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Unexplained ventilatory failure 

Unexplained ventilatory failure
Unexplained ventilatory failure

Stephen Chapman

, Grace Robinson

, John Stradling

, Sophie West

, and John Wrightson

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date: 23 January 2022



Ventilatory failure is conventionally divided into type I (hypoxia only, PaO2 <8kPa) and type II (hypoxia and hypercapnia, PaCO2 >6kPa): they are conceptually quite different. Type I is an increased A–a O2 gradient (implying increased V/Q mismatch), with adequately increased alveolar ventilation maintaining a normal PaCO2. The causes are numerous, including most of respiratory medicine, and requires the usual ‘history, examination, and investigations’.

A more difficult, less common clinical scenario is an unexplained rise in PaCO2 (>6kPa, type II), with no obvious cause following a standard assessment. This may occur in the outpatient, ward, A&E, or ICU setting.


A rise in PaCO2 can be due to V/Q mismatch with inadequate compensatory hyperventilation, e.g. overwhelming asthma, when there will also be a large A–a gradient indicating this increased V/Q mismatch. However, it can also be due to inadequate ventilatory drive or primary ventilatory pump failure where the A–a gradient will usually be normal. The following list contains mainly the causes that might not have been suspected from the initial assessment but, for completeness, also includes some more obvious causes. The conditions with asterisks are the ones most commonly discovered when the cause is not immediately obvious.

Failure of drive

Brainstem abnormality

  • Polio and post-polio syndrome* (exact mechanism unclear)

  • Brainstem stroke (involvement of respiratory centres bilaterally)

  • Arnold–Chiari malformation—herniation of cerebellum into foramen magnum, compressing the brainstem

  • Syringobulbia—expansion of a fluid compartment in the middle of the spinal cord extending up into the medulla (can be associated with Arnold–Chiari malformation)

  • Surgical damage during operations for Arnold–Chiari and syringobulbia

  • Encephalitis

  • Brainstem tumour

  • Congenital hypoventilation syndrome—usually presents soon after birth, can be later; abnormalities of neural crest development due to increased number of ‘alanine repeats’ in one of the homeobox genes (PHOX2B).


  • Sedative drugs, including alcohol, opiates, etc.*

  • Metabolic alkalosis (hypokalaemic alkalosis, diuretic-induced, prolonged vomiting).

Pump failure

Neurological (particularly if diaphragm involved)

  • Myopathies

    • Acid maltase deficiency (Pompe’s), diaphragm paralysis commonly occurs early on*

    • Duchenne muscular dystrophy

    • Myotonic dystrophy

    • Several other very rare primary or secondary myopathies, e.g. limb girdle, hypothyroid, drugs (hydroxychloroquine)

  • Neuropathy

    • MND* can affect diaphragm early on

    • Bilateral diaphragm paralysis*, e.g. trauma, bilateral neuralgic amyotrophy (also known as ‘brachial neuritis’, inflammatory damage to nerves of lower brachial plexus—cause unknown)

    • Guillain–Barré

    • Spinal muscular atrophy, autosomal recessive, spinal cord motor neurones

    • High cord transection

  • Neuromuscular junction abnormalities

    • Myasthenia gravis*

    • Lambert–Eaton myasthenic syndrome (LEMS)

  • Anti-acetylcholine esterase poisoning (usually from organophosphate insecticides)

  • Mixed

    • Post-ITU (‘critical care neuropathy’), post-muscle relaxants*.

Chest wall

  • Obesity, especially abdominal (obesity hypoventilation syndrome)*

  • Raised abdominal pressure, ‘abdominal compartment (or hypertension) syndrome’, e.g. ascites, or gut and mesentery oedema

  • Scoliosis*

  • Post-thoracoplasty (usually ‘three stage’, many ribs caved in, starting from the top down—done for TB prior to effective chemotherapy)

  • Flail chest

  • Pneumothorax/large pleural effusion

  • Severe ankylosing spondilitis.

Airways obstruction/mixed

  • Unrecognized COPD/severe asthma*

  • OSA and additional COPD/obesity/muscle weakness*, sometimes called ‘overlap syndrome’.

The ventilatory loading effects of obesity, COPD, and OSA commonly summate to produce ventilatory failure when each on their own would not be regarded as of sufficient severity. Estimating the contribution each is making to an individual’s ventilatory failure can influence therapy and expectations of success, e.g. if OSA dominant (>30, >4% SaO2 dips/h), the ventilatory failure is likely to respond to CPAP; dominant COPD (FEV1 <25% predicted) will need maximal lower airways dilator therapy (thresholds only for general guidance), but the likely poor response of the lower airways obstruction will mean that even limited additional weight reduction and/or treatment of milder OSA may be useful in this situation.

Clinical presentation

Slow onset

In several of the conditions listed previously, e.g. acid maltase deficiency, MND, and scoliosis, the onset of ventilatory failure can be insidious and include:

  • General fatigue and/or hypersomnolence

  • Headaches on awakening

  • Morning confusion

  • Morning cyanosis

  • Ankle oedema (fluid retention, cor pulmonale, from the hypoxia)

  • Orthopnoea, particularly if diaphragmatic weakness

  • Dyspnoea standing in the swimming pool (this usually indicates diaphragm paralysis, as the pressure of water, even at 1m depth, pushes the unopposed diaphragm further up into the chest)

  • Swallowing difficulties (often MND) or other evidence of a more generalized proximal neuromuscular problem.

Apparent rapid onset

Sometimes, the significance of these symptoms is missed for a while, and a relatively trivial respiratory tract infection, a general anaesthetic, or the prescription of a ventilatory depressant tips the balance and the patient goes into severe ventilatory failure, with impaired conscious level or coma. These individuals will end up ventilated on ICU and may be difficult to wean, or present again with ventilatory failure a few weeks after discharge.

Further information

Chuen-Im P et al. Heterozygous 24-polyalanine repeats in the PHOX2B gene with different manifestations across three generations. Pediatr Pulmonol 2014;49:E13–6.Find this resource:

Hedestierna G, Larsson A. Influence of abdominal pressure on respiratory and abdominal organ function. Curr Opin Crit Care 2012;18:80–5.Find this resource:

Resta O et al. Sleep-related breathing disorders, loud snoring and excessive daytime sleepiness in obese subjects. Int J Obes Relat Metab Disord 2001;25:669–75.Find this resource:

Clinical assessment and management

History, examination, and investigations


Carefully taken history, e.g. symptoms of subtle weakness prior to presentation, episode of shoulder pain (neuralgic amyotrophy), past history of polio, orthopnoea (diaphragm weakness), drug history. Often this is not available, as the patient may present unconscious.


Thorough examination, particularly neurological, e.g. fasciculation, diaphragm weakness (when supine, inward drawing of abdomen on inspiration or sniffing—masked if on positive pressure ventilation), myotonia, as well as rarer signs seen in some of the conditions listed previously.

Blood gases taken breathing air (following >20min off extra O2)

  • Degree of CO2 retention

  • Presence of a base excess indicating chronicity of CO2 retention

  • Calculate A–a gradient to detect any V/Q mismatch (see Unexplained ventilatory failure p. [link])

  • In pure hypoventilation, there should be no significant A–a gradient (<2kPa), unless there is 2° basal atelectasis from poor lung expansion and/or obesity.


(See Unexplained ventilatory failure p. [link].)

  • Presence of unexpected severe airways obstruction

  • Reduced VC (neurological or chest wall)

  • Further fall of VC on lying down (>20% change, definitely abnormal)—indicative of diaphragm paralysis. When supine, VC is <25% predicted, very likely to be the main cause of the raised PaCO2

  • Mouth pressures, sniff pressures, or transdiaphragmatic pressures; not much more helpful than the % fall in VC on lying down.

Specific tests—for some of the conditions listed previously such as:

  • EMG studies—MND, myotonia

  • MRI (gadolinium-enhanced)—Arnold–Chiari, brainstem lesion, syrinx

  • CPK—some myopathies

  • Sleep study—e.g. (i) REM hypoxia (early marker of ventilatory failure, when supine VC has usually dropped below 60% predicted normal), (ii) continuous nocturnal hypoventilation (when supine VC has dropped below 40% predicted), and (iii) additional OSA

  • Blood film for abnormal lymphocyte cytoplasmic vacuolation (mainly acid maltase deficiency)

  • Muscle biopsy—acid maltase deficiency (glycogen-containing vacuoles and low enzyme levels).


of the underlying condition, if possible, is paramount. Weak expiratory muscles and weak laryngeal adduction prevent effective coughing, with an increased incidence of serious chest infections. Clearing retained secretions can be a major problem. Physiotherapists can help teach patients and their carers sputum clearance techniques. Increasing the lung volume, prior to coughing, with positive pressure devices (e.g. using the patient’s own ventilator, the Bird device, or simple bag and face mask) and ‘breath stacking’ techniques generate a higher expiratory flow with improved sputum clearance. Mechanical insufflator/exsufflator devices are available that both increase inspiratory volume and speed expiratory flows. Their acute and prophylactic role is still being evaluated.

Lying down and sleeping with the whole bed tipped head up by about 15–20° greatly improves ventilation in the presence of bilateral diaphragm paralysis or major abdominal obesity. Just elevating the top half of the bed and bending the patient in the middle, leaving the abdomen and legs horizontal, does not work. The abdominal contents have to descend into the pelvis to effectively ‘offload’ the diaphragm. This posture will also improve the ability to wean from assisted ventilation.

When the underlying condition is irreversible, the decision will need to be taken as to whether long-term NIV is appropriate (see Unexplained ventilatory failure pp. [link][link]).


* The conditions most commonly discovered when the cause is not immediately obvious.