Metabolic acidosis with an elevated anion gap

Determining the cause of metabolic acidosis with a high anion gap may present a diagnostic challenge. Possible causes include ketoacidosis, certain toxic ingestions, renal failure and lactic acidosis. Many of these entities present with nausea, vomiting and changes in mental status; however, there are specific hallmarks in the signs, symptoms and laboratory findings that help to differentiate among them.     

Reliability of anion gap as an indicator of blood lactate in critically ill patients

Objective: To evaluate the sensitivity, specificity, and predictive values of an elevated anion gap as an indicator of hyperlactatemia and to assess the contribution of blood lactate to the serum anion gap in critically ill patients. Design: Prospective study. Setting: General intensive care unit of a university hospital. Patients: 498 patients, none with ketonuria, severe renal failure or aspirin, glycol, or methanol intoxication. Measurements and results: The anion gap was calculated as [Na⁺] − [Cl⁻] − [TCO₂]. Hyperlactatemia was defined as a blood lactate concentration above 2.5 mmol/l. The mean blood lactate concentration was 3.7 ± 3.2 mmol/l and the mean serum anion gap was 14.3 ± 4.2 mEq/l. The sensitivity of an elevated anion gap to reveal hyperlactatemia was only 44 % [95 % confidence interval (CI) 38 to 50], whereas specificity was 91 % (CI 87 to 94) and the positive predictive value was 86 % (CI 79 to 90). As expected, the poor sensitivity of the anion gap increased with the lactate threshold value, whereas the specificity decreased [for a blood lactate cut-off of 5 mmol/l: sensitivity = 67 % (CI 58 to 75) and specificity = 83 % (CI 79 to 87)]. The correlation between the serum anion gap and blood lactate was broad (r ² = 0.41, p < 0.001) and the slope of this relationship (0.48 ± 0.026) was less than 1 (p < 0.001). The serum chloride concentration in patients with a normal anion gap (99.1 ± 6.9 mmol/l) was comparable to that in patients with an elevated anion gap (98.8 ± 7.1 mmol/l). Conclusions: An elevated anion gap is not a sensitive indicator of moderate hyperlactatemia, but it is quite specific, provided the other main causes of the elevated anion gap have been eliminated. Changes in blood lactate only account for about half of the changes in anion gap, and serum chloride does not seem to be an important factor in the determination of the serum anion gap. Received: 22 May 1996 Accepted: 13 January 1997     

5-oxoprolinemia causing elevated anion gap metabolic acidosis in the setting of acetaminophen use

Background

Anion gap metabolic acidosis is typically encountered in the emergency department (ED) setting as the result of shock, other endogenous metabolic derangements, or from exogenous toxicants. The differential diagnosis for toxicant-related acidosis (exemplified by common mnemonics) emphasizes acute overdose.

Case Report

The case we present manifested an anion gap (AG) metabolic acidosis due to a chronic intoxication: acetaminophen (APAP) overuse over a period of weeks. Lactic acidemia did not account for the AG. In this case, chronic APAP overuse, combined with decreased caloric intake and weight loss, was associated with excess 5-oxoproline (pyroglutamic acid), an organic acid accounting for the AG metabolic acidosis. Overproduction of 5-oxoproline is attributed to depleted glutathione stores, leading to perturbation in the γ-glutamyl cycle. The patient was treated with supportive care and with N-acetylcysteine (NAC). By repleting glutathione, NAC may facilitate the resolution of excess 5-oxoproline.

Conclusions

The ED differential diagnosis of AG metabolic acidosis in chronic APAP overuse, especially with concomitant nutritional compromise, should include 5-oxoprolinemia.     

Alterations in anion gap following cardiopulmonary bypass.

OBJECTIVES: To evaluate the changes in the anion gap and their relation to hyperlactatemia and alterations in plasma proteins after cardiopulmonary bypass. DESIGN: Prospective study. SETTING: Cardiothoracic intensive therapy unit. PATIENTS: One hundred eleven consecutive patients after cardiopulmonary bypass. MEASUREMENTS AND MAIN RESULTS: Data were collected before cardiopulmonary bypass and every 6 hrs for 24 hrs after cardiopulmonary bypass. Results were analyzed for the entire cohort and for hyperlactatemic subgroups. The major finding of this study was that the anion gap decreased significantly at all sampling periods relative to precardiopulmonary bypass values, despite the presence of clinically important hyperlactatemia. No correlation between the decrease in plasma protein concentrations and the decrease in anion gap could be demonstrated. CONCLUSIONS: The decrease in anion gap after cardiopulmonary bypass appears to represent a balance between the influences of increased serum chloride and lactate concentrations and reduced plasma protein concentrations. This analysis demonstrates the limitations of the anion gap in the evaluation of a metabolic acidosis after cardiopulmonary bypass.     

Hypercholesterolemia increases endothelial superoxide anion production.

Indirect evidence suggests accelerated degradation of endothelium-derived nitric oxide (ENDO) by superoxide anion (O2-) in hypercholesterolemic vessels (HV). To directly measure O2- production by normal vessels (NV) and HV, we used an assay for O2- based on the chemiluminescence (CL) of lucigenin (L). HV (1 mo cholesterol-fed rabbits) produced threefold more O2- than NV (1.47 +/- 0.20 nM/mg tissue/min, n = 7 vs. 0.52 +/- 0.05 nmol/mg tissue/min, n = 8, P < 0.001). Endothelial removal increased O2- production in NV (0.73 +/- 0.08, n = 6, P < 0.05), while decreasing it in HV (0.76 +/- 0.15, n = 5, P < 0.05). There was no difference between denuded HV and denuded NV. Oxypurinol, a noncompetitive inhibitor of xanthine oxidase, normalized O2- production in HV, but had no effect in NV. In separate isometric tension studies treatment with oxypurinol improved acetylcholine induced relaxations in HV, while having no effect on responses in normal vessels. Oxypurinol did not alter relaxations to nitroprusside. Thus, the endothelium is a source of O2- in hypercholesterolemia probably via xanthine oxidase activation. Increased endothelial O2- production in HV may inactivate endothelium-derived nitric oxide and provide a source for other oxygen radicals, contributing to the early atherosclerotic process.     

Decreased anion gap in polyclonal hypergammaglobulinemia

OBJECTIVES: The anion gap has proved a valuable tool in the diagnosis of various forms of acid-base disorders, although the importance of slight rises in the anion gap remains unclear. The concept of the anion gap is often misunderstood and misapplied. The relationship between gammaglobulins and the serum anion gap has not received much attention except for reports of a narrowing of the gap associated with certain monoclonal immunoglobulin G gammopathies. We present patients with polyclonal gammopathy, the magnitude of which correlated strongly and negatively with the anion gap. DESIGN: The anion gap can be readily calculated from routine laboratory data, and anion gap was calculated as ([Na] +[K])- ([Cl] + [HCO3]). SUBJECTS: Serum anion gaps were determined in 206 patients with polyclonal hypergammaglobulinemia and 63 healthy subjects. MEASUREMENTS: Serum sodium and potassium ions concentration were determined by flame photometry. Serum bicarbonate level was measured as total carbon dioxide content. Serum chloride level was determined by chlorimetric titration with silver ions. RESULTS: All patients with polyclonal hypergammaglobulinemia had a statistically significant reduction in their mean serum anion gaps (6.4 +/- 1.2 mmol/L) when compared with normal control volunteers (15.3 +/- 2.4 mmol/L), p < 0.05. CONCLUSIONS: Our results show a negative correlation between serum anion gap and gammaglobulins concentration.     

The anion gap: its use in quality control.

Because the anion gap is useful in classifying acid-base disorders, quantitative information on this variable should be readily available. Three populations were studied and means and central 90% ranges were determined for the anion gap, calculated as sodium-(chloride + bicarbonate). In 1047 hospitalized patients the mean was 12 mEq/liter, 86 faster volunteers had a mean of 13 mEq/liter with a 90% range of 9--17 mEq/liter, and 203 plasmaphoresis donors had a mean of 11 mEq/liter with a 90% range of 7--16 mEq/liter. Most of this variability can be accounted for by analytical rather than physiological variation. This quantitation of the anion gap is useful for interchecking electrolyte values as an additional and inexpensive means of laboratory quality control. In 73 of 75 abnormal anion gaps, for which the data were verified to be correct, the clinical information provided a reasonable explanaation for the abnormality.     

Low sensitivity of the anion gap as a screen to detect hyperlactatemia in critically ill patients

The anion gap is commonly used as a screening test for the presence of lactic acidosis. Analysis of the distribution of anion gaps for 56 adult surgical ICU patients with peak blood lactate levels greater than or equal to 2.5 mmol/L showed the anion gap to be an insensitive screen for elevated lactate in a critically ill, hospitalized population. All patients (11/11) with a peak lactate greater than or equal to 10 mmol/L had an anion gap greater than or equal to 16 mmol/L; however, 50% (6/12) of patients with lactates between 5.0 and 9.9 mmol/L and 79% (26/33) of those with lactates between 2.5 and 4.9 mmol/L had anion gaps less than 16 mmol/L. Hyperlactatemia was associated with considerable mortality at all levels: 100% among patients with lactate levels greater than or equal to 10 mmol/L, 75% between 5.0 and 9.9 mmol/L, and 36.4% between 2.5 and 4.9 mmol/L. Acidosis (pH less than 7.30) did not significantly alter mortality by lactate level. The observation that, for 57% of patients in this study, an elevated lactate level was not accompanied by an elevated anion gap suggests that hyperlactatemia should be included in the differential diagnosis of nonanion gap acidosis.     

Negative anion gap in a young adult with multiple myeloma.

A young patient with multiple myeloma was found to have a negative anion gap, with marked asymptomatic hyponatremia. The cause for his negative anion gap is thought to be the myeloma protein, which acts as a cation at physiological pH. Such a hyponatremia responds to reduction in serum concentration of paraprotein and should not be treated by sodium replacement.     

Use of the anion gap in clinical medicine

The anion gap (AG) in the serum equals the concentrations of Na-(Cl + HCO3). It is becoming increasingly useful in the interpretation of acid-base disorders and in the diagnosis of other conditions. In an acidemic patient, an elevated AG usually indicates the presence of an organic acidosis, rhabdomyolysis, nonketotic hyperglycemic coma, uremia, or certain intoxications. An increased AG with alkalemia suggests severe alkalosis with hemoconcentration or use of anionic antibiotics (eg, carbenicillin) or salts of organic acids (eg, citrate). An elevated AG with a normal serum pH could be an artifact caused by prolonged exposure of the serum sample to air before processing. A decreased AG with a normal serum pH may indicate hypoalbuminemia, cationic paraproteinemia, halide poisoning, or lithium intoxication. The delta AG/delta HCO3 ratio and the urinary AG may also be quite useful in analyzing complex acid-base disorders.     

Early anion gap metabolic acidosis in acetaminophen overdose

Purpose

The study aimed to determine the incidence and clinical significance of early high (>15 mEq/L) anion gap metabolic acidosis in acetaminophen (APAP) overdose.

Methods

A retrospective review of a cohort of 74 patients presenting within 24 hours of APAP overdose was conducted.

Results

Early high anion gap metabolic acidosis was present in 41% of patients on admission and persisted for 1.5 ± 0.1 days. The anion gap was associated with an elevated lactate level (4.5 ± 1 mmol/L) (r² = 0.66, P < .05), which persisted for 1 day. The lactate level increased in proportion to the APAP concentration (r² = 0.75, P < .05). Patients with increased anion gap had a higher incidence of confusion (48% vs 3%; P < .001) and lethargy (39% vs 6%; P = .003). Early high anion gap metabolic acidosis was found in the absence of shock or liver failure. All patients were treated with N-acetylcysteine and, despite the early high anion gap metabolic acidosis, none developed hepatic failure or hypoglycemia.

Conclusion

Early high anion gap metabolic acidosis in patients with APAP overdose is self-limited and does not predict clinical or laboratory outcomes. Persistent or late metabolic acidosis in the absence of liver failure is not likely due to APAP and should prompt a search for other causes of metabolic acidosis. Finally, APAP overdose should be considered in patients presenting to the emergency department with altered mental status, as this is a treatable condition when detected early.     

Anion gap as a screening tool for elevated lactate in patients with an increased risk of developing sepsis in the Emergency Department

Objectives: Serum lactate levels are a useful tool in monitoring critically ill patients, especially those who are septic. However, lactate levels are often not routinely drawn or rapidly available in some institutions. The objective of this study was to determine if a readily available anion gap (AG) could be used as a surrogate marker for abnormal lactate level in Emergency Department (ED) patients at risk for sepsis. Methods: Prospective, observational cohort study of consecutive ED patients seen at an urban university tertiary care referral center with 46,000 annual ED visits. ED patients aged 18 years or older presenting with clinically suspected infection were eligible for enrollment if a serum chemistry and lactate levels were drawn during the ED visit. During the 9-month study period, 1419 patients were enrolled. The initial basic chemistry panels, calculated AG, and lactate levels drawn in the ED were collected. We defined, a priori, an AG > 12 and a lactate > 4 mmol/L to be abnormal. Analysis was performed with Student's t-test, operating characteristics with 95% confidence intervals, and logistic regression. Results: The mean AG was 11.8 (SD 3.6) and the mean lactate was 2.1 (SD 1.3). For an AG > 12, the mean lactate was 2.9 (SD 1.7), compared with 1.8 (SD 0.8) for an AG < 12. The sensitivity of an elevated AG (> 12) in predicting elevated lactate levels (> 4 mmol/L) was 80% (72–87%) and the specificity was 69% (66–71%). Patients with a gap > 12 had a 7.3-fold (4.6–11.4) increased risk of having a lactate > 4 mmol/L. The area under the curve was 0.84. Conclusion: This study suggests that an elevated AG obtained in the ED is a moderately sensitive and specific means to detect elevated lactate levels in ED patients at risk for sepsis. This information may be somewhat helpful to Emergency Physicians to risk-stratify their patients to provide more aggressive early resuscitation.     

Unmeasured anions identified by the Fencl-Stewart method predict mortality better than base excess, anion gap, and lactate in patients in the pediatric intensive care unit.

OBJECTIVES: This study was undertaken to compare three methods for the identification of unmeasured anions in pediatric patients with critical illness. We compared the base excess (BE) and anion gap (AG) methods with the less commonly used Fencl-Stewart strong ion method of calculating BE caused by unmeasured anions (BEua). We measured the relationship of unmeasured anions identified by the three methods to serum lactate concentrations and to mortality. DESIGN: Retrospective cohort study. SETTING: Tertiary care pediatric intensive care unit in an academic pediatric hospital. PATIENTS: The study population included 255 patients in the pediatric intensive care unit who had simultaneous measurements of arterial blood gases, electrolytes, and albumin during the period of July 1995 to December 1996. Sixty-six of the 255 patients had a simultaneous measurement of serum lactate. MEASUREMENTS AND MAIN RESULTS: The BEua was calculated using the Fencl-Stewart method. The AG was defined as (sodium plus potassium) - (chloride plus total carbon dioxide). BE was calculated from the standard bicarbonate, which is derived from the Henderson-Hasselbalch equation and reported on the blood gas analysis. A BE or BEua value of < or =-5 mEq/L or an AG > or =17 mEq/L was defined as a clinically significant presence of unmeasured anions. A lactate level of > or =45 mg/dL was defined as being abnormally elevated for this study. The presence of unmeasured anions identified by significantly abnormal BEua was poorly identified by BE or AG. Of the 255 patients included in the study, 67 (26%) had a different interpretation of acid base balance when the Fencl method was used compared with when BE and AG were used. Plasma lactate concentration correlated better with BEua (r2 = .55; p = .0001) than with AG (r2 = .41; p = .0005) or BE (r2 = .27; p = .025). Mortality was more strongly related to BEua < or =-5 mEq/L (relative risk of death = 10.25; p = .002) than to lactate > or =45 mg/dL (relative risk of death = 2.35; p = .04). In logistic regression analysis, mortality was more strongly associated with BEua (area under the receiver operating characteristic curve = 0.79; p = .0002) than lactate (receiver operating characteristic curve area = 0.63; p = .05), BE (receiver operating characteristic curve area = 0.53; p = .32), or AG (receiver operating characteristic curve area = 0.64; p = .08) in this patient sample. CONCLUSIONS: Critically ill patients with normal BE and normal AG frequently have elevated unmeasured anions detectable by BEua. The Fencl-Stewart method is better than BE and similar to AG in identifying patients with high lactate levels. Elevated unmeasured anions identified by the Fencl-Stewart method were more strongly associated with mortality than with BE, AG, or lactate in this patient sample.     

Association of anion gap with thyroid dysfunction and nodular goiter in CAPD patients.

OBJECTIVE: To investigate the association of clinical parameters and serum anion gap with thyroid dysfunction and nodular goiter in continuous ambulatory peritoneal dialysis (CAPD) patients. DESIGN: Cross-sectional study. SETTING: Single dialysis unit and outpatient clinic. PATIENTS: This study Included 89 uremic patients on CAPD. Gender ratio was 50 males to 39 females (M/F = 1.28); mean age was 54.8 years. MAIN OUTCOME MEASURES: We investigated the prevalence of nodular goiter and thyroid dysfunction with a 10-MHz high-frequency ultrasound scanner and immunoassay kits. RESULTS: Nodular goiter was detected in 52.8% (47/89) of the CAPD patients. Patients with nodular goiter were older than those without goiter (57.7 vs 51.5 years, p < 0.05). Nodular goiter was found more frequently in females than in males (66.7% vs 44.0%, p < 0.05). Patients with nodular goiter had longer duration of CAPD than patients without goiter (51.6 +/- 42.9 vs 31.0 +/- 28.1 months, p < 0.02). In addition, CAPD patients with goiter had a higher serum anion gap (AG) (16.8 +/- 3.3 vs 14.0 +/- 4.5 mEq/L, p < 0.02) and a lower weekly creatinine clearance (55.9 +/- 12.6 vs 64.6 +/- 21.1 L/week/1.73 m2, p < 0.05) than patients without goiter. As serum AG gradually Increased, significant alteration of thyroid parameters developed In the following sequence: (1) reduction of total T3 level at an AG level of 15, (2) elevation of thyrotropin (TSH) and Increased prevalence of goiter at an AG of 18, and (3) reduction of free T4 and total T4 levels and elevation of TSH, with further increased frequency of goiter at an AG of 20 mEq/L. CONCLUSION: According to this study, age, gender, dialysis duration, serum AG, and weekly creatinine clearance are correlated with prevalence of goiter in CAPD patients. Sequential alteration of thyroid function and Increasing frequency of nodular goiter correlated with higher serum AG. There are two explanations for this correlation: the level of serum AG may be an indirect index of the level of serum goitrogens, and higher serum AG and Increased frequency of nodular goiters might be a reflection of loss of residual renal function. Therefore, thyroid function screening and goiter detection using ultrasound should be considered when examining CAPD patients with progressively elevating serum anion gap.     

Persistent normal anion gap acidosis in the recovery phase of diabetic ketoacidosis

Diabetic ketoacidosis is associated with an increased anion gap but its recovery phase may be complicated by hyperchloraemic acidosis with a normal anion gap. We report a case where this complication developed. There was a delayed return to normal acid-balance, possibly aggravated by administration of hyperchloraemic fluids, and the true diagnosis was overlooked. Measurement of the anion gap remains an important part of the assessment of diabetic acid-base disturbances.     

Clinical utility of anion gap in deciphering acid–base disorders

The anion gap (AG) measurement is a very useful tool in the evaluation of patients with acid–base disorders. Once metabolic acidosis is identified, AG will provide the important first step in the differential diagnosis of disorders that either increase the AG and those that leave the AG unchanged. Delta gap is the comparison between change (delta) in the AG and the change (delta) in bicarbonate (HCO₃^?). Delta ratio, defined as delta AG:delta HCO₃^? is usually 1 : 1 in patients with an uncomplicated high AG acidosis. A value below 1 : 1 suggests a combined high and normal AG acidosis. A value above 2 : 1 suggests a combined metabolic alkalosis and a high AG acidosis. Urine AG (unmeasured anions–unmeasured cations) is an indirect estimate of the urine NH₄⁺ excretion. It is typically negative in patients with normal AG metabolic acidosis secondary to diarrhoea. Utilisation of AG calculations helps clinicians in identifying and treating acid–base disorders.