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.
Chronic obstructive pulmonary disease (COPD) is the fourth cause of mortality worldwide. It is a disease with increas-ing 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 symp-toms, 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 pre-hospital), oxygen use at high flows in patients with COPD considered CO2 retainers, generally with PaCO2 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 (PaCO2) is inversely proportional to the pH value; in patients with COPD CO2 retainers, the use of high O2 substitutions generates inhibition of the respiratory stimulus(6-8) and also to some extent altera-tions of the ventilation-perfusion (VQ) ratio(3).
In studies carried out at high altitude, the PaCO2 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 PaCO2 has been variable in different studies, ranging from 29 to 36 mmHg, and the normal ranges of PaCO2 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 PaCO2 when exposure to O2 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 PaO2 pressures in addition to PaCO2, changes that are appreciable in heights, but the normal value of these changes is still not clear, nor is the mag-nitude of change expected for the different fractions of O2(10,11).
The administration of high inspired fractions of oxygen from 50% to 100% in acute form in patients with hypoventilation (CO2 retainers) significantly worsens hypercapnia when compared to smaller fractions(3). However, the effect of oxygen and the levels of PaCO2 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 stud-ied, 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 CO2 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 PaCO2 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 PaCO2 considered high at high alti-tude (2,600 m a.s.l.), when supplemental oxygen is admin-istered 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 PaCO2 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 post-bronchodilator 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 PCO2 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 PaCO2 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 PaCO2, requiring 22 subjects in total to achieve a minimum power of 80% and alpha error of 0.05.
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 arte-rial gases by clinical history (with report of the gasometrical report) that would show a PaCO2 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.
Patients with increased dyspnea, cough or sputum produc-tion or sputum purulence in the last month, obesity (body mass index greater than 30), diagnosis of other causes of hypoventilation or increased PaCO2 (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, pres-ence 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 hypoven-tilation potential due to central nervous system depression.
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 exclu-sion criteria. In the subjects considered as potential, the spirom-etry 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 sched-uled 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 inclu-sion and exclusion criteria were performed with the data pro-vided by the patient in direct questioning at the first visit and in addition to a second verification of the data of his/her previ-ous clinical history. At the second visit, the absence of a recent exacerbation (one month) was verified and oxygen was admin-istered to the fraction inspired according to the previous rand-omization, which was generated by an epidemiologist unrelated to the medical review processes, application of inspired fractions of O2, 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 val-ues was generated, prior to the start of the statistical pro-cess. The validity of the PaCO2 values of the arterial gases was verified by means of the Kassirer-Bleich formula(15).
The gasometrical values were obtained by means of direct arterial puncture with heparinized syringe for arte-rial gases, after the negativity of the Allen test was verified. The procedure was carried out by two professionals in res-piratory 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, veri-fying the inspired fraction of O2 that these administer.
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 frac-tion 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.
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 verifica-tion 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 sig-nificant p<0.05 was considered.
The protocol was evaluated by the research subcommit-tee of the University of La Sabana to evaluate its methodo-logical 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.
During the study period, 276 clinical records of patients with COPD and spirometry inclusion criteria were evalu-ated; of these, 105 had gasometrical criteria and no exclu-sion 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 propor-tion 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 (FiO2) of 21% and the FiO2 of 28% and 50% are shown in Tables 2, 3 and 4. There was a statistical increase in PaCO2, 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 PaO2 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 HCO3=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 PaCO2 with FIO2 28% and FIO2 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 dif-ference in PaCO2 between FIO2 50% and FIO2 28% did not reach the threshold determined as clinically significant at 4 mmHg.
In this study it was found that the administration of oxy-gen to inspired fractions at 50% generated a greater increase in PaCO2 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 PaCO2 levels. In the pre‑hos-pital setting, patients with COPD exacerbation managed with high oxygen fractions have an increase in unfavorable out-comes associated with the development of respiratory acidosis and increased mortality(9,16,17).
Changes in PaCO2 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 CO2 intoxication. However, changes above 4 mmHg may be associated with some physiological changes(18).
In this study, a statistically significant elevation in PaCO2 levels was found between the treatments, although the difference of 4 mmHg assumed to be clinically significant was not reached, possibly due to the relatively low FiO2 used, since other studies found greater changes in the PaCO2 when admin-istering FIO2 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, PaO2 and SO2 increased with both treatments. However, the difference between the oxygen saturation obtained with FIO2 at 50% and with FIO2 28% does not have a great difference, which means that high concentrations of oxygen are not required to significantly improve SO2 in patients with severe and stable COPD. It is also observed that there are great changes in the levels of PaO2, even in some subjects it is appreciated until hyperoxemia, whose long-term results have not shown differences with the normoxemic patients(21-23).
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 PaCO2 is usually higher than 45 mmHg for this type of patients. However, the value over which patients were cho-sen for study entry is at the upper limit of the PaCO2 report-ed 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 admin-istration, which suggests that in patients with severe and high altitude COPD, abnormal responses to oxygen admin-istration can be obtained with baseline PaCO2 values of less than 45 mmHg.
In the patient with COPD, hypercapnia is initially attrib-uted to changes in the respiratory centers of the central nervous system. Patients with COPD gradually retain PaCO2, which leads to a diminished ventilatory response of the res-piratory centers to hypercapnia. In these subjects, the ven-tilatory 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 CO2 poisoning(6,23).
With time, more importance has been given to pulmo-nary physiological changes, where the imbalance of the V/Q ratio and specifically to the reversion of hypoxic vasocon-striction increase the ventilation of the dead space, by defi-nition incapable of gas exchange that contributes to the accumulation in blood of CO2.
Another factor is the Haldane effect, where non-oxy-genated hemoglobin is much more associated with CO2 than oxygenated hemoglobin, which means that oxygen admin-istration releases that CO2 previously bound to hemoglobin and increases PaCO2(3,20,24). The decrease of central origin of ventilation – minute is, generally, transient and PaCO2 continues to increase despite the recovery of it approxi-mately 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 sam-pling 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.
The administration of inspired fractions of O2 at 50% versus 28% in patients with severe stable COPD with baseline PaCO2 values greater than 37 mmHg at an altitude of 2,600 meters above sea level generates acute changes in PaCO2, pH and pO2, although achieve the threshold level of change in the pCO2 established as clinically significant.
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