RESPIRATORY FAILURE
Respiratory failure
and pneumonia respectively. The in-hospital mortalities of these
conditions are 38.3%, 9.8% and 49.4%, respectively.3e5 The
number of patients admitted with less severe respiratory failure is
probably greater, but as yet unquantified.
Eui-Sik Suh
Nicholas Hart
Pathophysiology
Respiratory failure can arise from abnormalities of the airways,
alveoli, pulmonary vasculature, central or peripheral nervous
systems, respiratory muscles and the chest wall. The different
types of respiratory failure can be distinguished by interpretation
of the PaO2, PaCO2 and serum bicarbonate concentration ðHCO
3 Þ.
Abstract
The respiratory system consists of two main components: the lungs and
the respiratory muscle pump. Respiratory failure is the consequence of
lung failure leading to hypoxaemia, or respiratory muscle pump failure
resulting in hypercapnia. Type 1 respiratory failure (hypoxaemic respiratory failure) is defined as a partial pressure of arterial oxygen (PaO2)
less than 8.0 kPa, and type 2 respiratory failure (hypercapnic respiratory
failure) as PaO2 less than 8 kPa and a partial pressure of arterial carbon
dioxide (PaCO2) over 6 kPa. Diagnosis is made easier by understanding
the pathophysiological mechanisms that cause hypoxaemia and hypercapnia. Furthermore, a basic knowledge of acidebase balance allows
distinction between acute, acute-on-chronic and chronic type 2 respiratory failure. In addition to the standard assessment, careful consideration
must be given to neurological conditions as well as obstructive sleep
apnoea as these are frequently overlooked causes of respiratory failure.
Imaging and pulmonary function tests provide useful information to
ascertain the diagnosis. Management of these patients will depend on
the underlying cause, but the objective of treatment must be to improve
oxygenation and/or ventilation to resolve hypoxaemia and hypercapnia.
Hypoxaemic respiratory failure
Hypoxaemic type 1 respiratory failure may be considered to
represent intrinsic lung failure, such as occurs with pneumonia,
interstitial lung disease and acute cardiac pulmonary oedema.
Hypercapnic type 2 respiratory failure can be regarded as respiratory muscle pump failure in which alveolar hypoventilation
predominates (Figure 1). Both respiratory muscle pump and lung
failure can occur in the same patient, as in COPD or acute lifethreatening asthma.
In considering the causes of type 1 respiratory failure, it is
useful to review the five pathophysiological mechanisms of
hypoxaemia:
ventilation/perfusion (V/Q) mismatch e the commonest
cause of hypoxaemia
impaired gas diffusion across the alveolarecapillary
interface
right-to-left intracardiac shunt
intrapulmonary shunts or alveolar hypoventilation
reduced inspired oxygen concentration.
It is necessary to stress that V/Q mismatch is the commonest
cause of hypoxaemia. The pathophysiological mechanism and
clinical causes of hypoxaemic respiratory failure are shown in
Figure 2.
Keywords hypercapnia; hypoxaemia; lung failure; oxygen therapy;
respiratory muscle pump failure; ventilation
Respiratory failure is defined in terms of arterial blood gas
measurements, and may be divided into (a) type 1, or hypoxaemic, respiratory failure defined as an arterial oxygen tension
(PaO2) less than 8 kPa with a normal or low arterial carbon
dioxide tension (PaCO2); and (b) type 2, or hypercapnic, respiratory failure (PaO2 <8 kPa with PaCO2 >6 kPa).
Hypercapnic respiratory failure
Again, it is useful to consider the pathophysiological mechanisms
of hypercapnic type 2 respiratory failure to generate a list of
Incidence
The incidence and prevalence of respiratory failure are difficult to
determine, as respiratory failure represents a syndrome rather than
a single pathological process. European data indicate an incidence
of acute life-threatening respiratory failure of between 77.6 and 88.6
cases per 100,000 population per year.1,2 In the UK, 2.9%, 1.7% and
5.9% of admissions to intensive care are the result of respiratory
failure due to chronic obstructive airways disease (COPD), asthma
Types of respiratory failure
Respiratory failure
Eui-Sik Suh MBBS MRCP is a Clinical Research Fellow at the Department
of Asthma, Allergy & Respiratory Science, King’s College London, and
Lane Fox Respiratory Unit, Guy’s and St. Thomas’ NHS Foundation
Trust, London, UK. Conflicts of interest: none declared.
Nicholas Hart BSc MRCP PhD is a Clinical Research Consultant at Lane Fox
Respiratory Unit, Department of Critical Care, NIHR Comprehensive
Biomedical Research Centre, Guy’s and St Thomas’ NHS Foundation Trust
and King’s College London, UK. Conflicts of interest: none declared.
MEDICINE 40:6
Lung failure
Pump failure
Type 1 hypoxaemic
respiratory failure
Type 2 hypercapnic
respiratory failure
Figure 1
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Ó 2012 Elsevier Ltd. All rights reserved.
RESPIRATORY FAILURE
causes. Hypercapnic respiratory failure arises as a result of an
imbalance between the three components of the respiratory
muscle pump: the load on the respiratory system, the capacity of
the respiratory muscle pump and neural respiratory drive
(Figure 3). By considering these pathophysiological causes, even
without an in-depth knowledge of respiratory physiology, a clinically relevant list of conditions can be devised (Figure 4).
Respiratory system load may be resistive, due to airways
obstruction, or elastic, due to reduced compliance of the respiratory system, as in pneumonia, acute respiratory distress
syndrome, kyphoscoliosis and obesity. There may also be
a threshold load on the respiratory system, in the form of intrinsic
positive end-expiratory pressure (PEEPi). PEEPi represents the
inspiratory pressure that the respiratory muscles are required to
generate before the onset of inspiratory flow; it is present in
patients with obstructive lung diseases due to high airways
resistance, which impairs complete lung emptying during expiration and leads to lung hyperinflation. PEEPi has also been
shown to be present in obese patients as a consequence of early
airways closure due to patients breathing at low lung volumes.6
The capacity of the respiratory muscle pump may be impaired
by weakness of the respiratory muscles, in conditions such as
muscular dystrophy and other myopathies (e.g. myotonic
dystrophy). High spinal cord lesions, motor neuropathies and
disorders of the neuromuscular junction can lead to failure of
transmission of central drive to the respiratory muscle pump.
Central respiratory drive itself may be reduced due to an intracranial insult and drugs (such as opiates and benzodiazepines).
Furthermore, an elevated serum bicarbonate, arising from
metabolic compensation in conditions such as COPD and
neuromuscular disease, may diminish central drive. In the
Type 2 hypercapnic respiratory failure is an imbalance
between neural respiratory drive, the load on the
respiratory muscles and capacity of the respiratory
muscles
DRIVE FAILURE
Cortical brainstem
HIGH LOAD
Resistive elastic
threshold
TRANSMISSION &
ACTION FAILURE
Spinal cord
Peripheral nerves
Neuromuscular junction
Respiratory muscles
RESPIRATORY MUSCLE
PUMP FAILURE
Type 2 hypercapnic
respiratory failure
Figure 3
absence of central drive failure or transmission failure, neural
respiratory drive reflects the balance between the load on the
respiratory system and its capacity. Neural drive has been shown
to be increased compared to healthy controls in stable COPD,
poorly-controlled asthma and obesity.6e8
Acute, chronic and acute-on-chronic respiratory failure
The distinction between these presentations is most apparent in
hypercapnic respiratory failure, where the arterial blood gas
measurements once again reflect the balance between neural
respiratory drive, respiratory system load and respiratory muscle
pump capacity. PaCO2 is directly proportional to the rate of
production of CO2 and inversely proportional to the rate of
elimination of CO2 from the alveoli:
Type 1 hypoxaemic respiratory failure
Using the five pathophysiological mechanisms of hypoxaemia,
a comprehensive list of conditions that cause hypoxaemia can
be generated
*Ventilation-perfusion
mismatch
Anatomical
R-L shunt
e.g. pulmonary
arteriovenous
malformation,
pneumonia
Low partial pressure
of inspired oxygen
e.g. flying
e.g. chronic obstructive
pulmonary disease,
asthma, pulmonary
embolus, pulmonary
oedema, cystic fibrosis,
bronchiectasis
Pa CO2 f
where VCO2 is the rate of production of CO2 and VA is alveolar
ventilation.
In acute hypercapnic respiratory failure, a rapid rise in PaCO2
results in an excess of hydrogen ions in arterial blood through the
dissociation of carbonic acid (H2CO3), leading to respiratory
acidosis (pH <7.35). By contrast, chronic hypercapnic respiratory
failure is characterized by a normal pH (7.35e7.45) despite the
presence of an elevated PaCO2; this is due to renal retention of
bicarbonate ðHCO
3 Þ, which results in an elevated serum HCO3
(>26 mmol/litre) that buffers the excess hydrogen ions. Acuteon-chronic respiratory failure occurs when a patient with chronic
respiratory failure deteriorates such that pH <7.35 despite the
increased serum bicarbonate. However, with the increased
serum HCO
3 , PaCO2 will be significantly higher than is seen in
patients with acute hypercapnic respiratory failure.
Impaired
diffusion
Hypoxaemia
e.g. diffuse
parenchymal
lung disease
Alveolar
hypoventilation
e.g. opiate overdose
*V/Q mismatch is the most important cause of hypoxaemia
Figure 2
MEDICINE 40:6
VCO
VA
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RESPIRATORY FAILURE
Type 2 hypercapnic respiratory failure
Using the model of imbalance between neural respiratory drive, respiratory muscle load,
transmission and respiratory muscle action a comprehensive list of conditions causing
hypercapnia can be generated
Nerves and neuromuscular
junction
GENERAL
Trauma, encephalitis, ischaemia,
haemorrhage, Cheyne-Stokes respiration
CENTRALLY ACTING DRUGS
Sedatives, opiates, anti-epileptics
METABOLIC COMPENSATION
COPD, NMD, OHS, skeletal deformity
TRANSMISSION FAILURE
Threshold load (Intrinsic PEEP)
COPD, asthma, bronchiectasis, CF
Resistive load
Elastic load
Respiratory muscles
HIGH LOAD
Bronchospasm, upper airways obstruction,
bronchiectasis, COPD, CF, OSA
Spinal cord lesion (above C3)
Polio
Motor neurone disease
Phrenic nerve injury
Guillain-Barr é syndrome
CINMA
Neuromuscular blocking agents
Aminoglycosides
Myasthenia Gravis
Botulism
LUNG – pneumonia, alveolar oedema,
atelectasis, ALI/ARDS, DPLD, COPD, CF
CHEST WALL – kyphoscoliosis, obesity,
OHS, abdominal distention, ascites
Muscular dystrophies
Inflammatory myopathies
Malnutrition myopathy
Acid maltase deficiency
Thyroid myopathy
Biochemical anomalies
Hypokalaemia
Hypophosphataemia
ACTION FAILURE
DRIVE FAILURE
Cortex and brainstem
COPD, chronic obstructive pulmonary disease; NMD, neuromuscular disease; OHS, occipital horn syndrome;
PEEP, positive end-expiratory pressure; CF, cystic fibrosis; OSA, obstructive sleep apnoea; ALI/ARDS, acute
lung injury/acute respiratory distress syndrome; DPLD, diffuse parenchymal lung disease; CINMA, critical
illness neuromuscular abnormalities.
Figure 4
History and examination
respiratory muscle pump failure may cause few problems unless
an additional load, such as pneumonia, is placed on the system.
Furthermore, a number of these conditions, such as Guillain
eBarre syndrome, botulism, and motor neurone disease can
present as an acute deterioration with hypercapnic encephalopathy, requiring immediate intubation and ventilation. Those
conditions with a slower presentation and a predicted decline,
including Duchenne muscular dystrophy, myotonic dystrophy
and scoliosis, require close observation. This is particularly
important in the case of Duchenne muscular dystrophy, which
affects young males in whom the requirement for ventilatory
support frequently occurs around the time of transition from
paediatric to adult specialist care.13
A number of clinical symptoms and signs should alert the
physician to the development of hypercapnic respiratory failure,
and specific features to focus on with progressive neurological
conditions include the following:
Dyspnoea is the most prominent symptom in respiratory failure.
Assessing type 1 respiratory failure and diagnosing the cause is
usually straightforward, and is based on the clinical history
and examination, clinic oximetry and plain chest X-ray (CXR).
Arterial blood gas measurement accurately defines the level of
hypoxaemia. A sleep history is important to consider, particularly in obese patients, as obstructive sleep apnoea (OSA) is
commonly overlooked as a cause.
Although less common, the assessment of type 2 respiratory
failure involves a more comprehensive approach. As well as
a detailed history and clinical examination of the cardiorespiratory system, detailed neurological and musculoskeletal assessments are required. COPD is a significant cause of respiratory
failure presenting both in the acute and chronic state, with
patients commonly presenting with wheeze, dyspnoea, cough
and sputum production. However, as a result of V/Q mismatch,
hypoxaemia rather than hypercapnic respiratory failure is a more
common presentation. With advanced disease, COPD patients
recruit their abdominal wall muscles in expiration due to expiratory flow limitation, and show evidence of low body weight,
peripheral muscle wasting and reduced physical activity, all of
which have prognostic implications.9e12
Despite breathlessness being a feature in patients with severe
neuromuscular disease and skeletal deformity, moderate
MEDICINE 40:6
sleep-disordered breathing e morning headache,
daytime sleepiness, disrupted sleep pattern, impaired
intellectual function, generalized fatigue, loss of appetite
and weight
respiratory muscle weakness e orthopnoea, breathlessness on immersion in water, breathlessness on leaning
forward, breathlessness on exertion, poor cough, poor
chest expansion, paradoxical abdominal motion during
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RESPIRATORY FAILURE
inspiration (inward motion of the anterior abdominal wall
due to diaphragm weakness), abdominal muscle recruitment in expiration
bulbar dysfunction e low-volume voice, difficulty swallowing, drooling, difficulty clearing secretions, poor cough,
staccato/slurred speech, coughing on swallowing.
suggest pulmonary hypertension. It should be noted that radiographic elevation of the diaphragm is of little help in diagnosing
diaphragm weakness. Where diaphragm weakness is suspected,
patients should be referred for specialist respiratory muscle
strength testing.16 Computed tomography (CT) scanning of the
chest can be useful in identifying the cause of respiratory failure,
in particular, CT pulmonary angiography to diagnose pulmonary
embolism17 and high-resolution CT to define the ground glass,
reticular and nodular changes in DPLD.
Investigations
Diagnosis of respiratory failure is based on arterial blood gas
measurement as discussed above. Simple clinic or bedside
spirometry measuring forced expiratory volume in 1 second
(FEV1) and forced vital capacity (FVC) can define the degree of
airways obstruction (FEV1/FVC <70% with severity based on
FEV1 % predicted) as in COPD, and also demonstrate a restrictive ventilatory defect (FEV1/FVC >75%) in the presence of
respiratory muscle weakness and interstitial lung disease. Vital
capacity (VC) can be used to monitor progression of neuromuscular disease, with a fall in VC of 20% from the sitting to
supine posture indicating diaphragm weakness. Other classical
findings with respiratory muscle weakness are a reduction in
total lung capacity (TLC), with a reduction in overall gas
transfer (TLCO) but with a ‘supranormal’ gas transfer corrected
for alveolar volume (KCO).14 A VC less than 1 litre has a high
predictive value in identifying significant respiratory muscle
weakness and respiratory failure, but due to the curvilinear
nature of the relationship between VC and inspiratory muscle
strength, maximal inspiratory pressure at the mouth and sniff
inspiratory pressure are better predictors of respiratory decline.
However, both tests should be used in combination with the VC
measurement.15
Special investigations
Patients with suspected neuromuscular disease should have
serum creatine kinase measurement, nerve conduction studies,
electromyography (EMG) and magnetic resonance imaging. A
muscle biopsy may be required. If the extent of respiratory
muscle and diaphragm weakness is unclear, a referral should be
considered to a specialist centre for tests of respiratory muscle
strength. Transdiaphragmatic pressures are measured using
gastric and oesophageal pressure balloon catheters during volitional and non-volitional respiratory manoeuvres.16 Oesophageal
catheter measurements of diaphragm EMG may be carried out to
assess neural respiratory drive.6,7,18,19 Techniques are being
developed for the non-invasive measurement of neural respiratory drive, using surface EMG electrodes positioned over the
parasternal intercostal muscles.8,20,21
Treatment
The mainstay of treatment of hypoxaemic respiratory failure is
supplementary oxygen. This may be delivered in a controlled
manner, for example through the Venturi mask system (FiO2
range 24e60%) or in an uncontrolled manner, such as through
nasal cannulae. In the absence of CO2 retention, target oxygen
saturation (SpO2) in acute hypoxaemic respiratory failure
should be 94e98%. If there is a risk of CO2 retention, as in
COPD, chest wall deformity, neuromuscular disease and OHS,
SpO2 should be aimed at the lower range of 88e92% to reduce
the risk of hyperoxia-induced hypercapnia. Long-term
oxygen therapy is reserved for those patients with a PaO2 less
than 7.3 kPa, or those patients with a PaO2 less than 8 kPa but
with evidence of cor pulmonale and/or polycythaemia. Guidelines for the administration of oxygen can be found on the
British Thoracic Society website at www.brit-thoracic.org.uk.
Non-invasive ventilation (NIV) has revolutionized the
management of hypercapnic respiratory failure.22 In acute
exacerbations of COPD with hypercapnia, NIV has become an
established first-line adjunct to medical therapy.23 Domiciliary
NIV is indicated in chronic hypercapnic respiratory failure
due to chest wall deformity, progressive neuromuscular
disease and OHS, although this is based on limited evidence. Its
role in stable COPD with persistent hypercapnia is unclear;24
although some studies have suggested a benefit25 further clinical trials are being conducted. Finally, there have been major
advances in invasive ventilation and the use of lung protective
strategies for patients with life-threatening respiratory failure
who require invasive ventilation, and more recently the use of
extracorporeal membrane oxygenation has been shown to be
beneficial.
A
Nocturnal studies
Patients with hypoxaemic respiratory failure due to suspected
OSA should undergo overnight monitoring including pulse oximetry to reveal the frequency and severity of overnight oxygen
desaturations. Respiratory muscle weakness initially presents as
daytime hypoxaemia, due to V/Q mismatch, with hypercapnia
developing as the weakness becomes more severe. Hypercapnic
respiratory failure in such patients commonly manifests first at
night, particularly during rapid eye movement (REM) sleep,
when neural drive and alveolar ventilation are reduced. Overnight oximetry and transcutaneous capnography are useful in
detecting the severity of nocturnal hypoventilation in these
patients, as well as those with hypercapnia due to chest wall
deformity or obesity hypoventilation syndrome (OHS). It can also
be useful in assessing risk of hypercapnia and respiratory
acidosis in COPD patients receiving long-term oxygen therapy.
As well as abnormal overnight oximetry and capnography,
elevated morning bicarbonate, chloride and base excess indicate
nocturnal hypercapnia.
Imaging
Plain CXR may detect many of the causes of hypoxaemic respiratory failure, such as pneumonia, diffuse parenchymal lung
disease (DPLD) and pulmonary oedema. Changes in the CXR
such as hyperinflation and increased lucency of the lung fields
may indicate COPD, and prominent pulmonary vasculature may
MEDICINE 40:6
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RESPIRATORY FAILURE
REFERENCES
1 Luhr OR, Antonsen K, Karlsson M, et al. Incidence and mortality after
acute respiratory failure and acute respiratory distress syndrome in
Sweden, Denmark, and Iceland. The ARF Study Group. Am J Respir
Crit Care Med 1999; 159: 1849e61.
2 Lewandowski K. Contributions to the epidemiology of acute respiratory failure. Crit Care 2003; 7: 288e90.
3 Woodhead M, Welch CA, Harrison DA, Bellingan G, Ayres JG.
Community-acquired pneumonia on the intensive care unit:
secondary analysis of 17,869 cases in the ICNARC Case Mix
Programme Database. Crit Care 2006; 10(suppl 2): S1.
4 Gupta D, Keogh B, Chung KF, et al. Characteristics and outcome for
admissions to adult, general critical care units with acute severe
asthma: a secondary analysis of the ICNARC Case Mix Programme
Database. Crit Care 2004; 8: R112e21.
5 Wildman M, Harrison D, Brady A, Rowan K. Case mix and outcomes
for admissions to UK adult, general critical care units with chronic
obstructive pulmonary disease: a secondary analysis of the ICNARC
Case Mix Programme Database. Crit Care 2005; 9(suppl 3): S38e48.
6 Steier J, Jolley CJ, Seymour J, Roughton M, Polkey MI, Moxham J.
Neural respiratory drive in obesity. Thorax 2009; 64: 719e25.
7 Jolley CJ, Luo YM, Steier J, et al. Neural respiratory drive in healthy
subjects and in COPD. Eur Respir J 2009; 33: 289e97.
8 Steier J, Jolley CJ, Polkey MI, Moxham J. Nocturnal asthma monitoring
by chest wall electromyography. Thorax 2011.
9 Man WD, Kemp P, Moxham J, Polkey MI. Skeletal muscle dysfunction
in COPD: clinical and laboratory observations. Clin Sci (Lond) 2009;
117: 251e64.
10 Waschki B, Kirsten A, Holz O, et al. Physical activity is the strongest
predictor of all-cause mortality in patients with chronic obstructive
pulmonary disease: a prospective cohort study. Chest 2011.
11 Benzo RP, Chang CC, Farrell MH, et al. Physical activity, health status
and risk of hospitalization in patients with severe chronic obstructive
pulmonary disease. Respiration 2010; 80: 10e8.
12 Garcia-Aymerich J, Lange P, Benet M, Schnohr P, Anto JM. Regular
physical activity reduces hospital admission and mortality in chronic
obstructive pulmonary disease: a population based cohort study.
Thorax 2006; 61: 772e8.
MEDICINE 40:6
13 Access to specialist neuromuscular care: the Walton report, All Party
Parliamentary Group for Muscular Dystrophy, www.musculardystrophy.org/assets/0000/9943/Walton_reportpdf; 2009.
14 Hart N, Cramer D, Ward SP, et al. Effect of pattern and severity of
respiratory muscle weakness on carbon monoxide gas transfer and
lung volumes. Eur Respir J 2002; 20: 996e1002.
15 Hart N, Polkey MI, Sharshar T, et al. Limitations of sniff nasal pressure
in patients with severe neuromuscular weakness. J Neurol Neurosurg
Psychiatr 2003; 74: 1685e7.
16 ATS/ERS Statement on respiratory muscle testing. Am J Respir Crit
Care Med 2002; 166: 518e624.
17 Stein PD, Woodard PK, Weg JG, et al. Diagnostic pathways in acute
pulmonary embolism: recommendations of the PIOPED II Investigators. Radiol 2007; 242: 15e21.
18 Luo YM, Moxham J. Measurement of neural respiratory drive in
patients with COPD. Respir Physiol Neurobiol 2005; 146: 165e74.
19 Luo YM, Moxham J, Polkey MI. Diaphragm electromyography using an
oesophageal catheter: current concepts. Clin Sci (Lond) 2008; 115:
233e44.
20 Reilly CC, Ward K, Jolley CJ, et al. Neural respiratory drive, pulmonary
mechanics and breathlessness in patients with cystic fibrosis. Thorax
2011; 66: 240e6.
21 Murphy PB, Kumar A, Reilly C, et al. Neural respiratory drive as
a physiological biomarker to monitor change during acute exacerbations of COPD. Thorax 2011; 66: 602e8.
22 Elliott MW. Non-invasive ventilation: established and expanding
roles. Clin Med 2011; 11: 150e3.
23 Ram FS, Picot J, Lightowler J, Wedzicha JA. Non-invasive positive
pressure ventilation for treatment of respiratory failure due to
exacerbations of chronic obstructive pulmonary disease. Cochrane
Database Syst Rev 2004. Issue 1. Art. No.: CD004104.
24 Wijkstra PJ, Lacasse Y, Guyatt GH, Goldstein RS. Nocturnal noninvasive positive pressure ventilation for stable chronic obstructive
pulmonary disease. Cochrane Database Syst Rev 2002. Issue 3. Art.
No.: CD002878.
25 McEvoy RD, Pierce RJ, Hillman D, et al. Nocturnal non-invasive nasal
ventilation in stable hypercapnic COPD: a randomised controlled
trial. Thorax 2009; 64: 561e6.
297
Ó 2012 Elsevier Ltd. All rights reserved.