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Original Research: Critical Care |

Albuterol Administration Is Commonly Associated With Increases in Serum Lactate in Patients With Asthma Treated for Acute Exacerbation of AsthmaAlbuterol Increases Lactate in Asthma Exacerbation FREE TO VIEW

Lawrence M. Lewis, MD; Ian Ferguson, BA; Stacey L. House, MD, PhD; Kristen Aubuchon; John Schneider, BA; Kirk Johnson, PhD; Kazuko Matsuda, MD, PhD
Author and Funding Information

From the Washington University School of Medicine in St. Louis (Drs Lewis and House, Messrs Ferguson and Schneider, and Ms Aubuchon), St. Louis, MO; and MediciNova, Inc (Drs Johnson and Matsuda), La Jolla, CA.

Correspondence to: Lawrence M. Lewis, MD, Washington University School of Medicine in St. Louis, 660 S Euclid Ave, Campus Box 8072, St. Louis, MO 63110; e-mail: lewisl@wusm.wustl.edu


For editorial comment see page 6

Part of this article was presented in abstract form at the Society for Academic Emergency Medicine Annual Meeting in Chicago, IL, May 9-12, 2012.

Funding/Support: This study was part of a larger industry-sponsored clinical study. There was no funding provided for manuscript preparation and submission.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2014;145(1):53-59. doi:10.1378/chest.13-0930
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Background:  Controversy exists around the incidence and cause of hyperlactatemia during asthma exacerbations. We evaluated the incidence, potential causes, and adverse events of hyperlactatemia in patients with acute asthma exacerbation.

Methods:  This study was a subanalysis of subjects receiving placebo from a prospective, randomized trial evaluating an IV β-adrenergic agonist in acute asthma exacerbation. Plasma albuterol, serum lactate, and bicarbonate concentrations were measured at baseline and 1.25 h, and dyspnea score and spirometry were measured at baseline and hourly for 3 h. All subjects had a therapeutic trial comprising 5 to 15 mg nebulized albuterol, 0.5 to 1 mg nebulized ipratropium, and at least 50 mg oral prednisone or its equivalent prior to initiation of the study. Following randomization, subjects were treated with continued albuterol and IV magnesium at the discretion of their treating physician. Subjects were followed to hospital admission or discharge with follow-up at 24 h and 1 week.

Results:  One hundred seventy-five subjects were enrolled in the parent trial, with 84 in the placebo group. Sixty-five had complete data. Mean ± SD albuterol administration prior to baseline was 12.3 ± 5.3 mg. Mean baseline lactate was 18.5 ± 8.4 mg/dL vs 26.5 ± 11.8 mg/dL at 1.25 h (P < .001). Forty-five subjects (69.2%) had hyperlactatemia. Mean baseline bicarbonate level was 22.6 ± 2.9 mEq/L vs 21.9 ± 4.0 mEq/L at 1.25 h (P = .11). Plasma albuterol concentration correlated with lactate concentration (β = 0.45, P < .001) and maintained a significant association after adjusting for asthma severity (β = 0.41, P = .001). Hyperlactatemia did not increase the risk of hospitalization or relapse (P = .26) or was associated with lower FEV1 % predicted at 3 h (P = .54).

Conclusions:  Plasma albuterol was significantly correlated with serum lactate concentration after adjusting for asthma severity. Hyperlactatemia was not associated with poorer pulmonary function as measured by 3-h FEV1 % predicted or increased hospitalization or relapse at 1 week.

Trial registry:  Clinicaltrials.gov; No.: NCT00683449; URL: www.clinicaltrials.gov

Figures in this Article

Previous reports have indicated increased serum lactate levels in patients with asthma receiving therapy for acute asthma exacerbation.14 Initially, these findings were observed only in patients with severe asthma and respiratory failure,13 but more recently it has been described in subjects with less severe exacerbations.46 Controversy exists regarding the likely causes of this increase in serum lactate levels. Some authors proposed that it is a side effect of therapy,79 whereas others have attributed the elevation to the increased work of breathing and increased lactate production.1,3 Controversy remains about whether the increase is associated with acidosis and poorer outcome.3,8 A number of articles suggested that in most cases, hyperlactatemia is more likely a result of therapy than a result of the disease4,9,10; however, these have been case reports,9 retrospective reviews with incomplete data,10 or small prospective studies.4 Furthermore, we are unaware of studies that have looked at this relationship regarding pharmacotherapy, such as through the measurement of serum or plasma concentrations of β-adrenergic agonists. Such a measurement should provide a more quantitative assessment of the association between β-adrenergic agonist administration and serum lactate concentration.

The primary goal of the present study was to determine whether a correlation exists between plasma albuterol and serum lactate concentrations in patients presenting to an ED with an acute exacerbation of asthma. The secondary goal was to determine whether elevated serum lactate level was more commonly associated with an adverse outcome (hospitalization or relapse within 8 days).

Study Design and Setting

This study was a prospectively planned subgroup analysis of a phase 2, randomized, double-blind, placebo-controlled study to evaluate the safety and efficacy of a proprietary IV β2-adrenergic agonist as an adjunct to standard therapy in adults with acute asthma exacerbation. This study involved nine US EDs and took place from January 15, 2009 through March 15, 2012. All sites met their local institutional review board requirements (e-Appendix 1) for study participation, including a formal informed consent process.

Selection of Subjects

The study population comprised adult patients with asthma (aged 18 to 65 years) and no history of COPD who presented to the ED with an acute asthma exacerbation. To qualify, subjects had to have an FEV1 < 50% predicted after a therapeutic trial of 5 to 15 mg nebulized albuterol, 0.5 to 1 mg nebulized ipratropium, and at least 50 mg oral prednisone or its equivalent. Exclusion criteria are provided in e-Table 1. All study subjects were allowed repeated dosing of albuterol, ipratropium, and other medications throughout the study period as deemed appropriate by the treating physician, who was blinded to the intervention and unaware of the study end points. This substudy was not randomized because we only included the placebo group. The novel β2-adrenergic agonist given to the active study drug group is a completely different molecule from albuterol and is not measured when using the albuterol assay but may have an effect on serum lactate level. Thus, we excluded these subjects to avoid any possible effects of the experimental drug on lactate levels. We have included a Consolidated Standards of Reporting Trials flow diagram for the parent trial, which includes the present substudy (Fig 1). This study was approved by the Washington University in St Louis Institutional Review Board (IRB ID #201101984).

Figure Jump LinkFigure 1. Consolidated Standards of Reporting Trials flow diagram. PK = pharmacokinetics.Grahic Jump Location
Measurements

Blood samples were drawn per the study protocol at baseline and at 0.25, 1, and 1.25 h. Baseline was defined as just prior to the start of study drug or placebo infusion. Sample collection occurred either by drawing blood from a previously placed IV catheter or venipuncture. Plasma albuterol and serum lactate, glucose, and electrolyte concentrations were analyzed in the blood drawn at both the baseline and the 1.25 h time points. Pharmacokinetic samples were drawn in K2 ethylenediaminetetraacetic acid tubes and placed immediately in an ice bath for 15 min before being centrifuged to separate plasma. The plasma aliquots were stored in a −80°C freezer prior to shipment and then shipped frozen (on dry ice) to the analyzing laboratory. Plasma albuterol level was analyzed by automated solid phase extraction (liquid handling system with Strata-X-C extraction plates; Phenomenex Inc) according to method SOP ANI 9566.01/02. The extracted samples were injected into a liquid chromatograph equipped with a Chirobiotic T2, 150 × 4.6 mm, 5-μm column (Sigma-Aldrich Co LLC). The detection was made with a tandem mass spectrometry detector (API 4000; Applied Biosystems/MDS Sciex). Total albuterol concentration was calculated by summing the concentrations of the R-enantiomer and S-enantiomer, which were directly measured. The R-enantiomer is the biologically active form of albuterol.

Blood for serum electrolytes and lactate determinations were drawn in a serum separator tube and allowed to clot for 30 min before centrifuging to separate serum. Serum aliquots for electrolyte and lactate concentration analysis were stored and shipped ambient. Serum electrolyte (including bicarbonate) and lactate levels were analyzed with a Roche/Hitachi analyzer (ICON Central Laboratories). Albuterol concentrations (ng × h/mL) were measured as the area under the curve from baseline to 1.25 h (AUC0-1.25). Serum lactate (mg/dL) and bicarbonate (mEq/L) concentrations were measured at baseline and at 1.25 h. We also determined total serum lactate concentration, measuring the AUC0-1.25. Normal values for lactate (4.5-19.8 mg/dL) and bicarbonate (20-31 mEq/L) were based on the ICON Central Laboratories reference range.

Dyspnea was measured at baseline and hourly thereafter for a total of 3 h with the Modified Borg Dyspnea Scale (DS).11 The modified scale, which runs from 0 to 10 and includes 0.5, is a subjective measurement of difficulty breathing or breathlessness. Several authors have validated this scale in both asthma and COPD.1215

The FEV1 was measured at baseline and hourly for a total of 3 h with an nSpire spirometer (nSpire Health, Inc) and expressed as % predicted (%FEV1) on the basis of age, height, weight, and sex. Spirometry was performed three times in succession at each time point, with the best effort recorded. A telephone follow-up at 8 ± 2 days was used to determine whether patients had a relapse defined as an unscheduled physician, ED, or hospital visit for an asthma exacerbation.

Primary Data Analysis

Descriptive statistics include mean ± SD baseline values for albuterol, lactate, and bicarbonate concentrations and mean baseline DS and %FEV1. We calculated the mean change in serum lactate and bicarbonate concentration between baseline and 1.25 h and evaluated the change for significance with a paired t test. We then performed a simple linear regression with total plasma albuterol level (AUC0-1.25) as the predictor variable and total serum lactate level (AUC0-1.25) as the outcome variable. Next, we performed a multiple regression, adjusting for the severity of asthma using baseline DS and %FEV1.

To adjust for any effect of albuterol administration on serum lactate concentration prior to entry into the study, we performed a multiple regression analysis using total plasma albuterol concentration (AUC0-1.25) to predict the 1.25-h serum lactate concentration, controlling for the baseline serum lactate concentration and adjusting for the severity of asthma using DS and %FEV1. We determined statistical significance for the various standardized regression coefficients (β) by two-sided t test. We used Fisher exact test to determine whether a small group of subjects with very high serum lactate levels had a worse prognosis than those with normal lactate levels, using a composite primary outcome of hospitalization and relapse rates between subjects with severe hyperlactatemia (40 mg/dL [4.49 mmol/L]) and those with normal serum lactate concentration (≤ 19.8 mg/dL [2.2 mmol/L]). We also compared the percent change in FEV1 (baseline to 3 h) between subjects with normal lactate and those with elevated lactate levels by two-sided t test. Finally, we compared final %FEV1 between subjects with normal serum lactate concentration and those with severe hyperlactatemia by two-sided t test. All statistical analyses were completed with SPSS, version 19 (IBM Corporation) software. For all analyses, statistical significance was set at P ≤ .05 (two tailed).

We randomized 175 subjects into the interventional trial, of whom 84 were allocated to the placebo group. Seventy-one subjects had at least one plasma albuterol measurement, of whom six did not have a reported lactate measurement at either baseline or 1.25 h, leaving a final sample of 65 subjects with at least one serum albuterol measurement and one lactate measurement at baseline and 1.25 h (Fig 1). The multiple regression analysis included 61 subjects because four were missing FEV1 data.

Demographic characteristics of the study population, plasma albuterol concentration (AUC0-1.25), maximum and Δ serum lactate concentration, minimum and Δ serum bicarbonate concentration, mean baseline FEV1, and mean baseline DS score are shown in Table 1. Twenty of the 65 subjects (30.7%) were hospitalized for asthma, and another six (9.2%) had a relapse during the follow-up period. Mean plasma albuterol concentration at baseline was 7.11 ng/mL and increased to 7.25 ng/mL at 1.25 h. Serum lactate concentration was 18.5 ± 8.4 mg/dL at baseline and increased to 26.5 ± 11.8 mg/dL at 1.25 h (P < .001). Forty-five subjects (69.2%) had at least one serum lactate value greater than the upper limit of normal (19.8 mg/dL [2.2 mmol/L]), and 10 (15.4%) had at least one serum lactate ≥ 40 mg/dL (4.49 mmol/L). Mean serum bicarbonate concentration did not differ significantly between baseline (22.6 ± 2.9 mEq/L) and 1.25 h (21.9 ± 4.0 mEq/L) (Table 1). Fourteen subjects (22.2%) had a 1.25-h serum bicarbonate concentration below normal (20 mEq/L), but only five (7.9%) had a concentration < 19 mEq/L. The lowest bicarbonate concentration seen in this population was 15 mEq/L.

Table Graphic Jump Location
Table 1 —Demographic and Clinical Data

AUC0-1.25 = area under the curve from baseline to 1.25 h; DS = Modified Borg Dyspnea Scale; %FEV1 = FEV1 % predicted.

a 

Total albuterol administered prior to baseline measurements.

b 

Lactate concentration (AUC0-1.25) (P value for paired t test comparing baseline value to 1.25 h).

c 

Minimum bicarbonate concentration for baseline and 1.25 h (P value for paired t test comparing baseline value to 1.25 h).

Simple linear regression showed a significant positive correlation between plasma albuterol concentration (AUC0-1.25) and serum lactate concentration (AUC0-1.25) (r = 0.45, P < .001) (Fig 2, Table 2, model 1). Multiple regression analysis showed that total plasma albuterol concentration (AUC0-1.25) continued to be significantly associated with total serum lactate concentration (AUC0-1.25), after adjusting for DS score and %FEV1 (Table 2, model 2). Baseline serum lactate concentration was a significant predictor of the 1.25-h serum lactate concentration (Table 3). However, even after correcting for baseline lactate level and using multiple regression to adjust for DS score and %FEV1, total albuterol concentration (AUC0-1.25) remained a significant predictor of the 1.25-h serum lactate concentration (Table 3). This model predicts that a 5 ng × h/mL increase in total plasma albuterol level would result in a 3.1 mg/dL increase in the 1.25-h serum lactate concentration.

Figure Jump LinkFigure 2. Bivariate fit of serum lactate AUC0-1.25hr by total plasma albuterol (R-enantiomer + S-enantiomer) AUC0-1.25hr. ● = subjects who were hospitalized or who relapsed. AUC0-1.25hr = area under the curve from baseline to 1.25 h.Grahic Jump Location
Table Graphic Jump Location
Table 2 —Linear Regression Models for Total Plasma Albuterol (AUC0-1.25) and Serum Lactate (AUC0-1.25) Concentrations

Model 1, F(1, 63) = 16.44, P < .001, R2 = 0.21, adjusted R2 = 0.19. Model 2, F(3, 57) = 8.33, P < .001, R2 = 0.30, adjusted R2 = 0.27. See Table 1 legend for expansion of abbreviations.

a 

P < .001.

b 

P < .05.

Table Graphic Jump Location
Table 3 —Multiple Regression for Total Plasma Albuterol (AUC0-1.25) and Serum Lactate Concentrations at 1.25 h After Adjusting for Baseline Serum Lactate Level

F(4, 53)=13.17, P < .001, R2 = 0.50, adjusted R2 = 0.46. See Table 1 legend for expansion of abbreviations.

a 

P < .01.

b 

P < .001.

In terms of serum lactate and outcome, the incidence of hospitalization and relapse did not differ between subjects with a serum lactate level of ≥ 40 mg/dL (n = 5 [50%]) and those with normal serum lactate values (n = 8 [40%], P = .26). The mean change in %FEV1 (baseline to 3 h) was not significantly different among subjects with normal serum lactate concentration compared with those with elevated lactate concentration (6.1% vs 10.6%, P = .12). The final (3-h) mean %FEV1 was not significantly different between subjects with normal lactate concentration and those with severe hyperlactatemia (45% vs 51%, P = .54).

Several distinct acid-base disorders occur in patients with an acute asthma exacerbation, including respiratory alkalosis and, less commonly, respiratory acidosis.3 Metabolic abnormalities include anion gap acidosis,3 nonanion gap acidosis,16 and hyperlactatemia without acidosis.4,7 Metabolic acidosis and hyperlactatemia in patients with status asthmaticus was first reported in a small study in 1968.17 Several years later in a larger prospective study, simple or combined metabolic acidosis was observed in nearly 38% of patients with status asthmaticus and was associated with hyperlactatemia believed to be secondary to anaerobic respiratory muscle activity from the increased work of breathing.18

Rabbat et al8 observed hyperlactatemia without acidosis in a large percentage of patients in the ICU with status asthmaticus and did not portend a poor prognosis. Although the authors postulated that the increased lactate levels may have been a result of β-adrenergic agonist therapy, serum catecholamine levels were not measured.

The first report of hyperlactatemia in association with the administration of IV β-adrenergic agonists was in patients treated for preterm labor.19 Since this description, there have been a number of reports of hyperlactatemia in subjects being treated with either IV or nebulized salbutamol for asthma.46,2024 The present study reaffirms the finding that the administration of nebulized albuterol is associated with elevated serum lactate concentration in a significant percentage of subjects and is the first in our knowledge to quantify this effect.

The β-coefficient for the present regression line for albuterol and lactate concentrations indicates that a 5 ng × h/mL increase in the plasma albuterol AUC would lead to a 3.1 mg/dL increase in serum lactate level. It also supports the previous finding that hyperlactatemia associated with treatment of acute asthma exacerbation is most often not accompanied by metabolic acidosis.8,20,23 The mean serum bicarbonate concentration was normal in the present study subjects at baseline and remained so, decreasing by only 0.7 mEq/L over the 75-min sampling period.

Patients with asthma are somewhat heterogeneous in their metabolic response to acute asthma exacerbation and its treatment. Why hyperlactatemia develops in some patients and not in others is unclear. Previous reports and the findings of the current larger study suggest that in the majority of patients, hyperlactatemia is more likely to be a result of β-adrenergic therapy than secondary to the increased work of breathing and anaerobic activity.2025 To differentiate between these two potential causes of hyperlactatemia in the present analysis, we first adjusted for %FEV1 and DS in a multivariate regression and found that plasma albuterol concentration remained a significant predictor of the 1.25-h serum lactate concentration (Table 3). We also compared the mean change in %FEV1 over the 3-h study period and the final 3 h %FEV1 in subjects with elevated serum lactate concentration with that in subjects with normal lactate levels, with the assumption that subjects with higher serum lactate concentrations secondary to the increased work of breathing would have less improvement in %FEV1 and a lower 3 h %FEV1 than those with normal serum lactate concentrations. No significant differences were found either in the mean change in %FEV1 or in the mean 3 h %FEV1 between these two groups, further supporting the idea that the administration of β-adrenergic agonists is the dominant cause of elevated serum lactate levels in patients treated for acute exacerbation of asthma. While recognizing this possibility, several investigators suggested that decreasing the dosage of β-adrenergic agonist in these patients may improve acidosis and work of breathing.7,9,10,21,22 Several reports7,21,22 suggest that dyspnea may improve in patients with hyperlactatemia and acidosis when further administration of β-adrenergic therapy is withheld.

Is an elevated serum lactate concentration associated with a poorer outcome? Whether using a surrogate outcome such as %FEV1 or the clinical outcome of hospitalization or relapse, there was no significant difference between subjects with normal and elevated serum lactate concentrations. Patients with markedly elevated serum lactate levels (> 40 mg/dL) experienced a trend toward increased hospitalization or relapse (50% vs 40%, P = .26). The number of these subjects was low (n = 10), and a type 2 error is possible.

This study has several limitations. The most important is that all subjects already had exposure to albuterol prior to the baseline measurements. Plasma albuterol concentration will account for the proximal dosing, but patients who had been taking large amounts of albuterol over an extended period (many hours to days) could have had much of the effect on serum lactate prior to the baseline sampling. Another limitation is that other medications besides albuterol were administered during the study period and may have contributed to the changes in serum lactate concentration. However, according to previous studies, albuterol is the most likely of the concomitant medications to be involved with lactate metabolism. The present lactate measurements occurred over a rather short duration, and it is possible that further changes may occur over time.

The study population was relatively small and comprised patients with moderate to severe asthma exacerbation whose condition, by study design, was refractory to initial therapy (requiring an FEV1 < 50% 30 min after standard therapy to be eligible for the study). This is likely to be the population most at risk for hyperlactatemia (regardless of the cause) because they are sicker and, thus, receive more albuterol. Finally, some of the analyses may have been underpowered (in particular the difference in hospitalization and relapse rates between subjects with severe hyperlactatemia and those with normal serum lactate concentration). Further work should focus on why hyperlactatemia is more apt to develop in some patients than in others, whether predisposing metabolic factors (eg, low potassium, low phosphorus) exist, whether a subset of subjects have worsening symptoms and improve with reduction of β-adrenergic agonist therapy as some authors have suggested, and whether other currently unrecognized adverse events may result from this metabolic abnormality.

Hyperlactatemia in patients being treated for asthma exacerbation is more likely to be caused by albuterol (β-adrenergic) therapy than disease severity. Elevated serum lactate levels did not portend a poorer outcome in terms of %FEV1, hospitalization on the index visit, or relapse within 8 days in this relatively small study population.

Author contributions: Dr Lewis had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis

Dr Lewis: contributed to the study conception, data review and analysis, and writing of the manuscript.

Mr Ferguson: contributed to the data entry and analysis and manuscript review.

Dr House: contributed to refining the study methodology, data analysis, and manuscript preparation.

Ms Aubuchon: contributed to refining the study methodology, data entry, and manuscript preparation.

Mr Schneider: contributed to refining the study methodology, data entry, and manuscript preparation.

Dr Johnson: contributed to the study conception, data review and analysis, and manuscript preparation.

Dr Matsuda: contributed to the study conception, data review and analysis, and manuscript preparation.

Financial/nonfinancial disclosures: The authors reported to CHEST the following conflicts of interest: Dr Lewis was a site principal investigator for the larger clinical trial on which the present study is based. Drs Johnson and Matsuda are employed by MediciNova, Inc, the sponsoring company for the larger clinical trial. Messrs Ferguson and Schneider, Dr House, and Ms Aubuchon have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Additional information: The e-Appendix and e-Table can be found in the “Supplemental Materials” area of the online article.

AUC

area under the curve

DS

Modified Borg Dyspnea Scale

%FEV1

FEV1 % predicted

Appel D, Rubenstein R, Schrager K, Williams MH Jr. Lactic acidosis in severe asthma. Am J Med. 1983;75(4):580-584. [CrossRef] [PubMed]
 
Alberts WM, Williams JH, Ramsdell JW. Metabolic acidosis as a presenting feature in acute asthma. Ann Allergy. 1986;57(2):107-109. [PubMed]
 
Mountain RD, Heffner JE, Brackett NC Jr, Sahn SA. Acid-base disturbances in acute asthma. Chest. 1990;98(3):651-655. [CrossRef] [PubMed]
 
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Figures

Figure Jump LinkFigure 1. Consolidated Standards of Reporting Trials flow diagram. PK = pharmacokinetics.Grahic Jump Location
Figure Jump LinkFigure 2. Bivariate fit of serum lactate AUC0-1.25hr by total plasma albuterol (R-enantiomer + S-enantiomer) AUC0-1.25hr. ● = subjects who were hospitalized or who relapsed. AUC0-1.25hr = area under the curve from baseline to 1.25 h.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1 —Demographic and Clinical Data

AUC0-1.25 = area under the curve from baseline to 1.25 h; DS = Modified Borg Dyspnea Scale; %FEV1 = FEV1 % predicted.

a 

Total albuterol administered prior to baseline measurements.

b 

Lactate concentration (AUC0-1.25) (P value for paired t test comparing baseline value to 1.25 h).

c 

Minimum bicarbonate concentration for baseline and 1.25 h (P value for paired t test comparing baseline value to 1.25 h).

Table Graphic Jump Location
Table 2 —Linear Regression Models for Total Plasma Albuterol (AUC0-1.25) and Serum Lactate (AUC0-1.25) Concentrations

Model 1, F(1, 63) = 16.44, P < .001, R2 = 0.21, adjusted R2 = 0.19. Model 2, F(3, 57) = 8.33, P < .001, R2 = 0.30, adjusted R2 = 0.27. See Table 1 legend for expansion of abbreviations.

a 

P < .001.

b 

P < .05.

Table Graphic Jump Location
Table 3 —Multiple Regression for Total Plasma Albuterol (AUC0-1.25) and Serum Lactate Concentrations at 1.25 h After Adjusting for Baseline Serum Lactate Level

F(4, 53)=13.17, P < .001, R2 = 0.50, adjusted R2 = 0.46. See Table 1 legend for expansion of abbreviations.

a 

P < .01.

b 

P < .001.

References

Appel D, Rubenstein R, Schrager K, Williams MH Jr. Lactic acidosis in severe asthma. Am J Med. 1983;75(4):580-584. [CrossRef] [PubMed]
 
Alberts WM, Williams JH, Ramsdell JW. Metabolic acidosis as a presenting feature in acute asthma. Ann Allergy. 1986;57(2):107-109. [PubMed]
 
Mountain RD, Heffner JE, Brackett NC Jr, Sahn SA. Acid-base disturbances in acute asthma. Chest. 1990;98(3):651-655. [CrossRef] [PubMed]
 
Rodrigo GJ, Rodrigo C. Elevated plasma lactate level associated with high dose inhaled albuterol therapy in acute severe asthma. Emerg Med J. 2005;22(6):404-408. [CrossRef] [PubMed]
 
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