A 45 y/o male with moderate persistent asthma presents with wheezing and cough following a viral URI. He is tachypneic and has diffuse wheezing. PEFR is 250 (>50% below his normal). Initial ABG is 7.46/33/70 on room air with a lactate of 2.0 mmol/L. He receives IV steroids and 4 rounds of albuterol nebulizers. On repeat evaluation, his work of breathing and wheezing have improved and his PEFR is now >300. He is completed alert and oriented with a BP of 118/70 and a HR of 110. Repeat ABG shows 7.35/35/100 on room air; however, his lactate is now 7 mmol/L.
QUESTION: Is the rise in his lactate expected following beta-agonist therapy?
A simple respiratory alkalosis is the most common acid-base disorder in acute asthma. However, lactic acidosis is frequently identified especially in cases of severe asthma.[2-4] Possible causes of lactic acidosis in asthma include:
- Tissue hypoxia due to hypoxemia and the decrease in venous return caused by elevated intrinsic PEEP
- Relative hepatic ischemia and impaired lactate clearance due to venous congestion
- Increased respiratory muscle work against constricted upper airways
- Beta-agonist therapy
Wait, β-agonist therapy can cause an elevated lactate? How?
Causes of lactic acidosis can be organized into two categories: [5-6]
- Type A: Secondary to tissue hypoxia (shock, cardiac arrest)
- Type B: Lactic acidosis without hypoxia. This can occur through several mechanisms including:
- Impaired pyruvate dehydrogenase activity (thiamine deficiency)
- Increased production by neoplastic cells
- Medication-induced mitochondrial dysfunction (antiretroviral therapy, linezolid, propofol, etc)
- Impaired conversion of lactate to glucose (hepatic dysfunction)
Lactic acidosis caused by β-agonist therapy is a type B lactic acidosis. The exact mechanism for the rise in lactate levels seen with beta-agonist therapy is unclear, but stimulation of beta-receptors causes a variety of metabolic effects which may increase lactate production including:
- Increased glycogenolysis and glycolysis
- Increased lipolysis leading to a rise in fatty acids levels which can inhibit conversion of pyruvate to acetyl-CoA
What is the literature supporting the existence if beta-agonist-induced lactic acidosis?
Two small prospective studies have addressed this issue:
- Rodrigo et al. Emerg Med J 2005 
- Enrolled 18 patients with acute severe asthma treated with albuterol 0.4 mg via inhaler every 10 minutes for 2 hours.
- Lactate levels were drawn at baseline and following treatment.
- At baseline, all patients had a lactate level <2.2 mmol/L.
- Following treatment, the mean plasma lactate 2.9 mmol/L (significantly higher than baseline) and 4 patients had a lactate of ≥4 mmol/L.
- Rabbat et al. Int Care Med 1998 
- Enrolled 29 patients admitted to an ICU with acute severe asthma.
- All patients received protocolized asthma care including frequent salbutamol 10 mg nebulizers and IV salbutamol 1 mg/hr.
- On admission to the ICU, the mean arterial lactate was 3.11 mmol/L (range 1.1-10.4)
- Six hours following admission, arterial lactate levels increased in all patients to a mean of 7.4 mmol/L (2.6-16). The average lactate rise was 4.6 mmol/L.
- An elevated lactate was not found to have any prognostic significance.
Multiple case reports have described a rise in lactate following either inhaled or IV beta-agonist therapy for acute asthma.[10-12] Importantly, several case reports have described beta-agonist therapy paradoxically worsening an asthmatic’s clinical course as they struggle to compensate for the rising lactic acidosis.[12-14]
- Inhaled and IV beta-agonists can contribute to lactic acidosis.
- How much a clinician should expect lactate to rise with frequent beta-agonist therapy is unclear, but studies have reported lactate levels >10 mmol/L.[10-12]
- Asthmatics noted to have an elevated lactate level following beta-agonist therapy should have a thorough assessment for evidence of true tissue hypoperfusion before lactic acidosis is attributed entirely to beta-agonist therapy.
- While the use of continuous nebulized beta-agonist therapy is supported by NIH’s EPR-3, patients requiring continuous nebulizers for more than a few hours should have a lactate checked. If a high lactate is found, clinicians should consider whether the rising lactate may be contributing to their patient’s respiratory distress and consider transitioning the patient to less frequent nebulized therapy.
- Mountain RD, Heffner JE, Brackett NC, Jr, Sahn SA. Acid-base disturbances in acute asthma. Chest. Sep 1990;98(3):651-655. PMID 2118447
- Roncoroni AJ, Adrougue HJ, De Obrutsky CW, Marchisio ML, Herrera MR. Metabolic acidosis in status asthmaticus. Respiration. 1976;33(2):85-94. PMID 778959
- Appel D, Rubenstein R, Schrager K, Williams MH, Jr. Lactic acidosis in severe asthma. Am J Med. Oct 1983;75(4):580-584. PMID 6414303
- Raimondi GA, Gonzalez S, Zaltsman J, Menga G, Adrogue HJ. Acid-base patterns in acute severe asthma. J Asthma. Dec 2013;50(10):1062-1068. PMID 23947392
- Luft FC. Lactic acidosis update for critical care clinicians. J Am Soc Nephrol. Feb 2001;12 Suppl 17:S15-19. PMID 11251027
- Andersen LW, Mackenhauer J, Roberts JC, Berg KM, Cocchi MN, Donnino MW. Etiology and therapeutic approach to elevated lactate levels. Mayo Clin Proc. Oct 2013;88(10):1127-1140. PMID 24079682
- Haffner CA, Kendall MJ. Metabolic effects of beta 2-agonists. J Clin Pharm Ther. Jun 1992;17(3):155-164. PMID 1353501
- Rodrigo GJ, Rodrigo C. Elevated plasma lactate level associated with high dose inhaled albuterol therapy in acute severe asthma. Emerg Med J. Jun 2005;22(6):404-408. PMID 15911945
- Rabbat A, Laaban JP, Boussairi A, Rochemaure J. Hyperlactatemia during acute severe asthma. Intensive Care Med. Apr 1998;24(4):304-312. PMID 9609407
- Claret PG, Bobbia X, Boutin C, Rougier M, de la Coussaye JE. Lactic acidosis as a complication of beta-adrenergic aerosols. Am J Emerg Med. Sep 2012;30(7):1319 e1315-1316. PMID 21802882
- Creagh-Brown BC, Ball J. An under-recognized complication of treatment of acute severe asthma. Am J Emerg Med. May 2008;26(4):514 e511-513. PMID 18410827
- Maury E, Ioos V, Lepecq B, Guidet B, Offenstadt G. A paradoxical effect of bronchodilators. Chest. Jun 1997;111(6):1766-1767. PMID 9187208
- Dodda VR, Spiro P. Can albuterol be blamed for lactic acidosis? Respir Care. Dec 2012;57(12):2115-2118. PMID 22613097
- Prakash S, Mehta S. Lactic acidosis in asthma: report of two cases and review of the literature. Can Respir J. May-Jun 2002;9(3):203-208. PMID 12068341
Additional Reading (added 1/13/14):
Lewis LM, Ferguson I, House SL, et al.Albuterol Administration Is Commonly Associated With Increases In Serum Lactate In Asthmatics Treated for Acute Exacerbation of Asthma. Chest. 2013 Aug 15. doi: 10.1378/chest.13-0930. [Epub ahead of print] PubMed PMID: 23949578.