m e d i c a l j o u r n a l a r m e d f o r c e s i n d i a 6 8 ( 2 0 1 2 ) 2 4 2 e2 4 4

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Case report

Metabolic acidosis due to inhaled salbutamol toxicity: A

hazardous side effect complicating management of suspected
cases of acute severe asthma

Lt Col R.P.S. Tomar a,*, Col R. Vasudevan b

a
Classified Specialist, Dept of Paediatrics & Neonatology, MH Jalandhar Cant, Punjab 144005, India
b
Senior Advisor, Dept of Paediatrics & Neonatology, MH Jalandhar Cant, Punjab 144005, India

article info abstract

Article history: Metabolic acidosis has seldom been reported during treatment of asthma with use of beta
Received 22 May 2011 agonist but not with much clinical consequence. We report two cases of metabolic acidosis
Received in revised form with hyperventilation as a direct effect of salbutamol that caused difficulty in assessment
14 September 2011 and management of their respiratory symptoms which resolved with appropriate tapering
Accepted 8 October 2011 of beta agonist.
Available online 10 May 2012 ª 2012, Armed Forces Medical Services (AFMS). All rights reserved.

Keywords:
Salbutamol toxicity
Metabolic acidosis
Acute asthma

Introduction asthma may be related to use of inhaled salbutamol. We

report two cases of metabolic acidosis with hyperventilation
Selective beta-2 agonists (salbutamol) have been the mainstay as a direct effect of salbutamol that caused difficulty in
of acute asthma management since the late 1970s. Their early assessment and management of their respiratory symptoms.
and aggressive use has decreased the number of children No common etiologies were found for this acidosis which
admitted to critical care units.1 Most adverse effects of b- resolved with appropriate tapering of beta agonist. We review
agonists in asthma are of cardiovascular nature such as the literature and discuss the mechanism by which lactic
tachycardia, increased QTc interval, dysrhythmia, hyperten- acidosis may occur in such patients.
sion or hypotension.2 Other adverse effects of b-agonists
include hypokalemia, tremor and worsening of ventilation/
perfusion mismatch.1 Metabolic acidosis has seldom been Case 1
reported with severe exacerbation of asthma and has been
hypothesized to result from lactic acidosis due inadequate A 20-month-old male child was admitted with complaints of
oxygen delivery to the exerting respiratory muscles.3 But the mild fever associated with cough for 3 days and progressive
development of this metabolic acidosis seen in children with breathlessness for 1 day. Before admission he was treated

* Corresponding author. Tel.: þ5533 (o), þ9876671871 (mobile).

E-mail address: [email protected] (R.P.S. Tomar).
0377-1237/$ e see front matter ª 2012, Armed Forces Medical Services (AFMS). All rights reserved.
doi:10.1016/j.mjafi.2011.10.002
 m e d i c a l j o u r n a l a r m e d f o r c e s i n d i a 6 8 ( 2 0 1 2 ) 2 4 2 e2 4 4 243

with oral amoxicillin and syrup salbutamol and later inter- theophylline were continued. During the next 8 h her condi-
mittent salbutamol nebulization, which was progressively tion gradually improved with decrease in dyspnoea, normal-
increased as his condition continued to deteriorate, when he ization of blood gases and blood glucose declining to 148 mg/
was referred for admission. There was no history of previous dl. All her medications were gradually stopped subsequently
wheezing, cyanosis, cough/choking spells suggestive of and she was discharged on the sixth day.
foreign body aspiration or family history of atopy or asthma.
On admission the child was drowsy but arousable to touch,
afebrile with respiratory rate 38 breaths/min, HR-166 beats/ Discussion
min, blood pressure 104/68 mm Hg, CFT<3 s, SpO2: 96% on 6 l/
min of oxygen. Respiratory examination revealed mild Salbutamol, a beta agonist is associated with side effects.1,2
suprasternal & subcostal recessions with inspiratory wheeze. One of the least recognized side effects of salbutamol treat-
Auscultation revealed bilateral ronchi. Other systems were ment is metabolic acidosis due to development of lactic
normal. He received three doses of salbutamol nebulization acidosis.3,4 It had been previously reported with intravenous
combined with ipratropium bromide followed with frequent beta agonist therapy used to prevent preterm labour5 or sal-
salbutamol nebulization, inj hydrocortisone along with butamol overdose.6 Till now there were isolated case reports
injectable cefalosporins. Laboratory investigations revealed in children describing beta agonist induced lactic acidosis,7
pH 7.28, PCO2 33 Torr, PO2 92 Torr, HCO3 15 mmol/L, anion gap but in a significant study, metabolic acidosis with hyperven-
19 mmol/L, blood sugar of 218 mg/dl, no glycosuria or keto- tilation was seen in 28% of the 53 children treated with beta
nuria with normal counts and a negative CRP. Chest radio- agonist for acute asthma.8 This was also reported by Dr
graph was normal. Blood lactate could not be done. During Ramnarayan et al from the UK Children’s Acute Transport
next 2 h, he continued to be tachypenic with blood gas Service.9
showing persistent acidosis despite clinical improvement. In In general, metabolic acidosis due lactic acidosis is
view of no prior history of wheezing and no other apparent commonly associated with increased production with
cause for persistent metabolic acidosis including hypoxia, decreased tissue perfusion either due to hypoperfusion,
hypovolemia or sepsis, a possibility of beta agonist toxicity hypoxia or sepsis. It could also be undermetabolized by
was considered and salbutamol nebulization was stopped a hypoxic liver. Increased production of lactic acidosis in
following which he showed rapid improvement with tachyp- respiratory distress such as in asthma has been proposed to
nea disappearing within next 6 h, blood glucose declined to result from overuse of respiratory muscles under hypoxic
138 mg/dl and blood gas normalized in next 24 h. He was conditions.3 However, increased lactic acidosis has been
subsequently discharged in a stable condition. found to occur even in those patients whose work of breathing
is minimized by mechanical ventilation and pharmacological
paralysis.4 Other proposed causes of lactic acidosis are
Case 2 reduced cardiac output due to elevated intrathoracic pres-
sures or hypovolemia. Hypovolemia may be significant in
An 8-year-old female child was admitted with complaints of children with respiratory distress due to decreased intake,
progressive cough, chest discomfort and shortness of breath increased insensible losses and hyperglycemia due to beta
for past 1 week. She was diagnosed as asthma 2 months back agonist and glucocorticoids.7 This hyperglycemia may cause
for persistent cough and had been taking salmeterol/flutico- glucosuria, osmotic diuresis, decreased tissue perfusion and
sone by inhalation twice a day and salbutamol by inhalation increased potential for lactic acidosis. Regardless of the
once a day. 2 Days before presentation she had taken several etiology of lactic acidosis, beta agonist therapy may exacer-
back to back doses of salbutamol nebulization without relief. bate its magnitude. Both of these children had no evidence of
Her examination revealed temperature of 37  C, respiratory renal or hepatic dysfunction. Neither there was any evidence
rate 42 breaths/min, heart rate of 152/min, blood pressure 114/ of hypoperfusion or hypotension as their urine output was
72 mm of Hg, capillary refill time <3 s, SpO2 of 92% on room air normal with normal mean pressures nor did they have any
with difficulty in speaking and wheezing associated with mild evidence of end organ dysfunction typical of shock.
chest retractions. She was treated with three doses of salbu- The mechanisms by which beta agonists produce lactic
tamol combined with ipratropim bromide, hydrocortisone acidosis remain uncertain. It has been hypothesized that beta
along with injectable amoxicillin/cluvanic acid. She continued adrenergic receptor stimulation causes enhanced cyclic
to have tachypnoea with respiratory rate-51 breaths/min. Her adenosine monophosphate (cAMP) mediated gluconeogenesis
blood showed pH of 7.23, PCO2 28 Torr, PO2 84 Torr, HCO3 and lipolysis. This increased plasma glucose concentration is
12 mmol/L, anion gap of 18 mmol/L with blood glucose of converted to pyruvate via glycolysis which is then converted
223 mg/dl. Blood lactate was 12.9 mmol/L. Her chest radio- to lactate. Skeletal muscle glycogenolysis is a major source of
graph was normal. With an impression of clinical deteriora- this lactate production since they lack glucose-6-phosphatase.
tion and impending respiratory failure she was give Therefore glucose-6-phosphate is converted to pyruvate via
subcutaneous injection of terbutaline, magnesium sulfate glycolysis (Fig. 1). Simultaneously the free fatty acids released
intravenously and theophylline infusion. As all common by lipolysis inhibit the oxidation of pyruvate to acetyl-
causes of metabolic acidosis in her case were excluded, this coenzyme A, thereby providing increased substrate for
lactic acidosis was suspected to be secondary to increased lactate formation.8,10 Finally, a number of other agents used to
nebulized salbutamol which was consequently reduced to treat asthma, such as glucocorticoids and theophylline, may
intermittent inhalation (6 h) while ipratropium and potentiate the metabolic effects of beta adrenergic agonists by
244 m e d i c a l j o u r n a l a r m e d f o r c e s i n d i a 6 8 ( 2 0 1 2 ) 2 4 2 e2 4 4

sufficiently to reduce beta 2 agonist therapy). It should alert

the physician for an urgent need for change in therapy so as to
resolve the symptoms. Ketonuria may act as an early marker
of salbutamol toxicity.9 The physician who decides to escalate
therapy based only on the amount of wheezing may make his
patient worse. Caution must always be taken in drawing
conclusions in relationship with persistent or worsening of
respiratory distress due metabolic acidosis and hyperventi-
lation in children treated with beta agonist since adverse
effects do not differ from the symptoms caused by asthma
itself. It is important to undertake the tapering strategy in
a secure intensive environment with the use of ABG analysis,
while looking at the alveolo-arterial oxygen gradient, to find
the right direction of management. In the first case we could
immediately stop the salbutamol while the second case was
sicker and hence we continued ipratropium as a reliever
therapy for any anticipated deterioration.

Fig. 1 e Biochemical pathways by which beta 2-agonist

Conflicts of interest
lead to increased lactate production.
None identified.

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