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Lactic acidosis in severe asthma
Lactic Acidosis in Severe Asthma
DAVID APPEL, M.D. ROY RUBENSTEIN, M.D. KENNETH SCHRAGER, M.D. M. HENRY WILLIAMS, Jr., M.D. Bronx, New York
Twelve patients with severe asthma in whom lactic acidosis developed are presented. All had an arterial blood pH level lower than that expected for the measured partial pressure of arterial carbon dioxide, all had an abnormally large anion gap, and the blood lactate level exceeded 2.8 mmol/liter. Respiratory acidosis subsequently developed in eight patients, and six required intubation. Lactic acidosis can develop in patients with severe asthma. Such patients are in danger of the development of respiratory failure and must be treated vigorously and observed closely. Acute asthma is usually associated with hyperventilation, and analysis of arterial blood gases reveals acute respiratory alkalosis with alkalemia [ 11. When airways obstruction becomes so severe as to preclude adequate ventilation, or so prolonged as to cause fatigue, respiratory acidosis may develop [ 11. Asthma has not been thought to produce metabolic acidosis in adults [ 21. However, we have noted that a number of patients hospitalized with asthma had an arterial pH lower than expected for the level of partial pressure of arterial carbon dioxide (Pace,). To verify this impression, we examined data on 60 consecutive patients hospitalized with asthma. Of these, 12 patients had a Pace, less than 40 mm Hg and a pH less than 7.37, a prevalence of metabolic acidosis of 20 percent. To study this further, we then identified patients admitted with asthma who had metabolic acidosis and followed them with measurements of serum lactate levels as well as electrolytes and arterial blood gases. We herein describe 12 adults recently hospitalized and treated for severe asthma in whom lactic acidosis developed during their hospital course. PATIENTS AND METHODS
From the Pulmonary Division, Department of Medicine, Alberl Einstein College of Medicine, the North Central Bronx Hospital, and the Bronx Municipal Hospital Center. Requests for reprints should be addressed to Dr. David Appel, North Central Bronx Hospital, 3424 Kossuth Avenue, Bronx, New York 10467. Manuscript accepted February 2. 1963. A continuing medical education quiz based on this article (one hour of Category 1 credit) appears on page A103 of this issue.
590
October 1983
Patients. Twelve adults hospitalized with severe asthma in either North Central Bronx Hospital or Van Etten Hospital, Bronx, New York, were studied. All these patients presented at the emergency room with severe dyspnea and chest tightness, and all had asthma as defined by the American Thoracic Society [3]. All had severe obstruction of expiratory airflow confirmed by repeated measurements of peak expiratory airflow. All failed to improve significantly after bronchodilator treatment in the emergency room and were then hospitalized. All 12 patients subsequently improved after treatment in the hospital with bronchodilators and cot-ticosteroids. All patients had arterial blood gas analysis as part of the admission work-up for asthma. Patients were then identified for this study if the arterial blood, either on admission or subsequently, revealed a pH lower than expected for the Paco2 [4]. Methods. Blood was taken anaerobically from a radial artery into a lightly heparinized syringe and the pH and P%on and P~Q were measured promptly. Serum electrolytes were analyzed, and the anion gap was determined by subtracting the sum of CI- i- HCOa- from the sum of Na+ f K+. Plasma
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LACTIC ACIDOSIS IN SEVERE ASTHMA-APPEL
ET AL
bicarbonate concentration was calculated from arterial blood gas data using the Henderson-Hasselbalch equation substituting a pK’ of 6.1 and a carbon dioxide solubility factor of 0.03. The arterial blood H+ concentration was calculated as cH+ = antilog (9 - pH). Another blood sample was obtained for subsequent determination of lactate level. In seven patients, lactate levels were measuredby anaerobically drawing 3 ml of whole venous blood into a syringe, adding 6 ml of 6 percent perchioric acid, centrifuging the mixture, drawing off and freezing the supernatant blood-plasma-perchloric acid mixture, and then measuring the lactate levels. In five patients, 6 ml of arterial blood was obtained anaerobically, placed into a heparinized tube, and centrifuged; the plasma frozen for subsequent analysis. Weight/weight concentrations were converted to weight/volume values by multiplying by appropriate conversion constants [ 51. Lactate was measured by enzymatic methods utilizing lactate dehydrogenase [6]. Normal venous plasma lactate levels have been previously determined to be 1.3 f 0.1 mmol/liter [7].
tmM/L)
RESULTS in Figure 1, the pH and Pacon in each of these patients are plotted against a 95 percent confidence band that defines acute respiratory acidosis/aikaiosis [4]. At the time of admission (Figure 1, top panel), the data from all but four patients fell within the 95 percent confidence band defining acute respiratory alkalosis. Subsequently, ail values were above this confidence band (Figure 1, middle panel) because the measured pH was lower or more acidemic than predicted from the measured Pacon. After treatment and improvement of asthma, metabolic acidosis resolved, and ail data returned to the 95 percent confidence band for acute respiratory alkalosis. Table I summarizes some of the pertinent general clinical information regarding these patients. The patients were young (mean age 30 years). Seven were women. The duration of acute asthma before admission ranged from a few hours to one week, with an average of two to three days. As outpatients, all had been taking beta-adrenergic and theophylline-containing preparations, and many took systemic corticosteroids as well. Upon presentation, all complained of chest tightness and dyspnea. Auscultation of the chest demonstrated wheezes, and all had severe reduction of peak expiratory flow rate. The mean peak expiratory flow rate for the group was 61 liters per minute. Two thirds of these patients were described by the housestaff to be utilizing accessory muscles for respiration at the time of admission, and 60 percent had P-puimonale on eiectrocardiography. In all patients, chest roentgenography revealed hyperaerated lung fields with no evidence of parenchymai infiltration or congestive heart failure. While hospitalized, all patients received supplemental oxygen and intravenous fluids. They were treated with frequent subcutaneous injections of epinephrine hydrochloride (1: 1,000) and parenteral aminophylline and
Figure 1. Arterial blood gas data on admission (top), at the time of metabolic acidosis (middle), and after recovery (bottom). The parallel lines embrace the confidence band for acute respiratory acidosis/alkalosis [4].
TABLE I PalletIt Number
Mean
1 2 3 4 5 8 7 8 9 10 11 12 f SEM
Cllnical Features Age (~4 6SeX
30F 30F 21F 32F 23F 45M 38M 38F 18F 18M 28M 44M 30 f 2.8 7F
PEFR = peak expiratory
October 1983
PEFR (liters per minute)
Using Accessory
130 0 30 80 100 110 30 30 105 30 30 80 81 f 12
Yes Yes No Yes Yes No Yes Yes Yes Yes No No 8 yes
MUSCkS
ElcctrOcardiographic P-pulmonale Yes Yes No Yes Yes No Yes Yes No No No Yes 7 yes
flow rate.
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Acid-Base Status
TABLE II Patient Number
%0,
PH 7.34 7.36 7.41 7.38 7.38 7.38 7.31 7.42 7.33 7.40 7.47 7.38 7.35 f 0.04
1 2 3 4 5 6 7
a 9 10 11 12 Mean f SEM
(ton)
34 32 31 34 34 33 34 32 39 30 26 12 36 f 3.9
HCO-, (msqlliter)
Anion Gap - 15 (meq/lHer)
Lactate (mmsllliter)
19
6 7 10 5 10 3 10 3 6 7 12 7 6.8 f 0.8
4.7 2.9 4.1 3.1 3.4 4.1 9.4 3.1 2.9 4.0 4.1 6.5 4.5 f 0.6
ia 20 20 20 23 17 20 21 19 la 22 20 f 0.5
tients. In four patients, metabolic acidosis was present on admission. In the remaining eight patients, lactic acidosis was noted within one to 11 hours from admission, with a mean interval of about three hours. The development of lactic acidosis was associated with persistent severe obstruction of expiratory airflow, although the peak expiratory flow rate was actually higher than on admission in three patients. On admission, the mean peak expiratory flow rate was 61 liters per minute; at the time lactic acidosis was noted, the mean peak expiratory flow rate was 56 liters per minute. This difference is not significant. In eight of the patients respiratory acidosis subsequently developed, and six required intubation. Respiratory acidosis occurred within 15 minutes to four and a half hours from the time metabolic acidosis was first noted, with a mean interval of about two hours. The development of respiratory acidosis was associated with a decrease in the peak ex-
cotticosteroids. None of the patients was hypotensive, febrile, or had evidence of sepsis. All were hypoxic with widened alveolar-arterial oxygen gradients, but in none was the Paon less than 55 torr (mean Pao, 64 torr). Table II presents the acid-base status of these patients when metabolic acidosis was first noted. Not all patients had acidemia, but all had a pH more acidemic than predicted from the measured Pko,. All had abnormally large anion gaps, and they had measured venous or arterial lactate levels that ranged from 2.3 to 7.3 times normal (mean 4.5 mmol/liter). The mean pH for the group was 7.35, whereas the mean PRO, was 36 torr. If the normal anion gap is defined as up to 15 meq/liter, then the measured anion gap minus 15 meq/liter quantitates the excess anions accumulated during metabolic acidosis. The mean excess anion gap for the group was 6.8 meq/liter. Table Ill illustrates the hospital course of these pa-
Development of Metabolic and Respiratory Acidosis
TABLE Ill Patient Number 1 2 3 4 5 6 7
a 9 10 11 12 Mean f SEM
Emergency Room PEFR (liters per minute) 130 0 30 80 100 110 30 30 105 30 30 60 61 f 12
Interval I’ (hours) 11 1.5 POA POA 2 0.75 POA 0.5 3 5 POA 3 3.3 f 1.2
Metabolic Acidosis PEFR (liters per minute)
Interval IV (hours)
105 110 30
3.5 3.5
51 47
0 0
80
b:i
so
30 70 30 60 100 75 30 50 56 f 9
6.25 0.5 4.5 . . . . 2 0.5 1.9 f 0.6
53. 49 47 . .
sg . 0 0 65 . . . .
Time between admission to emergency room and earliest detection of metabolic acidosis. t Time between earliest detection of metabolic acidosis and earliest detection of respiratory PEFR = peak expiratory flow rate; POA = present on admission to the emergency room.
PaO0,
l
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October 1983
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acidosis.
Respiratory Ackkets PEFR (liters per minute) (W
42 43 50 f 5
So 21 f 11
LACTIC ACIDOSIS IN SEVERE ASTHMA-APPEL
piratory flow rate. In the seven patients in whom it was measured, the peak expiratory flow rate averaged 21 liters per minute when they had respiratory acidosis compared with 72 liters per minute when they had metabolic acidosis. All patients continued to receive frequent subcutaneous injections of epinephrine, parenteral glucosecontaining fluids, aminophylline, corticosteroids, and supplemental oxygen. All eventually improved, and as the asthma became less severe, the metabolic acidosis disappeared (Figure 1, bottom panel). COMMENTS Although lactic acidosis has been described in association with other respiratory disorders [ 7,8], it is not considered to result from asthma [ 21. However, reports of arterial blood gas levels in patients with severe asthma contain data indicating that some of these patients had metabolic acidosis [9, lo]. Roncoroni et al [ 1 l] described a large group of patients with status asthmaticus who had lactic acidosis. We report on 12 adults with severe asthma and lactic acidosis. Most of them presented with acute respiratory alkalosis. During their hospital course, and in the setting of persistent airways obstruction, metabolic acidosis that was associated with an abnormally large anion gap developed in all, and in each patient, the accumulated anion measured was lactate. No other clinical process such as hypotension, severe hypoxia, or sepsis was found that might account for the lactic acidosis. It is possible that elevation of the Pacon contributed to the acidosis. In these patients with hyperventilation and resultant reduction of serum bicarbonate, an increased Pace,, even to a level of less than 40 torr, would be associated with acidosis. However, at the time of detection of acidosis in our patients, the Pace, was no higher than on admission. Furthermore, all patients had an abnormally large anion gap and increased serum lactate level. It is not clear why lactic acidosis developed in these patients. It is doubtful that the lactic acidosis resulted from hyperventilation. Eichenholz et al [ 121 found that after prolonged mechanical ventilation of dogs, significant lactate levels were produced to result in metabolic acidosis. Such lactate levels have not been produced in nonmechanically hyperventilated humans, and most investigators now believe that the lactic acidosis seen in the experiments of Eichenholz et al [ 121 resulted from adverse circulatory effects produced by positive pressure ventilators [ 13- 151. Nor can lactic acidosis be ascribed to treatment with glucose-containing solutions, epinephrine, or corticosteroids. Although intravenous glucose infusions and beta-adrenergic therapy have been shown or reasoned to produce elevations of the blood lactate level [ 13,15,18], the levels produced in these studies were far less than those seen in the patients described herein. Moreover, the patients
October
ET AL
described herein continued to receive glucose infusion, epinephrine, and corticosteroids after the lactic acidosis developed. Had this treatment been the cause of the disorder, lactate should have continued to accumulate. Instead, the patients’ asthma eventually improved and, as airways obstruction became less severe, lactic acidosis resolved. It is more likely that the lactic acidosis resulted from overproduction of lactate by respiratory muscles performing increased inspiratory and expiratory work [ 17-201, and from lactate underutilization resulting from hypoperfusion of skeletal muscle and the liver [21-251. The circulatory effects resulting in tissue hypoperfusion are probably essential to the process since studies of normal subjects breathing against high inspiratory resistances did not generate such high levels of lactate [20]. However, abnormalities of both right and left ventricular function may occur in patients with asthma. Markedly negative intrapleural pressures during inspiration result in relative pulmonary hypertension and increased right and left ventricular afterload [ 18,261, whereas markedly positive pressures on expiration produce increased right and left ventricular afterload and possible intraventricular septal shift with reduced left ventricular compliance [27-291. These changes may result in hypoperfusion of muscle and liver with resultant under-utilization of lactate. They may also cause increased right ventricular filling pressure resulting in hepatic congestion and decreased lactate metabolism. In 12 patients described herein, all had severe airways obstruction that, no doubt, generated marked swings in intrapleural pressures. At least two thirds of these patients were observed by the housestaff to be using accessory respiratory muscles, and at least 60 percent had electrocardiographic evidence of right heart strain at the time of admission before lactic acidosis was first noted. Although the mechanisms for the development of lactic acidosis in adults with severe asthma remain to be determined, lactic acidosis is an important indicator of severe asthma and should be recognized. It should be suspected whenever the pH is too low for the measured Pace, and the anion gap is abnormally large. The presence of metabolic acidosis in adults with asthma and severe obstruction of expiratory airflow identifies those in imminent danger of the development of respiratory failure. Of the 12 patients described herein, respiratory failure developed in eight, and six required intubation. In such patients, observation must be constant and treatment vigorous. lntubation of these patients may be required at a moment’s notice. ACKNOWLEDGMENT We are grateful to Dr. Henry Hoberman for carrying out many of the lactate analyses. 1993
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REFERENCES 1. 2. 3.
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6. 7.
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McFadden ER Jr, Lyons HA: Arterial blood gas tension in asthma. N Engl J Med 1968; 278: 1027-1031. McFadden ER Jr: Asthma: airway reactivity and pathogenesis. Semin Respir Med 1980; 1: 287-296. American Thoracic Society, Committee on Diagnostic Standards for Nontuberculous Respiratory Disease: Definitions and classifications of chronic bronchitis, asthma, and pUlNiOnWY emphysema. Am Rev Respir Dis 1962; 85: 762-768. Arbus GS, Herbert LA, Levesque PR. et al: Characterization and clinical application of the “significance band” for acute respiratory alkalosis. N Engl J Med 1969; 280: 117-123. Spector WD, ed: Handbook of biological data. Philadelphia: WB Saunders, 1956; 51. Sigma Technical Bulletin 726/826-UV-10-68; l-10. Fulop M, Horowitz M, Aberman A, et al: Lactic acidosis in pulmonary edema due to left ventricular failure. Ann Intern Med 1973; 79: 180-186. Aberman A. Hew E: Lactic acidosis presenting as acute respiratory failure. Am Rev Respir Dis 1976; 118: 961-963. Karetsky MS: Blood studies in untreated patients with acute asthma. Am Rev Respir Dis 1975; 112: 607-613. Tai E, Read J: Blood-gas tensions in bronchial asthma. Lancet 1967; I: 644-648. Roncoroni AJ, Adrogue HJA, DeObrutsky CW, Marchisio ML, Herrera MR: Metabolic acidosis in status asthmaticus. Respiration 1976; 33: 85-94. Eichenholz A, Mulhausen RO, Anderson WE, et al: Primary hypocapnia: a cause of metabolic acidosis. J Appl Physiol 1962; 17: 263-288. Huckabee WE: Relationships of pyruvate and lactate during anaerobic metabolism. I. Effect of infusion of pyruvate or glucose and of hyperventilation. J Clin Invest 1958; 37: 244-254. Eldridge F, Salzer J: Effect of respiratory alkalosis on blood lactate and pyruvate in humans. J Appl Physiol 1967; 22; 461-468. Oliva PB: Lactic acidosis. Am J Med 1970: 48: 209-225. Shires R, Jaffe BT, Heding LG, et al: Metabolic studies in acute
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asthma before and after treatment. Br J Dis Chest 1979; 73: 66-70. Park R, Arieff AL: Lactic acidosis. Adv Intern Med 1980; 25: 33-68. Permutt S: Physiologic changes in the acute asthma attack. In: Austen KF, Lichtenstein LM, eds. Asthma: physiology immunology, and treatment. New York: Academic Press, 1973; 15-24. Eldridge F: Anaerobic metabolism of the respiratory muscles. J Appl Physiol 1966; 21: 853-857. Jardim J, Farkas G, Prefaut C. et al: The failing inspiratory muscles under normoxic and hypoxic conditions. Am Rev Respir Dis 1981; 124: 274-279. Berry MN, Scheuer J: Splanchnic lactic acid metabolism in hyperventilation, metabolic alkalosis, and shock. Metabolism 1967; 16: 537-547. Lloyd MH, lies RA, Simpson BR, et al: The effect of simulated metabolic acidosis on intracellular pH and lactate metabolism in the isolated perfused rat liver. Clin Sci Mol Med 1973; 45: 543-549. Tashkin DP, Goldstein PJ, Simmons DH: Hepatic lactate uptake during decreased liver perfusion and hypoxia. Am J Physiol 1972; 223: 968-974. Freychuss U, Strandell T: Limb circulation during arm and leg exercise in supine position. J Appl Physiol 1967; 23: 163-170. Jorfeldt L: Metabolism of L-(+)-lactate in human skeletal muscle during exercise. Acta Med Stand 1970; 338 (suppl): l-67. Permutt S: Relation between pulmonary arterial pressure and pleural pressure during the acute asthmatic attack. Chest 1973; 63 (suppl): 25S-27s. Robotham JL, Rabson J, Permutt S, et al: Left ventricular hemodynamics during respiration. J Appl Physiol 1979; 47: 1295-1303. Robotham JL: Cardiovascular disturbances in chronic respiratory insufficiency. Am J Cardiol 1981; 47: 941-949. Buda AJ, Pinsky MR, lngels NB, et al: Effect of intrathoracic pressure on left ventricular performance. N Engl J Med 1979; 301: 453-459.
DAVID APPEL, M.D. ROY RUBENSTEIN, M.D. KENNETH SCHRAGER, M.D. M. HENRY WILLIAMS, Jr., M.D. Bronx, New York
Twelve patients with severe asthma in whom lactic acidosis developed are presented. All had an arterial blood pH level lower than that expected for the measured partial pressure of arterial carbon dioxide, all had an abnormally large anion gap, and the blood lactate level exceeded 2.8 mmol/liter. Respiratory acidosis subsequently developed in eight patients, and six required intubation. Lactic acidosis can develop in patients with severe asthma. Such patients are in danger of the development of respiratory failure and must be treated vigorously and observed closely. Acute asthma is usually associated with hyperventilation, and analysis of arterial blood gases reveals acute respiratory alkalosis with alkalemia [ 11. When airways obstruction becomes so severe as to preclude adequate ventilation, or so prolonged as to cause fatigue, respiratory acidosis may develop [ 11. Asthma has not been thought to produce metabolic acidosis in adults [ 21. However, we have noted that a number of patients hospitalized with asthma had an arterial pH lower than expected for the level of partial pressure of arterial carbon dioxide (Pace,). To verify this impression, we examined data on 60 consecutive patients hospitalized with asthma. Of these, 12 patients had a Pace, less than 40 mm Hg and a pH less than 7.37, a prevalence of metabolic acidosis of 20 percent. To study this further, we then identified patients admitted with asthma who had metabolic acidosis and followed them with measurements of serum lactate levels as well as electrolytes and arterial blood gases. We herein describe 12 adults recently hospitalized and treated for severe asthma in whom lactic acidosis developed during their hospital course. PATIENTS AND METHODS
From the Pulmonary Division, Department of Medicine, Alberl Einstein College of Medicine, the North Central Bronx Hospital, and the Bronx Municipal Hospital Center. Requests for reprints should be addressed to Dr. David Appel, North Central Bronx Hospital, 3424 Kossuth Avenue, Bronx, New York 10467. Manuscript accepted February 2. 1963. A continuing medical education quiz based on this article (one hour of Category 1 credit) appears on page A103 of this issue.
590
October 1983
Patients. Twelve adults hospitalized with severe asthma in either North Central Bronx Hospital or Van Etten Hospital, Bronx, New York, were studied. All these patients presented at the emergency room with severe dyspnea and chest tightness, and all had asthma as defined by the American Thoracic Society [3]. All had severe obstruction of expiratory airflow confirmed by repeated measurements of peak expiratory airflow. All failed to improve significantly after bronchodilator treatment in the emergency room and were then hospitalized. All 12 patients subsequently improved after treatment in the hospital with bronchodilators and cot-ticosteroids. All patients had arterial blood gas analysis as part of the admission work-up for asthma. Patients were then identified for this study if the arterial blood, either on admission or subsequently, revealed a pH lower than expected for the Paco2 [4]. Methods. Blood was taken anaerobically from a radial artery into a lightly heparinized syringe and the pH and P%on and P~Q were measured promptly. Serum electrolytes were analyzed, and the anion gap was determined by subtracting the sum of CI- i- HCOa- from the sum of Na+ f K+. Plasma
The American Journal of Medicine
Volume 75
LACTIC ACIDOSIS IN SEVERE ASTHMA-APPEL
ET AL
bicarbonate concentration was calculated from arterial blood gas data using the Henderson-Hasselbalch equation substituting a pK’ of 6.1 and a carbon dioxide solubility factor of 0.03. The arterial blood H+ concentration was calculated as cH+ = antilog (9 - pH). Another blood sample was obtained for subsequent determination of lactate level. In seven patients, lactate levels were measuredby anaerobically drawing 3 ml of whole venous blood into a syringe, adding 6 ml of 6 percent perchioric acid, centrifuging the mixture, drawing off and freezing the supernatant blood-plasma-perchloric acid mixture, and then measuring the lactate levels. In five patients, 6 ml of arterial blood was obtained anaerobically, placed into a heparinized tube, and centrifuged; the plasma frozen for subsequent analysis. Weight/weight concentrations were converted to weight/volume values by multiplying by appropriate conversion constants [ 51. Lactate was measured by enzymatic methods utilizing lactate dehydrogenase [6]. Normal venous plasma lactate levels have been previously determined to be 1.3 f 0.1 mmol/liter [7].
tmM/L)
RESULTS in Figure 1, the pH and Pacon in each of these patients are plotted against a 95 percent confidence band that defines acute respiratory acidosis/aikaiosis [4]. At the time of admission (Figure 1, top panel), the data from all but four patients fell within the 95 percent confidence band defining acute respiratory alkalosis. Subsequently, ail values were above this confidence band (Figure 1, middle panel) because the measured pH was lower or more acidemic than predicted from the measured Pacon. After treatment and improvement of asthma, metabolic acidosis resolved, and ail data returned to the 95 percent confidence band for acute respiratory alkalosis. Table I summarizes some of the pertinent general clinical information regarding these patients. The patients were young (mean age 30 years). Seven were women. The duration of acute asthma before admission ranged from a few hours to one week, with an average of two to three days. As outpatients, all had been taking beta-adrenergic and theophylline-containing preparations, and many took systemic corticosteroids as well. Upon presentation, all complained of chest tightness and dyspnea. Auscultation of the chest demonstrated wheezes, and all had severe reduction of peak expiratory flow rate. The mean peak expiratory flow rate for the group was 61 liters per minute. Two thirds of these patients were described by the housestaff to be utilizing accessory muscles for respiration at the time of admission, and 60 percent had P-puimonale on eiectrocardiography. In all patients, chest roentgenography revealed hyperaerated lung fields with no evidence of parenchymai infiltration or congestive heart failure. While hospitalized, all patients received supplemental oxygen and intravenous fluids. They were treated with frequent subcutaneous injections of epinephrine hydrochloride (1: 1,000) and parenteral aminophylline and
Figure 1. Arterial blood gas data on admission (top), at the time of metabolic acidosis (middle), and after recovery (bottom). The parallel lines embrace the confidence band for acute respiratory acidosis/alkalosis [4].
TABLE I PalletIt Number
Mean
1 2 3 4 5 8 7 8 9 10 11 12 f SEM
Cllnical Features Age (~4 6SeX
30F 30F 21F 32F 23F 45M 38M 38F 18F 18M 28M 44M 30 f 2.8 7F
PEFR = peak expiratory
October 1983
PEFR (liters per minute)
Using Accessory
130 0 30 80 100 110 30 30 105 30 30 80 81 f 12
Yes Yes No Yes Yes No Yes Yes Yes Yes No No 8 yes
MUSCkS
ElcctrOcardiographic P-pulmonale Yes Yes No Yes Yes No Yes Yes No No No Yes 7 yes
flow rate.
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LACTIC ACIDOSIS
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Acid-Base Status
TABLE II Patient Number
%0,
PH 7.34 7.36 7.41 7.38 7.38 7.38 7.31 7.42 7.33 7.40 7.47 7.38 7.35 f 0.04
1 2 3 4 5 6 7
a 9 10 11 12 Mean f SEM
(ton)
34 32 31 34 34 33 34 32 39 30 26 12 36 f 3.9
HCO-, (msqlliter)
Anion Gap - 15 (meq/lHer)
Lactate (mmsllliter)
19
6 7 10 5 10 3 10 3 6 7 12 7 6.8 f 0.8
4.7 2.9 4.1 3.1 3.4 4.1 9.4 3.1 2.9 4.0 4.1 6.5 4.5 f 0.6
ia 20 20 20 23 17 20 21 19 la 22 20 f 0.5
tients. In four patients, metabolic acidosis was present on admission. In the remaining eight patients, lactic acidosis was noted within one to 11 hours from admission, with a mean interval of about three hours. The development of lactic acidosis was associated with persistent severe obstruction of expiratory airflow, although the peak expiratory flow rate was actually higher than on admission in three patients. On admission, the mean peak expiratory flow rate was 61 liters per minute; at the time lactic acidosis was noted, the mean peak expiratory flow rate was 56 liters per minute. This difference is not significant. In eight of the patients respiratory acidosis subsequently developed, and six required intubation. Respiratory acidosis occurred within 15 minutes to four and a half hours from the time metabolic acidosis was first noted, with a mean interval of about two hours. The development of respiratory acidosis was associated with a decrease in the peak ex-
cotticosteroids. None of the patients was hypotensive, febrile, or had evidence of sepsis. All were hypoxic with widened alveolar-arterial oxygen gradients, but in none was the Paon less than 55 torr (mean Pao, 64 torr). Table II presents the acid-base status of these patients when metabolic acidosis was first noted. Not all patients had acidemia, but all had a pH more acidemic than predicted from the measured Pko,. All had abnormally large anion gaps, and they had measured venous or arterial lactate levels that ranged from 2.3 to 7.3 times normal (mean 4.5 mmol/liter). The mean pH for the group was 7.35, whereas the mean PRO, was 36 torr. If the normal anion gap is defined as up to 15 meq/liter, then the measured anion gap minus 15 meq/liter quantitates the excess anions accumulated during metabolic acidosis. The mean excess anion gap for the group was 6.8 meq/liter. Table Ill illustrates the hospital course of these pa-
Development of Metabolic and Respiratory Acidosis
TABLE Ill Patient Number 1 2 3 4 5 6 7
a 9 10 11 12 Mean f SEM
Emergency Room PEFR (liters per minute) 130 0 30 80 100 110 30 30 105 30 30 60 61 f 12
Interval I’ (hours) 11 1.5 POA POA 2 0.75 POA 0.5 3 5 POA 3 3.3 f 1.2
Metabolic Acidosis PEFR (liters per minute)
Interval IV (hours)
105 110 30
3.5 3.5
51 47
0 0
80
b:i
so
30 70 30 60 100 75 30 50 56 f 9
6.25 0.5 4.5 . . . . 2 0.5 1.9 f 0.6
53. 49 47 . .
sg . 0 0 65 . . . .
Time between admission to emergency room and earliest detection of metabolic acidosis. t Time between earliest detection of metabolic acidosis and earliest detection of respiratory PEFR = peak expiratory flow rate; POA = present on admission to the emergency room.
PaO0,
l
582
October 1983
The American Journal of Medicine
Volume 75
acidosis.
Respiratory Ackkets PEFR (liters per minute) (W
42 43 50 f 5
So 21 f 11
LACTIC ACIDOSIS IN SEVERE ASTHMA-APPEL
piratory flow rate. In the seven patients in whom it was measured, the peak expiratory flow rate averaged 21 liters per minute when they had respiratory acidosis compared with 72 liters per minute when they had metabolic acidosis. All patients continued to receive frequent subcutaneous injections of epinephrine, parenteral glucosecontaining fluids, aminophylline, corticosteroids, and supplemental oxygen. All eventually improved, and as the asthma became less severe, the metabolic acidosis disappeared (Figure 1, bottom panel). COMMENTS Although lactic acidosis has been described in association with other respiratory disorders [ 7,8], it is not considered to result from asthma [ 21. However, reports of arterial blood gas levels in patients with severe asthma contain data indicating that some of these patients had metabolic acidosis [9, lo]. Roncoroni et al [ 1 l] described a large group of patients with status asthmaticus who had lactic acidosis. We report on 12 adults with severe asthma and lactic acidosis. Most of them presented with acute respiratory alkalosis. During their hospital course, and in the setting of persistent airways obstruction, metabolic acidosis that was associated with an abnormally large anion gap developed in all, and in each patient, the accumulated anion measured was lactate. No other clinical process such as hypotension, severe hypoxia, or sepsis was found that might account for the lactic acidosis. It is possible that elevation of the Pacon contributed to the acidosis. In these patients with hyperventilation and resultant reduction of serum bicarbonate, an increased Pace,, even to a level of less than 40 torr, would be associated with acidosis. However, at the time of detection of acidosis in our patients, the Pace, was no higher than on admission. Furthermore, all patients had an abnormally large anion gap and increased serum lactate level. It is not clear why lactic acidosis developed in these patients. It is doubtful that the lactic acidosis resulted from hyperventilation. Eichenholz et al [ 121 found that after prolonged mechanical ventilation of dogs, significant lactate levels were produced to result in metabolic acidosis. Such lactate levels have not been produced in nonmechanically hyperventilated humans, and most investigators now believe that the lactic acidosis seen in the experiments of Eichenholz et al [ 121 resulted from adverse circulatory effects produced by positive pressure ventilators [ 13- 151. Nor can lactic acidosis be ascribed to treatment with glucose-containing solutions, epinephrine, or corticosteroids. Although intravenous glucose infusions and beta-adrenergic therapy have been shown or reasoned to produce elevations of the blood lactate level [ 13,15,18], the levels produced in these studies were far less than those seen in the patients described herein. Moreover, the patients
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described herein continued to receive glucose infusion, epinephrine, and corticosteroids after the lactic acidosis developed. Had this treatment been the cause of the disorder, lactate should have continued to accumulate. Instead, the patients’ asthma eventually improved and, as airways obstruction became less severe, lactic acidosis resolved. It is more likely that the lactic acidosis resulted from overproduction of lactate by respiratory muscles performing increased inspiratory and expiratory work [ 17-201, and from lactate underutilization resulting from hypoperfusion of skeletal muscle and the liver [21-251. The circulatory effects resulting in tissue hypoperfusion are probably essential to the process since studies of normal subjects breathing against high inspiratory resistances did not generate such high levels of lactate [20]. However, abnormalities of both right and left ventricular function may occur in patients with asthma. Markedly negative intrapleural pressures during inspiration result in relative pulmonary hypertension and increased right and left ventricular afterload [ 18,261, whereas markedly positive pressures on expiration produce increased right and left ventricular afterload and possible intraventricular septal shift with reduced left ventricular compliance [27-291. These changes may result in hypoperfusion of muscle and liver with resultant under-utilization of lactate. They may also cause increased right ventricular filling pressure resulting in hepatic congestion and decreased lactate metabolism. In 12 patients described herein, all had severe airways obstruction that, no doubt, generated marked swings in intrapleural pressures. At least two thirds of these patients were observed by the housestaff to be using accessory respiratory muscles, and at least 60 percent had electrocardiographic evidence of right heart strain at the time of admission before lactic acidosis was first noted. Although the mechanisms for the development of lactic acidosis in adults with severe asthma remain to be determined, lactic acidosis is an important indicator of severe asthma and should be recognized. It should be suspected whenever the pH is too low for the measured Pace, and the anion gap is abnormally large. The presence of metabolic acidosis in adults with asthma and severe obstruction of expiratory airflow identifies those in imminent danger of the development of respiratory failure. Of the 12 patients described herein, respiratory failure developed in eight, and six required intubation. In such patients, observation must be constant and treatment vigorous. lntubation of these patients may be required at a moment’s notice. ACKNOWLEDGMENT We are grateful to Dr. Henry Hoberman for carrying out many of the lactate analyses. 1993
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