ACLS
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Rashid, A. O.
Right arrow Articles by Khan, M. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Rashid, A. O.
Right arrow Articles by Khan, M. A.
Annals of Clinical & Laboratory Science 38:228-234 (2008)
© 2008 Association of Clinical Scientists

Non-Anion Gap Acidosis in Asthma: Clinical and Laboratory Features and Outcomes for Hospitalized Patients

Ashraf O. Rashid1, Hamad M. Azam3, Vincent A. DeBari2, Adel I. Blamoun1, Mahmoud Q. Moammar1 and M. Anees Khan1,3
1 Division of Pulmonary Diseases and 2 Department of Internal Medicine, School of Graduate Medical Education, Seton Hall University, South Orange, New Jersey; 3 Department of Internal Medicine, Mt. Sinai School of Medicine, St. Joseph’s Regional Medical Center, Paterson, New Jersey

Address correspondence to M. Anees Khan, M.D., Division of Pulmonary Diseases, St. Joseph’s Regional Medical Center, 703 Main St., Paterson, NJ 07503, USA; tel 973 754 2431; e-mail khana{at}sjhmc.org.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Metabolic acidosis secondary to lactic acidosis may occur in acute, severe asthma and its presence suggests that respiratory muscle fatigue and tissue hypoxia play a major part in the pathogenesis. Non-anion gap metabolic acidosis (NAG acidosis) has also been reported in acute asthma but its impact on the clinical outcome has not been evaluated. The objective of this study was to evaluate the prevalence of NAG acidosis, characterize the laboratory findings, and determine its impact on clinical outcomes. Acid-base and electrolyte status and clinical outcomes were examined over a 1-yr (2005 calendar yr) period in 109 adult patients (38 males, 71 females; age range 21 to 91 yr) hospitalized for asthma exacerbation. The cohort was divided into 3 groups: I. No metabolic acidosis (n = 66), II. Anion gap (AG) acidosis (n = 11), and III. NAG acidosis (n = 32). For each of the groups, laboratory findings were consistent, demonstrating a tendency to hyperchloremia in the NAG acidosis group. One subject in the NAG acidosis group died. NAG acidosis was associated with a statistically significant (p = 0.028) risk of requirement for mechanical ventilation necessitating admission to the Medical Intensive Care Unit (MICU); the odds ratio for intubation for NAG acidosis compared to other groups was 3.92. No difference, however, was detected in overall length of stay (LOS) in hospital for patients with NAG acidosis vs the other groups. NAG metabolic acidosis in acute asthma may be more prevalent than expected and may be associated with more frequent need for mechanical ventilation and admission to an intensive care unit.

Keywords: asthma, acidosis, anion gap, acid-base status, arterial blood gas analysis


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
One of the most important diagnostic tools for evaluating patients with acute asthma is measurement of arterial blood gases. Typically, hypocapnia and respiratory alkalosis are the most common disorders [1], but superimposed metabolic acidosis is seen in patients with severe attacks [2–4]. Two types of metabolic acidosis exist: anion gap acidosis (AG acidosis) secondary to hyperlactatemia, and non-anion gap acidosis (NAGA) as a result of excessive renal bicarbonate excretion in response to a period of hypocapnia.

NAGA has been infrequently studied [3] and, to date, its specific impact on the severity of asthma is unknown. Lactic acidosis is a well recognized entity in many previous studies [3,5,6–8]; however, conflicting results have been reported concerning its prognostic value in predicting respiratory failure and the need for mechanical ventilation [3,7].

The aim of this study was to assess the frequency of NAGA in patients admitted to the hospital with an acute exacerbation of asthma and also to determine the prognostic value of NAGA in regard to adverse clinical outcomes.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Setting.  The study was conducted at St. Joseph’s Regional Medical Center, a 750-bed tertiary, acute care teaching hospital in northern New Jersey. The St. Joseph’s Institutional Review Board classified the study in the Exempt category.

Subjects.  Adult (≥18 yr) admissions to the hospital with a principal diagnosis of acute asthma exacerbation between 1 January and 31 December 2005 were reviewed. All patients were diagnosed based on the recommended guidelines [7]. We excluded patients with sepsis, hypotension, chronic obstructive pulmonary disease (COPD), congestive heart failure (CHF), end-stage renal disease (ESRD), HIV disease, uncontrolled diabetes, alcohol intoxication, or drug overdose. Of the 322 admissions during the study period, a final cohort of 109 subjects met the criteria for inclusion in the study, as shown in Fig. 1Go. As the study was cross-sectional in design, subjects were evaluated for outcomes only for the duration of their hospital admission.


Figure 1
View larger version (24K):
[in this window]
[in a new window]

  		Fig. 1. Flow chart demonstrating the development of the cohort of asthma patients and the distribution of the subjects into the 3 study groups.

 
Assignment to groups.  Patients were assigned to 1 of 3 study groups according to the following criteria:

  1. No (metabolic) acidosis, defined as a pH consistent with the arterial PCO2, ie, subjects with respiratory acidosis or alkalosis in which the pH level is fully accounted for by the change in PCO2 without a superimposed metabolic acidosis.
  2. AG acidosis defined as a pH lower than that predicted from the arterial PCO2 in the presence of an AG >12 mmol/ L. The calculated AG = [Na+] - ([Cl–] + [HCO3–]), where brackets indicate concentrations in mmol/L.
  3. NAG acidosis, defined as a pH lower than predicted from the level of PCO2 in the presence of a calculated AG that is considered normal, ie, AG ≤12 mmol/L.

Clinical outcomes.  We evaluated 4 outcomes suggestive of disease severity: requirement for admission to the medical intensive care unit (MICU), requirement for intubation, mortality, and length of hospital stay (LOS).

Laboratory measurements.  Arterial blood samples were collected using an arterial blood gas (ABG) sampling kit (Portex Pulsator, Smiths Medical ASD, Inc., Keene, NH) using sodium heparin as an anticoagulant. The GEM Premier 3000 system (Instrumentation Laboratory, Lexington, MA) was used to assay ABG analytes (pH, PaCO2, PaO2, HCO3–). Serum Na+, Cl–, K+, and HCO3– were measured using ion selective electrodes (ISE, Beckman-Coulter LX 20, La Brea, CA). Quality control (QC) for all assays conformed to criteria set forth by the College of American Pathologists and all data reported were derived from "in-control" runs.

Clinical measurements.  Respiratory rate, mean arterial pressure, pulse rate, and hemoglobin O2 saturation were recorded as part of the initial evaluation in the Emergency Department. All chest radiograph reports were reviewed and the presence or absence of hyperinflation was documented.

Data analysis and presentation.  An a priori power analysis was based on an expected odds ratio (OR) of 3.0 for intubation and MICU admission and a rate for the other groups of 10%.This yielded a sample size of 100 subjects at {alpha} = 0.05 and β = 0.2 (power = 80%).

All interval data were tested for fit-to-normality by the D’Agostino-Pearson omnibus normality test. For comparisons in which all groups were normally distributed, group-wise comparisons were made by one-way ANOVA with the Neuman-Keuls post-hoc test used for pair-wise comparisons of groups for which the overall group demonstrated a statistically significant difference. For comparisons for which one or more groups were not normally distributed, the Kruskal-Wallis test was used with Dunn’s test for post-hoc comparison of pairs. Because most distributions were non-normal, all descriptive statistical data are provided as medians and inter-quartile ranges (IQR), with graphical presentations showing medians, IQR, and range in box-and-whisker plots.

Categorical data were analyzed as contingency tables with statistical significance assessed by the chi-square test for 2x3 tables and by Fisher’s exact test for 2x2 cross-tabulations. We used the odds ratio (OR) as the clinical likelihood measure derived from the 2x2 analyses.

For this study, {alpha} was set at 0.05 and p values were two-tailed (or two-sided in the case of categorical data). Thus, p <0.05 was considered a statistically significant comparison. All statistical analyses were performed using Prism software (GraphPad Corp., San Diego, CA) running on a Windows XP (Microsoft Corp., Seattle WA) platform.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Distribution of asthma patients by acid-base status.  As noted in Fig. 1Go, 109 of 322 (33.9 %) adult admissions during the 1-yr study period were cases of asthma exacerbations uncomplicated by major co-morbidities. Of the 109 subjects, a majority, 66 patients (60.6%), did not develop metabolic acidosis, 11 (10.1%) developed AG acidosis, and 32 (29.4%) developed NAG acidosis.

Demographic, clinical, and therapeutic characteristics of the groups are presented in Table 1Go. The only significant difference observed among the groups for any of these measures was a difference in the age of the subjects with NAG acidosis compared to the patients with no acidosis. The median age of the NAG acidosis group was the lowest among all groups; 13.5 yr lower than subjects with no acidosis and 7 yr lower than the AG acidosis group.


View this table:
[in this window]
[in a new window]

  		Table 1. Baseline characteristics of subjects studied. Interval data are medians (IQR); confidence intervals (CI) are 95% CI. Dichotomous categorical data are given as users/non-users (% users of total) except for hyperinflation, given analogously as present/absent (% of total).
 
Acid-base and electrolyte measurements.  The results of parameters from ABG analysis are shown in Fig. 2Go. In terms of arterial O2 content, small but significant differences were observed in PaO2 and O2 saturation between the no acidosis and NAG acidosis groups. It should be noted that nearly all patients were receiving O2 supplemental therapy, as indicated; several on 100% O2 as demonstrated by the PaO2 range.


Figure 2
View larger version (30K):
[in this window]
[in a new window]

  		Fig. 2. Parameters measured and derived from arterial blood gas analysis. Box-and-whisker plots show medians, IQR, and range for each group and parameter. The p values are for overall comparison of the 3 groups for each parameter; pair-wise comparisons given beneath the p value give the level of statistical significance for those pairs which achieved statistically significant differences (* p <0.05, ** <0.01, and *** <0.001) by post-hoc tests.

 
Significant differences were observed in pH between the no acidosis and the NAG acidosis groups. Despite the fact that the medians for both groups with metabolic acidosis were comparable, the dispersion among the 11 subjects with AG acidosis precluded the demonstration of a statistically significant difference in pH between the AG acidosis and NAG acidosis groups. This comparability in pH and arterial HCO3– is reflected, as expected, in the PaCO2 data. The anion gap was significantly elevated among the AG acidosis patients, compared to the patients in both other groups.

Venous values for serum electrolytes are shown in Fig. 3Go. No difference was observed for the concentrations of the cations; however the subjects who did not have metabolic acidosis had significantly higher serum HCO3– compared to those in both of the other groups as noted with arterial HCO3–. The NAG acidosis group demonstrated significantly higher Cl– concentration, tending toward hyperchloremia. In fact when compared to the other groups (no acidosis and AG acidosis, combined), a significantly greater proportion of patients in the NAG acidosis group were hyperchloremic (6.1% in the no acidosis + AG acidosis groups vs 35.5% in the NAG acidosis group; p = 0.0004; OR = 8.53, 95% CI: 2.44 – 29.78).


Figure 3
View larger version (28K):
[in this window]
[in a new window]

  		Fig. 3. Electrolyte measurements in the three groups. Data are provided in the same manner as in Fig. 2Go.

 
Clinical outcomes.  With regard to mortality, only one patient died, that subject being from the NAG acidosis group.

Table 2Go provides an analysis of the requirement for intubation and MICU admission among the subjects in the study groups. It should be noted that subjects requiring intubation were the only ones who were admitted to the MICU. Thus, although we had originally considered these as two separate outcomes, they were combined for analysis. A statistically significant difference was detected when all 3 groups were compared for this outcome; approximately 3 times as many subjects with NAG acidosis required intubation during the course of their admission (Table 2AGo). The OR for requirement of intubation compared to no intubation being required suggests a nearly 4-fold likelihood of this negative outcome (Table 2BGo). It should be noted that one comparison, NAG vs AG acidosis, did not achieve statistical significance; however, the paucity of subjects in the AG acidosis group probably precluded our being able to detect that comparison achieving significance.


View this table:
[in this window]
[in a new window]

  		Table 2. Requirement for intubation and consequent MICU admission for the subjects in each group.
 
In Table 3Go the LOS for patients in the study groups is given. No significant difference was detected among the 3 groups.


View this table:
[in this window]
[in a new window]

  		Table 3. Length of stay (LOS) in hospital for subjects in the study.
 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Bronchial asthma is one of the most common chronic diseases in the United States, affecting more than 22 million persons [9]. The characteristic blood gas pattern is hypoxemia with respiratory alkalosis [1–5,7,10]. Several clinical and laboratory measurements are suggestive of severe acute asthma and should alert the clinician to recognize patients in danger of developing respiratory failure and the need for mechanical ventilation. Among these, NAG acidosis has received scant attention.

Metabolic acidosis in patients with severe asthma was first described in 1976 by Roncoroni et al [5]. Curiously, Mc Fadden and Lyons [1], in a study of 101 asthma patients, found no evidence of acidosis. However, many other studies have suggested that metabolic acidosis is relatively common, with a prevalence ranging from 16 to 40 % [2–6,10].

In a study by Okrent et al [11], 10 of 22 patients (45%) had NAG acidosis and none had AG acidosis. However, that study was not designed to investigate NAG acidosis as a prognostic factor, since all of their patients were discharged from the emergency department and, thus, were unselected for severity.

From a mechanistic standpoint, NAG acidosis is the result of excessive renal bicarbonate excretion as a compensatory mechanism for respiratory alkalosis [7,11,12]. In a rat model, respiratory alkalosis inhibits bicarbonate reabsorption in the proximal tubule and decreases acid secretion in the distal tubule by inhibiting the renal proton pump, resulting in lowering the plasma bicarbonate concentration. These findings usually occur within 6 hr [13]. The observation that, among our cohort admitted for uncomplicated, acute exacerbation of asthma, NAG acidosis was observed in nearly one-third of patients is of considerable interest.

A study by Appel et al [3] found an association between lactic acidosis and respiratory failure requiring mechanical support, however, another study by Rabbat et al [7] suggested that lactic acidosis has no prognostic value in acute asthma. The pathophysiology of hyperlactatemia is multi-factorial and includes the synergistic effect of lactic acid production by hypoperfused respiratory muscles and inadequate O2 delivery with typical subsequent metabolic events [2,3,5,6,9,11]. Lactic acidosis has been reported as a complication of high doses of β2 agonist therapy for tocolysis in premature labor [14,15] and asthmatic patients [6,16,17]. The proposed mechanisms are complex [18]. Lactic acidosis is also observed in patients with adult respiratory distress syndrome [19].

The clinical outcomes we observed suggest that asthmatics who develop NAG acidosis represent a group of patients at high risk for impending respiratory failure and the necessity of mechanical ventilation and MICU admission. We were not able to detect an increased LOS for the subjects in the NAG acidosis group; in fact, the no acidosis group had the greatest LOS, based on medians and IQR values. This finding, however, is likely due to the fact that caregivers of these subjects, recognizing that their patients had generally fewer ventilation-requiring admissions and being somewhat older, seized the opportunity of their admission to perform other, medically-indicated, diagnostic or therapeutic procedures. Nevertheless, it should be recognized that a limitation of this study is that it was not powered to detect differences in mortality or length of stay.

Our data suggest that surveillance for NAG acidosis should be considered when evaluating subjects presenting with severe acute asthma. Thorough analysis of acid-base and electrolyte status is certainly warranted when a physician is confronted with a patient with an acute exacerbation of bronchial asthma. We observed a significantly greater prevalence of hyperchloremia in our NAG acidosis group, suggesting that the presence of an elevated serum chloride concentration could help to identify high-risk asthmatics. Moreover, serum lactate measurements could be useful as it has been suggested [20] that the anion gap is, essentially, a surrogate for lactate. Unfortunately, measurements of serum lactate were not available to us. This may be considered a limitation of our study and we suggest that in any future prospective study, lactate assays be included in the protocol.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. McFadden ER, Lyons HA. Arterial blood gas tension in asthma. NEJM 1968;278:1027–1032.[Medline]
  2. Mountain RD, Heffner JE, Brackett NC, Sahn SA. Acid-base disturbances in acute asthma. Chest 1990;98: 651–655.[Medline]
  3. Appel D, Rubenstein R, Schrager K, Williams MH Jr. Lactic acidosis in severe asthma. Am J Med 1983;75: 580–584.[Medline]
  4. Alberts WM, Williams JH, Ramsdell JW. Metabolic acidosis as a presenting feature in acute asthma. Ann Allergy 1986;57:107–109.[Medline]
  5. Roncoroni AJ, Adrogue HJA, De Obrutsky CW, Marcisio ML, Herrera MR . Metabolic acidosis in status asthmaticus. Respiration 1976;33:85–87.[Medline]
  6. Rodrigo GJ, Rodrigo C. Elevated plasma lactate level associated with high dose inhaled albuterol therapy in acute severe asthma. Emerg Med J 2005;22:404–408.[Abstract/Free Full Text]
  7. Rabbat A, Laaban JP, Boussairi A, Rochemaure J. Hyperlactatemia during acute severe asthma. Intensive Care Med 1998;24:304–312.[Medline]
  8. Prakash S, Metha S. Lactic acidosis in asthma: report of two cases and review of literature. Can Respir J 2002;9: 203–208.[Medline]
  9. National Heart, Lung and Blood Institute, National Institutes of Health. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. 2007 http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln/htm.
  10. Manthous CA. Lactic acidosis in status asthmaticus. Three cases and review of the literature. Chest 2001;119: 1599–1602.[Medline]
  11. Okrent DG, Tessler S, Twesky RA, Tashkin DP. Metabolic acidosis not due to lactic acidosis in patients with severe acute asthma. Crit Care Med 1987;15:1098–2002.[Medline]
  12. Gennari FJ, Goldstein MB, Schwartz WB. The nature of the renal adaptation to chronic hypocapnia. J Clin Invest. 1972;51:1722–1730.[Medline]
  13. Eiamong S, Laski ME, Kurtzman NA, Sabatini S. Effect of respiratory acidosis and respiratory alkalosis on renal transport enzymes. Am J Physiol 1994;267:F390–399.[Medline]
  14. Cotton DB, Strassner HT, Lipson LG, et al. The effects of terbutaline on acid base, serum electrolytes, and glucose homeostasis during the management of preterm labor. J Obstet Gynecol 1981;141:617–624.
  15. Richards SR, Chang EE, Stempel LE. Hyperlactacidemia associated with acute ritodrine infusion. Am J Obstet Gynecol 1983;146:1–5.[Medline]
  16. Stratakos G, Kalomenidis J, Routsi C, Papiris S, Roussos C. Transient lactic acidosis as a side effect of inhaled salbutamol. Chest 2002;122:385–386.[Medline]
  17. St. Jean O, Rohan Chabot P, Thaler F, et al. Hyper-lactatemia during treatment of acute bronchospasm with salbutamol. Presse Med 1987;16:965–966.[Medline]
  18. Haffner CA, Kendall MJ (1992) Metabolic effects of β2-agonists. J Clin Pharm Ther 1992;17:155–164.[Medline]
  19. De Backer D, Creteur J, Zhang H, Norrenberg M, Vincent JL. Lactate production by the lungs in acute lung injury. Am J Respir Crit Care Med 1997;156:1099–1104.[Abstract/Free Full Text]
  20. Rocktaeschel J, Morimatsu H, Uchino S, Bellomo R. Unmeasured anions in critically ill patients: can they predict mortality? Crit Care Med 2003;31:2244–2245.[Medline]




This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Rashid, A. O.
Right arrow Articles by Khan, M. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Rashid, A. O.
Right arrow Articles by Khan, M. A.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS