CONTENTS

primary hypercapnia (respiratory acidosis)

1. Clinical manifestations
2. Laboratory diagnosis
3. Causes
4. Evaluation
5. Management

primary hypocapnia (respiratory alkalosis)

1. Clinical manifestations
2. Laboratory diagnosis
3. Causes
4. Evaluation
5. Management

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clinical manifestations of hypercapnia

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relationship of acuity to symptoms

• Acute hypercapnia in a previously normocapnic patient will often cause robust tachypnea. This may manifest with symptoms of dyspnea.
• Chronic hypercapnia leads to blunting of the respiratory drive.  This may cause patients with acute-on-chronic hypercapnia to present with somnolence (rather than dyspnea).

hypercapnic encephalopathy (“CO2 narcosis”)

• Symptoms:
  • Initially: Anxiety, dyspnea, restlessness.
  • Later on: Delirium, somnolence, and eventually coma.
  • Other features: coarse tremor, multifocal myoclonus, and asterixis.
• Hypercapnic encephalopathy is more likely with severe hypercapnia (e.g., pCO2 >80 mm). (Irwin 2023)

headache

• Nocturnal hypoventilation may cause headache upon awakening.

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permissive hypercapnia in an intubated patient

general concept of permissive hypercapnia

• Permissive hypercapnia involves an intentional strategy of allowing the pCO2 to increase during mechanical ventilation (with a goal of avoiding barotrauma). The limits of safe hypercapnia are unclear. Specifically, there is no pCO2 level above which obvious harm is noted.
• Patients with COPD or obesity hypoventilation syndrome may live for years despite very substantial chronic hypercapnia. Although this isn't a desirable physiological state, its existence proves that hypercapnia itself isn't necessarily an immediate life-threat.

potential risks of permissive hypercapnia 

• Dyspneic agitation:
  • Acute hypercapnia may cause severe dyspnea with agitation. Among intubated patients, it may cause tachypnea and “bucking” the ventilator.
  • At higher pCO2 levels, CO2 narcosis may have a predominant effect (which leads to sedation, rather than dyspneic agitation).
• Pulmonary vasoconstriction:
  • Global vasoconstriction of the pulmonary vasculature will increase the pulmonary vascular resistance.
  • This may not be well tolerated among patients with substantial pulmonary hypertension, or with right ventricular failure.
• Increased intracranial pressure:
  • Hypercapnia causes vasodilation of cerebral arteries, which will tend to increase intracranial pressure.
  • For neurocritically ill patients who already have elevated intracranial pressure, hypercapnia could exacerbate this.
  • Among patients without neurologic disease, this may cause headache.

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laboratory diagnosis of hypercapnia

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diagnosis is based on VBG or ABG

• (1) Hypercapnia is defined as PaCO2 >45 mm. Hypercapnia may also be diagnosed from a venous blood gas (more on comparing VBG vs. ABG here).
• (2) Primary hypercapnia is hypercapnia that isn't a compensatory response to metabolic alkalosis.

acute, chronic, or acute-on-chronic?

• The patient's baseline bicarbonate level may help determine whether hypercapnia is acute or chronic (table above, bottom panel). In chronic hypercapnia, there will be a greater compensatory metabolic alkalosis.
• However, this analysis assumes the following:
  • (1) The kidneys are working correctly.
  • (2) There are no other factors affecting the bicarbonate level (i.e., no metabolic acidosis or metabolic alkalosis).
• ⚠️ In reality, there are often many other factors which can also affect the bicarbonate level. This prevents the bicarbonate level from being an accurate arbiter of whether the hypercapnia is acute or chronic (figure below).

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causes of hypercapnia

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Below are various potential causes of hypercapnia. A patient with substantial hypercapnia may have several factors promoting this simultaneously. For example, hypercapnia in asthma is generally due to a combination of bronchospasm and diaphragmatic muscle fatigue. Another example is that of a patient with chronic hypercapnia due to COPD, who may experience worsening hypercapnia due to any deterioration in lung function (e.g., pneumonia or cardiogenic pulmonary edema – disease processes that don't typically cause hypercapnia).

[1/3] respiratory drive problem (“won't breathe”)

• Respiratory suppressive medications, e.g.:
  • Opioids.
  • Benzodiazepines, barbiturates.
  • Intoxicants (e.g., ethanol).
• Brainstem dysfunction, e.g.:
  • Trauma.
  • Encephalitis.
  • Infarction.
  • Tumor.
• Hypothyroidism.
• Central sleep apnea. 📖

[2/3] neuromuscular/chest/airway problem (“can't breathe”)

• Spinal cord problem, e.g.:
  • C-spine injury (C3-C5).
  • Transverse myelitis (e.g., multiple sclerosis).
  • Tumor.
• Neuromuscular weakness, e.g.:
  • Neuropathy, e.g.:
    • Guillain-Barre syndrome.
    • Amyotrophic lateral sclerosis.
    • Phrenic nerve injury.
  • Neuromuscular junction disorder, e.g.:
    • Myasthenia gravis.
    • Botulism.
    • Tick paralysis.
  • Myopathy, e.g.:
    • Hypokalemia.
    • Hypophosphatemia.
    • Thyroid disease.
    • Polymyositis, dermatomyositis.
    • Muscular dystrophy.
    • Critical illness myopathy.
    • Muscular fatigue.
• Restriction of lung inflation, e.g.:
  • Abdominal distension, e.g.:
    • Abdominal compartment syndrome.
    • OHS (obesity hypoventilation syndrome).
  • Pleural disease:
    • Pleural effusion.
    • Pneumothorax.
  • Thoracic cage dysfunction:
    • Kyphoscoliosis.
    • Ankylosing spondylitis.
    • Pectus excavatum.
• Upper airway problem, e.g.:
  • Angioedema.
  • Epiglottitis.
  • Foreign body.
  • Tracheal stenosis, tumor.
  • Vocal cord paralysis or vocal cord dysfunction.
• Small airway problem, e.g.:
  • COPD.
  • Asthma.
  • Bronchiolitis obliterans.

[3/3] increased dead space (“breathing isn't working”)

• Alveolar disease, e.g.:
  • Pneumonia.
  • ARDS.
  • Severe interstitial lung disease.
• Vascular disease, e.g.:
  • Severe pulmonary embolism.

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evaluation of hypercapnia

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The causes of hypercapnia are very broad, so the evaluation will need to be tailored substantially depending on the clinical context. Below are some investigations which may be helpful: 

physical examination

• Low respiratory rate suggests opioid intoxication or a central nervous system abnormality (consider a therapeutic trial of naloxone).
• Lack of distress suggests either:
  • (1) Chronic or acute-on-chronic hypercapnia, with blunting of the respiratory drive.
  • (2) Neurologic disease causing a respiratory drive problem.
• Neurological exam: Signs of brainstem or spinal cord pathology? Weakness?
• Auscultate over lungs & trachea: Bronchospasm? Stridor? How much air is the patient moving?
• For an intubated patient:
  • Peak pressures may suggest airway obstruction below the level of the endotracheal tube. However, this may fail to detect an upper airway obstruction which is bypassed by the endotracheal tube.
  • If the patient is hypercapnic despite a normal minute ventilation (e.g., ~7-8 liters/minute), this implies an increase in the dead space. An elevated gap between the ABG/VBG pCO2 versus the end tidal CO2 further supports an increase in dead space.

bedside pulmonary function tests (FVC, NIF)

• ⚠️ These tests aren't extremely sensitive or specific, but they can be helpful if extreme values are obtained. Since they are inexpensive and readily available, they may be worth obtaining. It's essential to ensure that patients are exerting themselves maximally during the test, because suboptimal effort will result in poor results.
• Negative inspiratory force (NIF) tests strength of diaphragm:
  • Impaired NIF may suggest neuromuscular weakness.
  • Preserved NIF largely exonerates the diaphragm and peripheral nerves.
• Forced Vital Capacity (FVC) is an integrated measurement of the diaphragmatic strength, restriction to lung inflation, and airway obstruction:
  • Reduced FVC and reduced NIF suggests neuromuscular weakness.
  • Reduced FVC with normal NIF suggests airway obstruction or restriction to lung inflation.
• Review of any prior pulmonary function tests (PFTs) may be helpful.

labs

• Electrolytes including Ca/Mg/Phos.
• Thyroid Stimulating Hormone (TSH).
• CBC (polycythemia suggests chronic hypoxemia, often seen with COPD).
• Creatinine kinase (may be elevated in myopathies, or hypothyroidism).
• Review of archival labs:
  • Prior blood gas measurements are the most useful.
  • If blood gas measurements aren't available, then chronically elevated bicarbonate levels support the possibility of chronic hypercapnia.

imaging

• Chest X-ray.
• MRI of brain/spine, if neurological examination suggests a lesion in those locations.
• CT scan of the neck & lungs (if evidence of upper airway pathology and/or pulmonary dysfunction). CT angiography of the thorax may be indicated if there is a concern for PE as a cause of hypercapnia.

electromyography (EMG)

• Among patients with neuromuscular weakness, this may facilitate diagnosis of neuropathies which require directed management (e.g., IVIG for management of Guillain-Barre syndrome).

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management of hypercapnia

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There is no universal approach to treating hypercapnia, since this will vary widely depending on the clinical context. Among patients with chronic hypercapnia, the therapeutic goal is generally to return the patient to their baseline pCO2 level. Some examples of potential therapies are:

• Hypercapnia due to opioid intoxication may involve naloxone (depending on the severity; more on this here).
• Hypercapnia due to neuromuscular weakness may often be improved with noninvasive ventilation (e.g., BiPAP). Additionally, the underlying disorders may require specific management.
• Hypercapnia due to asthma or COPD requires specific treatment pathways for these disorders:
  • More on COPD exacerbation here.
  • More on asthma exacerbation here.
  • More on the use of noninvasive ventilation here.
• Mild-moderate hypercapnia in an intubated patient may often be monitored without intervention (permissive hypercapnia).

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clinical manifestations of hypocapnia

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neurologic

• Clinical symptoms may include:
  • Anxiety.
  • Delirium, confusion.
  • Seizure.
• Reduced CO2 triggers cerebral vasoconstriction. This has two major consequences: a reduction in intracranial pressure, and a reduction in brain perfusion. Generally, the dominant effect is a deleterious reduction in brain perfusion. In very rare situations with impending herniation, hypocapnia may have therapeutic benefit (further discussion of this here).
  • Cerebral hypoperfusion due to hypocapnia may contribute to symptoms of a panic attack (e.g., confusion and dizziness).

respiratory

• Hypocapnia will suppress the respiratory drive. Among intubated patients with ventilator-induced hypocapnia, this may cause patients to stop triggering breaths and simply “ride” the ventilator (generally not a desirable situation, as it may promote atelectasis and muscle atrophy).
• Global hypocapnia throughout the lung causes bronchoconstriction and attenuation of hypoxic pulmonary vasoconstriction. The net effect is an impairment in ventilation-perfusion matching, which may exacerbate hypoxemia.(12097540)

metabolic

• Hypocalcemia: 📖 (alkalemia reduces ionized calcium level)
  • Paresthesias of extremities and mouth.
  • Cramps, carpopedal spasm, rarely tetany.
• Lactic alkalosis: Hypocapnia stimulates phosphofructokinase, leading to increased production of lactate.
• Hypophosphatemia.
• Hypokalemia.

cardiac

• Arrhythmia.
• Coronary vasospasm may occur. (37341662)

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laboratory diagnosis of hypocapnia

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laboratory findings that may occur in hypocapnia

• Hyperlactatemia.
• Elevated anion gap by ~3-5 mM (may be due to elevated lactate and/or increased negative charge on albumin). (37341662)
• NAGMA (non anion-gap metabolic acidosis) due to metabolic compensation.
• Acute hypocapnia may cause hypophosphatemia and hypokalemia. (37341662)
• Reduced iCa (ionized calcium level).

diagnosis of primary hypocapnia

• ABG/VBG allows for:
  • [1] Definitive diagnosis of hypocapnia (pCO2 < 35 mm).
  • [2] Determination of whether hypocapnia is primary (what this section is about) or compensatory in response to metabolic acidosis.
• End tidal CO2 << 30 mm suggests hypocapnia. However, this may also be caused by pulmonary dysfunction with an increase in dead space volume. Therefore, correlation between the end tidal CO2 and an ABG/VBG measurement is needed to confirm the diagnosis of hypocapnia.

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causes of hypocapnia

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In most cases, the cause of hypocapnia will be evident and this won't require further investigation. However, occasionally patient may be discovered with unexplained, significant hypocapnia – which warrants additional evaluation.

[1/6] respiratory disease 

• Hypocapnia can be caused by nearly any pulmonary disease. Hypoxemia itself can stimulate the respiratory drive, causing hypocapnia. Pulmonary irritation can also drive dyspnea and increases in ventilation, likewise leading to hypocapnia.
  • (1) Abnormal chest radiograph may suggest pulmonary disease as the cause.
  • (2) Normal chest radiograph may still occur with some respiratory causes of hypocapnia:
    • Mild cardiogenic pulmonary edema.
    • Pericardial tamponade.
    • Asthma.
    • Pulmonary embolism.
• Excessive mechanical ventilation among intubated patients (iatrogenic).

[2/6] neurologic

• Panic disorder, anxiety.
• Pain.
• Central neurogenic hyperventilation, e.g.:
  • Meningitis.
  • Encephalitis.
  • Traumatic brain injury.
  • Stroke.
  • (Different breathing patterns due to neurologic disease: 📖)

[3/6] toxicologic/medications

• Beta-agonists.
• Methylxanthines (theophylline, caffeine).
• Nicotine.
• Progesterone.
• Quetiapine. (37341662)
• Salicylates.
• Topiramate.
• Withdrawal (e.g., alcohol).

[4/6] endocrine

• Thyrotoxicosis.
• Pregnancy.

[5/6] cirrhosis

• Cirrhosis is a common cause of persistent respiratory alkalosis that is often encountered among intubated patients. This often reflects an accumulation of progesterone, due to impaired hepatic metabolism. Another possible etiology of hypocapnia in cirrhosis may be hepatopulmonary syndrome. (37341662)

[6/6] sepsis

• Respiratory alkalosis may be an early sign of sepsis, preceding hypoxemia or hypotension. (Remember, one of the classic features of systemic inflammatory response syndrome is tachypnea).
• This may especially be caused by gram-negative infections that secrete endotoxin, which stimulates central chemoreceptors. (37341662)

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evaluation of hypocapnia

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The cause of respiratory alkalosis will often be evident from the history and physical examination. If the cause remains unclear, the following evaluations might be considered.

potentially relevant investigations

• Salicylate level.
• Theophylline level (if the patient is on theophylline).
• Thyroid stimulating hormone (TSH).
• Liver function tests.
• beta-HCG (if relevant).
• Evaluation for pulmonary embolism (e.g., D-dimer and/or CT angiography, cardiopulmonary POCUS).
• Evaluation for sepsis.
• Neuroimaging +/- lumbar puncture (if clinical features of stroke or CNS infection).

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management of hypocapnia

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treat any identifiable etiology

• Ensure that pain and agitation are properly managed. 📖

if the patient is intubated:

• If the patient isn't triggering the ventilator, then reduce the minute ventilation (i.e., tidal volume and/or respiratory rate).
• If the patient is breathing over the ventilator:
  • (i) A slight reduction in ventilator support may be considered. However, the ventilator should continue to provide a non-fatiguing amount of mechanical support.
  • (ii) Additional analgesia and/or sedation should be considered.

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questions & discussion

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To keep this page small and fast, questions & discussion about this post can be found on another page here.

• When encountering hypercapnia, the first response is often to try to fix the hypercapnia (e.g., by using noninvasive ventilation or intubation). This often is not the correct approach (e.g., for patients with opioid intoxication). Thus, the treatment should always focus on identifying and treating the underlying disease.
• Consider sepsis as a cause of hypocapnia, if other etiologies are unlikely or excluded.

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References

• 12097540 Laffey JG, Kavanagh BP. Hypocapnia. N Engl J Med. 2002 Jul 4;347(1):43-53. doi: 10.1056/NEJMra012457 [PubMed]
• 37341662 Palmer BF, Clegg DJ. Respiratory Acidosis and Respiratory Alkalosis: Core Curriculum 2023. Am J Kidney Dis. 2023 Sep;82(3):347-359. doi: 10.1053/j.ajkd.2023.02.004 [PubMed]
• 38382181 Tregidgo L, D'Cruz RF. Supporting patients with hypercapnia. Clin Med (Lond). 2024 Jan;24(1):100007. doi: 10.1016/j.clinme.2023.100007 [PubMed]