Effect of supplemental oxygen on hypercapnia in patients with stable chronic obstructive pulmonary disease, in Bogotá, Colombia

Pneumologia Effect of supplemental oxygen on hypercapnia in patients with stable chronic obstructive pulmonary disease, in Bogotá, Colombia Efectul oxigenului suplimentar asupra hipercapniei la pacienții cu bronhopneumopatie cronică obstructivă stabilă în Bogotá, Columbia Abstract Introduction. The oxygen administration in COPD patients at sea level increases PaCO 2 ; above sea level this behavior is unknown. The objective of this study is to describe the difference between PaCO 2 levels in patients with stable COPD after the administration of supplemental FiO 2 of 28% and 50% at an altitude of 2,600 meters above sea level. Method. Randomized controlled crossover trial, involving severe COPD patients with baseline PaCO 2 >37 mmhg, with the administration of FiO 2 of 28% and 50% in two different days, with the measurement of arterial blood gases before and 30 minutes after the exposure. Results. Twenty-two patients were evaluated, the mean FEV1 was 41% of the predicted (SD=7.17). A significant increase in the PaCO 2 of 2.16 mmhg (IC 95%; 0.42-3.91) with FiO 2 of 50% versus 28% compared to baseline values, p=0.025, was found, the ph decreased with 0.02 (95% CI; -0.03-0.004), p=0.015. No period of interaction effect was detected. Conclusions. The administration of FiO 2 of 50% versus 28% in severe stable COPD patients with baseline PaCO 2 >37 mmhg at an altitude above 2,600 m produces an increase in PaCO 2 and a decrease in ph that achieved statistical significance. Caution is recommended when treating hypercapnic COPD patients with oxygen. Keywords: altitude, carbon dioxide, oximetry, chronic obstructive pulmonary disease Rezumat Introducere. Administrarea de oxigen pacienților cu BPOC la nivelul mării este urmată de creșterea PaCO 2 ; deasupra nivelului mării efectele sunt însă necunoscute. Obiectivul acestui studiu este să descrie diferențele între nivelurile PaCO 2 la pacienți cu BPOC stabil după administrare de oxigen suplimentar la FiO 2 de 28% și 50% la o altitudine de 2600 de metri deasupra nivelului mării. Metodă. Este un studiu randomizat controlat crossover, implicând pacienți cu BPOC sever cu PaCO 2 bazal mai mare de 37 mmhg, cărora li s-a administrat oxigen la FiO 2 de 28% și 50% în două zile diferite, cu determinarea gazometriei arteriale înainte și la 30 de minute după administrare. Rezultate. Au fost evaluați 22 de pacienți, valoarea medie a FEV1 a fost de 41% din prezis (SD=7,17). S-a observat o creștere semnificativă a PaCO 2 de 2,16 mmhg (IC 95%; 0,42-3,91), cu FiO 2 de 50% versus 28% raportat la valorile bazale, cu o valoare p=0,025, iar ph a scăzut cu 0,02 (IC 95%; -0,03-0,004), p=0,015. Nu a fost detectată nicio perioadă de efect de interacțiune. Concluzii. Administrarea de FiO 2 de 50% vs. 28% pacienților cu BPOC sever stabil cu PaCO 2 bazal >37 mmhg la o altitudine de peste 2600 m produce o creștere a PaCO 2 și o scădere a ph-ului, cu semnificație statistică. Se recomandă deci prudență când li se administrează oxigen pacienților hipercapnici cu BPOC. Cuvinte-cheie: altitudine, dioxid de carbon, oximetrie, boală pulmonară obstructivă cronică Juan José Duque 1, Hernán Darío Aguirre 2, Jaime Alvarado 3, Alirio Bastidas Goyes 4, Daniel Martin Arsanios 5 1. Internist Medical University of La Sabana, Chia, Colombia. 2. Internist and Clinical Epidemiologist (c), Clínica Bolivariana / Fundación Instituto Colombiano de Neurología / General Hospital of Medellín, Colombia 3. Pulmonologist, IPS Clinical Comprehensive Care Programs S.A.S., Bogotá, Colombia. 4. Pulmonologist and Clinical Epidemiologist, La Sabana University Clinic, Chía, Colombia 5. La Sabana University Physician Corresponding author: Alirio Bastidas, MD, MSc. E-mail: alirio.bastidas@ unisabana.edu.co Introduction Chronic obstructive pulmonary disease (COPD) is the fourth cause of mortality worldwide. It is a disease with increasing prevalence, that generates high social and economic costs (1,2). For decades, the treatment with supplemental oxygen has been one of the pillars of management in patients with severe COPD; in addition to offering improvement in symptoms, it is one of the few therapeutic measures that when used correctly, changes outcomes in mortality. However, it is known that in different environments (laboratory, hospital and prehospital), oxygen use at high flows in patients with COPD considered CO 2 retainers, generally with PaCO 2 of more than 45 mmhg can generate physiological changes associated with a greater number of complications and fatal outcomes (3-5). An increase in arterial oxygen pressure (PaCO 2 ) is inversely proportional to the ph value; in patients with COPD CO 2 retainers, the use of high O 2 substitutions generates inhibition of the respiratory stimulus (6-8) and also to some extent alterations of the ventilation-perfusion (VQ) ratio (3). In studies carried out at high altitude, the PaCO 2 values considered as normal vary in comparison with the values considered normal at sea level; they can be seen at 2,600 meters above sea level, in Bogotá, Colombia; but also, the mean PaCO 2 has been variable in different studies, ranging from 29 to 36 mmhg, and the normal ranges of PaCO 2 go from 28.3 to 38.7 mmhg in men and from 26.3 to 39.8 in women. This variability in the findings has made it difficult to interpret the expected values compared to PaCO 2 when exposure to O 2 substitution is performed (8,9). The standard hospital and pre-hospital COPD treatment includes oxygen that can be administered in different ways, being able to provide different inspired fractions of oxygen, thus generating different changes in PaO 2 pressures in addition to PaCO 2, changes that are appreciable in heights, but the normal value of these changes is still not clear, nor is the magnitude of change expected for the different fractions of O 2 (10,11). The administration of high inspired fractions of oxygen from 50% to 100% in acute form in patients with hypoventila- 135

tion (CO 2 retainers) significantly worsens hypercapnia when compared to smaller fractions (3). However, the effect of oxygen and the levels of PaCO 2 on which this type of response can be generated at altitudes above 1,600 m a.s.l. and especially at high altitude (2,500-3,500 m a.s.l.) has been minimally studied, so that the ventilatory and oxygenation changes in these patients could reorient therapeutic behavior (12,13). It is feasible that the physiological responses that occur with the change in altitude influence in a different way COPD patients who are CO 2 retainers and who live at high altitude, even in clinically stable conditions (10-12). The aim of this study was to describe the change in PaCO 2 levels in patients with stable COPD (absence of exacerbation or symptoms that have led to a change in management in the last month) and with PaCO 2 considered high at high altitude (2,600 m a.s.l.), when supplemental oxygen is administered at 28% and 50% flows after 30 minutes. Materials and method Design, measurements and subjects A randomized crossover trial was conducted in patients with stable COPD who had PaCO 2 levels greater than 37 mmhg, from places with heights of approximately 2,600 m a.s.l., during the months of October and November 2014. Stable COPD patients were defined as patients with a postbronchodilator FEV1/FVC ratio of less than 70, who had not had exacerbations or symptoms of exacerbation of the disease for at least four weeks before entering the study. Hypercapnia was defined as PCO 2 greater than or equal to 37 mmhg, value based on data for Bogotá (14). The sample size was calculated for a 2x2 crossover clinical trial with a quantitative outcome based on previous studies in subjects at sea level and in Bogotá, where the standard deviation of PaCO 2 levels with 21% oxygen was 1.27 mmhg with 50% oxygen of 1.16 mm Hg, rho of 0.6 and a clinically significant expected difference of 4 mm Hg in PaCO 2, requiring 22 subjects in total to achieve a minimum power of 80% and alpha error of 0.05. Inclusion criteria Patients older than 40 years were included, with COPD defined as FEV1/FVC less than 70 in addition with a FEV1 less than 50 ml post-bronchodilator in spirometry performed in a period of less than 2 years and reviewed and evaluated by an external pulmonologist in the group of investigators with arterial gases by clinical history (with report of the gasometrical report) that would show a PaCO 2 greater than 37 mmhg to the ambient air and that resided in places with height of 2,600 meters above sea level for a time not less than a month and that they voluntarily accept to participate in the study, as well as being able to understand and sign the informed consent. Exclusion criteria Patients with increased dyspnea, cough or sputum production or sputum purulence in the last month, obesity (body mass index greater than 30), diagnosis of other causes of hypoventilation or increased PaCO 2 (neuromuscular diseases), acute respiratory infections in the last month, arteriovenous fistulas, presence of contraindications for the performance of gas sampling in the radial artery (bilateral positive Allen test, infection or vascular disease at the puncture site), the presence of coagulation disorders or on anticoagulant therapy, patients with permanent home oxygen (more than 18 hours a day), change in clinical condition in the study washout period, presence of other pulmonary diseases (diffuse interstitial lung disease), advanced heart failure, sleep apnea in treatment with positive pressure devices and the use of drugs with hypoventilation potential due to central nervous system depression. Data collection The preliminary selection of patients was performed with the database of the IPS Clinical Comprehensive Care Programs S.A.S., reviewing the histories to evaluate inclusion and exclusion criteria. In the subjects considered as potential, the spirometry test was evaluated by a pulmonologist of the study team without fulfilling selection criteria. The patients were invited to participate in the study and two appointments were scheduled for the execution of the study in which it was proceeded to administer oxygen with inspired fraction of 28% or 50%. Recording of demographic data and a verification of inclusion and exclusion criteria were performed with the data provided by the patient in direct questioning at the first visit and in addition to a second verification of the data of his/her previous clinical history. At the second visit, the absence of a recent exacerbation (one month) was verified and oxygen was administered to the fraction inspired according to the previous randomization, which was generated by an epidemiologist unrelated to the medical review processes, application of inspired fractions of O 2, taking samples and typing and keeping information. The data was transcribed into a data collection format created by the researchers and the gas results were archived together with the format. The results were transcribed from the collection forms filled out by the researchers to an Excel spreadsheet, with subsequent revision and verification of the data from the Excel sheet with the original source by another researcher. In the case of disparate data, a new review of gasometrical reports and correction of these values was generated, prior to the start of the statistical process. The validity of the PaCO 2 values of the arterial gases was verified by means of the Kassirer-Bleich formula (15). Measurement The gasometrical values were obtained by means of direct arterial puncture with heparinized syringe for arterial gases, after the negativity of the Allen test was verified. The procedure was carried out by two professionals in respiratory therapy contracted exclusively for this study. The reports were generated by a Cobas B221 blood gas analysis team (Roche), using only reliable samples and discarding the coagulated ones. Functional test of the Venturi systems of 28% and 50% was carried out in the Exercise Physiology System Quick Setup gas analyzer of La Sabana Clinic, verifying the inspired fraction of O 2 that these administer. Exposure Before starting the procedure, the patient was expected to have a minimum of 30 minutes of physical rest and then proceed to basal arterial gas sampling with an inspired fraction of oxygen of 21%, after which the fraction of oxygen was administered for 30 minutes. It was assigned according to the previous randomization to then measure a new arterial gas value after exposure; all the arterial gas samples were transported immediately to the processing center of the clinical laboratory Dinámica SA hired for the study. 136

Pneumologia Statistical analysis Initially, two data analysis were performed using Excel spreadsheet to evaluate data agreement and later in the statistical program SPSS (version 20 IBM ) licensed by the Universidad de La Sabana. A description of the data obtained with summary measures was made, after verification of statistical normality (Kolmogórov-Smirnov and Shapiro Wilk). Afterwards, the averages were compared by means of student T for paired tests, analysis of treatment effect, period and interaction according to the parameters established for cross-clinical trials, and a statistically significant p<0.05 was considered. Ethical considerations The protocol was evaluated by the research subcommittee of the University of La Sabana to evaluate its methodological rigor to be subsequently evaluated and approved by the Ethics Committee of the University of La Sabana. The protocol adhered to the declarations of Helsinki and the Colombian legislation for the development of patient research. The informed consent of each one of the studied individuals was obtained, keeping the reservation of the same ones, being used only for its identification a sequential number in the study. There were civil liability policies for the researchers before the start of the study. Results During the study period, 276 clinical records of patients with COPD and spirometry inclusion criteria were evaluated; of these, 105 had gasometrical criteria and no exclusion criteria, so they were contacted. Of these, 63 answered the telephone call, 20 did not agree to participate in the study, eight were excluded due to residence at a height of less than 2,600 meters, seven did not attend appointment number one, three were excluded on the first date due to obesity, three patients did not attend visit number two, so finally we had an analyzable sample of 22 patients who met the previously described criteria and thus achieved all the activities and measures proposed (Figure 1). The average age was 64 years old, with an equal proportion in gender and average body mass index of 24.5. The baseline values of spirometry and prior arterial blood gases are shown in Table 1. The change in gas values between the inspired fraction of oxygen (FiO 2 ) of 21% and the FiO 2 of 28% and 50% are shown in Tables 2, 3 and 4. There was a statistical increase in PaCO 2, with a difference of 2.16 mmhg (95% CI; 0.42-3.91; p=0.025); a difference in ph was also observed, of -0.02 (95% CI; -0.03 to -0.004; p=0.015), in PaO 2 of 23.5 (95% CI; 15.5-31.5; p<0.001). No differences were observed with the treatment of different inspired fractions of oxygen in HCO 3 =0.25 mmhg (95% CI; -0.62 to 1.12; p=0.578), nor in the excess of base -0.02 (95% CI; -0.94 to 0.90; p=0.97). The rho between PaCO 2 with FIO 2 28% and FIO 2 50% was 0.66. The analysis of period and interaction did not present differences in any of the analyzed variables (Table 5) and the basal gases of both doses were similar. The difference in PaCO 2 between FIO 2 50% and FIO 2 28% did not reach the threshold determined as clinically significant at 4 mmhg. 276 patients with COPD and spirometry 105 patients met gasometric criteria 63 patients answered the phone call 43 patients interested in participating 35 patients scheduled to 28 patients attended 25 patients scheduled to appointment 2 22 patients completed the study 171 patients without gasometric criteria 42 patients did not answer phone call 20 patients not interested in participating 8 patients did not live in the surroundings of Bogotá 7 patients did not attend 3 patients with BMI >30 3 patients did not attend appointment 2 Figure 1. Flowchart of patient selection and collection Discussion In this study it was found that the administration of oxygen to inspired fractions at 50% generated a greater increase in PaCO 2 levels when compared with the changes generated with a fraction inspired at 28%. These findings are similar to those found in studies in patients with COPD and alveolar hypoventilation, where administrations of high oxygen flows are associated with an increase in PaCO 2 levels. In the pre hospital setting, patients with COPD exacerbation managed with high oxygen fractions have an increase in unfavorable outcomes associated with the development of respiratory acidosis and increased mortality (9,16,17). Changes in PaCO 2 levels related to severe physiological alterations have been recorded above 10 mmhg, the increase of these values can be related to cerebral vasoconstriction and sensorial alterations and CO 2 intoxication. However, changes above 4 mmhg may be associated with some physiological changes (18). In this study, a statistically significant elevation in PaCO 2 levels was found between the treatments, although the differ- 137

Table 1 Characteristics of the population Table 2 Arterial gases with oxygen administration n=22 Age 64.7 ± 10.5 BMI 24.5 ± 3.96 Pulmonary function FEV1/CVF (%) 50.95 ± 10.65 VEF1 (%) 41 ± 7.17 Diagnostic spirometry (pattern) (%) Mixed 63 Obstructive 36 Severity (%) Severe 90.9 Very severe 9.1 Basal arterial gases FIO 2 21 % ph 7.39 ± 0.019 pco 2 mmhg 42.6 ± 4.07 po 2 mmhg 45.8 ± 6.43 SO 2 % 80.3 ± 6.57 HCO 3 mmhg x 26 ± 1.58 BE* mmol/l x 1.2 ± 1.5 Table 3 FIO 2 21%* FIO 2 28% FIO 2 50% n=22 n=22 n=22 ph 7.39 ± 0.025 7.39± 0.019 7.38 ± 0.027 pco 2 mm Hg 41.96 ± 4.53 42.6 ± 4.07 43.4 ± 5.54 po 2 mm Hg 49.01 ± 6.48 45.8 ± 6.43 93.7 ± 21.9 SO 2 % 83.01 ± 6.16 80.3 ± 6.57 95.5 ± 5.2 HCO3 x(ds) 24.82 ± 1.94 26 ± 1.58 25.3 ± 2.46 BE** (mmol/l) -0.95 ± 1.9 1.2 ± 1.5 0.33 ± 2.41 * Average basal in both visits,** BE: excess base x (DS) Difference of averages of basal gases in each parameter ph PCO 2 PO 2 SaO 2 HCO 3 BE* 0.01± 0.02 1.26±2.65-3.56±6.06-3.01±4.97 1.76±1.57 1.96±1.89 Table 4 Changes in gasometrical values with inspired oxygen fractions FIO 2 21-28% FIO 2 21-50% X ± ds 95% CI X ± ds 95% CI ph 0.010 0.001-0.019-0.008-0.016-0.002 pco 2 mm Hg -0.616-2.2-0.97 1.548-0.199-3.295 po 2 mmhg 21.28 17.8-24.8 44.7 36.4-53.2 SO 2 % 10.06 8.13-12 12.52 10.11-14.93 HCO 3 mmhg 0.318-0.57-1.20 0.56-0.330-1.466 BE* mmol/l 0.452-0.434-1.339 0.434-0.445-1.313 Table 5 Results of oxygen treatment in gasometrical values Treatment effect Period effect Interaction effect Δ50-28* 95% CI P value*** P value P value ph -0.02-0.03-0.004 0.015 0.608 0.228 pco 2 mmhg 2.16 0.42-3.91 0.025 0.144 0.549 po 2 mmhg 23.5 15.52-31.52 <0.001 0.375 0.375 SO 2 % 2.46 0.39-4.53 0.031 0.862 0.202 HCO 3 mmhg 0.25-0.62-1.12 0.578 0.213 0.184 BE** mmol/l -0.02-0.94-0.90 0.97 0.309 0.137 * Δ50-28: Difference between treatment with FIO 2 50% and FIO 2 28%; ** BE: excess base; *** Statistically significant: p 0.05 ence of 4 mmhg assumed to be clinically significant was not reached, possibly due to the relatively low FiO 2 used, since other studies found greater changes in the PaCO 2 when administering FIO 2 at 75% and 100% in similar periods of time (19,20). The ph values also had statistical changes; however, the value of their change is low to be considered of any clinical implication. As expected, PaO 2 and SO 2 increased with both treatments. However, the difference between the oxygen saturation obtained with FIO 2 at 50% and with FIO 2 28% does not have a great difference, which means that high concentrations of oxygen are not required to significantly improve SO 2 in patients with severe and stable COPD. It is also observed that there are great changes in the levels of PaO 2, even in some subjects it is appreciated until hyperoxemia, whose long-term results have not shown differences with the normoxemic patients (21-23). 138

Pneumologia This is one of the first studies performed at an altitude of 2,600 meters above sea level, where the response to oxygen of patients with COPD is evaluated from values lower than those usually used at sea level, where the average PaCO 2 is usually higher than 45 mmhg for this type of patients. However, the value over which patients were chosen for study entry is at the upper limit of the PaCO 2 reported value for this altitude (9). This fact may eventually explain the entry of some study subjects who present a normal hypocapnic response to the administration of oxygen, but it is also clear that subjects with values less than 45 mmhg have an abnormal hypercapnic response to oxygen administration, which suggests that in patients with severe and high altitude COPD, abnormal responses to oxygen administration can be obtained with baseline PaCO 2 values of less than 45 mmhg. In the patient with COPD, hypercapnia is initially attributed to changes in the respiratory centers of the central nervous system. Patients with COPD gradually retain PaCO 2, which leads to a diminished ventilatory response of the respiratory centers to hypercapnia. In these subjects, the ventilatory stimulus is given by the low levels of PaO2; if the levels in the oxygenation decrease, then the respiratory center is stimulated. However, if the concentrations are high, the response decreases, which explains the hypercapnia and the risk of clinical deterioration and CO 2 poisoning (6,23). With time, more importance has been given to pulmonary physiological changes, where the imbalance of the V/Q ratio and specifically to the reversion of hypoxic vasoconstriction increase the ventilation of the dead space, by definition incapable of gas exchange that contributes to the accumulation in blood of CO 2. Another factor is the Haldane effect, where non-oxygenated hemoglobin is much more associated with CO 2 than oxygenated hemoglobin, which means that oxygen administration releases that CO 2 previously bound to hemoglobin and increases PaCO 2 (3,20,24). The decrease of central origin of ventilation minute is, generally, transient and PaCO 2 continues to increase despite the recovery of it approximately after 20 minutes of oxygen administration, which reinforces the influence of the other two factors such as predominant in hypercapnia in COPD (3). Among the strengths of the study are the correct and exhaustive selection of patients, in addition to the crossed design that decreased the presence of confounding factors and variability. Also, the adequate processing and handling of the samples to guarantee a good quality of the data. Among the weaknesses is the single arterial blood gas sampling on treatment administration, which can be affected by the variability that a single sampling could show. On the other hand, the results can only be extrapolated to patients in a similar condition, without being able to generalize to patients with not so severe or exacerbated COPD, where physiological changes may be greater; nevertheless, a highly prevalent problem is addressed regarding the altitude, where patients with stable severe COPD will increase. Conclusion The administration of inspired fractions of O 2 at 50% versus 28% in patients with severe stable COPD with baseline PaCO 2 values greater than 37 mmhg at an altitude of 2,600 meters above sea level generates acute changes in PaCO 2, ph and po 2, although achieve the threshold level of change in the pco 2 established as clinically significant. n References 1. Caballero A, Torres-Duque CA, Jaramillo C, Bolívar F, Sanabria F, Osorio P, et al. Prevalence of COPD in five Colombian cities situated at low, medium, and high altitude (PREPOCOL study). Chest. 2008 Feb; 133(2):343 9. 2. Vogelmeier CF, Criner GJ, Martínez FJ, Anzueto A, Barnes PJ, Bourbeau J, et al. Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Lung Disease 2017 Report: GOLD Executive Summary. Arch Bronconeumol. 2017 Mar; 53(3):128 49. 3. Abdo WF, Heunks LMA. Oxygen-induced hypercapnia in COPD: myths and facts. Crit Care. 2012 Oct 29; 16(5):323. 4. Austin MA, Wills KE, Blizzard L, Walters EH, Wood-Baker R. Effect of high flow oxygen on mortality in chronic obstructive pulmonary disease patients in prehospital setting: randomised controlled trial. BMJ. 2010 Oct 18; 341:c5462. 5. Plant PK, Owen JL, Elliott MW. One year period prevalence study of respiratory acidosis in acute exacerbations of COPD: implications for the provision of non-invasive ventilation and oxygen administration. Thorax. 2000 Jul; 55(7):550 4. 6. Davies CE, Mackinnon J. Neurological effects of oxygen in chronic cor pulmonale. Lancet (London, England). 1949 Nov 12; 2(6585):883 5, illust. 7. Donald K, Simpson T, Mcmichael J LB. Neurological Effects of Oxygen. Lancet. 1949; 254(6588):1056 7. 8. Lasso J. Interpretation of arterial blood gases in Bogota (2640 meters above sea level) based on the SiggaardAndersen nomogram A proposal for simplifying and unifying reading. Rev Colomb Neumol. 2014; 26(1):25 36. 9. Maldonado D, Gonzalez, Garcia M, Barrero M, Casas A TC. Reference Values For Arterial Blood Gases At An Altitude Of 2640 Meters. C76. Available from: http://www.atsjournals.org/doi/pdf/10.1164/ajrccmconference.2013.187.1_meetingabstracts.a4852 10. Penaloza D, Arias-Stella J. The heart and pulmonary circulation at high altitudes: healthy highlanders and chronic mountain sickness. Circulation. 2007 Mar 6; 115(9):1132 46. 11. Naeije R. Physiological adaptation of the cardiovascular system to high altitude. Prog Cardiovasc Dis. 2010; 52(6):456 66. 12. Vogel JH, McNamara DG, Hallman G, Rosenberg H, Jamieson G, McCrady JD. Effects of mild chronic hypoxia on the pulmonary circulation in calves with reactive pulmonary hypertension. Circ Res. 1967 Nov; 21(5):661 9. 13. Durrington HJ, Flubacher M, Ramsay CF, Howard LSGE, Harrison BDW. Initial oxygen management in patients with an exacerbation of chronic obstructive pulmonary disease. QJM. 2005 Jul; 98(7):499 504. 14. O, Barrero M, Casas A, Torres-Duque CA, Maldonado D, Gonzalez-Garcia M, et al. Reference values for arterial blood gases at an altitude of 2640 meters. In: C76 Exercise, Hypoxia, and Altitude. American Thoracic Society. 2013; p. A4852 A4852. (American Thoracic Society International Conference Abstracts). 15. Kassirer JP, Bleich HL. Rapid estimation of plasma carbon dioxide tension from ph and total carbon dioxide content. N Engl J Med. 1965 May 20; 272:1067 8. 16. DeGaute JP, Domenighetti G, Naeije R, Vincent JL, Treyvaud D, Perret C. Oxygen delivery in acute exacerbation of chronic obstructive pulmonary disease. Effects of controlled oxygen therapy. Am Rev Respir Dis. 1981 Jul; 124(1):26 30. 17. Wijesinghe M, Perrin K, Healy B, Hart K, Clay J, Weatherall M, et al. Prehospital oxygen therapy in acute exacerbations of chronic obstructive pulmonary disease. Intern Med J. 2011 Aug; 41(8):618 22. 18. Guais A, Brand G, Jacquot L, Karrer M, Dukan S, Grévillot G, et al. Toxicity of carbon dioxide: a review. Chem Res Toxicol. 2011 Dec 19; 24(12):2061 70. 19. Aubier M, Murciano D, Milic-Emili J, Touaty E, Daghfous J, Pariente R, et al. Effects of the administration of O 2 on ventilation and blood gases in patients with chronic obstructive pulmonary disease during acute respiratory failure. Am Rev Respir Dis. 1980 Nov; 122(5):747 54. 20. Crossley DJ, McGuire GP, Barrow PM, Houston PL. Influence of inspired oxygen concentration on deadspace, respiratory drive, and PaCO 2 in intubated patients with chronic obstructive pulmonary disease. Crit Care Med. 1997 Sep; 25(9):1522 6. 21. Moore RP, Berlowitz DJ, Denehy L, Pretto JJ, Brazzale DJ, Sharpe K, et al. A randomised trial of domiciliary, ambulatory oxygen in patients with COPD and dyspnoea but without resting hypoxaemia. Thorax. 2011 Jan; 66(1):32 7. 22. Bradley JM, O Neill B. Short-term ambulatory oxygen for chronic obstructive pulmonary disease. Cochrane database Syst Rev. 2005 Oct 19; (4):CD004356. 23. Robinson TD, Freiberg DB, Regnis JA, Young IH. The role of hypoventilation and ventilation-perfusion redistribution in oxygen-induced hypercapnia during acute exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2000 May; 161(5):1524 9. 24. Hanson CW, Marshall BE, Frasch HF, Marshall C. Causes of hypercarbia with oxygen therapy in patients with chronic obstructive pulmonary disease. Crit Care Med. 1996 Jan; 24(1):23 8. 139