Standard Therapies For Pulmon... Health Article

Oxygen Therapy

The value of long-term oxygen supplementation therapy in patients with PAH has not been evaluated by well-designed clinical trials. Recommendations and guidelines for oxygen therapy in patients who have PAH have been extrapolated from the clinical data available for chronic obstructive pulmonary disease (COPD). Pathophysiologically, hypoxemia is a potent stimulus for pulmonary vasoconstriction [38]. In COPD patients who have hypoxemia, two well-designed, prospective, randomized, non–placebo-controlled trials [39,40] have shown that there is marked improvement in long-term survival with the use of supplemental oxygen ( Table 1) [31,39,40].

One trial [40] studied 87 patients who had COPD and a history of right heart failure (RHF) along with arterial oxygen partial pressure <60 mm Hg. Patients were randomly assigned to receive 15 h/d of oxygen supplementation therapy or no therapy. Five-year mortality rate in the oxygen treatment group was 46% versus 67% in control group (number needed to treat to save one life in approximately five). The study also showed an increase in PVR in the control group over the study period but no increase in PVR in the oxygen therapy group. The study was not powered to evaluate this parameter, however.

The other prospective, randomized, controlled study of 203 patients who had chronic hypoxemic COPD showed that in patients who were hypoxemic at rest during the daytime, the use of nocturnal oxygen supplementation (12 h/d) was associated with a higher 3-year mortality rate (42% versus 22%) when compared with the group that used continuous (at least 19 h/d) supplemental oxygen [39]. The number needed to treat to save one life was approximately five. The survival advantage was more pronounced in patients with less severe pulmonary hypertension at baseline (mean pulmonary arterial pressure <27 mm Hg). Continuous oxygen supplementation therapy improved long-term survival in patients who had COPD with significant hypoxemia (PaO 2 <55 mm Hg at rest) even if there was no significant improvement in pulmonary hemodynamics with acute oxygen supplementation. Patients with low baseline PVR had an improved mortality on continuous oxygen supplementation therapy, but the patient with high baseline PVR did not experience a survival benefit. Patients who showed a large decrease in PVR on repeat right heart catheterization after 6 months of continuous oxygen therapy had greater mortality compared with patients with smaller decrease in PVR [39]. This finding suggests that mortality benefit in hypoxemic patients who have COPD and are on continuous long-term oxygen therapy is probably not derived from any reduction in PVR. This observation is important from the standpoint of oxygen therapy in patients who have PAH.

Because of the substantial survival (and hemodynamic) benefit observed in COPD patients who have hypoxemia, the oxygen supplementation therapy is widely used in PAH patients who have hypoxemia. The principles and criteria used for oxygen therapy in PAH are derived from the studies and practice guidelines for treatment of hypoxemic patients who have COPD [41].

Many patients who have PAH have hypoxemia at rest, with exertion, or during sleep. Hypoxemia in PAH is thought to be caused by low mixed-venous oxygen tension secondary to low cardiac output, altered diffusion capacity, and ventilation-perfusion mismatch. Some patients who have PAH present with relatively rapid worsening of hypoxemia secondary to opening of a patent foramen ovale, which results in right-to-left shunt. In such patients, hypoxemia is relatively refractory to oxygen supplementation. In most other patients, however, with the exception of patients with advanced disease, the hypoxemia at rest and at night can be corrected by oxygen supplementation at 2 to 6 L/min via nasal cannula, although increased oxygen supplementation is frequently required during activity or exertion.

Most current guidelines [29,32–34] from American or European professional societies recommend that all patients with PAH whose PaO 2 is consistently <55 mm Hg or in whom oxyhemoglobin saturation is ≤88% at rest, during sleep, or with ambulation should be prescribed sufficient supplemental oxygen therapy to keep the pulse oximetry oxyhemoglobin saturation >90% at all times. In patients with laboratory or clinical findings that suggest chronic hypoxemia (eg, hematocrit >55%), clinical signs of RHF, or suggestion of RHF on EKG or echocardiography, long-term oxygen supplementation therapy should be initiated at PaO 2 <60 mm Hg or oxyhemoglobin saturation of ≤89%. Such patients should be retested for oxygen requirement 3 months after the initiation of oxygen therapy. All patients with moderate to severely decreased diffusion capacity (DLCO <60% of predicted) at rest should be tested for possibility of oxyhemoglobin desaturation with activity and while sleeping [42,43]. It should be noted that all such recommendations are based on expert opinion in the absence of any direct evidence in IPAH or any form of APAH except pulmonary hypertension (PH) associated with COPD.

Many patients with congenital heart disease have hypoxemia secondary to right-to-left shunt. Such hypoxemia is relatively refractory to oxygen supplementation therapy. The use of oxygen supplementation therapy in patients who have congenital heart disease and Eisenmenger syndrome remains controversial. A study of 15 pediatric patients with PAH associated with congenital heart disease and hypoxemia initially reported improved mortality with oxygen supplementation for a minimum of 12 h/d for 5 years [44]. A well-designed, prospective, randomized, controlled study of 23 adult patients who had hypoxemia and Eisenmenger syndrome showed that nocturnal oxygen supplementation had no effect on survival, quality of life, hematocrit, or 6-minute walking distance [31]. Some studies suggest that oxygen supplementation in these patients may reduce need for phlebotomy and may reduce neurologic complications [35]. Nocturnal oxygen supplementation in children who have PAH associated with congenital heart disease has been shown to decrease the rate of progression of polycythemia. Similarly in the PAH pediatric population, oxygen therapy has been shown to improve symptoms [44,45].

PaO 2 during sleep is almost always lower than PaO 2 while awake [46] , which is probably secondary to sleep-induced hypoventilation and the resultant rise in PCO 2. In normal individuals with a normal wake PaO 2 , nocturnal oxyhemoglobin desaturation is not seen because the oxyhemoglobin dissociation curve is relatively flat for PaO 2 above 90 mm Hg. Patients who are hypoxemic at rest while awake are always more hypoxemic during sleep, however [47]. This reduction in arterial oxygenation is even more pronounced during rapid eye movement sleep. The long-term value of treating nocturnal hypoxemia in patients who have PAH remains unclear, however. Screening with nocturnal oximetry may be performed to evaluate possibility of nocturnal hypoxemia when clinically suspected. Oxyhemoglobin saturation <90% for less than 5% of the recording time may be considered clinically insignificant regardless of the lowest recorded oxyhemoglobin saturation value. After initiation of oxygen supplementation, it is suggested that a repeat nocturnal oximetry study be obtained to assess the adequacy of nocturnal oxygen supplementation therapy.

In most patients without significant right-to-left shunt, a nocturnal oxygen supplementation at 2 to 3 L/min above the resting oxygen requirement is sufficient to maintain adequate oxygenation during sleep. The exception to this rule is presence of obstructive sleep apnea (OSA), in which nasal continuous positive airway pressure (CPAP) (or BiPAP) therapy is needed to correct the sleep-disordered breathing and hypoxemia. An overnight polysomnogram should be ordered for patients in whom OSA is suspected because of history of snoring, excessive daytime sleepiness, or witnessed apneas. Routine ordering of polysomnogram in all patients who have PAH is not indicated [48].

Prevalence of PH in OSA is much higher than the prevalence of IPAH in the general population; the reported prevalence of PH in OSA is 17% to 53% [48–60]. In contrast, the estimated incidence of IPAH in the general population is 1 to 2 new cases per million [61] , which suggests a prevalence of <10 to 20 per million. Most of the studies [48–60] that estimated prevalence of PH in OSA used right heart catheterization for defining PAH. Data are difficult to interpret, however, because many of these studies defined PH as mPAP ≥20 mm Hg (less than the standard used to define PAH) or used estimated pressures by echocardiogram. Generally PH associated with OSA is mild in the absence of obesity-hypoventilation syndrome [47–59]. Any moderate or severe PH should not be attributed to OSA alone, no matter how severe the OSA. Modest improvement in PA pressures is expected from the treatment of OSA; the expected median decrease in pulmonary artery pressure is 3 to 6 mm Hg and expected median decrease in PVR is approximately 0.5 wood units [59,62,63]. Patients who have OSA and PH with hypoxemia who are treated with CPAP and oxygen supplementation have a more pronounced decrease in mPAP and PVR than patients who are treated with oxygen therapy alone. Resolution of PH is not an expected outcome of even the most successful therapy by CPAP, regardless of the severity of OSA and the duration of the CPAP therapy [59,62,63].

Obesity-hypoventilation syndrome (usually associated with body mass index >34 and always associated with the presence of daytime hypercapnia, ie, PCO 2 of ≥45 mm Hg) can be associated with severe PAH and RHF, regardless of presence or absence of concurrent OSA [64]. Oxygen supplementation or CPAP therapy or both combined are not adequate treatments for nocturnal hypoxemia in such patients; noninvasive positive pressure ventilation or bilevel positive pressure ventilation should be used. In patients who cannot tolerate this therapy (eg, because of claustrophobia), tracheostomy should be offered along with chronic outpatient mechanical ventilation. Near complete reversal of hypercapnia and signs of RHF within a few months with invasive or noninvasive mechanical ventilation therapy usually are seen in patients who do not have concurrent factors contributing to the development of PAH [65]. Weight loss after gastric surgery for morbid obesity also has been shown to substantially decrease the PCO 2 (mean, 52 mm Hg to 42 mm Hg) and mPAP (mean, 36 mm Hg to 23 mm Hg) at right heart catheterization [66]. In patients who have PH and a body mass index >34, an arterial blood gas analysis obtained on room air, should be performed to rule out possibility of obesity-hypoventilation syndrome (OHS) because the management principles of OHS associated PAH are different than those of OSA [65,66].

There is reluctance on the part of some physicians and many patients to consider oxygen supplementation as part of therapy. Oxygen supplementation is a major lifestyle change for patients (with the exception nocturnal oxygen supplementation therapy alone). Factors such as cost, the type of equipment required, and the inconvenience of many ambulatory oxygen systems impact on patients' acceptance and use of prescribed supplemental oxygen. In clinical practice most patients agree to the use of oxygen if prescribed by physician but do not like the oxygen tubing they need to wear in public. This has an impact on their perceptions of themselves and others' perceptions of them. Falls associated with long cords and tubing attached to oxygen concentrators and other oxygen delivery systems can occur.