Acid-Base Physiology
References for Chapter 8 - Types of Metabolic Acidosis

Adrogue HJ et al. Plasma Acid-Base Patterns in Diabetic Ketoacidosis. New Engl J Med. 1982; 307: 1603-1610.
Boyer EW et al. Severe ethylene glycol ingestion treated without hemodialysis. Pediatrics 2001 Jan;107(1):172-173
Abstract: Fomepizole (4-methylpyrazole, Antizol) is being increasingly used in the treatment of ethylene glycol toxicity in adults. Little experience exists with this drug, however, in the pediatric population. We present a case of ethylene glycol poisoning in a child where use of fomepizole averted intravenous ethanol infusion and hemodialysis, limited the duration of intensive care monitoring, and decreased the overall cost of treatment.
Brent J. Current management of ethylene glycol poisoning. Drugs 2001;61(7):979-988
Abstract: Ethylene glycol, a common antifreeze, coolant and industrial solvent, is responsible for many instances of accidental and intentional poisoning annually. Following ingestion, ethylene glycol is first hepatically metabolised to glycoaldehyde by alcohol dehydrogenase. Glycoaldehyde is then oxidised to glycolic acid, glyoxylic acid and finally oxalic acid. While ethylene glycol itself causes intoxication, the accumulation of toxic metabolites is responsible for the potentially fatal acidosis and renal failure, which characterises ethylene glycol poisoning. Treatment of ethylene glycol poisoning consists of emergent stabilisation, correction of metabolic acidosis, inhibition of further metabolism and enhancing elimination of both unmetabolised parent compound and its metabolites. The prevention of ethylene glycol metabolism is accomplished by the use of antidotes that inhibit alcohol dehydrogenase. Historically, this has been done with intoxicating doses of ethanol. At a sufficiently high concentration, ethanol saturates alcohol dehydrogenase, preventing it from acting on ethylene glycol, thus allowing the latter to be excreted unchanged by the kidneys. However, ethanol therapy is complicated by its own inherent toxicity, and the need to carefully monitor serum ethanol concentrations and adjust the rate of administration. A recent alternative to ethanol therapy is fomepizole, or 4-methylpyrazole. Like ethanol, fomepizole inhibits alcohol dehydrogenase; however it does so without producing serious adverse effects. Unlike ethanol, fomepizole is metabolised in a predictable manner, allowing for the use of a standard, validated administration regimen. Fomepizole therapy eliminates the need for the haemodialysis that is required in selected patients who are non-acidotic and have adequate renal function.

Brivet F et al. Hyperchloraemic Acidosis during Grand Mal Seizure Lactic Acidosis. Intensive Care Med. 1994; 20: 27-31.

Cohen RD & Woods HF. Lactic Acidosis Revisited. Diabetes 1983; 32: 181

Eder AF et al. Ethylene Glycol Poisoning: Toxicokinetic and Analytical Factors Affecting Laboratory Diagnosis. Clin Chem. 1998; 44: 168-177

Felig P. Diabetic Ketoacidosis. New Engl J Med. 1974; 290: 1360-1363

Felts PW. Ketoacidosis. Med Clin Nth Am. 1983; 67: 831-843.

Foster DW & McGarry JD. The Metabolic Derangements and Treatment of Diabetic Ketoacidosis. New Engl JMed.1983; 309: 159-169.

Halperin ML. Lactic Acidosis and Ketoacidosis: Biochemical and Clinical Implications. CMA Journal. 1977; 116: 1034-1038.

Halperin ML. Selected Aspects of the Pathophysiology of Metabolic Acidosis in Diabetic Mellitus. Diabetes. 1981; 30: 781

Halperin ML et al. The Excretion of Ammonium Ions and Acid Base Balance. Clin Biochem 1990; 23: 185-188.
Haviv Y et al. Pseudo-normal osmolal and anion gaps following simultaneous ethanol and methanol ingestion. Am J Nephrol 1998; 18(5): 436-438
Abstract: Methanol, ethylene glycol, and isopropyl alcohol are associated with acute intoxication. The diagnosis is dependent upon high anion-gap metabolic acidosis, and an osmolal gap between the calculated and the measured osmolality. Normal anion gap has been reported in some cases of concomitant methanol and ethanol ingestion, where the high serum levels of ethanol inhibited the metabolism of methanol by alcohol dehydrogenase. The osmolal gap in these cases was higher than expected for methanol, and served as a constant
marker for a metabolic derangement. Herewith, we present a patient who presented with normal osmolal and anion gaps 36 h after ethanol and methanol ingestion, yet progressively developing ocular toxicity. Normal anion and osmolal gaps should not rule out earlier methanol poisoning.
Heckerling PS. Ethylene glycol poisoning with a normal anion gap due to occult bromide intoxication. Ann Emerg Med 1987 Dec;16(12):1384-1386
Abstract: Ethylene glycol poisoning causes metabolic acidosis with an increased anion gap, due to production of organic acid anions during its metabolism. Bromide poisoning may cause a spuriously decreased anion gap when chloride determination is performed with a colorimetric technique. A 39-year-old woman with ethylene glycol poisoning presented in coma, with a hyperchloremic normal anion gap acidosis. The serum bromide level was found to be in the toxic range, confirming the diagnosis of bromide poisoning. Hemodialytic therapy resulted in resolution of electrolyte and acid-base abnormalities, and restoration of a normal state of consciousness. In this patient, clinically occult bromide intoxication caused a spurious lowering of the anion gap, normalizing what was in reality an increased anion gap due to ethylene glycol poisoning.
Kaehny WD & Anderson RJ. Bicarbonate Therapy of Metabolic Acidosis. Crit Care Med. 1994; 22: 1525-1527.
Kitabchi AE & Wall BM. Diabetic Ketoacidosis. Med Clin North Am 1995; 79: 9-36.
Kruse J & Carlson R. Lactate metabolism. Crit Care Clin 1987 Oct;3(4):725-46
Abstract: Lactate is the end product of the anaerobic metabolism of glucose, and its accumulation in the blood signals an increase in production or a decrease in utilization, or both. The most common etiology of lactic acidosis is hypoperfusion, which represents an imbalance between systemic oxygen demand and oxygen availability with resultant tissue hypoxia. A wide variety of other etiologies of hyperlactatemia have been identified or implicated. However, most of these are uncommon causes, and many actually represent an associated perfusion failure. Clinical recognition of hyperlactatemia is facilitated by an awareness of the clinical settings in which it is likely to occur. Serum electrolyte and arterial blood gas studies are helpful to recognize lactic acidosis, but direct assay of blood lactate is necessary to identify milder degrees of lactate elevation, to confirm and quantitate the severity of more severe degrees, and to monitor the progress of therapy. Therapy should be directed toward measures to ensure adequate systemic oxygen delivery and specific treatment of the underlying causes

Lash JP & Arruda JA. Laboratory Evaluation of Renal Tubular Acidosis. Clin Lab Med. 1993; 13: 117-129.

Lebovitz HE. Diabetic Ketoacidosis. The Lancet. 1995; 345: 767-772.
Luft F. Lactic acidosis update for critical care clinicians. J Am Soc Nephrol 2001 Feb;12 Suppl 17:S15-9
Abstract: Lactic acidosis is a broad-anion gap metabolic acidosis caused by lactic acid overproduction or underutilization. The quantitative dimensions of these two mechanisms commonly differ by 1 order of magnitude. Overproduction of lactic acid, also termed type A lactic acidosis, occurs when the body must regenerate ATP without oxygen (tissue hypoxia). Circulatory, pulmonary, or hemoglobin transfer disorders are commonly responsible. Overproduction of lactate also occurs with cyanide poisoning or certain malignancies. Underutilization involves removal of lactic acid by oxidation or conversion to glucose. Liver disease, inhibition of gluconeogenesis, pyruvate dehydrogenase (thiamine) deficiency, & uncoupling of oxidative phosphorylation are the most common causes. The kidneys also contribute to lactate removal. Concerns have been raised regarding the role of metformin in the production of lactic acidosis, on the basis of individual case reports. The risk appears to be considerably less than with phenformin and involves patients with underlying severe renal and cardiac dysfunction. Drugs used to treat lactic acidosis can aggravate the condition. NaHCO(3) increases lactate production. Treatment of type A lactic acidosis is particularly unsatisfactory. NaHCO(3) is of little value. Carbicarb is a mixture of Na(2)CO(3) and NaHCO(3) that buffers similarly to NaHCO(3) but without net generation of CO(2). The results from animal studies are promising; however, clinical trials are sparse.Dichloroacetate stimulates pyruvate dehydrogenase and improves laboratory values, but unfortunately not survival rates, among patients with lactic acidosis. Hemofiltration has been advocated for the treatment of lactic acidosis, on the basis of anecdotal experiences. However, kinetic studies of lactate removal do not suggest that removal can counteract lactate production in any meaningful way. The ideal treatment is to stop acid production by treating the underlying disorder.
Megarbane B et al. Treatment of acute methanol poisoning with fomepizole. Intensive Care Med 2001; 27(8):1370-1378
OBJECTIVE: To assess the efficacy and safety of fomepizole, a competitive alcohol dehydrogenase inhibitor, in methanol poisoning and to test the hypothesis that fomepizole obviates the need for hemodialysis in selected patients.
DESIGN AND SETTING: Retrospective clinical study in three intensive care units in university-affiliated teaching hospitals. 
PATIENTS: All methanol-poisoned patients admitted to these ICUs and treated with fomepizole from 1987-1999 (n=14). 
MEASUREMENTS AND RESULTS: The median plasma methanol concentration was 50 mg/dl (range 4-146), anion gap 22.1 mmol/l (11.8-42.2), arterial pH 7.34 (7.11-7.51), and bicarbonate 17.5 mmol/l (3.0-25.0). Patients received oral or intravenous fomepizole until blood methanol was undetectable. The median cumulative dose was 1250 mg (500-6000); the median number of twice daily doses was 2 (1-16). Four patients underwent hemodialysis for visual impairment present on admission. Four patients with plasma methanol concentrations of 50 mg/dl or higher and treated without hemodialysis recovered fully. Patients without pretreatment visual disturbances recovered, with no sequelae in any case. There were no deaths. Fomepizole was safe and well tolerated, even in the case of prolonged treatment. Analysis of methanol toxicokinetics in five patients demonstrated that fomepizole was effective in blocking methanol's toxic metabolism.
CONCLUSIONS: Fomepizole appears safe and effective in the treatment of methanol-poisoned patients. If our results are confirmed in prospective analyses, hemodialysis may prove unnecessary in patients presenting without visual impairment or severe acidosis.
McKinney PE et al. Butoxyethanol ingestion with prolonged hyperchloremic metabolic acidosis treated with ethanol therapy. J Toxicol Clin Toxicol 2000;38(7):787-793
Abstract: Severe toxic ingestions of butoxyethanol (CAS No. 111-76-2) are rare despite the prevalence of this glycol ether in products such as glass and surface cleaners. Manifestations of acute butoxyethanol toxicity include metabolic acidosis, hemolysis, hepatorenal dysfunction, and coma, but vary widely in reported cases. Furthermore, the optimal therapeutic approach is not yet established. Much of the toxicity of butoxyethanol has been ascribed to its aldehyde and acid metabolites which are similar to those produced by oxidative metabolism of methanol and ethylene glycol. Although the roles of alcohol dehydrogenase inhibition with ethanol or fomepizole and hemodialysis are clear in the case of toxic ingestions of methanol and ethylene glycol, they remain poorly defined for butoxyethanol poisoning. CASE REPORT: We report the case of a 51-year-old female who ingested up to 8 ounces of Sanford Expo White Board Cleaner (butoxyethanol and isopropanol). She developed prolonged hyperchloremic metabolic acidosis and mental status depression and was treated with ethanol therapy but not hemodialysis. This patient recovered without apparent sequelae. The kinetics of butoxyethanol metabolism in this case are described and the potential therapeutic options are discussed.

Munro JF et al. Euglycaemic Diabetic Ketoacidosis. Br Med J. 1973; 2: 578-80.

Narins RG & Cohen JJ. Bicarbonate Therapy for Organic Acidosis: The Case for Its Continued Use. Ann Int Med.
1987;106: 615-618.

Oh MS et al. Hyperchloremic Acidosis During the Recovery Phase of Diabetic Ketosis. Ann Int Med. 1978; 89:

Oster JR & Epstein M. Acid-Base Aspects of Ketoacidosis. Am J Nephrol. 1984; 4: 137


Schade DS & Eaton RP. Differential Diagnosis and Therapy of Hyperketonemic State. JAMA 1979; 241: 2064-

Sebastian A & Morris RC. Renal Tubular Acidosis. Clin. Nephrol. 1977; 7: 216-230.

Stacpoole P. Lactic acidosis. Endocrinol Metab Clin North Am 1993 Jun;22(2):221-45
Abstract: Lactic acidosis is the most common metabolic acidosis. At clinical presentation, several causes usually can be identified. The liver is a major site of removal of lactate and hydrogen ions, and abnormalities in the aerobic metabolism of lactate by mitochondria in hepatocytes and other cells may contribute to many clinical conditions in which overproduction and underuse of lactate occur. To date, no therapy specifically designed to lower arterial blood lactate levels has reduced mortality significantly. Prompt recognition and treatment of the underlying causes of lactic acidosis remain the cornerstone of treatment.


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All material Copyright - Kerry Brandis, 2001

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