Unidentified anion gap metabolic acidosis

A 35−month−old female with nonketotic hyperglycinemia (NKH) presented to the Emergency department with severe hypoglycemia, fever, and several episodes of seizures. Due to worsening respiratory status, additional seizures and anion gap worsening metabolic acidosis the patient was transferred to the pediatric intensive care unit. The useful mnemonics for causes of high anion gap metabolic acidosis are the classic MUDPILES (representing Methanol, Uraemia, Diabetes, Paraldehyde, Iron (and Isoniazid), Lactate, Ethylene glycol, and Salicylate) and the more recently proposed GOLD MARK (Glycols [ethylene and propylene], Oxoproline, l-lactate, d-lactate, Methanol, Aspirin, Renal failure, and Ketoacidosis) as causes of the anion gap metabolic acidosis were all ruled out. Relatively stable concentrations of salicylate (approximately 10 mg/dL, 0.7 mmol/L) were noted, despite no evidence the patient received aspirin Therefore further laboratory testing was performed. A Basic-Acid-Neutral (BAN) gas chromatography mass-spectroscopy (GC–MS) Drug screen of urine was undertaken. A large benzoic acid peak was identified by spectral match, which supported the clinical history that the patient was taking sodium benzoate powder 1175 mg as a dietary supplement three times a day. However, salicylate was not identified. This patient had benzoic acid concentration in excess of 2000 μg/mL. Given that benzoic acid is a weak acid, with a pK of approximately 4 it is almost completely ionized at pH 7. Therefore, the large amount of benzoic acid was not only thought to be contributing to the patient's anion gap metabolic acidosis, but the source of the interference in the salicylate assay.     

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.     

High anion gap metabolic acidosis associated with aminocaproic acid

OBJECTIVE: To report a case of high anion gap metabolic acidosis related to infusion of aminocaproic acid (ACA) that temporarily corrected during hemodialysis and resolved upon ACA discontinuation. CASE SUMMARY: A 65-year-old white woman with staphylococcal sepsis complicated by acute renal failure was treated with ACA to control a hemorrhagic coagulopathy. After receiving an initial 5-g bolus of ACA, she received a continuous intravenous infusion of 500 mg/h for just over 5 days, then 250 mg/h for a final 12 hours. Immediately after beginning ACA therapy, she developed a severe anion gap metabolic acidosis that briefly improved after hemodialysis. The condition resolved completely only after the discontinuation of ACA and therapy with a systemic alkalinizer. DISCUSSION: ACA is not among the previously identified causes of high anion gap metabolic acidosis. The temporal profile relating anion gap to ACA initiation, hemodialysis treatment, and ACA discontinuation supports causality in this case. The magnitude of increase in the anion gap appears to have been proportional to the dose of ACA. CONCLUSIONS: In patients with renal impairment, ACA administration may produce a dose-related, high anion gap metabolic acidosis that might be reversible during hemodialysis. Insufficient data are available, but when ACA must be used in such patients, a more conservative dosing of ACA should be coupled with close monitoring.     

对乙酰胺基酚过量患者早期高阴离子间隙代谢性酸中毒的意义

目的 探索对乙酰胺基酚(APAP)过量患者早期高阴离子间隙(≥16 mmol/L)代谢性酸中毒的发生率和临床意义.方法 回顾性研究我院2004-01～2010-01期间62例APAP过量后24 h内就诊的患者.结果 43%患者出现早期高阴离子间隙代谢性酸中毒;阴离子间隙与血乳酸水平呈相关关系(r2 =0.69,P<0.05);高阴离子间隙的患者意识障碍发生率高(44.4% vs 5.7%,P<0.01).结论 APAP过量患者的早期高阴离子间隙代谢性酸中毒是自限性的,不能预测患者的临床预后;乳酸性酸中毒在其发生过程中可能起重要作用,但还需进一步研究;对于有意识障碍的急诊患者,应该考虑到APAP过量.     

Profound metabolic acidosis from pyroglutamic acidemia: an underappreciated cause of high anion gap metabolic acidosis

The workup of the emergency patient with a raised anion gap metabolic acidosis includes assessment of the components of “MUDPILES” (methanol; uremia; diabetic ketoacidosis; paraldehyde; isoniazid, iron or inborn errors of metabolism; lactic acid; ethylene glycol; salicylates). This approach is usually sufficient for the majority of cases in the emergency department; however, there are many other etiologies not addressed in this mnemonic. Organic acids including 5-oxoproline (pyroglutamic acid) are rare but important causes of anion gap metabolic acidosis. We present the case of a patient with profound metabolic acidosis with raised anion gap, due to pyroglutamic acid in the setting of malnutrition and chronic ingestion of acetaminophen.     

Pyroglutamic acidemia: a cause of high anion gap metabolic acidosis

OBJECTIVE: To report four cases of pyroglutamic acidemia in adults causing clinically significant acidosis. DATA SOURCES: Patients admitted to the intensive care units of the Alfred Hospital (a quaternary referral center) and Geelong Hospital (a major regional center) with an unexplained high anion gap acidosis. CONCLUSIONS: Pyroglutamic acidemia (5-oxoprolinemia) is a rare cause of high anion gap metabolic acidosis that should be suspected in patients presenting with sepsis, hepatic, and/or renal dysfunction who are receiving drugs such as acetaminophen, flucloxacillin, and vigabatrin after the more common causes of a high anion gap acidosis have been excluded. Should pyroglutamic aciduria be present, known precipitants should be ceased, infection should be managed aggressively, and supportive management should be instituted.     

The Denver Seizure Score: anion gap metabolic acidosis predicts generalized seizure

Objectives

Anion gap (AG) and serum bicarbonate concentration (BICARB) may help confirm a diagnosis of seizure in an unwitnessed collapse; however, little data exist to support this practice. Our objective was to assess the association between AG metabolic acidosis and generalized seizure and to derive a simple score to predict seizure.

Methods

This was a case-control study at an urban teaching hospital. Patients transported to our emergency department with witnessed loss of consciousness and final confirmed diagnoses of generalized seizure (cases) or syncope (controls) were eligible for enrollment. Multivariable logistic regression analysis was used to model associations between AG, BICARB, and seizure.

Results

In 49 cases and 40 controls, patients in the seizure group were more likely to have a lower median BICARB (17 [range, 14-34] vs 23 [range, 20-24], P < .0001) and a higher median AG (22 [range, 9-42] vs 13 [range, 7-21], P < .0001). The Denver Seizure Score was defined, using regression coefficient weighting, as the Δ BICARB plus twice the Δ AG [(24 − BICARB) + (2×(AG − 12))]. The score ranged from −16 to +74 and identified patients as low likelihood (score <0), moderate likelihood (score 0-20), or high likelihood (score >20), with 21% (95% confidence interval [CI], 5%-51%), 40% (95% CI, 26%-56%), and 96% (95% CI, 82%-100%) being categorized as seizure, respectively.

Conclusions

Anion gap metabolic acidosis is associated with generalized seizure. A Denver Seizure Score greater than 20 predicts generalized seizure in the emergency department and may be useful for differentiating patients with unwitnessed loss of consciousness.     

Metabolic acidosis and coma following a severe acetaminophen overdose

OBJECTIVE: To report a case of metabolic acidosis and coma in a severe acetaminophen overdose. CASE SUMMARY: A 29-year-old white woman was admitted to the emergency department with a diminished level of consciousness and metabolic acidosis. The toxicology screen revealed a serum acetaminophen concentration of 1072 microg/mL, and she was consequently treated with intravenous acetylcysteine. Despite the elevated concentration, the patient did not manifest signs of hepatotoxicity. DISCUSSION: Metabolic acidosis and coma are rare manifestations in acetaminophen overdoses. In published case reports, severe acetaminophen ingestion independently causes metabolic acidosis and coma in the absence of hepatotoxicity. The mechanism by which metabolic acidosis occurs is not clearly defined. Studies conducted on animals demonstrated that in severe overdoses, acetaminophen may cause lactic acidosis by inhibiting mitochondrial respiration. The mechanism by which acetaminophen can cause coma is still unknown. CONCLUSIONS: Severe acetaminophen overdoses can independently cause metabolic acidosis and coma in the absence of hepatotoxicity.     

Hyperlactataemia and metabolic acidosis following paracetamol overdose

Plasma lactate concentrations and acid-base status were determined in 53 patients poisoned with paracetamol. Eleven patients (Group 1) had plasma paracetamol concentrations below the standard treatment decision line; 19 cases (Group 2) presenting within 15 h of overdose had plasma paracetamol concentrations above the treatment line and received N-acetylcysteine. The remaining 23 patients (Group 3) arrived at hospital too late (more than 15 h after overdose) for treatment with N-acetylcysteine to be completely effective. Compensated metabolic acidosis was present on admission in 55 per cent of Group 1 and 42 per cent of Group 2 patients, and a further 21 per cent of cases in Group 2 had an uncompensated metabolic acidosis. Half the patients in Group 3 were acidotic: 22 per cent had a compensated and 26 per cent an uncompensated metabolic acidosis. On admission, the mean plasma lactate concentration was elevated in both Group 2 and Group 3 patients though not in Group 1 cases. Plasma lactate concentration then fell to normal in patients in Group 2 but became mildly elevated again in some cases at a time which coincided closely with the peak in serum aspartate aminotransferase activity. In patients presenting within 15 h of overdose there was a significant correlation between the elevation in plasma concentrations of lactate and paracetamol at admission. In patients presenting late (Group 3), plasma lactate remained elevated for longer than in Group 2 and acidosis and hyperlactataemia were prominent features in the four patients who died. This study demonstrates first that hyperlactataemia, with or without significant acid-base disturbance, is common following paracetamol overdose particularly in those who are severely poisoned. As uncompensated metabolic acidosis is found in 20 per cent of patients who present early and require protective therapy, it should be sought and corrected if it does not remit spontaneously. Second, half the patients presenting too late for effective treatment are acidotic and those with an uncompensated metabolic acidosis resistant to correction have a poor prognosis. Paracetamol poisoning should be considered in the differential diagnosis of metabolic acidosis of unknown aetiology.     

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.     

A life-threatening double gap metabolic acidosis

Double gap metabolic acidosis represents the high anion gap metabolic acidosis combined with raised serum osmolal gap due to retention of unmeasured osmole with accompanied metabolite. We describe a 62-year-old man diagnosed with community-acquired pneumonia undergoing continuous sedation in the context of asynchronous mechanical ventilation. High anion gap metabolic acidosis coupled with high plasma osmolal gap was noted with resultant severe bradyarrhythmia. D-Lactic acidosis and high serum concentration of propylene glycol (PG) eventually established the diagnosis of lorazepam-induced PG intoxication. Discontinuation of lorazepam followed by emergent long-extended hemodialysis effectively resolved the metabolic derangement without further recurrence. Serum osmolal gap is a sensitive and convenient surrogate for both early bedside detection and monitoring the therapeutic efficacy. Therefore, PG intoxication must be considered in the differential diagnosis of double gap metabolic acidosis. Early recognition with prompt hemodialysis intervention can avoid a life-threatening catastrophe.     

Normal "anion gap" (hyperchloremic) acidosis

Hyperchloremic metabolic acidosis in which the anion gap is within normal limits is a common condition in the hospital population, and often presents a difficult diagnostic problem. We describe nine typical cases of this disorder and suggest a logical approach to its evaluation.     

Unaccounted for anion in metabolic acidosis during severe sepsis in humans

OBJECTIVE: To quantitate the contribution of lactate, phosphate, urate, total serum proteins, and unidentified anions to the anion gap in patients with severe sepsis. DESIGN: Thirty critically ill patients with evidence of severe sepsis and systemic hypoperfusion were prospectively studied. MEASUREMENTS: The anion gap was calculated as [Na+] + [K+] - [Cl-] - [HCO3]. A corrected anion gap was calculated as the anion gap minus the anionic contribution of lactate, phosphate, urate, and total serum proteins. The corrected anion gap is a marker of unmeasured anion less unmeasured cation concentration. RESULTS: The mean anion gap was 21.8 +/- 1.4 mmol/L and the corrected anion gap was 3.7 +/- 0.8 mmol/L. The mean arterial blood lactate concentration was 5.9 +/- 0.8 mmol/L. The magnitude of the lactate concentration correlated linearly with the anion gap (r2 = .61, lactate = 0.4 anion gap - 3.9, n = 30, p less than .01). The corrected anion gap was greater than 0 in 24 (80%) of 30 patients. The magnitude of the corrected anion gap correlated linearly with the anion gap (r2 = .66, corrected anion gap = 0.5 anion gap - 6.3, n = 30, p less than .01). Since the slope of the regression line for estimating corrected anion gap from anion gap was 0.5, the contribution of unmeasured anions was as important as lactate in determining the anion gap. CONCLUSION: These data indicate that lactic acidosis does not entirely account for the metabolic acidosis during severe sepsis. Furthermore, the increased corrected anion gap suggests the presence of an unidentified anion (or anions) that is (or are) responsible, in large part, for the development of metabolic acidosis in patients with sepsis.     

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.