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Lactic acidosis associated with a deceptively normal anion gap
Lactic acidosis associated with a deceptively normal anion gap Barbara H. Schwartz-Goldstein, MD, Amer R. Malik, MD, Akmal Sarwar, MD, and Robert D. Brandstetter, MD, FCCP, FCCM, New Rochelle, N.Y.
actic acidosis is the most c o m m o n and most i m p o r t a n t acidosis e n c o u n t e r e d in the i n t e n s i v e care u n i t (ICU). An e l e v a t e d a n i o n gap suggests lactate as t h e cause in the absence of k e t o a c i d o s i s , uremia, or the ingest i o n of certain toxins. We r e p o r t a p a t i e n t w i t h n o r m a l a n i o n gap m e t a b o l i c a c i d o s i s a n d markedly elevated arterial lactate levels. E x p l a n a t i o n s for this d e c e p t i v e l y n o r m a l a n i o n gap are offered,
L
CASE REPORT A 39-year-old woman was admitted to the ICU for respiratory insufficiency associated with presumed pneumococcal sepsis. Four previous admissions in the preceding year disclosed human immunodeficiency virus (HIV) infection (T4-lymphocyte count 1 week before admission: 612), cryptogenic pulmonary hypertension, hepatic cirrhosis, and malnutrition (Table). In the ICU, she had a rapid respiratory rate of 30 breaths/rain, pulse 130 beats/rain, and a blood preSsure of 130/70 mm Hg. Neurologic function was intact, and the pulmonary examination revealed crackles in the right infrascapular region with decreased air entry at the right lung base and left basilar crackles. The results of abdominal and pelvic examinations were unremarkable. Stool tested positive for occult blood. There was no palpable adenopathy, with lower extremities disclosing 2+ edema. Laboratory tests demonstrated leukocytosis 15 x 10S/mm~, a hemoglobin of 7 gm/dl, a platelet count of 1000 x 103/mms, and a prothrombin time of 17 seconds. There were minimal elevations in hepatic transaminases, with a total bilirubin of 4.9 mg/dl. Electrolytes, arterial lactate, and blood gases are listed in the Table. Chest roentgenogram demonstrated left upper lobe and right lower lobe infiltrates. From the Department of Medicine, New Rochelle Hospital Medical Center. Reprint requests: Robert D. Brandstetter, MD, New Rochelle Hospital Medical Center, 16 Guion Place, New Rochelle, NY 10801. HEARTLUNG| 1996;25:79~80, Copyright 9 1996 Mosby-Year Book, Inc. 0147~9563/96/$5.00 + 0 211169580
HEART & LUNG
VOL. 25, NO. I
Over the next 6 hours, during treatment with high-dose penicillin, gentamicin, and fluids, the patient's condition deteriorated, with worsening acidosis and respiratory muscle fatigue necessitating intubation. Sputum was obtained and the results revealed polymorphonuclear cells and gram-positive diplococci. In spite of hemodynamic monitoring and ventilatory support for 12 hours, her blood pressure began to progressively fall, with worsening metabolic acidosis, rising lactate, and normal anion gap. Fresh frozen plas~ ma followed by cryoprecipitate was administered for dis~ seminated intravascular coagulation and the patient subsequently died in refractory shock 24 hours after admission.
DISCUSSION The a n i o n gap is a u s e f u l m e a s u r e m e n t in the classification of causes of m e t a b o l i c acidosis. Lactate l e v e l s greater t h a n 5 m m o l / L are considered d i a g n o s t i c of lactic acidosis and are typi~ cally associated w i t h an e l e v a t e d a n i o n gap.' Our p a t i e n t had t h r e e e l e v a t e d lactate l e v e l s w i t h i n 24 hours of h e r death, and each was associated w i t h a n o r m a l a n i o n gap (8 to 16 mEq/L). R e v i e w of t h r e e of h e r p r e v i o u s f o u r a d m i s s i o n s w i t h i n a year of h e r d e a t h d i s c l o s e d e x t r e m e l y l o w a n i o n gaps (Table). She d i d n o t suffer from m u l t i p l e m y e l o m a or h a l o g e n i n h a l a t i o n and was n o t r e s u s c i t a t e d w i t h large v o l u m e s of chlor i d e - c o n t a i n i n g f l u i d s to e x p l a i n a l o w a n i o n gap. 2 We b e l i e v e , however, that o t h e r c o e x i s t e n t i l l n e s s e s e x p l a i n her d e c e p t i v e l y n o r m a l a n i o n gap at t h e t i m e of h e r death. Our p a t i e n t ' s serum a l b u m i n was e x t r e m e l y l o w as a result of h e p a t i c cirrhosis and p o o r n u t r i t i o n a l intake. A l b u m i n n o r m a l l y accounts for 75% of the a n i o n gap. 3 A l b u m i n , as an u n m e a s u r e d anion, t e n d s to l o w e r the a n i o n gap w h e n it is decreased. T h e r e f o r e in all l i k e l i h o o d h e r h y p o a l b u m i n e m i a c o n t r i b u t e d to our p a t i e n t ' s n o r m a l a n i o n gap 4 in the face of severe lactic acidosis. I n d e e d n o r m a l a n i o n gaps have
79
Table ! Laboratory values 6/94 3/93 Na § (mEq/L) K + (mEq/L) El- ( m E q / L ) H C O 3- ( r n E q / L ) Anion gap (mEq/L)
135 3.6 107
11/93 143 4.0 115
26.8
18.5
1
9
130 4.6 110 22.4 -2
4/94
0 hr
6 hr
12 h r
129
140
139
137
4.9 105 24.1 0
4.5 116
5.4
4.8
115
112
24 hr 139 5,8 116
16
12
14
7
8
12
11
16
pH
--
--
--
--
Paco 2 ( m m Hg)
--
--
--
--
24
24
28
26
7.38
7.29
7,18
6.99
188
83
Pao 2 (turn Hg)
--
--
--
--
57
68
Lactate (mmol/L)
--
--
--
--
--
11.5
13.1
14.7
Albumin
(gm/dl)
Total protein (gm/dl)
2.0 --
1.9 --
been reported previously in critically ill patients suffering from hyperlactatemia. ~ Another factor responsible for the normal anion gap metabolic acidosis in our patient was hypergammaglobulinemia. Her HIV infection, in addition to cirrhosis, may explain the elevated globulins (IgG 58 gm/L, normal, 6.5 to 18.7 gm/L). It has been shown that HIV infection is associated with hypergammaglobulinemia in particular, with elevations of IgG and lgA due to an increased number of i m m u n o g l o b u l i n secreting B cells secondary to a failure in immunoregulation. 6 In this setting, the lowering of the anion gap is the result of the cationic charge on lgG. 7 A previous case of a patient infected with HIV, with hypergammaglobulinemia and low anion gap bass been reported. 8 The researchers conclude that in some patients with a decreased 'anion gap and an associated polyclonal increase in gammaglobulin, it may be diagnostically useful to consider a work-up for infection with HIV. In this study, sera from 18 patients who were positive for HIV and who had normal renal function, and 18 patients without HIV, were examined. The conclusion stated previously was complicated b y analysis that showed that the mean anion gap of the 18 patients who were positive for HIV was actually significantly higher than in the 18 patients without HIV. The reason for this observation is
80
12/93
--
1.9
1.4
--
--
--
--
9.6
9.0
--
--
--
unknown, but they postulate that the elevated anion gap found in the patients who were positive for HIV may be associated with increased acid levels secondary to opportunistic infection, drug therapy, or H1V infection itself. 8 In conclusion, we believe that a normal anion gap can be misleading when lactic acidosis is present in critically ill patients, in particular those with H1V. Knowledge of a previous anion gap can be of value in this setting, as was found in our patient. Accordingly, the demonstration of hyperlactatemia in normal anion gap metabolic acidosis should prompt a search for coexisting illnesses responsible for a low anion gap.
REFERENCES 1. Oliva P Lactic acidosis. Am J Med 1970;48:209-25. 2. Emmett M, Narrins RG. Clinical use of the anion gap. Medicine 1977;56:38-54. 3. Pitts RE Physiology of the kidney and body fluids. 3rd ed. Chicago: Yearbook Medical Publishers, 1974. 4. Nanii AA, Campbell DJ, Pudek MR. Decreased anion gap associated with hypoalbuminemia and polyclonal gammopathy. JAMA 1981;246:859-60. 5. Iberti TJ, Leibowitz AB, Papadakos PJ. Low sensitivity of anion gap as a screen to detect hyperlactatemia in critically ill patients. Crit Care Med 1990;18:275-7. 6. Lane HC, Masur H, Edgar LC, eta[. Abnormalities of B cell activation and immume regulation in patients with AIDS. N Engl J Med 1983;309:453-8. 7. Nanji AA, Halstead AC. Changes in serum anion gap and sodium level in monoclonal gammopathies. Can Med Assoc I 1982;127:32-5. 8. Slucher B, Levinson SS. Human immunodeficiency virus infection and anion gap. Ann Clin Lab Sci 1993;23:249-55.
JANUARY/FEBRUARY
1996
HEART
& LUNG
actic acidosis is the most c o m m o n and most i m p o r t a n t acidosis e n c o u n t e r e d in the i n t e n s i v e care u n i t (ICU). An e l e v a t e d a n i o n gap suggests lactate as t h e cause in the absence of k e t o a c i d o s i s , uremia, or the ingest i o n of certain toxins. We r e p o r t a p a t i e n t w i t h n o r m a l a n i o n gap m e t a b o l i c a c i d o s i s a n d markedly elevated arterial lactate levels. E x p l a n a t i o n s for this d e c e p t i v e l y n o r m a l a n i o n gap are offered,
L
CASE REPORT A 39-year-old woman was admitted to the ICU for respiratory insufficiency associated with presumed pneumococcal sepsis. Four previous admissions in the preceding year disclosed human immunodeficiency virus (HIV) infection (T4-lymphocyte count 1 week before admission: 612), cryptogenic pulmonary hypertension, hepatic cirrhosis, and malnutrition (Table). In the ICU, she had a rapid respiratory rate of 30 breaths/rain, pulse 130 beats/rain, and a blood preSsure of 130/70 mm Hg. Neurologic function was intact, and the pulmonary examination revealed crackles in the right infrascapular region with decreased air entry at the right lung base and left basilar crackles. The results of abdominal and pelvic examinations were unremarkable. Stool tested positive for occult blood. There was no palpable adenopathy, with lower extremities disclosing 2+ edema. Laboratory tests demonstrated leukocytosis 15 x 10S/mm~, a hemoglobin of 7 gm/dl, a platelet count of 1000 x 103/mms, and a prothrombin time of 17 seconds. There were minimal elevations in hepatic transaminases, with a total bilirubin of 4.9 mg/dl. Electrolytes, arterial lactate, and blood gases are listed in the Table. Chest roentgenogram demonstrated left upper lobe and right lower lobe infiltrates. From the Department of Medicine, New Rochelle Hospital Medical Center. Reprint requests: Robert D. Brandstetter, MD, New Rochelle Hospital Medical Center, 16 Guion Place, New Rochelle, NY 10801. HEARTLUNG| 1996;25:79~80, Copyright 9 1996 Mosby-Year Book, Inc. 0147~9563/96/$5.00 + 0 211169580
HEART & LUNG
VOL. 25, NO. I
Over the next 6 hours, during treatment with high-dose penicillin, gentamicin, and fluids, the patient's condition deteriorated, with worsening acidosis and respiratory muscle fatigue necessitating intubation. Sputum was obtained and the results revealed polymorphonuclear cells and gram-positive diplococci. In spite of hemodynamic monitoring and ventilatory support for 12 hours, her blood pressure began to progressively fall, with worsening metabolic acidosis, rising lactate, and normal anion gap. Fresh frozen plas~ ma followed by cryoprecipitate was administered for dis~ seminated intravascular coagulation and the patient subsequently died in refractory shock 24 hours after admission.
DISCUSSION The a n i o n gap is a u s e f u l m e a s u r e m e n t in the classification of causes of m e t a b o l i c acidosis. Lactate l e v e l s greater t h a n 5 m m o l / L are considered d i a g n o s t i c of lactic acidosis and are typi~ cally associated w i t h an e l e v a t e d a n i o n gap.' Our p a t i e n t had t h r e e e l e v a t e d lactate l e v e l s w i t h i n 24 hours of h e r death, and each was associated w i t h a n o r m a l a n i o n gap (8 to 16 mEq/L). R e v i e w of t h r e e of h e r p r e v i o u s f o u r a d m i s s i o n s w i t h i n a year of h e r d e a t h d i s c l o s e d e x t r e m e l y l o w a n i o n gaps (Table). She d i d n o t suffer from m u l t i p l e m y e l o m a or h a l o g e n i n h a l a t i o n and was n o t r e s u s c i t a t e d w i t h large v o l u m e s of chlor i d e - c o n t a i n i n g f l u i d s to e x p l a i n a l o w a n i o n gap. 2 We b e l i e v e , however, that o t h e r c o e x i s t e n t i l l n e s s e s e x p l a i n her d e c e p t i v e l y n o r m a l a n i o n gap at t h e t i m e of h e r death. Our p a t i e n t ' s serum a l b u m i n was e x t r e m e l y l o w as a result of h e p a t i c cirrhosis and p o o r n u t r i t i o n a l intake. A l b u m i n n o r m a l l y accounts for 75% of the a n i o n gap. 3 A l b u m i n , as an u n m e a s u r e d anion, t e n d s to l o w e r the a n i o n gap w h e n it is decreased. T h e r e f o r e in all l i k e l i h o o d h e r h y p o a l b u m i n e m i a c o n t r i b u t e d to our p a t i e n t ' s n o r m a l a n i o n gap 4 in the face of severe lactic acidosis. I n d e e d n o r m a l a n i o n gaps have
79
Table ! Laboratory values 6/94 3/93 Na § (mEq/L) K + (mEq/L) El- ( m E q / L ) H C O 3- ( r n E q / L ) Anion gap (mEq/L)
135 3.6 107
11/93 143 4.0 115
26.8
18.5
1
9
130 4.6 110 22.4 -2
4/94
0 hr
6 hr
12 h r
129
140
139
137
4.9 105 24.1 0
4.5 116
5.4
4.8
115
112
24 hr 139 5,8 116
16
12
14
7
8
12
11
16
pH
--
--
--
--
Paco 2 ( m m Hg)
--
--
--
--
24
24
28
26
7.38
7.29
7,18
6.99
188
83
Pao 2 (turn Hg)
--
--
--
--
57
68
Lactate (mmol/L)
--
--
--
--
--
11.5
13.1
14.7
Albumin
(gm/dl)
Total protein (gm/dl)
2.0 --
1.9 --
been reported previously in critically ill patients suffering from hyperlactatemia. ~ Another factor responsible for the normal anion gap metabolic acidosis in our patient was hypergammaglobulinemia. Her HIV infection, in addition to cirrhosis, may explain the elevated globulins (IgG 58 gm/L, normal, 6.5 to 18.7 gm/L). It has been shown that HIV infection is associated with hypergammaglobulinemia in particular, with elevations of IgG and lgA due to an increased number of i m m u n o g l o b u l i n secreting B cells secondary to a failure in immunoregulation. 6 In this setting, the lowering of the anion gap is the result of the cationic charge on lgG. 7 A previous case of a patient infected with HIV, with hypergammaglobulinemia and low anion gap bass been reported. 8 The researchers conclude that in some patients with a decreased 'anion gap and an associated polyclonal increase in gammaglobulin, it may be diagnostically useful to consider a work-up for infection with HIV. In this study, sera from 18 patients who were positive for HIV and who had normal renal function, and 18 patients without HIV, were examined. The conclusion stated previously was complicated b y analysis that showed that the mean anion gap of the 18 patients who were positive for HIV was actually significantly higher than in the 18 patients without HIV. The reason for this observation is
80
12/93
--
1.9
1.4
--
--
--
--
9.6
9.0
--
--
--
unknown, but they postulate that the elevated anion gap found in the patients who were positive for HIV may be associated with increased acid levels secondary to opportunistic infection, drug therapy, or H1V infection itself. 8 In conclusion, we believe that a normal anion gap can be misleading when lactic acidosis is present in critically ill patients, in particular those with H1V. Knowledge of a previous anion gap can be of value in this setting, as was found in our patient. Accordingly, the demonstration of hyperlactatemia in normal anion gap metabolic acidosis should prompt a search for coexisting illnesses responsible for a low anion gap.
REFERENCES 1. Oliva P Lactic acidosis. Am J Med 1970;48:209-25. 2. Emmett M, Narrins RG. Clinical use of the anion gap. Medicine 1977;56:38-54. 3. Pitts RE Physiology of the kidney and body fluids. 3rd ed. Chicago: Yearbook Medical Publishers, 1974. 4. Nanii AA, Campbell DJ, Pudek MR. Decreased anion gap associated with hypoalbuminemia and polyclonal gammopathy. JAMA 1981;246:859-60. 5. Iberti TJ, Leibowitz AB, Papadakos PJ. Low sensitivity of anion gap as a screen to detect hyperlactatemia in critically ill patients. Crit Care Med 1990;18:275-7. 6. Lane HC, Masur H, Edgar LC, eta[. Abnormalities of B cell activation and immume regulation in patients with AIDS. N Engl J Med 1983;309:453-8. 7. Nanji AA, Halstead AC. Changes in serum anion gap and sodium level in monoclonal gammopathies. Can Med Assoc I 1982;127:32-5. 8. Slucher B, Levinson SS. Human immunodeficiency virus infection and anion gap. Ann Clin Lab Sci 1993;23:249-55.
JANUARY/FEBRUARY
1996
HEART
& LUNG