Lactic Acidosis and Beta Agonist Therapy in Asthma

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.

Clinical Question

Is the rise in his lactate expected following beta-agonist therapy?

The Evidence

A simple respiratory alkalosis is the most common acid-base disorder in acute asthma.[1] 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:[7]

• 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 [8]
  
  • 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 [9]
  
  • 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]

Take-Home Points

• 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.

References

1. Mountain RD, Heffner JE, Brackett NC, Jr, Sahn SA. Acid-base disturbances in acute asthma. Chest. Sep 1990;98(3):651-655. PMID 2118447
2. Roncoroni AJ, Adrougue HJ, De Obrutsky CW, Marchisio ML, Herrera MR. Metabolic acidosis in status asthmaticus. Respiration. 1976;33(2):85-94. PMID 778959
3. 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
4. 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
5. Luft FC. Lactic acidosis update for critical care clinicians. J Am Soc Nephrol. Feb 2001;12 Suppl 17:S15-19. PMID 11251027
6. 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
7. Haffner CA, Kendall MJ. Metabolic effects of beta 2-agonists. J Clin Pharm Ther. Jun 1992;17(3):155-164. PMID 1353501
8. 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
9. Rabbat A, Laaban JP, Boussairi A, Rochemaure J. Hyperlactatemia during acute severe asthma. Intensive Care Med. Apr 1998;24(4):304-312. PMID 9609407
10. 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
11. 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
12. Maury E, Ioos V, Lepecq B, Guidet B, Offenstadt G. A paradoxical effect of bronchodilators. Chest. Jun 1997;111(6):1766-1767. PMID 9187208
13. Dodda VR, Spiro P. Can albuterol be blamed for lactic acidosis? Respir Care. Dec 2012;57(12):2115-2118. PMID 22613097
14. 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.

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