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(Chest. 2003;124:1312-1317.)
© 2003 American College of Chest Physicians

Effects of Short-term 28% and 100% Oxygen on PaCO2 and Peak Expiratory Flow Rate in Acute Asthma*

A Randomized Trial

Gustavo J. Rodrigo, MD; Mario Rodriquez Verde, MD; Virginia Peregalli, MD and Carlos Rodrigo, MD

* From the Departamento de Emergencia (Drs. G. Rodrigo and Peregalli), Hospital Central de las Fuerzas Armadas, Montevideo; Centro de Tratamiento Intensivo (Dr. Rodriguez Verde), Hospital de Paysandú, Paysandú; and Unidad de Cuidado Intensivo (Dr. C. Rodrigo), Asociación Española 1a de Socorros Mutuos, Montevideo, Uruguay.

Correspondence to: Gustavo J. Rodrigo, MD, Departamento de Emergencia, Hospital Central de las Fuerzas Armadas. Av. 8 de Octubre 3020, Montevideo 11600, Uruguay; e-mail: gurodrig{at}adinet.com.uy


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objective: We conducted the first randomized controlled study to assess the effects of short-term 28% and 100% oxygen on PaCO2 and peak expiratory flow rate (PEFR) in patients with acute severe asthma.

Patients and interventions: Seventy-four patients (mean age, 37.9 ± 9.7 years [± SD]; PEFR, 41.0 ± 12.1% of predicted) from two emergency departments were randomized to receive 28% or 100% oxygen during 20 min.

Results: The administration of 100% oxygen significantly increases PaCO2 (p = 0.03) and decreases PEFR (p = 0.001) as compared with administration of 28% oxygen. PaCO2 before and during oxygen administration correlated significantly (p = 0.001) in both groups. Patients breathing 28% oxygen experienced a PaCO2 fall; on the contrary, patients who received 100% oxygen showed an increase in PaCO2, particularly those with PaCO2 before oxygen treatment > 40 mm Hg.

Conclusions: This study confirmed previous observations that oxygen dose should be variable and based on achieving and maintaining target arterial oxygen saturation measured by pulse oximetry >= 92% rather than on prescribing predetermined concentrations or flow rates of inspired oxygen.

Key Words: acute severe asthma • emergency department treatment • gas exchange • hyperoxia • oxygen • oxygen therapy • uncontrolled oxygen administration


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Asthma exacerbations are potentially life threatening. Studies of near-fatal asthma suggest that hypoxemia is probably an important cause of death1 2 ; therefore, oxygen supplementation is a critical part of the management of patients with acute asthma.3 4 5 Because hypoxemia is produced by ventilation/perfusion (/) mismatch, mostly, it can be corrected by the administration of moderate doses of inspired oxygen.6 7 In spite of this, the use of high-flow oxygen by a mask with reservoir bag has been assumed to be harmless and the best way to deliver it to patients with acute asthma.8 9 10 11 Uncontrolled oxygen has been postulated to correct the effects of hypoxemia and to compensate any trend for PaO2 to fall with ß-agonist therapy. Nevertheless, there is rising evidence that hyperoxia may be unsafe for some patients. One noncontrolled study12 suggests that PaCO2 may worsen in some patients receiving 100% oxygen, especially those with more severe airflow obstruction; however, to our knowledge, there are no controlled trials that evaluate the use of oxygen in acute asthma.13 14 In fact, the Global Strategy for Asthma Management and Prevention report15 on asthma states that "these data need to be validated in a controlled trial, but for now suggest that oxygen therapy should be titrated according to oximetry." Consequently, we conducted a randomized controlled study to assess the effect of administration of two oxygen concentrations on gas exchange in adult patients with acute severe asthma.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Subjects
We recruited all adult patients with acute asthma who were seen in two emergency departments of Uruguay (Hospital Central de las Fuerzas Armadas in Montevideo, and Hospital de Paysandú, in Paysandú) over a 6-month period (March to August 2002). The inclusion/exclusion criteria for patients were as follows: (1) diagnosis criteria of asthma of the American Thoracic Society16 ; (2) age from 18 to 50 years; (3) peak expiratory flow rate (PEFR) < 60% of predicted value; and (4) patients were excluded if they had a temperature > 38°C, or a history of cardiac, hepatic, renal disease, or other medical disease, or pregnancy; and (5) an expressed willingness to participate in the study, with written informed consent obtained. The Hospitals Ethics Committees approved the study.

Design
After baseline measures (the investigators made all measures unaware of the patient group assignments), subjects were randomized (using a computer-generated method) to receive one of two treatments arms. Those in the first treatment arm (28% group) received 28% oxygen for 20 min via a standard facemask (model 1088; Hudson RCI; Temecula, CA). Those in the second treatment arm (100% group) received 100% oxygen for 20 min via a standard nonrebreathing facemask (model 1060; Hudson RCI). Because facemasks used are obvious different (eg, a reservoir bag is only present in the nonrebreathing facemask), the study was not blinded. At the end of oxygen protocol, all patients received albuterol and ipratropium bromide (120 µg of albuterol sulfate and 21 µg of ipratropium bromide per actuation) delivered by a metered-dose inhaler into a spacer device (Volumatic; Allen & Hanburys; Greenford, UK) in a dose of four puffs at 10-min intervals in accordance with previous evidence.17 18 Additionally, patients with a poor response received hydrocortisone, 400 mg IV.

Measures
The following variables were measured in each patient immediately before starting oxygen administration and during the oxygen treatment (at 20 min): PEFR, respiratory rate, heart rate, and arterial blood gases. At baseline, we also assessed the presence of accessory muscle use, dyspnea, and wheezing. PEFR was measured with a mini-Wright peak flowmeter (Clement Clarke; Harlow, UK). The highest of three values was recorded. Heart rate was measured from continuous ECG. Accessory muscle use was defined as visible retraction of the sternocleidomastoid muscles.19 Dyspnea was defined as the patient’s own assessment of breathlessness. Wheezing was defined as musical or whistling breath sounds heard with a stethoscope during expiration. These clinical factors were graded in a scale from 0 to 3, in which 0 denoted absent, 1 indicated mild, 2 indicated moderate, and 3 indicated severe. Arterial blood samples were obtained via puncture of the radial artery; and pH, PaO2, and PaCO2 were measured with a blood gas analyzer using routine techniques (ABL 500 system; Radiometer America; Westlake, OH). Arterial saturation (pulse oximetric saturation [SpO2]) was monitored during oxygen administration by pulse oximetry with a finger oximeter (Nellcor N-180; Nellcor; Hayward, CA). Primary outcome measure was PaCO2 (difference between the two groups and variation from baseline) at the end of oxygen administration. Secondary outcomes variables were pH, PEFR, PaO2, heart rate, and respiratory rate (differences between groups and variation from baseline) at the end point. Patients unable to maintain a SpO2 > 90% and/or presented clinical deterioration during the oxygen protocol were excluded and received inhaled bronchodilators and systemic corticosteroids.

Statistical Analysis
The study was designed a priori with a sample size of 36 subjects per group to have 80% power to detect ({alpha} = 0.05, two-tailed test) a mean difference between groups in PaCO2 of 2.4 mm Hg, with a SD of 5 mm Hg. Mean values ± SD were calculated for continuous variables. The 95% confidence intervals (CIs) were calculated with standard formulas.20 The two groups were compared with respect to continuous variables using a repeated-measures two-way analysis of variance; post hoc pairwise multiple comparisons were performed using the Scheffé method. Pearson {chi}2 with Yates correction or the Fisher exact test was used for categorical variables. All data were analyzed with SPSS 10.0 for Windows software (SPSS; Chicago, IL).


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
A total of 79 consecutive adults with an acute exacerbation of asthma were recruited for entry into this study. Two patients were excluded because they were unable to maintain a SpO2 >= 90%. Seventy-seven adults were randomly assigned to treatment: 38 patients to the 28% group and 39 patients to the 100% group. Three patients (two patients in the 28% group, and one patient in the 100% group) refused the use of the facemask. Finally, 74 patients (36 patients in the 28% group, and 38 patients in the 100% group) completed the study (mean age, 37.9 ± 9.7 years). They had severe airway obstruction (mean PEFR, 41.0 ± 12.1% of predicted), moderate hypoxemia (mean PaO2, 77.8 ± 12.9 mm Hg), hypocarbia (mean PaCO2, 36.4 ± 4.4 mm Hg), and normal pH (7.39 ± 0.02). Eight percent of patients (n = 6) showed normoxemia and normocarbia; 76% (n = 56) presented hypoxemia or normoxemia (range, 58 to 97 mm Hg) and hypocarbia (range, 28 to 39 mm Hg); and 16% of patients (n = 12) presented hypoxemia (range, 63 to 90 mm Hg) and hypercarbia (range, 40 to 46 mm Hg). Table 1 shown baseline demographic data. There were no significant differences between the two groups, except for heart rate.


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  		Table 1.. Demographic and Baseline Characteristics of Patients*

 
Table 2 presents data at the end of oxygen administration (20 min). There were no differences between groups in heart and respiratory rates. Heart rate showed a trend toward a decrease, and respiratory rate was stable in both groups; however, patients treated with 100% oxygen presented a statistically significant decrease in pH (mean difference, 0.03; 95% CI, 0.00 to 0.05) and a significant increase in PaCO2 (mean difference, 2.7 mm Hg; 95% CI, 4.7 to 0.7 mm Hg) associated with a significant decrease in PEFR (mean difference, 31.7 L/min; 95% CI, 16.7 to 46.8 L/min) compared with patients treated with 28% oxygen. As anticipated, patients who received 100% oxygen showed a substantial increase in PaO2 compared with patients treated with 28% oxygen (mean difference, 158.4 mm Hg; 95% CI, 185.1 to 131.8 mm Hg). Figure 1 shows the relationship between PaCO2 before and at 20 min of oxygen administration. The scatterplot revealed that this relationship is curvilinear, particularly in patients treated with 100% oxygen. We tested different curve estimation regression models, and a polynomial model was the best fit to the data. Both variables correlated significantly (r = 0.53, p = 0.01 in the 28% group, and r = 0.88, p = 0.001 in the 100% group). A close examination of the relationship showed two different responses to oxygen administration. When patients received 28% oxygen, PaCO2 had a tendency to fall; on the contrary, patients who received 100% oxygen showed an increase in PaCO2, particularly in those patients with PaCO2 before oxygen treatment > 40 mm Hg. Post hoc analysis of PaCO2 changes from baseline during oxygen administration are shown in Table 3 . Twenty patients (55.6%) in the 28% group and 12 patients (31.6%) in the 100% group had PaCO2 decreases (p = 0.05). Eight patients (22.2%) in the 28% group and eight patients (21.0%) in the 100% group (p = 0.9) presented small PaCO2 increases (< 2 mm Hg) consistent with the physiologic Haldane effect.21 Finally, only 6 patients (16.6%) in the 28% group presented a PaCO2 increase > 2 mm Hg (mean increase, 3.4 ± 1.9 mm Hg; range, 2 to 5.9 mm Hg), compared with 16 patients (42.1%) [mean increase, 5.0 ± 3.8 mm Hg; range, 2.4 to 14.3 mm Hg] in the 100% group (p = 0.02). At the end of the protocol, this subgroup of patients showed a significant difference in PEFR (PEFR deterioration of 11.9 ± 30.0 L/min in the 100% group, compared with an increase of 18.3 ± 25.4 L/min in the 28% group, p = 0.03). Whereas PaCO2 did not correlate with PEFR in the 28% group (r = 0.21, p = 0.6), the 100% group showed an inverse curvilinear correlation between PEFR before oxygen administration and PaCO2 during oxygen treatment (Fig 2 ). Low values of PEFR were associated with high levels of PaCO2 (r = 0.53, p = 0.01, polynomial model).


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  		Table 2.. Heart and Respiratory Rates, Pulmonary Function, and Arterial Blood Gas Levels at 20 min of Oxygen Administration*

 


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  		Figure 1.. PaCO2 during oxygen administration as a function of PaCO2 before oxygen treatment. The variables correlated significantly in both groups (p < 0.01). Patients breathing 28% oxygen had a PaCO2 fall (left panel); on the contrary, patients who received 100% oxygen showed an increase in PaCO2, particularly those with PaCO2 before oxygen treatment > 40 mm Hg (right panel).

 

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  		Table 3.. Distribution of PaCO2 Changes From Baseline During Oxygen Administration*

 


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  		Figure 2.. Relationship between airway obstruction before oxygen administration as measured by PEFR (as percentage of predicted) and PaCO2 during the administration of 100% oxygen. Low values of PEFR were associated with high levels of PaCO2 (r = 0.54, p = 0.01).

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
To our knowledge, this is the first randomized controlled trial that provided data on the effect of two oxygen concentrations on PaCO2 and PEFR in adult patients with acute severe asthma. The results showed that 100% of inspired oxygen resulted in a significant increase in PaCO2. Forty-two percent of the 100% oxygen group patients had increases in PaCO2 averaging 5.0 mm Hg (range, 2.4 to 14.3 mm Hg). As shown in Figures 1 and 2 , PaCO2 during oxygen administration highly correlated with the PaCO2 level before oxygen treatment and moderately with the baseline airway obstruction (PEFR). Thus, baseline PaCO2 and PEFR > 40 mm Hg and < 35% of predicted respectively appears to be significant factors in the development of hyperoxic-induced hypercapnia. Additionally, the gas exchange deterioration was associated with a significant decrease in pulmonary function. On the contrary, the administration of 28% oxygen overall improved the patient condition. Thus, low oxygen concentration rectified hypoxemia (mean PaO2 at the end of protocol, 99.4 ± 16.3 mm Hg), produced a small mean PaCO2 decrease (1.3 ± 4.0 mm Hg), and improved pulmonary function (24.1 ± 38.6 L/min). In spite of this, 16.6% of patients experienced an increase in PaCO2 (range, 2.0 to 5.9 mm Hg).

These findings are in accordance with previous studies. More than 10 years ago, two noncontrolled trials22 23 found that acute asthma patients treated with high inspired oxygen concentration presented a significant increase in PaCO2 (of the order of 3 to 5 mm Hg). More recently, Chien et al12 demonstrated that the administration of 100% oxygen to acute asthma patients with moderate-to-severe airway obstruction (FEV1 of 49.1% of predicted) may adversely influence carbon dioxide elimination. With 100% oxygen administration, FEV1 fell by 4.3%, pH decreased by 0.02, and PaCO2 rose by 2.3 mm Hg). Almost 41% of patients had elevations in PaCO2 > 2 mm Hg, averaging 5.9 mm Hg. In general, the tendency toward hypercarbia was the greatest in the patients with the most abnormal baseline condition (FEV1 and PaCO2).

Although our study did not look closely at any changes in minute ventilation, there seemed to be no significant modifications before and during oxygen administration in respiratory rate. Hyperoxia associated with hypercarbia occurring in asthma exacerbations, and especially without any evidence of respiratory suppression, would be more easily explained by the regional release of hypoxic pulmonary vasoconstriction. This factor had a major role in determining / matching, as / inequality worsened considerably after administration of 100% oxygen. This has been shown in patients with acute asthma receiving ventilation and not receiving ventilation22 23 ; therefore, patients with most severe baseline condition probably have more hypoxic vasoconstriction, and they had the greatest increase in PaCO2 while breathing 100% oxygen.

Our trial sample presented the typical features of severe adult asthmatic patients when they presented for care to an emergency department on average: a mean level of PEFR of 41% of predicted, a mean age of 38 years, and a female/male ratio of 2:1. Finally, 76% of our patients presented the most characteristic arterial blood gas pattern: mild-to-moderate hypoxemia (range, 58 to 97 mm Hg) along with hypocapnia (range, 28 to 39 mm Hg).24 25

In summary in this randomized, controlled trial, we have confirmed previous observations that administration of 100% oxygen for 20 min significantly increases PaCO2 and decreases PEFR as compared with administration of 28% oxygen. These observations strongly support Global Strategy for Asthma Management and Prevention recommendations15 that oxygen dose in severe acute asthma should be variable and should be based on achieving and maintaining target SpO2 values with a pulse oximeter > 92% for adults26 and 95% for children. Because severe asthma may give rise to hypoxemia and ß-agonist therapy may worsen hypoxemia, monitoring therapy of acute asthma with pulse oximetry is ideal.27 The results should be used to control the administration and dose of oxygen therapy. In circumstances where acute asthma must be treated without pulse oximetry, a clinical judgment must be made as to whether oxygen therapy (if is available) is warranted to prevent life-threatening hypoxemia, despite its potential adverse effects. However, uncontrolled high-flow oxygen should be avoided.


   Footnotes
 
Abbreviations: CI = confidence interval; PEFR = peak expiratory flow rate; SpO2 = pulse oximetric saturation; / = ventilation/perfusion

Received for publication November 12, 2002. Accepted for publication March 3, 2003.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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