primary lactic alkalosis

I I Primary Lactic Alkalosis ROBERT M, BERSIN, M.D., ALLEN I. ARIEFF, M.D. San Francisco, California

T he accumulation of lactic acid in the blood is generally associated with metabolic acidosis [1]. The

most frequent and clinically important cause of lactate accumulation in these circumstances is tissue hypoxia, which directly stimulates anaerobic lactic acid production [2].

However, increases in the blood lactate concentration may also occur in both metabolic and respiratory alkalosis [3-8]. In these instances, the mechanism of increased lactic acid production has been ascribed to enhanced activity of intracellular enzymes, principally phosphofructokinase, that accelerate lactate production [9]. Phosphofructokinase is an important regulatory enzyme in the glycolytic pathway, and its activity is largely controlled by the intracellular pH (pHi). As pHi increases with alkalosis, the activity of phosphofructokinase is accelerated, resulting in increased production of lactic acid. In experimental studies, increased lactic acid production with alkalosis has been demonstrated in skeletal muscle [9,10], cardiac muscle [11-13], brain tissue [14-16], and red blood cells [17]. However, the regulatory effect of pHi on glycolysis is such that the concentration of hydrogen ions must fall by about 50 percent (or the pHi must rise by 0.3 units) for lactic acid production to double [9,10]. Balanced against this, the liver has the capacity to increase its lactate consumption by approximately 10 times its basal rate if the delivered load of lactate increases [18]. Thus, although lactic acid production may increase with alkalosis, the increase is not marked because it is ordinarily accompanied by an equally large increase in hepatic lactate consumption. As a result, arterial blood lactate concentrations are at most modestly elevated in patients with alkalosis and generally do not exceed 1 to 3 mmol/liter (normal range, 0.2 to 1.2 mmol/liter) [3,19,20]. In cases in which marked elevations of blood lactate levels have been reported, other causes of increased lactate production have usually been identified, including shock, tissue hypoperfu- sion, and sepsis [21]. Tissue hypoxia has been suggest- ed to be an additional mechanism by which lactic acid production is stimulated during alkalosis. Oxygen-hemoglobin binding is increased by alkalosis, tending to reduce tissue oxygen availability [22,23]. In addition, many of the metabolic effects of alkalosis resemble those of hypoxia [9]. Yet attempts to demonstrate an

From the Cardiology and Geriatrics Divisions, Department of Medicine, Veterans Administration Medical Center, and the University of California School of Medicine, San Francisco, California. This work was supported by Grant HL01791 from the National Heart, Lung, and Blood Institute, Grant 88-1185 from the American Heart Association, and the Research Service of the Veterans Administration. A portion of this work was presented at the 19th Annual Meeting, American Society of Nephrology, Washington,,D.C., December, 1986. Dr Sersin is a recipient of the Physician-Scientist Award, National Institutes of Health. Requests for reprints should be addressed to Dr. Robert M. Bersin, Cardiology Division, Box 0124, UCSF Moffitt Hospital, 505 Parnassus Avenue, San Francisco, California 94143. Manuscript sub- mitted April 11, 1988, and accepted in revised form September 26, 1988.

effect of pH on tissue oxygen consumption have thus far been unsuccessful.

In this report, we present data on four patients with extreme metabolic alkalosis, hypocapnea, and marked elevations of both the anion gap and the blood lactate concentration. These patients also had evidence of impaired tissue oxygen use, suggesting that tissue hypoxia was the cause of the elevation of the blood lactate and hyperventilation. We investigated the possibility of an effect of alkalosis on oxygen use and lactic acid production in these patients and experimentally in a group of normoxic swine with acute metabolic alkalosis.

PATIENTS AND METHODS Patient Studies

Four patients with extreme metabolic alkalosis (pH greater than 7.65) were studied. All four patients were men (aged 46 to 61 years) with gastrointestinal disorders, protracted vomiting, and loss of gastric hydrogen ion concentration as the cause of metabolic alkalosis. The specific conditions were esophagitis, radiation gastritis, gastric ulcer, and pancreatitis (Table I). All four patients had normal blood-oxygen-carrying ca- pacities, with a mean arterial partial pressure of oxygen (pO2) of 84:1= 3 mm Hg and mean hemoglobin contents of 12 g/dl. No patient had a history or physi- cal findings to suggest heart disease or liver disease (congenital or acquired).

Arterial and venous blood gases were measured at 37°C using automated blood gas analyzers. Oxygen saturations were calculated using measured oxygen tensions, a correction for the Bohr effect (A log pO2 = -0.48ApH) [22], and a fifth-order polynomal regres- sion analysis of the oxygen-hemoglobin binding curve of normal adult human hemoglobin. The hemoglobin content of blood was measured on arterial samples using the cyanomethemoglobin method. The oxygen content of blood (volume percent) was then calculated by the formula: 02 content = 1.34 x Hb (hemoglobin) X percent O2 saturation. Systemic oxygen transport (in ml O2/minute) was calculated by the formula: systemic oxygen transport = arterial 02 content x cardiac output (CO); systemic oxygen extraction (AVDO2 in volume percent) by the formula: AVDO2 -- arterial 02 content - mixed-venous 02 content; systemic oxygen consumption (VO2 in ml O2/minute) by the formula: V02 = AVDO2 x CO.

Electrolyte concentrations were measured by flame photometry. The plasma glucose level was measured using the glucose oxidase method. Lactate was measured on venous samples using the NAD/NADH assay (Sigma Chemicals, St. Louis, Missouri).

Cardiac output was measured in triplicate by the thermodilution technique using a flow-directed cathe- ter placed in the pulmonary arterial bed. Evidence for vascular orthostasis was considered present if there

December 1988 The American Journal of Medicine Volume 85 867

PRIMARY LACTIC ALKALOSIS / BERSIN ANDARIEFF

TABLE I

Demographic Data on Four Patients with Primary Lactic Alkalosls

Duration Patient of Emesis Number Age Sex Diagnosis (days)

1 52 M Duodenal ulcer 7 2 46 M Alcoholic pancreatitis 5-6 3 61 M Alcoholic esophagitis 7-14 4 57 M Radiation gastritis 14

ARTERIAL BLOOD GASES

11 oo 9o 80 7o 60 50 ,4 0 30 20 10

0

! o

, , f o

o

[H+] pCO2 pO2 [HCO3-] (nM/I} (mm Hg) (mm Hg) (mEq/I)

Figure 1. Arterial blood gas values of the four patients with lactic alkalosis. Each symbol represents the values for an individual patient. The normal range (± 2 SD from the mean) for each parameter measured is represented by open rectangles. [H+] = hydrogen ion; [HC03] = bicarbonate,

was 10 mm Hg fall or more in systolic blood pressure, a 20 beat/minute rise or more in heart rate, or both, upon rising from the supine position.

Laboratory Investigations Studies were carried out in laboratory swine, mean

weight of 23 kg, as follows: Swine were anaesthetized with sodium pentobarbitol (25 mg/kg, intravenous), intubated, and mechanically ventilated with room air using an anaesthesia machine (Harvard). The tidal volume was fixed at 15 ml/kg, and the ventilatory rate was adjusted between 10 and 15 cycles/minute to nor- malize the arterial partial pressure of carbon dioxide (pCO2) (to between 35 to 43 mm Hg).

Blood gases were measured at 37°C using an automated blood gas analyzer (Radiometer, Copenhagen, Denmark). Oxygen saturations were measured using an automated oximeter (model OSM-3, Radiometer). Measurements of the blood hemoglobin, oxygen content, systemic oxygen transport, extraction, and consumption were performed as described in the patient studies section and were indexed per kilogram of body weight . Blood l a c t a t e was m e a s u r e d s imi la r ly . Splanchnic and hind limb blood flow were measured using ultrasonic flowmeters (Transonic model 201 TCS, Cornell, New York). Systemic oxygen consumption was then calculated by the formula: systemic 02 consumption = (aortic-pulmonary artery) 02 content difference x CO. Similarly, hind limb oxygen consumption was estimated with the formula: hind limb O2 consumption = ~femoral artery-femoral vein) 02

content difference x femoral artery flow, and gut oxygen consumption was estimated with the formula: gut 02 consumption = (aortic-hepatic portal vein) 02 content difference X hepatic portal vein flow. Net systemic lactate production was determined by the formula: (pulmonary artery - arterial) lactate difference X CO. Net lactate production by the gut and hind limb was estimated by determining the difference in blood lactate levels in the appropriate arteries and veins and by multiplying the differences by the organ blood flow.

After measurement of the forementioned parame- ters under general anaesthesia to establish a baseline, the blood pH was then raised acutely with the administration of a bolus of 1M sodium bicarbonate (2.5 mmol/kg body weight intravenous) at a rate of 1 mmol/kg body weight/minute. After administration of the bolus of sodium bicarbonate, the forementioned measurements were repeated at 30 and 60 minutes to assess the effects of changes in blood pH on oxygen consumption and lactate metabolism.

Statistical analysis was accomplished by comparing the 30- and 60-minute values to individual baseline values using paired two-tailed t-tests. The differences between the 30- and 60-minute time points and baseline values were considered significant when p <0.05. Data are shown as means ± SE unless designated oth- erwise. Statistical analyses were accomplished with a Macintosh Plus computer and a StatView 512+ (ver- sion 1.1) statistical software package (Calabassas, Cal- ifornia).

RESULTS Patient Studies

BLOOD GASES, ELECTROLYTES, AND LACTATES: All four patients experienced volume contraction as a result of protracted vomiting, as evidenced by significant orthostasis on blood pressure measurements. The blood pressure fell from mean values of 130/75 mm Hg (supine) to 96/62 mm Hg (standing), and the corresponding heart rates rose from 93 to 112 beats/minute. The mean arterial pH was 7.76 ± 0.06 (range, 7.65 to 7.91). The mean arterial pCO2 value was 28 ± 3 mm Hg (range, 22 to 36 mm Hg) and the concentration of bicarbonate was 43.1 + 7.6 mmol/li ter (range, 31 to 65 mmol/liter). Thus, all patients had pr imary metabolic alkalosis and respiratory alkalosis (F igure 1).

The plasma sodium level was 135 ± 7 mmol/li ter (range, 123 to 149 mmol/liter), the potassium level was 3.5 q- 0.7 mmol/li ter (range, 2.0 to 5.3 mmol/liter), and the chloride level was 57 ± 10 mmol/li ter (range, 28 to 68 mmol/liter). The plasma anion gap was markedly elevated in all patients at 35 ± 6 mEq/li ter (range, 25 to 49 mEq/liter; normal range, 10 to 12 mEq/liter). The blood lactate concentration was also strikingly elevated at 11.5 ± 3 mmol/li ter (range, 4.6 to 23 mmol/ liter). The blood lactate concentration accounted on average for 50 percent of the increase in the plasma anion gap (F igure 2).

BLOOD OXYGENATION: Although all patients were hyperventilating on the basis of their arterial pCO2 measurements, no patient had arterial hypoxemia. The mean arterial pO2 value was 84 ± 3 mm Hg (range, 69 to 107 mm Hg) (Figure 1). The cause of the hyperventilation in each case could not be explained on clinical grounds. However, in two of the four patients, mixed-venous blood samples were obtained for blood

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PRIMARY LACTIC ALKALOSIS / BERSIN AND ARIEFF

gas analysis. In both cases, the mixed-venous pO2 and 0,2 contents were significantly elevated, and AVDO2 was thus critically narrowed. The mixed-venous pO2 values were 62 and 66 mm Hg, and the corresponding AVDO2 values were 0.5 and 0.7 volume percent, re- spectively. In one of these two patients, cardiac out- puts were also obtained, allowing direct measurement of systemic oxygen transport and systemic 02 consumption. In this patient (pH 7.72, arterial pO2 88 mm Hg, venous pO2 62 mm Hg, blood lactate 14 mmol/ liter), the cardiac output was normal (7.4 liter/minute), as was systemic oxygen transport (1,043 ml 02/ minute). However, because AVDO2 was critically narrowed (0.7 volume percent), systemic oxygen consumption was reduced markedly to approximately 20 percent of normal resting values (53 ml OJminute, normal = 250 ml O2/minute).

With the administration of 6 liters of 154 mM sodium chloride and 20 mmol of 0.1M hydrogen chloride, the arterial pH fell to 7.48 and the hyperventilation ceased. In fact, compensatory hypoventilation ensued and the arterial pCO2 value rose to 51 mm Hg. Within 24 hours, the acid-base disturbance resolved, as did the electrolyte abnormalities, elevation of the anion gap, and increase in blood lactate level. Similarly, in the other three patients, the hyperventilation, increased anion gap, and elevated blood lactate concentration all resolved promptly with volume replace- ment with 154 mM sodium chloride.

Laboratory Investigations Acute changes in blood pH were accomplished by

the intravenous administration of sodium bicarbonate in 11 normoxic swine. The arterial pH rose by a mean of 0.07 pH units (from 7.34 to 7.41) at 30 mintues, but then returned toward normal at 60 minutes (mean, 7.37). With the increase in arterial pH, systemic oxygen transport decreased from 19.7 ml O2/kg body weight/minute at baseline, to 16.6 at 30 minutes (p <0.02), and 14.8 at 60 minutes (p <0.01). The AVDO2 value increased slightly, but not significantly, to par- tially offset the fall of systemic oxygen transport (from 6.2 volume percent to 7.0 at 30 minutes and 7.3 at 60 minutes, p = NS). As a result, systemic 02 consumption fell, but to a lesser degree than systemic oxygen transport (from 7.8 to 7.1 ml O2/kg body weight/ minute at 30 minutes, and 7.0 at 60 minutes, p = O.O6).

Arterial lactate concentration rose 37 percent from 2.8 to 3.4 mmol/liter at 30 minutes and 3.9 mmol/liter at 60 minutes. Systemic lactate production increased a mean of 580 #mol/kg body weight/hour at 30 minutes and 290 at 60 minutes. A direct relation between systemic oxygen consumption and lactate production, but not blood pH, was found (r = 0.70, p <0.02) (Fig- ure 3). As systemic oxygen consumption fell with alkalinization, systemic lactate production increased, and vice versa. The increase of systemic lactate production was due largely to an increase of gut lactate production (from 11 ~mol/kg body weight/hour, to 520 pmol/kg body weight/hour at 30 minutes and 595 #mol/kg body weight/hour at 60 minutes, p <0.02). Lactate prOduc- tion by skeletal muscle and the carcass also increased, but by a lesser amount (+94 #mol/kg body weight/ hour at 30 minutes and +111 ~mol/kg body weight/ hour at 60 minutes, p = NS). Thus, acute alkalinization with the administration of sodium bicarbonate is

70

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BLOOD LACTATE AND ANION GAP

O

o 8 i n

tL

6 o

n i i

8 , I I ANION GAP LACTATE % OF ANION GAP

(mEq/I) (mmol/I) (%)

Figure 2. Anion gap and blood lactate values of the four patients with lactic alkalosis. Each symbol represents the values for an individual patient. The values presented as "% of anion gap" represent the percentage of the increase in the anion gap that is due to lactate. The normal range (4- 2 SD from the mean) for the anion gap and blood lactate is represented by open rectangles.

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~; -400¢ UJ ¢j~ -5000

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S Y S T E M I C O X Y G E N C O N S U M P T I O N

( m l 0 2 J r n l n )

Figure 3. Relationship between changes in systemic 02 consumption (ml O2/kg body weight/minute) and lactate consumption (#mol/kg body weight/hour) during alkalinization. Negative values for lactate consumption represent net lactate production.

associated with reductions of systemic oxygen delivery and, to a lesser degree, of systemic oxygen consumption. Because there are regional differences in oxygen transport, lactate production increases markedly, principally by the gut.

COMMENTS These data demonstrate that in patients with ex-

treme metabolic alkalosis (blood pH greater than 7.65), tissue oxygen consumption is reduced, the blood lactate concentration rises markedly, and the plasma anion gap increases. The reduction of tissue oxygen consumption is inappropriate for resting tissue oxygen demands, resulting in an oxygen debt, stimulating anaerobic lactate production, and hyperventilation. When the blood pH falls below a certain threshold value, in the region of approximately 7.50, the effect of pH on oxygen extraction and consumption is no longer physiologically important, and both anaerobic lactate production and hyperventilation cease.

The most striking finding of this study was the marked elevation of the plasma lactate concentration in the patients with extreme alkalosis. Elevation of the plasma lactate in metabolic alkalosis has been described; however, the elevation of the plasma lactate


PRIMARY LACTIC ALKALOSlS / BERSIN ANDARIEFF

level in such cases is generally modest (2 to 5 mmol/ liter range) and normally accounts for only 10 to 15 percent of the increase in the plasma anion gap [3,19]. The remainder of the increase in the anion gap has been attributed to an increase of plasma organic an- ions, short chain fatty acids, and acids other than ke- toacids, and to changes in the net negative charge of plasma proteins due to the low ambient hydrogen ion concentration [3,19,24]. In our patients, the plasma lactate concentration was much higher than previous- ly reported in alkalemic patients (mean, 11.5 mmol/ liter) and accounted for a much higher proportion of the increased plasma anion gap (mean, 50 percent). The increase in blood lactate concentration has previ- ously been ascribed to enhanced glycolysis because of the sensitivity of phosphofructokinase to pH [9,10]. Indeed, glycolysis and lactate production have been amply documented to increase as the ambient pH is raised. However, lactate production generally only increases two-fold for every 0.3 pH unit rise [9,10]. Since the blood pH was increased at most only 0.51 pH units, at most only a four-fold rise in lactate production was anticipated. Under normal circumstances, a four-fold increase in lactate production would more than ade- quately be metabolized by the liver and kidney. The arterial lactate concentration would not necessarily increase. Therefore, in our patients, lactate production must have been stimulated substantially beyond the level that would have been anticipated from the magnitude of the blood pH change alone, or lactate consumption by the liver and kidney was impaired, or both. Hepatic and renal function indices were normal in our patients, and so an impairment of lactate metabolism is unlikely. The more likely cause is the en- hancement of lactate production as a result of tissue hypoxia. Systemic oxygen extraction and consumption were reduced well below normal levels of demand.

The mechanism for the reduction of oxygen consumption with alkalosis appears to be in part related to increased oxygen-hemoglobin binding. The p50 of blood (the pO2 at which blood is 50 percent saturated) was reduced from 26.6 to 16.6 and 19.5 mm Hg in the two patients with mixed-venous blood oxygen measurements. Oxygen extraction is certainly affected by such changes in hemoglobin binding. However, the magnitude of increased oxygen-hemoglobin binding seen in our patients would not be expected to impair oxygen consumption to the degree observed. Studies in dogs have demonstrated at most a 20 percent variation in systemic oxygen consumotion with variation of the blood pH between 7.10 and 7.55 [25,26]. Mitochon- drial respiration also does not appear to be substantially affected by the extracellular pH, as mitochondrial oxygen consumption was found to be constant in incubated liver tissue slices over a pH range of 6.0 to 9.0 [27]. However, there is evidence that alkalosis af- fects the cytosolic redox potential, citric acid cycle oxidation, and the structure of cytochrome Ct, suggesting that cellular respiration could be affected ad- versely by alkalosis [9]. Another potential mechanism by which oxygen consumption may be impaired by alkalosis is vascular. Alkalosis is a potent stimulus for vasoconstriction [2,28]. Selective vasoconstriction in the precapillary arterioles may result in vascular shunting, which may then result in the shunting of highly oxygenated blood away from tissue capillary beds. Since systemic oxygen consumption was reduced by approximately 80 percent in the presence of a nor-

mal cardiac output and normal systemic oxygen transport, it is likely that both vascular shunting and an impairment of mitochondrial respiration occurred in addition to an increase in oxygen-hemoglobin binding in our patients to reduce systemic oxygen consumption to this degree.

The animal data presented here would support the notion that there i~ a vascular component that con- tributes to the fall of oxygen consumption with alkalinization of the blood. In these animals, the changes in blood pH were modest in comparison to those of our patients. Nonetheless, systemic oxygen transport de- clined as did systemic 02 consumption. The magnitude of the blood pH change was not sufficient to cause any change in tissue oxygen extraction; however, because systemic blood flow decreased, systemic 02 consumption also decreased. Since blood flow was reduced more in the splanchnic and peripheral circula- tions (as it is with hypoxia), oxygen delivery and consumption were reduced more to the gut and carcass than in other vascular beds. These regional reductions in oxygen availability then caused a transient oxygen supply-demand mismatch, resulting in a transient oxygen debt that in turn stimulated anaerobic lactate production to a much greater extent than would be anticipated on the basis of the blood pH change alone.

These data therefore suggest that extreme alkalosis may reduce tissue oxygen delivery, extraction, and consumption. The mechanisms for these effects vary and may include increased oxygen-hemoglobin binding, impaired mitochondrial respiration, and pre-ca- pillar vascular shunting. Regardless of the mechanism, the reduction of oxygen consumption is inappropriate for oxygen demands and results in an oxygen debt. The tissue oxygen debt in turn stimulates anaerobic lactate production and hyperventilation. With more modest degrees of alkalosis, oxygen-hemoglobin binding and mitochondrial respiration are less affected, but the vascular component is still present and causes regional reductions of tissue oxygen delivery and consumption.

ACKNOWLEDGMENT We thank Ann Horton, B.S., Kevin Tanaka, B.S., and Payman Khorhami, B.S. for their technical assistance with the laboratory investigations.

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primary lactic alkalosis

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