Oxygen-induced hypercapnia in COPD: myths and facts
© BioMed Central Ltd 2012
Published: 29 October 2012
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© BioMed Central Ltd 2012
Published: 29 October 2012
During our medical training, we learned that oxygen administration in patients with chronic obstructive pulmonary disease (COPD) induces hypercapnia through the 'hypoxic drive' mechanism and can be dangerous. This mindset frequently results in the reluctance of clinicians to administer oxygen to hypoxemic patients with COPD. However, this fear is not based on evidence in the literature. Here, we will review the impact and pathophysiology of oxygen-induced hypercapnia in patients with acute exacerbation of COPD and recommend a titrated oxygen management.
In 1949, Davies and Mackinnon  described oxygen-induced neurological symptoms in patients with cyanosis due to emphysema with chronic cor pulmonale. After encountering two such cases, including one with a fatal coma, the authors set up a study to examine the effect of oxygen on intracranial pressure (that is, cerebrospinal fluid pressures measured through a lumbar puncture) in similar patients. The authors found that, in all four studied subjects with emphysema and cyanosis, oxygen therapy led to increased cerebrospinal fluid pressures, which returned to baseline when oxygen was stopped. Davies and Mackinnon hypothesized that oxygen intoxication could have led to accumulation of carbon dioxide (CO2) in the body and cautioned against the use of oxygen in these patients. In response to this article, Donald  described an emphysema patient who developed a hypercapnic (16 kPa) coma during oxygen therapy and who had rapid clinical improvement after oxygen therapy was discontinued. The author, referring to such patients, stated the following theory: 'their respiratory activity depends mostly upon anoxic stimulation of the sino-aortic zones. The removal of the anoxic stimulus causes them to hypoventilate with further retention of carbon dioxide'.
Reading these early reports about oxygen-induced hypercapnia in patients with chronic obstructive pulmonary disease (COPD), one might think that not much has changed over the years. Despite subsequent studies and reviews  describing the effect of oxygen on the ventilator drive in patients with COPD, disproving the 'hypoxic drive' theorem, many clinicians are still being taught during their medical training that administration of oxygen in patients with COPD can be dangerous given that it induces hypercapnia through the 'hypoxic drive' mechanism; that is, increasing arterial O2 tension will reduce the respiratory drive, leading to a (dangerous) hypercapnia. This misconception has resulted in the reluctance of clinicians and nurses to administer oxygen to hypoxemic patients with COPD. In most cases, this is an unwise decision, putting at risk the safety of patients with acute exacerbation of COPD. In this concise paper, we will discuss the impact and pathophysiology of oxygen-induced hypercapnia in patients with acute exacerbation of COPD.
In 1980, Aubier and colleagues  studied the effect of high-flow oxygen (15 L/minute) on arterial CO2 tension (PaCO2) in patients with acute exacerbation of COPD (that is, Global Initiative for Chronic Obstructive Lung Disease (GOLD) grade IV). The authors found that PaCO2 increased from 8.4 to 11.4 kPa but that arterial O2 tension (PaO2) increased from 4.9 to 29 kPa. More than two decades later, this study was repeated . In patients with very severe COPD (forced expiratory volume in 1 second (FEV1) ± 30% predicted), administration of 100% oxygen for 20 minutes increased PaO2 from 7.6 to 53 kPa whereas PaCO2 showed a non-significant increase (6.9 and 7.3 kPa). Subsequently, patients were subdivided in a group of CO2 retainers and a group of non-retainers. Although the two groups had similar lung function, retainers were significantly more hypoxemic before oxygen administration.
These and earlier studies confirmed that uncontrolled oxygen administration to patients with acute exacerbation of very severe COPD can induce hypercapnia and that the level of hypoxemia is a predictor for development of hypercapnia. Therefore, it is important to review the mechanisms of oxygen-induced hypercapnia in patients with COPD, in particular the role of oxygen-induced hypoventilation.
In another study, Aubier and colleagues  studied the respiratory drive in 20 patients with both COPD and acute respiratory failure. The authors reported an increase in PaCO2 from 8.1 to 9.1 kPa and a marginal (14%) reduction in minute ventilation on oxygen administration . Respiratory drive was determined by mouth occlusion pressure in the first 100 ms of inspiratory effort (P0.1). Oxygen administration reduced P0.1 from 8.3 ± 0.8 cm H2O to 4.9 ± 0.7 cm H2O. The latter value is still well above normal, indicating a high respiratory drive. Moreover, the authors showed that there was no correlation between change in minute ventilation and change in PaCO2 after oxygen administration. This study underscores the markedly increased respiratory drive in patients during an exacerbation of COPD, even after oxygen administration, despite an increase in PaCO2. The authors concluded that reduction in respiratory drive is not a major contributor to oxygen induced hypercapnia in patients with acute exacerbation of COPD.
In conclusion, uncontrolled oxygen administration in acute exacerbation of severe COPD has a limited effect on minute ventilation and thus does not explain the total increase in PaCO2. Rarely, one might encounter an apneic response in decompensated COPD patients approaching hypercapnic coma.
Amine groups of proteins, in particular hemoglobin, combine with CO2 to form carbamino compounds. But the ability of deoxygenated hemoglobin to bind CO2 is much higher than that of oxygenated hemoglobin, as can be shown with Formula 2 (below). Thus, oxygen induces a rightward shift of the CO2 dissociation curve and this is known as the Haldane effect. A rightward shift in the CO2 dissociation curve will increase PaCO2, which normally is excreted through elevated minute ventilation, normalizing PaCO2. However, in patients with severe COPD, who are unable to increase minute ventilation, the Haldane effect will increase PaCO2. Indeed, in the study by Aubier and colleagues , the Haldane effect explained ± 25% of the total PaCO2 increase due to O2 administration. Formula 2 is HbCO2 ↔ O2 × HbO2 + PaCO2, where HbCO2 is carbaminohemoglobin and HbO2 is oxyhemoglobin.
Patients most susceptible to oxygen-induced hypercapnia are those with the most severe hypoxemia. How can oxygen-induced hypercapnia be avoided without withholding oxygen therapy from these hypoxemic patients? Administration of high-flow oxygen concentrations has been associated with higher mortality in comparison with a more tailored approach of oxygen therapy [8–10]. Some data, including those of a randomized controlled trial, provide evidence for the best strategy in patients with an acute exacerbation of COPD . These data show that a titrated oxygen administration to achieve an oxygen saturation of between the 88% to 92% compared with higher saturations results in less respiratory acidosis and better outcome. This is in accordance with the British Thoracic Society guideline for oxygen therapy in patients with COPD .
In patients with COPD, hypoxic pulmonary vasoconstriction is the most efficient way to alter the Va/Q ratios to improve gas exchange. This physiological mechanism is counteracted by oxygen therapy and accounts for the largest increase of oxygen-induced hypercapnia. A titrated oxygen therapy to achieve saturations of 88% to 92% is recommended in patients with an acute exacerbation of COPD to avoid hypoxemia and reduce the risk of oxygen-induced hypercapnia.
chronic obstructive pulmonary disease
fraction of inspired oxygen
mouth occlusion pressure in the first 100 ms of inspiratory effort
arterial partial pressure of carbon dioxide
arterial partial pressure of oxygen