(Chest. 2001;119:1599-1602.)
© 2001
American College of Chest Physicians
Lactic Acidosis in Status Asthmaticus*
Three Cases and Review of the Literature
Constantine A. Manthous, MD, FCCP
*
From the Pulmonary and Critical Care Division, Bridgeport Hospital and Yale University School of Medicine, Bridgeport, CT.
Correspondence to: Constantine A. Manthous, MD, FCCP, Bridgeport Hospital, 267 Grant St, PO Box 5000, Bridgeport, CT 06610
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Abstract
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Lactic
acidosis is a frequent laboratory finding in patients with severe
exacerbations of asthma. The pathogenesis of lactic acidosis in asthma
is not well understood, but it has been presumed, by some, to be
generated by fatiguing respiratory muscles. We herein report the cases
of three patients with status asthmaticus and lactic acidosis despite
pharmacologic muscle relaxation. No common etiologies were found for
lactic acidosis that abated after bronchospasm improved and the
intensity of pharmacologic therapies was reduced. We review the
literature describing lactic acidosis with asthma and discuss
mechanisms by which lactic acidosis may occur in patients with status
asthmaticus.
Key Words: albuterol • asthma • bronchodilators • lactate • lactic acid • lactic acidosis • status asthmaticus • sympathomimetic
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Introduction
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Lactic acidosis is a well-described phenomenon in
patients with severe asthma1
2
3
4
5
6
7
8
and has been hypothesized,
by some, to result from inadequate oxygen delivery to the respiratory
muscles to meet an elevated oxygen demand.1
We report the
cases of three patients with status asthmaticus (SA) in whom
respiratory muscle activity could not have accounted for lactic
acidosis. We then delineate possible mechanisms underlying the
pathogenesis of lactic acidosis in SA.
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Case Reports
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Case 1
A 27-year-old white woman with a history of steroid-dependent
asthma, with no previous intubations, presented with an acute
exacerbation of asthma. After being found by emergency technicians in
extreme respiratory distress at her private physician’s office, she
was emergently intubated for respiratory arrest. She received two doses
of subcutaneous epinephrine and 100 mg of IV cortisol before transport.
After transport to the emergency department, her BP was 164/84 mm Hg,
heart rate was 100 to 110 beats/min, respiratory rate was 30
breaths/min (with a set ventilatory rate of 12/min), and temperature
was 36.1°C. Physical examination of the lungs revealed bilateral
diffuse rhonchi and wheezing. Chest radiography demonstrated
hyperinflation with mild pneumomediastinum and pneumopericardium. On
assist-control mode, with a set respiratory rate of 12/min, an actual
rate of 30 breaths/min, tidal volume (VT) of 500 mL, a
fraction of inspired oxygen of 40%, and no positive end-expiratory
pressure (PEEP), her arterial blood gas levels were pH, 7.20;
PCO2, 43 mm Hg; and
PO2, 200 mm Hg. She received IV
methylprednisolone, 125 mg q6h; IV magnesium sulfate, 4 g; and
continuously nebulized albuterol. She did not receive parenteral
ß-agonists in the hospital. She was sedated with midazolam, 1 to 3 mg
every 1 to 3 h as needed, and received a muscle relaxant
(pancuronium) (with no triggered breaths and a "train of 4" of two
twitches) to prevent excessive tachypnea and associated dynamic
hyperinflation. With this regimen, her arterial blood gas levels
improved to pH, 7.23; PaCO2, 35 mm
Hg; and PaO2, 192 mm Hg on 40%
inspired oxygen. Peak airway pressure was 71 cm
H2O, static pressure was 21 cm
H2O, and intrinsic PEEP was 7 to 8 cm
H2O. She became increasingly tachycardic, with a
heart rate of 120 to 130 beats/min, and did not respond to 5 mg of
lorazepam or 500 mL of normal saline solution infusion (her
theophylline level was 2.1 µg/mL, and she had not received
theophylline in the hospital). Culture results of urine, blood, and
sputum were negative, and she did not demonstrate other signs of
sepsis. Her oxygen saturation remained 
90% throughout her ICU
stay, and she never exhibited signs of shock. Her anion gap metabolic
acidosis was found to be secondary to lactic acid (Table 1
), which persisted until the second hospital day, when continuous
ß-agonist aerosols were reduced to four puffs of albuterol via
metered-dose inhaler with holding chamber q4h after airway pressures
had further decreased. By this time, she had received in excess of 100
mg (cumulatively) of aerosolized albuterol > 24 h. Her tachycardia
and lactic acidosis promptly improved, and she was extubated
successfully on her third hospital day without complications.
Case 2
A 36-year-old Hispanic woman with a history of heroin and
tobacco abuse and severe asthma requiring hospitalizations on several
previous occasions presented with 3 days of upper-respiratory-tract
infection and increasing shortness of breath. On physical examination,
she had severe wheezing and peak flows < 200 L/min. After treatment
with eight nebulized treatments of albuterol, 2.5 mg, and IV
methylprednisolone, 125 mg, she continued to worsen. A trial of heliox
also failed to alleviate her severe dyspnea, and she was electively
intubated for increasing respiratory extremis (respiratory rate > 40
breaths/min; pulsus paradoxus, 25 mm Hg). After intubation, with
initial VT of 500 mL delivered with 60 L/min constant
inspiratory flow, peak inspiratory pressure was 52 cm
H2O with a static airway pressure of 25 cm
H2O and intrinsic PEEP of 4 cm
H2O. Tachypnea while receiving mechanical
ventilation led to administration of benzodiazepines, and,
subsequently, vecuronium was also added to control her ventilation and
avoid barotrauma. She was sedated with midazolam, 1 to 3 mg every 1 to
3 h as needed, and received a muscle relaxant (pancuronium) (with
no triggered breaths and a "train of 4" of two twitches). A
strategy of permissive hypercapnia was required to maintain static
airway pressures < 35 cm H2O; a consequent pH
of 7.10 and PCO2 of 59 mm Hg prompted
institution of IV bicarbonate therapy. She remained hemodynamically
stable throughout. A lactic acid level drawn 8 h after intubation
was 5.0 mmol/L. On her second hospital day, airway pressures remained
elevated despite muscle relaxation and nebulized albuterol at 2.5 mg/h;
lactic acid remained elevated at 3.1 mmol/L (Table 2
). After doses of vecuronium, lorazepam, and morphine sulfate, she
experienced an acute increase in airway pressures (peak > 90 cm
H2O; static, 33 cm H2O on
60 L/min constant flow). A chest radiograph did not reveal
pneumothorax. Shortly thereafter, her systolic BP dropped from the 120
to 130 mm Hg range to 50 mm Hg. IV fluids were administered acutely at
maximal rates but failed to retrieve her BP. Caregivers entertained a
diagnosis of acute hypotension secondary to dynamic hyperinflation. One
milligram of IV epinephrine was administered, leading to an abrupt
increase in her BP and a gradual decrease in her airway pressures. Five
hours later, while she continued to receive hourly aerosolized
ß-agonists, airway pressures had decreased to peak of 44 cm
H2O and static of 26 cm H2O
on continuous inspiratory flows of 60 L/min. A lactic acid drawn 6
h later was 0.6 mmol/L and remained normal for the remainder of her
stay. Airway pressures remained in a similar range for the next 36
h, and permissive hypercapnia was reversed. She was awakened and
successfully extubated without difficulty.
Case 3
A 28-year-old black woman with a history of severe asthma, who
was most recently intubated 2 months before admission, presented with a
2-day history of increasing shortness of breath and nonproductive
cough. Her symptoms failed to improve after self-administration of
three "back-to-back" treatments of albuterol. She was brought to
the hospital by ambulance, where personnel administered 125 mg of IV
methylprednisolone, two more albuterol nebulizers, and one dose of
1:1,000 subcutaneous epinephrine. In the emergency department, she was
very short of breath and was intubated because of extremis; arterial
blood gas values were: pH, 7.10; PCO2, 86 mm
Hg. She was sedated and received a muscle relaxant (vecuronium); on
initial ventilator settings of 14/min, 400-mL VT, and 100%
oxygen, her pH increased to 7.17 and
PCO2 was 63 mm Hg. Airway pressures
were very high (peaks > 70 cm H2O), airway
resistance was 65 cm H2O/L/s, and plateau airway
pressure was 27 cm H2O with an auto-PEEP of 6 cm
H2O. Treatment with propofol was started at 0.005
mg/kg/min for sedation, and vecuronium was continuously infused to
maintain the minimal dose that prevented triggering of the ventilator.
She continued to receive hourly nebulized albuterol; every 4 h,
ipratropium bromide was added to nebulized treatments. She also
received a second dose of 125 mg of methylprednisolone 6 h after
intubation. Airway pressures improved dramatically, allowing gradual
increases in VT (maintaining static airway pressures < 25
cm H2O). Nearly 14 h after intubation, she
was eucapnic (pH, 7.23; PCO2, 40 cm
H2O) with airway resistance of 29 cm
H2O/L/s and static airway pressures of 21 cm
H2O. Hourly nebulized treatments were reduced in
frequency to every 4 h, and vecuronium treatment was stopped. The
lactic acid level, drawn before cessation of vecuronium to define the
etiology of her metabolic acidosis, was 4.9 mmol/L. She continued to
improve clinically; the next morning, treatment with propofol was
stopped and 45 min later she was successfully extubated. She continued
to improve with nebulized treatments every 4 to 6 h and
methylprednisolone, 60 mg q6h. Her lactic acidosis abated over the next
24 h (Table 3 ), and she was discharged home on the sixth hospital day.
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Discussion
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The most common acid-base abnormality accompanying an acute
exacerbation of asthma is respiratory alkalosis.2
However,
concurrent metabolic acidosis occurs in upwards of 28% of patients
with severe exacerbations of asthma. The pathogenesis of lactic
acidosis in asthma has been hypothesized to be related to production by
the respiratory muscles and/or tissue hypoxia.2
As discussed in a recent review,9
lactic acidosis results
from overproduction and/or inadequate clearance of lactic acid.
Therefore, lactic acidosis of SA could result (1) if patients were in
occult shock, (2) if produced by overloaded respiratory muscles
(ie, respiratory muscle oxygen demand outstripping oxygen
supply), (3) if produced by the lung parenchyma, or (4) if changes in
glycolysis were caused by ß-agonist administration. Lactic acid could
also be undermetabolized by the liver.
We cannot discount the possibility that the three patients in this
report were in occult shock, although they continued to urinate, had
mean arterial pressures that were normal or high, and experienced no
clinical signs of end-organ dysfunction typical of shock. Because all
three patients had received muscle relaxants, it is not tenable to
attribute their lactic acidemia to respiratory muscle production. One
previous case report4
has similarly ruled out the
possibility of lactic acid production by the respiratory muscles in
patients with SA. Although the lungs of patients with ARDS may produce
lactate,10
this has not been described in SA. Our patients
showed no laboratory evidence of liver or renal dysfunction during
their hospitalizations, reducing the likelihood that underclearance
contributed to these findings.
We performed a literature search and found that no other medications
administered to our patients have been associated with lactic acidemia.
One author8
states, "This finding [lactic acidosis]
is, as a rule, related to massive doses of ß2
adrenergic agents given parenterally: subsequent elevated lactate is in
no way a marker of cellular hypoxia and has no pejorative meaning in
this event." However, there are no convincing data to substantiate
this claim. Previous studies have suggested that administration of
ß-agonists can lead to lactic acidemia in the absence of hypoxia or
shock. Ensinger et al11
infused epinephrine into eight
normal volunteers and found that consequent hypertension and
tachycardia were associated with a more than fivefold increase in
plasma lactate concentrations. Stevenson et al12
demonstrated that epinephrine infusion in dogs resulted in increased
lactate levels despite increased uptake of lactate by the liver. They
also demonstrated that epinephrine caused a dose-dependent increase in
glucose production via stimulation of glycogenolysis and
gluconeogenesis. Reverte et al13
demonstrated that
salbutamol infusion in rabbits caused an increase in lactate that was
attenuated by prazosin. Sympathomimetic agents used for tocolysis have
also been associated with lactic acidemia.14
15
We could
find no experimental studies of the effects of injected, ingested, or
inhaled albuterol on plasma lactate levels. However, oral carbuterol,
another selective ß-agonist, has been associated with lactic acidosis
in stable asthmatic patients.16
The mechanisms by which ß-agonists may cause lactic acidemia remain
uncertain.1
2
Stimulation of ß-adrenergic receptors
leads to a variety of metabolic effects, including increases in
glycogenolysis, gluconeogenesis, and lipolysis.12
17
Stimulation of ß-adrenergic receptors increases activity of adenylate
cyclase activity, which in turn leads to increased intracellular cyclic
adenosine monophosphate (cAMP). The mechanism by which cAMP leads to
additional metabolic events is unclear. Stimulation of
ß-adrenoceptors increases lipolysis17
18
; and
ß2 stimulation appears to increase lipolysis to
a greater degree than does ß1 stimulation.
Increased free fatty acids inhibit conversion of pyruvate to
acetyl-coenzyme A with consequent increases in lactic acid. Moreover,
stimulation of ß-adrenergic receptors increases plasma glucose
concentrations,12
thus increasing substrate for
glycolysis. Thus, a number of mechanisms may explain lactic acidemia in
patients with asthma who receive high doses of ß-agonists. Finally,
glucocorticoids and theophylline, frequently used concomitantly with
ß-agonist inhalants in patients with obstructive airways disease,
also increase the level of intracellular cAMP and may enhance the
sensitivity of ß-receptors to ß-adrenergic agents that may further
amplify the above-described events.4
Notwithstanding these discussions, patient 2 kept receiving
continuously aerosolized ß-agonists at a time when lactic acid levels
had returned to normal, which argues against ß-agonist–induced
lactic acidosis. Another event that corresponded to resolution of
lactic acidosis in all these patients was improvement in bronchospasm,
as measured by reductions in resistive airway pressures, and gradual
increases in minute ventilation, ie, reversal of permissive
hypercapnia. One study10
demonstrated that lactic acidosis
can be produced by the lung parenchyma in patients with ARDS; it is not
clear whether this is a result of altered substrate metabolism because
of lung injury itself or to mechanical effects engendered by mechanical
ventilation. Accordingly, another potential hypothesis, albeit
far-flung, is that the lungs of patients with severe asthma produce
lactic acid. We were unable to find in vitro data to examine
this hypothesis. This would be difficult to prove in humans because
most patients with SA do not undergo right-heart catheterization that
could allow determination of gradients of lactic acid concentration
across the lungs. Finally, permissive hypercapnia, which was reversed
in these patients (arguably in patient 1) as respiratory pressures (and
lactic acid) diminished, has been associated with improved systemic
oxygenation of tissues and reduced lactic acid
production.19
In conclusion, our cases demonstrate that lactic acidemia associated
with severe exacerbations of asthma may occur in the absence of
respiratory muscle action. These data do not preclude the possibility
that the respiratory muscles of nonintubated patients with severe SA
contribute to lactic acidosis, only that lactic acid can be produced
even during pharmacologic muscle relaxation. The mechanism by which
this occurs in not evident from these cases. Although both animal and
human data suggest that ß-agonists could theoretically contribute to
lactic acidosis in severe asthma, one of our cases suggests that this
is not the sole explanation. Accordingly, further studies are required
to delineate the mechanisms that account for lactic acidosis in
patients with SA.
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Footnotes
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Abbreviations: cAMP = cyclic adenosine monophosphate;
PEEP = positive end-expiratory pressure; SA = status asthmaticus;
VT = tidal volume
Received for publication September 6, 2000.
Accepted for publication October 17, 2000.
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Abstract
Introduction
