Use of oxygen in patients with hypercapnia

Authors

David J Feller-Kopman, MD

Richard M Schwartzstein, MD Section Editor

James K Stoller, MS, MD Deputy Editor

Helen Hollingsworth, MD

Last literature review version 18.1: February 2010 | This topic last updated: September 24, 2009 (More)

INTRODUCTION — Clinicians have observed for many years that the administration of oxygen to patients with chronic obstructive pulmonary disease (COPD) may be followed by hypercapnia. Traditional teaching emphasizes that hypercapnia results from suppression of hypoxic ventilatory drive and warns that "patients will stop breathing" if given oxygen. However, this interpretation does not account for the many factors that contribute to the control of breathing in these patients, and has resulted in oxygen being withheld inappropriately from some patients with acute respiratory failure. (See "Control of ventilation".)

The major processes which contribute to worsening hypercapnia in the setting of administration of supplemental oxygen to patients with COPD (in order of decreasing importance) are:

•Worsened ventilation-perfusion matching due to attenuation of hypoxic pulmonary vasoconstriction

•Decreased binding affinity of hemoglobin for carbon dioxide

•Decreased minute ventilation

Regardless of the mechanism of hypercapnia, it is essential to administer oxygen to patients with significant hypoxemia to avoid the potentially life-threatening complications of a low PaO2. In addition, a meta-analysis of 31 studies confirmed that administering supplemental oxygen to hypoxemic patients reduced dyspnea and minute ventilation during exercise [1].

The relevant physiology of ventilatory control, the causes and effects of hypercapnia, and the use of oxygen in the treatment of patients with acute on chronic respiratory failure will be presented here. The use of chronic oxygen therapy and general issues related to the management of acute exacerbations of COPD are discussed separately. (See "Long-term supplemental oxygen therapy" and "Management of acute exacerbations of chronic obstructive pulmonary disease".)

CONTROL OF VENTILATION — There are many reflexes, feedback loops, and control systems that match gas exchange with the metabolic needs of an individual [2-5]. The respiratory system is under negative feedback control that is regulated primarily by the PaCO2 (via changes in local pH in the brainstem) and, to a much lesser degree in normal individuals, by the PaO2. Both neural and chemical regulators act to maintain PaCO2 within a very tight range; in experimental studies of the ventilatory response to hypercapnia a 1 mmHg rise in PaCO2 normally produces an increase in ventilation of 2 to 4 L per minute (graph 1) [5]. (See "Control of ventilation".)

The central pattern generator in the medulla is thought to control the rate, depth, and timing of ventilation during quiet respirations, although additional neurons in the brainstem, sensorimotor cortex, limbic system, amygdala, and hypothalamus also play a role. However, under conditions of respiratory distress, the stimulus to breathe and the resulting mechanical output of the system become more complex because of mechanical loading of the respiratory system, stimulation of pulmonary and chest wall receptors, and behavioral factors.

Mechanoreceptors — There are a variety of receptors in the upper airways, lungs, and chest wall that are responsive to both mechanical and chemical factors. Mechanical stimuli associated with changes in flow, pressure, or volume tend to have an inhibitory effect on ventilation and are mediated by flow or temperature receptors in the nasopharynx, slowly

adapting pulmonary stretch receptors located in airway smooth muscle, and muscle spindle cells and Golgi tendon organ receptors in the chest wall. (See "Control of ventilation".)

Chemical or irritant stimuli, which tend to have a stimulatory effect on ventilation, are transmitted primarily via the rapidly adapting pulmonary stretch receptors and c-fiber nerve endings located throughout the airways and lung parenchyma [5]. Thus, acute tracheobronchitis, pneumonia, interstitial edema, bronchospasm, and hyperinflation resulting from a variety of causes may stimulate pulmonary and chest wall receptors and lead to increased respiratory drive.

Chemoreceptors — pH, determined primarily by changes in the PaCO2, is the main chemical stimulus for respiration; its effects are mediated through both peripheral and central chemoreceptors. (See "Chapter 11C: Effect of arterial pH on ventilation".)

•The central chemoreceptors lie within the brainstem, close to the ventrolateral surface of the medulla. They are highly sensitive to changes in hydrogen ion concentration due to the low buffering capacity of the cerebrospinal fluid (CSF).

•The peripheral arterial chemoreceptors are located in the carotid and aortic bodies, with the carotid body playing the more important role in humans. Both sympathetic and parasympathetic innervation of the carotid body contribute to the rate of discharge at any given level of PaCO2 and PaO2, and changes in PaO2 and PaCO2 act synergistically to affect chemoreceptor activity. However, carotid body input contributes only approximately 10 to 15 percent of the resting ventilatory drive [5].

There is a linear relationship between PaCO2 and minute ventilation (graph 1). As PaO2 is decreased, the slope of the curve becomes steeper and shifts to the left, resulting in a greater sensitivity to changes in the level of PaCO2.

The relationship between minute ventilation and PaO2 is somewhat different (figure 1). Minute ventilation does not significantly increase until the PaO2 falls below approximately 60 mmHg, at which point there is usually an increase in alveolar ventilation which will increase PaO2, decrease PaCO2, and blunt the subsequent ventilatory response. A greater

minute ventilation response to hypoxemia is noted when secondary hypocapnia fails to occur.

Patients who have a robust ventilatory response to CO2 also generally have a greater response to hypoxemia. The sensitivity of an individual's ventilatory response to hypoxemia and hypercapnia may be partially determined by genetics; families have been identified that have subnormal responses to hypercapnia and hypoxemia. Members of these families are more likely to retain CO2 if COPD develops [6].

Behavioral control — The respiratory system is unique among the physiologic systems essential to life in that its function is regulated both by automatic mechanisms originating in the brainstem and by voluntary inputs originating in the cortex. The emotional or affective condition of the patient influences respiratory drive; as an example, anxiety, pain, or general discomfort may be associated with ventilation that is excessive for the metabolic demands of the body [7,8]. A rapid shallow breathing pattern may result, particularly when behavioral factors coexist with acute respiratory insufficiency.

CAUSES OF HYPERCAPNIA — PaCO2 is dependent upon both CO2 production and alveolar ventilation, according to the formula:

PaCO2 = (k x VCO2) ÷ VA = (k x VCO2) ÷ (VE x [1 - (VD/VT)])

where k is a constant, VCO2 is CO2 production, VA is alveolar ventilation (the component of the minute ventilation that reaches perfused alveoli), VE is expired minute volume, and VD/VT is the ratio of physiologic dead space to tidal volume.

Hypercapnia therefore can result from an increase in CO2 production or a decrease in alveolar ventilation (due either to decreased minute ventilation or an increased ratio of dead space to tidal volume). Reduced alveolar ventilation is the most common cause of hypercapnia. Unless a patient has limited pulmonary reserve, increased CO2 production (as may occur with sepsis, overfeeding, lactic acidosis, or thyrotoxicosis) will not result in clinically important hypercapnia.

The differences between oxygen and carbon dioxide binding to hemoglobin explain why hypoxemia is much more common than hypercapnia in conditions in which alveolar hypoventilation is due to ventilation/perfusion (V/Q) mismatch; the linear relationship of the

CO2-Hgb curve permits well ventilated alveoli to compensate for poorly ventilated lung units.

Central nervous system (CNS) injury or CNS depressant drugs can produce hypercapnia by decreasing overall minute ventilation. In contrast, rapid shallow breathing can contribute to hypercapnia by increasing the dead space to tidal volume ratio, because the anatomic dead space in the central airways comprises a larger proportion of the smaller tidal breath.

EFFECTS OF HYPERCAPNIA — Acute hypercapnia may produce a depressed level of consciousness, increases in cerebral blood flow and intracranial pressure, and depression of myocardial contractility [9]. It also depresses diaphragmatic function and shifts the oxyhemoglobin dissociation curve to the right, leading to increased release of O2 to tissues [10].

The development of hypercapnia is associated with increases in brain glutamine and gamma-aminobutyric acid (GABA), as well as reductions in glutamate and aspartate. This change in the CNS milieu can negatively impact the level of consciousness and depress minute ventilation and inspiratory drive [11].

The degree of acute hypercapnia required to provoke these responses is variable. Normal individuals do not exhibit a depressed level of consciousness until the PaCO2 is greater than 60 to 70 mmHg, while patients with chronic hypercapnia may not develop symptoms until the PaCO2 rises acutely to greater than 90 to 100 mmHg. The latter patients have a compensatory increase in the plasma bicarbonate concentration; as a result, a larger elevation in PaCO2 is required to produce the same reduction in pH.

EFFECTS OF HYPOXEMIA — Hypoxemia can adversely affect every tissue in the body. Cellular hypoxia is a state in which there is insufficient oxygen to meet the metabolic demands of a given tissue. It can result from impaired perfusion (ischemia) and/or diminished arterial oxygen content (due to anemia or hypoxemia).

Cellular tolerance of hypoxia is variable. As examples, skeletal muscle cells can recover fully after 30 minutes of hypoxia, but irreversible damage occurs in brain cells after only 4 to 6 minutes of similar hypoxic stress [12,13]. Therefore, life-threatening hypoxemia needs to be treated with the administration of oxygen (and sometimes with red cell transfusion) while measures are being initiated to treat the primary cardiopulmonary insult.

Cellular mechanisms that contribute to hypoxic cell injury include depletion of ATP, development of intracellular acidosis, increased concentrations of metabolic by-products, generation of oxygen free radicals, and destruction of membrane phospholipids. There is also a dramatic increase in intracellular calcium concentration, contributing to cellular injury via a variety of mechanisms, including direct damage to the cytoskeleton and induction of genes that contribute to apoptosis [12]. Hypoxia also induces an inflammatory reaction characterized by neutrophilic infiltration, thus augmenting cellular damage via release of cytokine mediators, oxygen free radicals, and by intensifying ischemia due to disruption of the microcirculation.

The American Thoracic Society (ATS) statement on the detection, correction, and prevention of tissue hypoxia, as well as other ATS guidelines, can be accessed through the ATS web site at www.thoracic.org/sections/publications/statements/index.html.

HYPERCAPNIA IN COPD — The major cause of hypercapnia in patients with COPD is impaired matching of ventilation (V) and perfusion (Q), which, if sufficiently severe, is functionally equivalent to increasing the amount of dead space [14]. Normocapnic patients with COPD have a higher minute ventilation in order to compensate for this inefficient removal of CO2 created by worsened ventilation-perfusion matching. This prevents hypercapnia in some patients but increases the work of breathing. The classic "pink puffer" phenotype exemplifies the normocapnic patient with COPD and dyspnea. (See "Disorders of ventilatory control".)

Mechanical inefficiency of the respiratory system also contributes to the hypercapnia of COPD via several mechanisms [15]:

•Airflow obstruction leads to hyperinflation, causing the diaphragm to operate at a lower position within the thorax. Laplace's law states that the pressure developed is inversely proportional to the radius of curvature; as a result, there is less pressure produced by a flattened diaphragm for any given effort.

•The shortened muscle fibers generate less force at a given level of stimulation because the diaphragmatic configuration negatively affects sarcomere length and actin/myosin overlap.

•Lung compliance is reduced at larger volumes, producing less change in lung volume for the same change in pressure.

The breathing pattern in patients with COPD and hypercapnia is different from that found in their normocapnic counterparts; hypercapnic patients tend to have lower tidal volumes and an increased respiratory rate, which increases VD/VT [16-18]. The lower tidal volumes seem to reflect a shortened inspiratory time rather than a reduction in respiratory drive, as measured by mouth occlusion pressure or inspiratory flow rate [16,19]. The mechanisms of this abnormal breathing pattern remain unclear and at least three factors may contribute: hypoxemia [18]; stimulation of pulmonary irritant and J receptors by coexisting chronic bronchitis [16,17]; and reduced inspiratory reserve due to hyperinflation [20].

Effects of supplemental oxygen — There have been many mechanisms postulated to explain why patients with COPD sometimes develop hypercapnia when given supplemental oxygen. It had been thought that patients with COPD rely on their hypoxic ventilatory drive due to a blunted sensitivity to CO2 (ie, pH), and that hypercapnia in this setting resulted from "removal" of hypoxic drive with a consequent reduction in alveolar ventilation. One report described different ventilatory responses to oxygen in the same patients when they were stable, compared to responses obtained during episodes of acute respiratory insufficiency [21].

Two studies have improved the understanding of the effects of supplemental oxygen in patients with COPD [19,22]:

The first study examined 20 patients with COPD, both in the chronic state and during acute respiratory failure (ARF); their responses to supplemental oxygen were compared to those of normal controls [19]. No differences in minute ventilation were observed between the groups when breathing air. However, the patients with ARF had a different respiratory pattern when breathing air; specifically, they had a significantly increased respiratory rate and lower tidal volume when compared to normal controls. Mouth occlusion pressure, an index of ventilatory drive, was five times greater in patients with ARF than in normal subjects.

When patients with ARF were given supplemental O2 at 5 L/min, minute ventilation dropped by 14 percent, due to a small decrease in respiratory rate without a compensatory change in tidal volume. The reduction in minute ventilation could not account for the entire increase in PaCO2, and hypercapnia was postulated to result primarily from an increase in the dead space to tidal volume ratio. Ventilatory drive, as measured by mouth occlusion pressure,

decreased, but remained three times greater than in normal controls, implying that ventilatory drive was still being augmented by factors other than hypoxemia, such as input from mechanoreceptors and behavioral factors.

Viewed from the standpoint of reducing dyspnea and the work of breathing, the slight reduction in ventilatory drive is actually one of the goals of treatment with oxygen. The dramatically increased ventilatory drive in patients with ARF cannot be sustained for a long period of time in a patient with a mechanically disadvantaged respiratory system without the risk of developing respiratory muscle fatigue.

The second study examined the effects of administration of an FiO2 of 1.0 to patients with COPD and ARF [22]. All patients had an initial decrease in minute ventilation of approximately 18 percent, which then returned to approximately 93 percent of baseline after 12 minutes despite continued oxygen administration. The initial decrease in minute ventilation was due to reductions in both tidal volume and respiratory rate.

After 15 minutes of oxygen administration, PaCO2 increased an average of 23 mmHg, which was due to three components:

•Only about 5 mmHg (22 percent) could be directly attributed to the small (7 percent) decrease in minute ventilation.

•An additional 7 mmHg (30 percent) was attributed to decreased hemoglobin affinity for CO2 (the Haldane effect). The Haldane effect refers to the rightward displacement of the CO2-hemoglobin dissociation curve in the presence of increased oxygen saturation. This occurs because oxyhemoglobin binds CO2 less avidly than deoxyhemoglobin, thereby increasing the amount of CO2 dissolved in blood, which in turn determines PaCO2 (graph 2) [23]. The Haldane effect is most pronounced when the SaO2 changes most per mmHg of PaO2, ie, on the steep part of the oxygen-hemoglobin dissociation curve, which is between a PaO2 of 20 and 60 mmHg.

•The largest component of acute hypercapnia (11 mmHg, 48 percent) was due to an increase in dead space ventilation. This probably reflects worsening of V/Q matching due to a loss of hypoxic pulmonary vasoconstriction (HPV). HPV serves to limit blood flow to poorly

ventilated units and to redirect blood flow to units with high V/Q ratios at baseline; this compensatory response improves V/Q homogeneity and decreases the physiologic dead space. As with the Haldane effect, the effect of loss of HPV is most pronounced in patients with a low initial PaO2. The importance of V/Q mismatching has been confirmed in other studies [24].

However, a subsequent study concluded that the primary cause of hypercapnia in patients who retain CO2 is actually due to a reduction in ventilation [25]. A limitation of this study is the definition of CO2 retention as an increase in PaCO2 of 3 mmHg. This is likely clinically insignificant and makes the physiologic differences between retainers and non-retainers less clear. Additionally, both retainers and non-retainers had mean PaO2 levels >54 mmHg. This would minimize the role of hypoxic pulmonary vasoconstriction and the Haldane effect, both of which are more prominent at lower partial pressures of oxygen.

The relative contributions of a reduction in minute ventilation, the Haldane effect, and changes in V/Q matching have been confirmed by computer models of gas exchange and pulmonary hemodynamics [26]. Subsequent trials have documented more modest degrees of hypercapnia when lower fractions of inspired oxygen are administered. As an example, one study of 12 intubated but spontaneously breathing patients with COPD and CO2 retention who were recovering from ARF found that increases in FiO2 from 0.3 or 0.4 to 0.7 did not result in worsening hypercapnia [27]. No changes in PaCO2, minute ventilation, tidal volume, respiratory rate, dead space, or mouth occlusion pressure were noted, possibly because the baseline PO2 was greater than 60 mmHg, a setting in which HPV would be minimized.

Response to oxygen administration — There are three possible outcomes when administering uncontrolled oxygen therapy to a patient with COPD and respiratory insufficiency [28]:

•The patient's clinical state and PaCO2 may improve or not change

•The patient may become drowsy but can be roused to cooperate with therapy; in these cases, the PaCO2 generally rises slowly by up to 20 mmHg and then stabilizes after approximately 12 hours

•The patient rapidly becomes unconscious, cough becomes ineffective, and the PaCO2 rises at a rate of 30 mmHg or more per hour

The risk for developing severe hypercapnia and CO2 narcosis is greater in patients with a low initial pH and/or PaO2 [28,29].

In a retrospective study of 95 patients with COPD and hypercapnia who presented with acute respiratory distress, oxygen therapy targeting a PaO2 >74 mmHg was associated with increased length of stay, increased need for noninvasive mechanical ventilation, and increased rate of admission to an ICU [30]. A causal relationship cannot be concluded, however, due to the study's observational design.

Effect of withdrawing oxygen — The major danger facing patients who develop hypercapnia during treatment with oxygen is that the abrupt removal of supplemental oxygen may cause the PaO2 to fall to a level lower than when oxygen therapy was begun. The development of hypoxemia in this setting is more rapid than the resolution of hypercapnia, and subsequent tissue hypoxia can potentially worsen the patient's acidemia.

HYPERCAPNIA IN NEUROMUSCULAR DISEASE — The risk of hypercapnia in patients with neuromuscular disease (eg, amyotrophic lateral sclerosis and inflammatory neuropathies) when supplemental oxygen is administered has been less well studied than among patients with COPD. One series of eight retrospectively identified patients with neuromuscular disease found that seven had baseline hypercapnia, and six had worsening of their hypercapnia by a mean of 28 mmHg after receiving low flow supplemental oxygen [31]. There were no measurements of breathing pattern, respiratory drive, or dead space, and it is unclear if these findings are due to the same mechanisms that are operative in patients with COPD.

SUMMARY AND RECOMMENDATIONS — It is important to understand the goals of oxygen therapy and the multiple factors that can contribute to hypercapnia when considering the use of supplemental oxygen in the treatment of patients with ARF. An elevation in FiO2 may cause PaCO2 to rise, but it is unlikely to result in severe CNS depression unless the PaCO2 exceeds 85 to 90 mmHg. Many patients with acute on chronic respiratory failure have a chronic compensated respiratory acidosis (in which the arterial pH is only modestly reduced) and are at greater risk from hypoxemia than hypercapnia. The primary goal of therapy should be the maintenance of an SaO2 of 88 to 93 percent or a PaO2 of 60 to 70 mmHg [21,32]. Further increases in the FiO2 above the level needed to achieve the latter goals do

not add significantly to the oxygen content of blood but do increase the potential for more severe secondary hypercapnia.

Optimal oxygen therapy can be achieved using the following approach:

•Increase the inspired concentration of oxygen initially by 4 to 7 percent (eg, 32 to 36 percent FIO2) with close monitoring of both PaO2 and PaCO2. Venturi masks should be used when possible to permit tight regulation of FiO2 (figure 2) [33]. The goal is an SaO2 of 88 to 90 percent, and higher concentrations of inspired oxygen should be given if this goal is not achieved. When using nasal cannula, the oxygen flow rate should generally be increased by 1 L per minute at a time; remembering that it is very difficult to predict the FIO2 when administering supplemental oxygen by nasal cannula.

•Simultaneous administration of bronchodilators and diuretics (if clinically indicated) should be considered for patients with COPD and ARF. (See "Management of acute exacerbations of chronic obstructive pulmonary disease".)

•The development of acute hypercapnia leading to significant acidemia (eg, pH<7.20) and/or a marked depression in the level of consciousness is an indication for intubation and mechanical ventilation. Oxygen should not be removed entirely from the patient in an effort to avert intubation. (See "Mechanical ventilation in acute respiratory failure complicating COPD".)

•Noninvasive positive pressure ventilation may help avoid the need for endotracheal intubation. (See "Noninvasive positive pressure ventilation in acute respiratory failure in adults".)

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