RespiRatoRy failuRe

Respiratory failure
Nicholas Hart

European data from patients admitted to intensive care requiring invasive mechanical ventilation for more than 24 hours, the estimate of acute life-threatening respiratory failure is between 77.6 and 88.6 cases per 100,000 population per year.1 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 and pneumonia respectively, and this accounts for around 24,000 admissions per year. The in-hospital mortalities of these conditions are 38.3%, 9.8% and 49.4%, respectively.24 The number of patients admitted with less severe respiratory failure is probably greater, but there are limited data available.

Abstract
Respiratory failure is the consequence of lung failure leading to hypox aemia or respiratory muscle pump failure resulting in alveolar hypoventi lation and hypercapnia. type 1 respiratory failure is defined as a partial pressure of arterial oxygen (pao2) less than 8.0 kpa or hypoxaemic respira tory failure, and type 2 respiratory failure is defined as pao2 <8 kpa and a partial pressure of arterial carbon dioxide (paCo2) >6 kpa or hypercapnic respiratory failure. Diagnosis is made easier by understanding the patho physiological mechanisms that cause hypoxaemia and hypercapnia. fur thermore, a basic knowledge of acidbase balance allows distinction between acute, acuteonchronic 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 apnoeas 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.

Pathophysiology
It is easier to consider hypoxaemic respiratory failure as lung failure, such as occurs with pneumonia, interstitial lung disease and acute cardiac pulmonary oedema, and hypercapnic respiratory failure as respiratory muscle pump failure in which alveolar hypoventilation predominates (Figure 1). Obviously, both respiratory muscle pump and lung failure can occur in the same patient, as in chronic obstructive pulmonary disease (COPD) or in an asthmatic crisis in which hypercapnia develops only if the hypoxaemic process progresses or persists. In order to generate a clinical conditions list, it is useful to consider the five pathophysiological mechanisms of hypoxaemia: ventilation/perfusion (V/Q) mismatch impaired diffusion right-to-left intracardiac intrapulmonary shunts or alveolar hypoventilation reduced inspired oxygen concentration (Figure 2). It is necessary to highlight that V/Q mismatch is the commonest cause of hypoxaemia. As with hypoxaemic respiratory failure, it is useful to consider the pathophysiological mechanisms of hypercapnic type 2 respiratory failure and then to generate a conditions list based on these mechanisms. First, we must consider that hypercapnia is a result of the respiratory muscle pump failure caused by an imbalance between neural respiratory drive, the load on the respiratory system and respiratory muscle capacity (Figure 3). Drive failure,

Keywords hypoxaemia; hypercapnia; lung failure; oxygen therapy; respiratory muscle pump failure; ventilation

The two principal components of the respiratory system are the lungs and the respiratory muscle pump. Both are essential for sustaining life and work in a complementary fashion to ensure that adequate gas exchange and ventilation occurs. Respiratory failure results from the inability of the respiratory system to carry out one or both of its gas exchange functions: oxygenation of, and/or elimination of carbon dioxide from, mixed venous blood. The definition of respiratory failure is derived from the arterial blood gas measurements and defined as an arterial oxygen tension (PaO2) less than 8.0 kPa and arterial carbon dioxide tension (PaCO2) greater than 6.0 kPa. This is further subdivided into type 1 hypoxaemic respiratory failure (PaO2 <8 kPa) and type 2 hypercapnic respiratory failure (PaO2 <8 kPa with PaCO2 >6 kPa).

Types of respiratory failure

Respiratory failure

Lung failure

Pump failure

Incidence
Despite this clear definition of respiratory failure, the incidence of respiratory failure is difficult to determine. However, using

Type 1 hypoxaemic respiratory failure

Type 2 hypercapnic respiratory failure

Nicholas Hart MRCP PhD is Consultant Physician and Honorary Senior Lecturer at St Thomas Hospital, Guys and St Thomas NHS Foundation Trust, London, UK. Competing interests: none declared.

Figure 1

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RespiRatoRy failuRe

Type 1 hypoxaemic respiratory failure

Using the five pathophysiological mechanisms of hypoxaemia, a comprehensive list of conditions that cause hypoxaemia can be generated
e.g. chronic obstructive pulmonary disease, asthma, pulmonary embolus, pulmonary oedema, cystic fibrosis, bronchiectasis

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 Cortex brainstem HIGH LOAD Resistive elastic threshold

*Ventilationperfusion mismatch

Anatomical R-L shunt

e.g. pulmonary arteriovenous malformation, pneumonia

Hypoxaemia

Impaired diffusion
e.g. diffuse parenchymal lung disease

TRANSMISSION & ACTION FAILURE Spinal cord Peripheral nerves Neuromuscular junction Respiratory muscles RESPIRATORY MUSCLE PUMP FAILURE Type 2 hypercapnic respiratory failure

Low partial pressure of imspired oxygen

e.g. flying

Alveolar hypoventilation
e.g. opiate overdose

Figure 3
*V/Q mismatch is the most important cause of hypoxaemia.

Figure 2

However, with the increased HCO3 the PaCO2 level will be significantly higher than seen in patients with acute hypercapnic respiratory failure.

high respiratory muscle load and neuromuscular transmission and respiratory muscle action failure are all important and impairment at one or more levels can result in hypercapnic respiratory failure. 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).

History and examination

In general, type 1 hypoxaemic respiratory failure will be a relatively straightforward diagnosis based on a standard assessment including a history, examination and chest X-ray. However, the most important exception to this rule is obstructive sleep apnoea (OSA), which is commonly overlooked and requires both a sleep and respiratory history to be taken. Although type 2 hypercapnic respiratory failure is a less common clinical problem it is more difficult and requires a more careful and considered approach and often includes a thorough neurological examination to observe for signs such as tongue and peripheral muscle fasciculation, muscle wasting and weakness and sensory loss. The clinical presentation can be fairly insidious (see conditions listed in Figure 4) and despite breathlessness being a feature in patients with severe neuromuscular disease and skeletal deformity, moderate respiratory muscle pump failure may cause few problems unless an addition load is placed on the system, such as pneumonia. Furthermore, a number of these conditions, such as GuillainBarr 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 with a predicted decline, including Duchenne muscular dystrophy, myotonic dystrophy and scoliosis require close observation. COPD is another, not insignificant, cause of respiratory failure presenting both in the acute and chronic state. However, as a result of V/Q mismatch, hypoxaemia rather than hypercapnic respiratory failure is a more common presentation. In contrast to the conditions with respiratory muscle weakness, with COPD patients there will be greater focus during the consultation on features such as cough, wheeze
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Acute, chronic and acute-on-chronic respiratory failure

This is an important distinction to be aware of as the clinical presentation and the arterial blood gas measurements are very different. In this section, we will focus on hypercapnic type 2 respiratory failure. Acute hypercapnic respiratory failure is defined by an acute rise in PaCO2 with accompanying respiratory acidosis (pH <7.35). As PaCO2 is directly proportional to the rate of production of CO2 and inversely proportional to the rate of removal of CO2,(PaCO2 VCO2/VA: VCO2 is the rate of production of CO2 and VA is the alveolar ventilation), the approach of considering the respiratory muscle load, capacity and neural respiratory drive to form a diagnostic list is still valid for acute, chronic and acute-on-chronic respiratory failure. In contrast to acute respiratory failure, patients with chronic respiratory failure have a pH within the normal range (7.357.45), but with an elevated bicarbonate level (>26 mmol.L1) as renal retention of bicarbonate is promoted. The bicarbonate concentration (HCO3) acts to buffer the hydrogen ions (H+) that are increased as a consequence of an elevated PaCO2 combining with water and dissociating to produce increased quantities of H+. The term acute-on-chronic respiratory failure is a clinical description of an acute deterioration in a patient with chronic respiratory failure. Although the bicarbonate level will be elevated, the patient will have an acidosis and the pH level will be less than 7.35.

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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 Cortex and brainstem DRIVE FAILURE TRANSMISSION FAILURE GENERAL Trauma, encephalitis, ischaemia, haemorrhage, CheyneStokes respiration CENTRALLY ACTING DRUGS Sedatives, opiates, anti-epileptics METABOLIC COMPENSATION COPD, NMD, OHS, skeletal deformity Threshold load (Intrinsic PEEP) COPD, asthma, bronchiectasis, CF Resistive load Bronchospasm, upper airways obstruction, bronchiectasis, COPD, CF, OSA Elastic load LUNG pneumonia, alveolar oedema, atelectasis, ALI/ARDS, DPLD, COPD, CF CHEST WALL kyphoscoliosis, obesity, OHS, abdominal distenstion, ascites HIGH LOAD Nerves and neuromuscular junction Spinal cord lesion (above C3) Polio Motor neurone disease Phrenic nerve injury GuillainBarre syndrome CINMA Neruomuscular blocking agents Aminoglycosides Myasthenia gravis Botulism Respiratory muscles Muscular dystrophies Inflammatory myopathies Malnutrition myopathy Acid maltase deficiency Thyroid myopathy Biochemical anomalies Hypokalaemia Hypophosphataemia ACTION FAILURE
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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

and sputum production, as well as activity and nutritional status (BMI; body mass index) as these have prognostic implications. There are a number of clinical symptoms and signs that should alert the physician to the development of hypercapnic respiratory failure, and specific features to focus on with progressive neurological conditions include the following: sleep-disordered breathing morning headache, daytime sleepiness, disrupted sleep pattern, impaired intellectual function, generalized fatigue, loss of appetite and weight respiratory muscle weakness orthopnoea, breathlessness on immersion in water, breathlessness on leaning forward, breathlessness on exertion, poor cough, poor chest expansion, paradoxical abdominal motion during inspiration (inward motion of the anterior abdominal wall due to diaphragm weakness), abdominal muscle recruitment in expiration bulbar dysfunction low-volume voice, difficulty swallowing, drooling, difficulty clearing secretions, poor cough, staccato/ slurred speech, coughing on swallowing.

Investigations
Pulmonary function tests The diagnosis of respiratory failure is made by obtaining PaCO2 and PaO2 on arterial blood gas measurements. As described above, the HCO3 will provide evidence for duration of CO2 retention. However, respiratory assessment using some simple
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bedside tests is useful. Basic spirometry will measure the forced expiratory volume in 1 second (FEV1) and the forced vital capacity (FVC). This will not only identify airways obstruction (mild FEV1/FVC 5070%; moderate FEV1/FVC 3050% and severe FEV1/FVC <30%), as in COPD, but also demonstrate a restrictive ventilatory defect (FEV1/FVC >75%) in the presence of respiratory muscle weakness and interstitial lung disease. In addition to the restrictive ventilatory defect, the finding in patients with respiratory muscle weakness is a reduced VC with a fall in supine VC of >20%. The 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).5 A VC less than 1 litre has a high predictive value to identify patients with 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 (MIP) and sniff inspiratory pressure (SNIP) are better predictors of respiratory decline. However, both tests should be used in combination with the VC measurement.6 Nocturnal studies Patients with hypoxaemic respiratory failure and/or a history suggestive of OSA should undergo an overnight oximetry, which can identify the frequency and severity of overnight desaturations. Respiratory muscle weakness initially leads to daytime

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hypoxaemia, as a result of V/Q mismatch, and hypercapnic respiratory failure does not occur until there is profound weakness. Any cause of nocturnal hypoventilation, such as skeletal deformity, neuromuscular disease or COPD, predominates during rapid eye movement (REM) sleep as there is a reduction in the respiratory drive and a decrease in ventilation with a resultant rise in PaCO2. This can be measured by combined overnight capnography and oximetry, which is performed in the sleep laboratory or ward. It is important to identify nocturnal hypoxaemic hypercapnia as this develops prior to established daytime respiratory failure and can act as a signal that a patient is developing respiratory failure and will be at risk of developing acute respiratory failure at times of crisis. In patients with COPD, the monitoring of oximetry and capnography overnight, whilst using nocturnal oxygen therapy, is useful for identifying those COPD patients who are at risk of retaining CO2 and developing respiratory acidosis during oxygen administration. As well as abnormal overnight oximetry and capnography, elevated morning bicarbonate, chloride and base excess indicate nocturnal hypercapnia. Imaging A plain chest radiograph is useful in all patients with type 1 and type 2 respiratory failure. In addition to any acute changes, such as pneumonia or acute cardiac pulmonary oedema, the chest X-ray is useful for demonstrating hyperinflation and prominent pulmonary vessels as observed in COPD and pulmonary hypertension, as well as the reticular and nodular shadowing seen in diffuse parenchymal lung disease (DPLD). However, it must be remembered that the chest X-ray can be misleading in patients with diaphragm weakness as diaphragm elevation is of little value in the diagnosis of diaphragm weakness. For a detailed evaluation of diaphragm function it is best to refer to a specialist centre that can measure the transdiaphragmatic pressure using a nonvolitional technique involving stimulation of the phrenic nerves. Special investigations In patients with suspected neurological disease, one must consider measuring the level of muscle creatinine kinase, an electromyogram (EMG), nerve conduction studies (NCS), magnetic resonance imaging scanning as well as a muscle biopsy. Patients with suspected DPLD will require a high-resolution chest CT scan to further define the abnormality and determine the diagnosis.

skeletal deformity, oxygen should be prescribed to maintain the saturations at 8892%. This approach not only reduces the risk of hyperoxia-induced hypercapnia, but also ensures the effects of oxygen toxicity, such as myocardial ischaemia and depression, are minimized. Further information can be found in the Guidelines for Emergency Oxygen Therapy on the British Thoracic Society website (http://www.brit-thoracic.org.uk/). In the chronic setting, the use of longterm oxygen therapy (LTOT), minimum use 15 hours per day, is reserved for those patients with a PaO2 less than 7.3 kPa or those patients with a PaO2 <8 kPa but with evidence of cor pulmonale and/or polycythaemia. There have been major advances in invasive ventilation and the use of lung protective strategies for patients with lifethreatening respiratory failure who require invasive ventilation.7,8 Furthermore, there has been a revolution in the management of patients with acute and chronic respiratory failure with the widespread use of non-invasive ventilation (NIV) in the hospital and home setting. In particular, for patients with acute exacerbations of COPD with type 2 respiratory failure that fail to respond to medical therapy, the first-line treatment is NIV, which has been shown to reduce mortality compared with conventional therapy, including invasive ventilation.911

Management
Hypoxaemic type 1 respiratory failure is treated with supplemental oxygen. The diagnosis will determine the definitive management strategy, but the aim must be to ensure the patient is adequately oxygenated and ventilating sufficiently. Supplemental oxygen can be given in a controlled manner, such as using the Venturi system of face-masks (fraction of inspired oxygen (FiO2) from 24% to 60%), or in an uncontrolled manner, such as nasal cannulae, where the FiO2 is variable and must be used with caution. In general, targeted oxygen delivery must be adhered to and in the acute setting all patients should be prescribed oxygen therapy to target and maintain the saturations between 94 and 98% (<70 years age) and 9298% (>70 years age). However, for those patients at risk of developing hypercapnic respiratory failure, such as those with COPD, neuromuscular disease and
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ReFeReNceS 1 lewandowski K. Contributions to the epidemiology of acute respiratory failure. Crit Care 2003; 7: 28891. 2 Woodhead M, Welch C, Harrison D, Bellinghan G, ayres J. Community acquired pneumonia on the intensive care unit: a secondary analysis of the iCNaRC case mix programme database. Crit Care 2006; 10: s1s9. 3 Gupta D, Keogh B, Chung K, et al. Characteristics and outcomes 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; 9: s14s24. 4 Wildman M, Harrison D, Brady a, Rowan K. Case mix and outcomes for admissions to uK adult general critical caree units with chronic obstructive airways disease: a secondary analysis of the iCNaRC case mix programme database. Crit Care 2005; 9: s3848. 5 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: 9961002. 6 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: 168587. 7 tobin M. advances in mechanical ventilation. N Engl J Med 2001; 344: 1896996. 8 tobin M. principles and practices on mechanical ventilation, 2nd ed. New york: MacgrawHill, 2006. 9 Brochard l, Mancebo J, Wysocki M, et al. Noninvasive ventilation for acute exacerbations of chronic obstructive pulmonary disease. N Engl J Med 1995; 333: 81722. 10 British thoracic society guidelines for noninvasive ventilation in acute respiratory failure. Thorax 2002; 57: 192221. 11 Decramer M, Roussos C. Respiratory failure. Eur Respir J 2003; 22(s47): s164.

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