Oxygen-induced hypercapnia in COPD: myths and facts

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 [1] described oxygeninduced 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 eff ect of oxygen on intracranial pressure (that is, cerebrospinal fl uid pressures measured through a lumbar puncture) in similar patients. Th e authors found that, in all four studied subjects with emphysema and cyanosis, oxygen therapy led to increased cerebrospinal fl uid pressures, which returned to baseline when oxygen was stopped. Davies and Mackinnon hypothesized that oxygen intoxication could have led to accumulation of carbon dioxide (CO 2 ) in the body and cautioned against the use of oxygen in these patients. In response to this article, Donald [2] 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. Th e author, referring to such patients, stated the following theory: 'their respiratory activity depends mostly upon anoxic stimulation of the sino-aortic zones. Th e 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 [3] describing the eff ect 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' mecha nism; that is, increasing arterial O 2 tension will reduce the respiratory drive, leading to a (dangerous) hyper capnia. Th is 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.

Oxygen-induced hypercapnia
In 1980, Aubier and colleagues [4] studied the eff ect of high-fl ow oxygen (15 L/minute) on arterial CO 2 tension (PaCO 2 ) in patients with acute exacerbation of COPD (that is, Global Initiative for Chronic Obstructive Lung Disease (GOLD) grade IV). Th e authors found that PaCO 2 increased from 8.4 to 11.4 kPa but that arterial O 2 tension (PaO 2 ) increased from 4.9 to 29 kPa. More than two decades later, this study was repeated [5]. In patients with very severe COPD (forced expiratory volume in 1 second (FEV1) ± 30% predicted), administration of 100% oxygen for 20 minutes increased PaO 2 from 7.6 to 53 kPa whereas PaCO 2 showed a non-signifi cant increase (6.9 and 7.3 kPa). Subsequently, patients were subdivided in a group of CO 2 retainers and a group of non-retainers. Although the two groups had similar lung function, retainers were signifi cantly more hypoxemic before oxygen administration.

Abstract
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.
Th ese and earlier studies confi rmed that uncontrolled oxygen administration to patients with acute exacer bation of very severe COPD can induce hypercapnia and that the level of hypoxemia is a predictor for development of hypercapnia. Th erefore, it is important to review the mechanisms of oxygen-induced hypercapnia in patients with COPD, in particular the role of oxygen-induced hypoventilation. Figure 1 shows that uncontrolled oxygen administration leads to an early initial decrease in minute ventilation with an elevation of PaCO 2 [4]. After 15 minutes of continued oxygen therapy, minute ventilation recovers from the initial decrease and is only marginally reduced in comparison with baseline. However, PaCO 2 increases further despite the recovery of the minute ventilation. Additionally, no signifi cant correlation was found between the oxygen-induced increase in PaCO 2 and the reduction in minute ventilation. Formula 1 (below) can be used to show that, in this example, the change in minute ventilation explains a PaCO 2 increase of only 0.65 kPa (of the total rise of 3.0 kPa). Subsequent studies have essentially confi rmed these observations [5]. In Formula 1, PaCO 2 = (K × V CO2 ) / V E (1 − V D /V T ), where K is a constant of 0.863, V CO2 is CO 2 production, V E is minute ventilation, and V D /V T is dead space/tidal volume ratio.

The role of hypoventilation
In another study, Aubier and colleagues [6] studied the respiratory drive in 20 patients with both COPD and acute respiratory failure. Th e authors reported an increase in PaCO 2 from 8.1 to 9.1 kPa and a marginal (14%) reduction in minute ventilation on oxygen adminis tration [6]. Respiratory drive was determined by mouth occlusion pressure in the fi rst 100 ms of inspiratory eff ort (P 0.1 ). Oxygen administration reduced P 0.1 from 8.3 ± 0.8 cm H 2 O to 4.9 ± 0.7 cm H 2 O. Th e 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 PaCO 2 after oxygen administration. Th is study underscores the markedly increased respiratory drive in patients during an exacerbation of COPD, even after oxygen administration, despite an increase in PaCO 2 . Th e authors concluded that reduction in respiratory drive is not a major contributor to oxygeninduced hypercapnia in patients with acute exacerbation of COPD.
In conclusion, uncontrolled oxygen administration in acute exacerbation of severe COPD has a limited eff ect on minute ventilation and thus does not explain the total increase in PaCO 2 . Rarely, one might encounter an apneic response in decompensated COPD patients approaching hypercapnic coma.

The role of ventilation-perfusion mismatching
Physiologically, alveolar ventilation and perfusion are well matched. Two extremes of ventilation-perfusion (Va/Q) mismatch may occur: (a) no ventilation of an alveolus but adequate perfusion, resulting in shunting, and (b) adequate ventilation but no perfusion, resulting in dead space ventilation. Th e body has protective mechanisms to optimize the Va/Q ratio. When alveolar oxygen tension decreases (for example, in bronchoconstriction), local mediators induce vasoconstriction of pulmonary capilla ries supporting this particular alveolus, counteracting possible shunting, a mechanism called hypoxic pulmo nary vasoconstriction (Figure 2). Th e strongest mediator for hypoxic pulmonary vasoconstriction is alveolar pO 2 (partial pressure of oxygen). Th erefore, a high fraction of inspired O 2 (FiO 2 ) will increase O 2 tension in alveoli with a low level of ventilation, inhibiting hypoxic pulmonary vasoconstriction. As a result, alveoli with relatively impaired ventilation are well perfused, leading to an increase in Va/Q mismatch. Indeed, the study by Aubier and colleagues [4] revealed that high FiO 2 impaired Va/Q matching and increased dead space ventilation from 77% to 82%. Robinson and colleagues [5] also studied the Va/Q mismatch during oxygen therapy. Th e Va/Q mismatch increased in both the retainer and non-retainer groups of patients. Th e authors also concluded that this was due to less hypoxic pulmonary vasoconstriction in both groups. Although overall During 15 minutes of high oxygen administration, an initial decrease in minute ventilation, which recovers substantially, is seen in patients with acute exacerbation of chronic obstructive pulmonary disease. However, the oxygen-induced hypercapnia does not recover. CO 2 , carbon dioxide; V E , minute ventilation. Based on data of Aubier and colleagues [4].
Abdo and Heunks Critical Care 2012, 16:323 http://ccforum.com/content/16/5/323 ventilation decreased in the retainer group, ventilation to lung units with higher Va/Q mismatch increased, leading to increased alveolar dead space ventilation in the retainer group. An earlier report using a computer model to simulate pulmonary circula tion found that the increased physiologic dead space through worsened Va/ Q was suffi cient to account for the oxygen-induced hypercapnia [7].

The Haldane eff ect
Amine groups of proteins, in particular hemoglobin, combine with CO 2 to form carbamino compounds. But the ability of deoxygenated hemoglobin to bind CO 2 is much higher than that of oxygenated hemoglobin, as can be shown with Formula 2 (below). Th us, oxygen induces a rightward shift of the CO 2 dissociation curve and this is known as the Haldane eff ect. A rightward shift in the CO 2 dissociation curve will increase PaCO 2 , which normally is excreted through elevated minute ventilation, normalizing PaCO 2 . However, in patients with severe COPD, who are unable to increase minute ventilation, the Haldane eff ect will increase PaCO 2 . Indeed, in the study by Aubier and colleagues [4], the Haldane eff ect explained ± 25% of the total PaCO 2 increase due to O 2 administration. Formula 2 is HbCO 2  O 2 × HbO 2 + PaCO 2 , where HbCO 2 is carbaminohemoglobin and HbO 2 is oxyhemoglobin.

Safe oxygen administration
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-fl ow oxygen concen trations has been associated with higher mortality in com parison with a more tailored approach of oxygen therapy [8][9][10]. Some data, including those of a randomized controlled trial, provide evidence for the best strategy in patients with an acute exacerbation of COPD [11]. Th ese 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. Th is is in accordance with the British Th oracic Society guideline for oxygen therapy in patients with COPD [12].

Conclusions
In patients with COPD, hypoxic pulmonary vaso constriction is the most effi cient way to alter the Va/Q ratios to improve gas exchange. Th is 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.
Abbreviations CO 2 , carbon dioxide; COPD, chronic obstructive pulmonary disease; FiO 2 , fraction of inspired oxygen; P 0.1 , mouth occlusion pressure in the fi rst 100 ms of inspiratory eff ort; PaCO 2 , arterial partial pressure of carbon dioxide; PaO 2 , arterial partial pressure of oxygen; Va/Q, ventilation-perfusion.