Hypercapnia From Hyperoxia in COPD: Another Piece of the Puzzle or Another Puzzle Entirely? 4 ˙ Embarrassment is a powerful teacher. I was barely et al found that the reduction in minute ventilation (VE) 3 months into my internship, on night float at my residen- was transient and inadequate to explain the degree of hy- cy’s Veterans Affairs hospital, when I received a page percapnia. from a concerned ward nurse. A patient was unresponsive. In another study, Aubier et al5 found no correlation be- ˙ He was admitted for a severe COPD exacerbation. I ex- tween the degree of hypercapnia and the decrease in VE. amined him, and he only groaned with a vigorous sternal Instead, they hypothesized that the excess hypercapnia was rub. Suspecting hypercapnic narcosis, I drew an arterial caused by 2 factors. The first was the Haldane effect (ie, blood gas. The results confirmed my suspicion. The pa- the release of CO2 when deoxyhemoglobin converts to tient was suffering from acute respiratory acidosis. In a panic, I paged the resident taking ICU admissions. The patient needed to go to the ICU and be intubated. The SEE THE ORIGINAL STUDY ON PAGE 328 resident said he would see the patient. He wordlessly slipped into the room and went straight to the oxygen flow meter. He turned the flow down several liters and waited. He did oxyhemoglobin). This mechanism was later confirmed by not have to wait long: it was as if the patient had received Luft et al.6 The second was a decrease in pulmonary ven- a naloxone injection. Within 90 seconds, he woke sud- tilation/perfusion matching due to the release of hypoxic denly and looked around the room, puzzled. “What is ev- pulmonary arterial vasoconstriction. This leads to a sub- eryone doing in here?” he asked. The resident, again word- sequent increase in functional dead space. This hypothesis lessly, slipped out of the room. was supported in a later study by Robinson et al.7 Others I learned my lesson, and I will never forget it. I take found that hyperoxia also lessens the hyperventilation that minor consolation in Tobin and Jubran’s1 grievance, “This follows acute hypercapnia in subjects with COPD.8 Still others found the increase in P from hyperoxia to be a perennial problem apparently must be rediscovered by each aCO2 new rotation of house-staff personnel.” I have heard an- function of both increased functional dead space and de- ecdotal reports of internal medicine and emergency de- creased ventilatory response to hypercapnia.9 partment attending physicians doubting the existence of Unfortunately, emerging with a single reliable explana- this phenomenon: hyperoxia-induced hypercapnia in pa- tion from all these results is doomed to fail for many tients with COPD. Why are we so recalcitrant? Part of the reasons. Some studies used mouthpieces to measure tidal ˙ 4,5,8 reason may be that the pathophysiologic mechanism be- volumes and VE, a technique known to alter the vari- 1 hind it defies a simple explanation. In this issue of RESPI- ables of interest. Some subjects were in the midst of 4,5 RATORY CARE, Rialp et al2 address the complicated mech- a COPD exacerbation, whereas others were stable anisms behind this phenomenon. out-patients who resided at an altitude of 5,400 feet.6 Some Campbell3 first hypothesized about the mechanism in subjects had even been mechanically ventilated for at least 1960. His hypothesis was attractive in its simplicity: chron- 1 week.9 Additionally, patients with COPD are not a ho- ically hypercapnic COPD patients are dependent solely on mogenous group; it seems that there are subjects who re- their hypoxic respiratory drive, as the chronic hypercapnia tain (ie, become hypercapnic when hyperoxemic) and those blunts their hypercapnic respiratory drive. Unfortunately, who do not.7 We know that subjects who are more hypox- this hypothesis was too simple. When it was tested, Aubier emic and hypercapnic on room air experience greater de- grees of hypercapnia with hyperoxia.10 In this issue of RESPIRATORY CARE, we add a new study 2 8 Dr Littleton has disclosed no conflicts of interest. to the existing disarray. As in the study of Dunn et al, these subjects were mechanically ventilated and ready for Correspondence: Stephen W Littleton MD, Division of Pulmonary/Crit- a spontaneous breathing trial. They were placed on pres- ical Care Medicine, Cook County Hospital, 1900 West Polk Street, Room 1416, Chicago, IL 60612. sure support of 7 cm H2O and PEEP of zero, and a hy- percapnic rebreathing test was conducted. Blood gases, DOI: 10.4187/respcare.03979 end-tidal P ,V˙ , and respiratory drive (using airway- CO2 E RESPIRATORY CARE • MARCH 2015 VOL 60 NO 3 473 HYPERCAPNIA FROM HYPEROXIA IN COPD occlusion pressure 0.1 s after the start of inspiratory flow through a process of elimination. End-tidal P was mon- CO2 [P0.1]) were measured. The test was then repeated 1 h later, itored in each subject, so the ratio of dead space to tidal with the subjects breathing 100% oxygen. volume could have been easily calculated in the normoxic The authors demonstrated that their method of measur- and hyperoxic states, but unfortunately, the authors did not ⌬ ⌬ record these data. ing P0.1/ PaCO (ie, the change in respiratory drive per 2 Still, I will use the authors’ findings in one very impor- mm Hg increase in arterial CO2) was highly reproducible, noteworthy because the day-to-day variability in hyper- tant situation: spontaneous breathing trials. In all venti- capnic ventilatory response is quite large.11 They also found lated patients, hypercapnia is a risk factor for re-intuba- ˙ tion.14 In a patient with COPD, hypercapnia that develops a small but insignificant decrease in VE when comparing ˙ during a spontaneous breathing trial could be interpreted the normoxic and hyperoxic states. The change in VE did not correlate with the change in P , similar to a previ- as merely resulting from hyperoxia. This study shows that aCO2 ous study.5 The respiratory drive was unchanged between this interpretation is inaccurate. Hyperoxia during a spon- the 2 conditions, also similar to previous findings.5,12 Ad- taneous breathing trial causes only modest hypercapnia (a ditionally, hyperoxia did not affect the rate of change in mean increase of 3 mm Hg) and should not cause any ˙ V˙ and respiratory drive per mm Hg increase in P .In significant change in respiratory drive or VE. Using the E aCO2 other words, the slope of the relationship was unchanged. data provided by the authors, the upper limit of the 95% CI If the respiratory drive were blunted, the slope would be- for the difference between the 2 conditions is 10 mm Hg. Ն come less steep. Therefore, they concluded that these sub- Therefore, if a patient develops hypercapnia of 10 mm Hg, it should be interpreted as a sign of respiratory failure, and jects became hypercapnic because of the Haldane effect, the patient should either be extubated to noninvasive ven- ventilation/perfusion mismatching, and increase in func- tilation or kept on the ventilator.15 tional dead space, or some combination of the three. There is (and has been for decades) a relative paucity of The study is interesting, but like the many studies before research funding that goes toward respiratory physiology. it, its external validity is limited; it is difficult to extrap- Until this is corrected, we are unlikely to gain a firm grasp olate the authors’ findings outside of the very controlled on this phenomenon, and house staff will have to continue setting in which the experiment was conducted. The au- their rediscovery. In the meantime, we will have to rely on thors were careful to explain the limitations of the study, a long series of studies like this one, a very small piece of although I will add to them and elaborate further. a very large puzzle. First, in this study, all COPD subjects were treated as a homogenous group. Visual inspection of Figures 1 and 3 Stephen W Littleton MD seems to show 2 distinct groups: one that becomes hyper- Division of Pulmonary/Critical Care Medicine capnic when hyperoxic and one that does not. It would be Cook County Hospital extremely difficult to identify such patients before they are Chicago, Illinois intubated for respiratory failure, but if it were feasible, it could drastically change the findings. Second, the subjects were mechanically ventilated. Al- though the authors claimed that pressure-support ventila- REFERENCES tion is unlikely to change the P or work of breathing 0.1 1. Tobin MJ, Jubran A. Oxygen takes the breath away: old sting, new compared with subjects on a T-piece, they did not mention setting. Mayo Clin Proc 1995;70(4):403-404. ˙ the possible effects on VE. There is very little variability in 2. Rialp G, Raurich JM, Llompart-Pou, JA, Ayestara´n I. Role of respi- breathing frequency in mechanically ventilated normal sub- ratory drive in hyperoxia-induced hypercapnia in ready-to-wean sub- jects.13 Therefore, it is theoretically possible that there is a jects with COPD. Respir Care 2015;60(3):328-334. ˙ 3. Campbell EJ. Respiratory failure: the relation between oxygen con- floor of VE below which these subjects could not drop, centrations of inspired air and arterial blood. Lancet 1960;2(7140): ˙ and their decline in VE during the hyperoxic state was 10-11. masked. 4. Aubier M, Murciano D, Milic-Emili J, Touaty E, Daghfous J, Pari- Third, the baseline out-patient characteristics of the ente R, Derenne JP. Effects of the administration of O2 on ventilation subjects were unknown. Although none required home and blood gases in patients with chronic obstructive pulmonary dis- ease during acute respiratory failure.