UK, and Chair of the Surrey Peri-operative
Anaesthesia Critical Care Collaborative Research Group (SPACeR).
Competing interests: none declared.
MEDICINE 44:6
Key points
C All causes of hypoxaemia can be explained by five patho-
physiological mechanisms: ventilation/perfusion mismatch
(either impaired perfusion with preserved ventilation or,
conversely, preserved perfusion with impaired ventilation),
diffusion limitation, decreased inspired oxygen or alveolar
hypoventilation
C Alveolar hypoventilation inevitably causes hypercapnia,
because of either an insufficient neural respiratory drive (or its
transmission) or a load that cannot be overcome by the ca-
pacity of the respiratory muscle pump
C Treatment must be directed at the underlying disorder and be
supportive by preserving oxygenation and ventilation
curve. The major limitation of using pulse oximetry in isolation is
that it provides no direct information about carbon dioxide
concentrations.
A more complete picture is obtained by sampling the arterial
blood, usually from the radial artery, and analysing the partial
pressure of oxygen (PaO2), partial pressure of carbon dioxide
(PaCO2), pH and bicarbonate concentration e the ‘blood gases’.
Puncture of the radial artery to measure blood gases is painful so
local anaesthetic should be used. An alternative is sampling
blood from an arterialized ear lobe, but this has the limitation
that PaO2 is underestimated by 0.5e1.0 kPa and diverges from
arterial values at higher concentrations of inspired oxygen. Pa-
tients who require repeat blood gases are often best cared for
with an indwelling arterial cannula, but this is usually only
available in critical care environments. Continuous estimation of
arterial carbon dioxide can be achieved by using transcutaneous
carbon dioxide monitoring in all patients, or end-tidal carbon
dioxide in ventilated patients.
Categorizing respiratory failure
Hypoxaemia is commonly but arbitrarily defined as a PaO2 less
than 8 kPa (historically termed type 1 respiratory failure with a
PaCO2 <6 kPa), and associated hypercapnia is commonly
defined as a PaCO2 greater than 6 kPa (type 2 respiratory failure).
Describing the underlying cause is, however, arguably more
useful than dividing respiratory failure into types 1 and 2.
A diverse range of pathological conditions can cause acute
and chronic respiratory failure but they all share common
mechanisms.
Pathophysiology of hypoxaemia
Five pathophysiological mechanisms can cause hypoxaemia
(Table 1 and Figure 1):
 Diffusion limitation is best exemplified by idiopathic pul-
monary fibrosis. The oxygen concentration in the alveoli is
unchanged (PAO2), but the gas transfer capability of the
alveolar membrane is impaired, leading to arterial
342 Ó 2016 Elsevier Ltd. All rights reserved.
 RESPIRATORY FAILURE

Pathophysiological mechanisms causing hypoxaemia

Mechanism Alveolar partial pressure Alveolarearterial oxygen PaO2 response to increased
of oxygen (PAO2) difference (‘Aea gap’) inspired oxygen (FiO2)

Diffusion limitation Normal Increased Improves

Hypoventilation Reduced Normal Improves
Decreased inspired oxygen Reduced Normal Improves
Low ratio of ventilation to perfusion (V/Q Reduced locally Increased Improves
mismatch)
Shunt Reduced locally Increased Minimal

Table 1

hypoxaemia (low PaO2) and a resultant increase in the
alveolarearterial oxygen difference.
 Any cause of significant hypoventilation (a classic example
being acute opiate toxicity) leads to hypercapnia because
of the inverse relationship between alveolar ventilation
and arterial CO2 (PaCO2). Increases in PaCO2 result in
matched increases in alveolar CO2 (PACO2). In the absence
of an increased fraction of inspired oxygen (FiO2), an
increased PACO2, via the law of partial pressures, causes a
decrease in the PAO2. This is an often underappreciated
cause of hypoxaemia in hypoventilation and can be
completely masked by the use of an increased FiO2.
 An area of lung can receive little ventilation in proportion to
the extent to which it is being perfused. A common example
is lobar pneumonia, with one lobe receiving (almost)
normal perfusion but decreased ventilation because the air
spaces are congested with inflammatory exudate. The
ventilation/perfusion (V/Q) mismatch is partially offset by
the protective mechanism of hypoxic pulmonary vasocon-
striction. A less common example is heterogeneous
emphysema and the demonstration of diminished ventila-
tion in the upper lobes (relative to the lower lobes) with the
use of nuclear medicine imaging (V/Q scans). This
technique is practically useful in planning best-therapy
options for patients with advanced COPD who are being
considered for lung volume reduction surgery.
 The opposite type of V/Q mismatch is normal ventilation
and decreased perfusion, which can be termed a right-to-
left shunt. This is best exemplified by a very significant
pulmonary embolism e the lungs are adequately venti-
lated in the face of compromised perfusion.
Pathophysiology of hypercapnia
By contrast there is only one clinically practical cause of hyper-
capnia e alveolar hypoventilation, which results from failure of
the respiratory muscle pump. It is useful to consider the com-
ponents of the pump. First is the neural respiratory drive. This
refers to the central neurological impetus to breathe, which is
paired with the normal function of the spinal cord, peripheral
nerves and neuromuscular transmission. Second is the capacity
of the muscular pump, and finally is the load. Alveolar hypo-
ventilation results from an impairment of normal physiological
function of the neural respiratory drive or muscular pump, or an
increase in load that cannot be overcome (Figure 2).
Respiratory muscle capacity can be impaired by a range of
diverse processes, including muscular dystrophy, inflammatory

Pathophysiological mechanisms of hypoxaemia

Impaired ventilation, Impaired perfusion,

preserved perfusion V/Q mismatch preserved ventilation
e.g. lobar pneumonia e.g. pulmonary embolism

HYPOXAEMIA

Diffusion limitation
Alveolar hypoventilation
e.g. idiopathic pulmonary
e.g. opiate overdose

Low inspired oxygen

Figure 1

MEDICINE 44:6 343 Ó 2016 Elsevier Ltd. All rights reserved.

 RESPIRATORY FAILURE
myopathies and profound electrolyte impairments. Neural res-
piratory drive can be compromised at the level of the brain by
encephalopathies, cerebral ischaemia or infection, a mass effect
from space-occupying lesions or centrally acting drugs. It can
also be compromised below the brain, for example by spinal cord
injuries (above C3), motor neurone disease, GuillaineBarre
syndrome and neuromuscular blocking drugs.
Conditions primarily affecting the lung predominantly pre-
dispose to respiratory failure by increasing the load on the res-
piratory muscle pump. There are three main components of the
load:
 Resistive load refers to the effort required to breathe in and
is increased in conditions such as upper airway obstruc-
tion, bronchospasm and COPD.
 Elastic load refers to the effort required to breathe out and
is increased when the lung has lost its inherent elastic
recoil, for example in emphysema, or if the chest wall is
adversely affecting respiratory mechanics, for example in
kyphoscoliosis or obesity.
 Threshold load is the additional work that may be required
to overcome intrinsic positive end-expiratory pressure
(PEEP), which is common in obstructive airways diseases.
Intrinsic PEEP results from incomplete lung emptying due
to expiratory flow limitation and insufficient time to
breathe out.
Determining chronicity of respiratory failure
Hypercapnia is associated with excess hydrogen ions through the
dissociation of carbonic acid, which tends to lead to acidaemia
(pH < 7.35). If the hypercapnia is chronic, renal compensation
occurs via the retention of bicarbonate ions to avoid acidaemia
and maintain a normal pH.
Diagrammatic representation of the respiratory muscle pump
Neural
drive
Muscles
Capacity
Capacity >> Load Capacity > Load
Comfortable Uncomfortable
compensation
Dyspnoea
Figure 2
MEDICINE 44:6 344
Logically therefore, if hypercapnia occurs acutely, this mech-
anism has insufficient opportunity to work, resulting in acid-
aemia (pH < 7.35), normal bicarbonate (<23 mmol/litre) and
high CO2 (>6 kPa). By contrast, patients with an acute decom-
pensation of chronic respiratory failure have acidaemia (pH <
7.35), high bicarbonate (>23 mmol/litre) and a higher CO2 (>>6
kPa).
There is no parallel laboratory investigation to assist in
determining the chronicity of hypoxaemia. Although secondary
erythrocytosis occurs in response to chronic hypoxaemia, it is
surprisingly uncommon in contemporary COPD cohorts.
Acute respiratory failure
Clinical features
The signs and symptoms of ARF vary according to the cause.
Respiratory distress and associated breathlessness (dyspnoea)
characterize most forms, with the notable exception of hypo-
ventilation caused by impaired neural respiratory drive, typically
from drugs such as narcotics. Respiratory distress is character-
ized by increased respiratory rate, use of accessory muscles of
respiration (including the scalene muscles and sternocleido-
mastoids), tachycardia and often diaphoresis (sweating).
Causes
Table 2 lists some common causes of acute respiratory failure.
Treatment
Treatment must be directed at the underlying disorder and pre-
serve oxygenation and ventilation. In general terms, hypoxaemia
can be easily treated with supplemental oxygen, whereas hy-
percapnia may require more involved measures. The British
Thoracic Society produces guidelines that cover the use of sup-
plemental oxygen and the management of hypercapnic
Load
Capacity < Load
Unable to
compensate
Respiratory
failure
Ó 2016 Elsevier Ltd. All rights reserved.
 RESPIRATORY FAILURE
Common causes of acute respiratory failure
Parenchyma Pulmonary vascular
Pneumonia Pulmonary embolism
(venous or other)
Pulmonary oedema (cardiogenic or non-
cardiogenic, including acute respiratory
distress syndrome)
Haemorrhage
Table 2
respiratory failure. Supplemental oxygen can be delivered via a
range of devices, each with different characteristics including the
range of FiO2, the interface, humidification and rate of flow.
Studies of newer non-invasive methods of providing a high flow
of humidified oxygen via comfortable delivery devices (high-flow
nasal cannulae) show tentative signs that they may be superior to
traditional oxygen delivery systems in hypoxaemic ARF.2,3
Hypercapnia reflects inadequate alveolar ventilation. It is
therefore intuitive that assisted ventilation has the potential to
reduce PaCO2 and the associated acidaemia that accompanies
acute hypercapnia. Assisted ventilation can occur via interfaces
that are either non-invasive (a tight-fitting facemask, non-
invasive ventilation (NIV)) or invasive (usually via an endotra-
cheal tube, which requires sedation). These involve a cyclical
delivery of positive pressure to augment or replace the patient’s
inspiratory effort. Such positive-pressure ventilation is not
without limitations, primarily the risk of ventilator-induced lung
injury. Ventilation should be delivered without excessive delay
and in an appropriately monitored environment.
Extracorporeal gas exchange. Following the influenza
pandemic of 2009, the number of referral centres providing
extracorporeal membrane oxygenation increased, and it has now
become the established therapy for refractory respiratory failure.
Less invasive extracorporeal gas exchange systems are available
and being evaluated as a therapy to be applied before the res-
piratory failure becomes refractory, perhaps as an alternative to
positive-pressure ventilation in patients with the highest risk of
complications.4
Chronic respiratory failure
Clinical features
Patients with chronic disorders affecting gas exchange are likely
to experience symptoms from their underlying disorder. If
chronic hypoxaemia develops, then patients can experience
additional limitation in exercise capacity, which can contribute to
increased dependency. If chronic hypercapnia develops, patients
characteristically experience early-morning headaches, a flap-
ping tremor and daytime somnolence.
Complications
Long-standing chronic respiratory failure causes pulmonary
vasoconstriction and consequent pulmonary arterial
MEDICINE 44:6
Airway Respiratory muscle
Bronchospasm Central nervous system depression (drugs,
(COPD and asthma) etc.)
Occlusion Neuromuscular failure (e.g. GuillaineBarre
syndrome)
Myopathy
hypertension, which puts strain on the right ventricle of the
heart. Over time, right ventricular function becomes impaired
and clinical features of right heart failure, such as peripheral
oedema, ensue.
Treatment
Hypoxaemic respiratory failure. There are detailed guidelines
for the use of chronic supplemental oxygen usage. Based on
evidence of improved survival, a consistent recommendation is
that patients whose clinical condition is stable with a resting
PaO2 of 7.3 kPa or lower (or 8 kPa if there are features of right
ventricular failure) should be given long-term oxygen therapy for
at least 15 hours a day.
Hypercapnic respiratory failure. Domiciliary NIV is indicated in
chronic hypercapnic respiratory failure due to chest wall defor-
mity, progressive neuromuscular disease and obesity-related
respiratory failure, although this is based on limited evidence.5
The benefits of using domiciliary NIV in patients with stable
COPD with persistent hypercapnia are yet to be fully
demonstrated. A
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cannula in acute hypoxemic respiratory failure. N Engl J Med 2015;
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3 Spoletini G, Alotaibi M, Blasi F, et al. Heated humidified high-flow
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4 Beloncle F, Friedrich J, Wald R, et al. Extracorporeal carbon dioxide
removal in patients with chronic obstructive pulmonary disease: a
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FURTHER READING
British Thoracic Society guidelines. Available from: www.brit-thoracic.
org.uk/guidelines-and-quality-standards/.
345 Ó 2016 Elsevier Ltd. All rights reserved.