P A Gabow
Disorders associated with an altered anion gap.
Kidney Int. 1985 Feb;27(2):472-83.
Abstract/Text
Jeffrey A Kraut, Nicolaos E Madias
Serum anion gap: its uses and limitations in clinical medicine.
Clin J Am Soc Nephrol. 2007 Jan;2(1):162-74. doi: 10.2215/CJN.03020906. Epub 2006 Dec 6.
Abstract/Text
The serum anion gap, calculated from the electrolytes measured in the chemical laboratory, is defined as the sum of serum chloride and bicarbonate concentrations subtracted from the serum sodium concentration. This entity is used in the detection and analysis of acid-base disorders, assessment of quality control in the chemical laboratory, and detection of such disorders as multiple myeloma, bromide intoxication, and lithium intoxication. The normal value can vary widely, reflecting both differences in the methods that are used to measure its constituents and substantial interindividual variability. Low values most commonly indicate laboratory error or hypoalbuminemia but can denote the presence of a paraproteinemia or intoxication with lithium, bromide, or iodide. Elevated values most commonly indicate metabolic acidosis but can reflect laboratory error, metabolic alkalosis, hyperphosphatemia, or paraproteinemia. Metabolic acidosis can be divided into high anion and normal anion gap varieties, which can be present alone or concurrently. A presumed 1:1 stoichiometry between change in the serum anion gap (DeltaAG) and change in the serum bicarbonate concentration (DeltaHCO(3)(-)) has been used to uncover the concurrence of mixed metabolic acid-base disorders in patients with high anion gap acidosis. However, recent studies indicate variability in the DeltaAG/DeltaHCO(3)(-) in this disorder. This observation undercuts the ability to use this ratio alone to detect complex acid-base disorders, thus emphasizing the need to consider additional information to obtain the appropriate diagnosis. Despite these caveats, calculation of the serum anion gap remains an inexpensive and effective tool that aids detection of various acid-base disorders, hematologic malignancies, and intoxications.
メトホルミンの適正使用に関する Recommendation（2020年3月18日改訂）．http://www.fa.kyorin.co.jp/jds/uploads/recommendation_metformin.pdf.
R A Kreisberg
Lactate homeostasis and lactic acidosis.
Ann Intern Med. 1980 Feb;92(2 Pt 1):227-37.
Abstract/Text
The roles of changes in cellular redox, interorgan lactate flux and balance, and quantitative aspects of lactate metabolism in the pathogenesis of lactic acidosis are discussed. Altered metabolism of pyruvate is central to the development of lactic acidosis and hyperlactatemia. Lactic acidosis occurs as a result of a relative or absolute imbalance in lactate production and utilization. Lactate utilization for oxidative purposes and for the resynthesis of glucose is essential for the maintenance of acid-base balance. Because of its role in lactate homeostasis the liver may play a central role in acid-base balance. Impairment of hepatic utilization of lactate may produce lactic acidosis.
N E Madias
Lactic acidosis.
Kidney Int. 1986 Mar;29(3):752-74.
Abstract/Text
M Fulop, M Horowitz, A Aberman, E R Jaffe
Lactic acidosis in pulmonary edema due to left ventricular failure.
Ann Intern Med. 1973 Aug;79(2):180-6.
Abstract/Text
M H Weil, A A Afifi
Experimental and clinical studies on lactate and pyruvate as indicators of the severity of acute circulatory failure (shock).
Circulation. 1970 Jun;41(6):989-1001.
Abstract/Text
J D Lalau, P F Westeel, X Debussche, H Dkissi, M Tolani, B Coevoet, B Temperville, A Fournier, J Quichaud
Bicarbonate haemodialysis: an adequate treatment for lactic acidosis in diabetics treated by metformin.
Intensive Care Med. 1987;13(6):383-7.
Abstract/Text
Lactic acidosis in diabetics on metformin therapy is rare but still associated with poor prognosis. The authors report here five cases. Three patients were initially with a cardiovascular collapse and all had an acute renal failure. Sodium bicarbonate haemodialysis therapy led to a dramatic improvement. Consciousness and hemodynamic status recovered rapidly. Severe metabolic and blood gases derangements were also rapidly corrected. Plasma metformin removal, appreciated by repeated blood samplings in 3 cases, was satisfactory. All patients survived. However, blood metformin levels remained abnormally high at the end of the dialytic therapy. In conclusion, (1) bicarbonate dialysis is an adequate treatment of lactic acidosis observed in diabetic patients treated with metformin since it rapidly corrects the acid-base disorders and partially removes metformin; (2) the sole accumulation of metformin is not sufficient to explain lactic acidosis since this latter might be corrected in spite of persisting high levels of blood metformin.
D Heaney, A Majid, B Junor
Bicarbonate haemodialysis as a treatment of metformin overdose.
Nephrol Dial Transplant. 1997 May;12(5):1046-7.
Abstract/Text
M E Coghlan, J P Sommadossi, N C Jhala, W J Many, M S Saag, V A Johnson
Symptomatic lactic acidosis in hospitalized antiretroviral-treated patients with human immunodeficiency virus infection: a report of 12 cases.
Clin Infect Dis. 2001 Dec 1;33(11):1914-21. doi: 10.1086/323783. Epub 2001 Oct 24.
Abstract/Text
We retrospectively investigated the clinical and histopathologic features of hospitalized patients infected with human immunodeficiency virus who had symptomatic lactic acidosis syndrome at a university teaching hospital during 1995-2000. Twelve patients were identified, 11 during 1998-2000; of these, 5 died with rapid progression to otherwise unexplained multiple-organ failure. All had extensive prior exposure to nucleoside analog reverse-transcriptase inhibitors (NRTIs). At presentation, the most commonly identified NRTI component of antiretroviral regimens was stavudine plus didanosine. Eleven patients presented with abdominal pain, nausea, and/or emesis. Eight patients had prior acute weight loss (mean [+/-SD], 12+/-5.3 kg). Median venous plasma lactate levels were > or =2-fold greater than the upper limit of normal (2.1 mmol/L). Serum transaminase levels were near normal limits at presentation. Histopathologic studies confirmed hepatic macrovesicular and microvesicular steatosis in 6 patients. Concurrent chemical pancreatitis was identified in 6 patients. The increasing number of cases identified during the study period suggests that physicians better recognize symptomatic lactic acidosis and/or that cumulative NRTI exposure may increase the risk for this syndrome.
Mina John, Simon Mallal
Hyperlactatemia syndromes in people with HIV infection.
Curr Opin Infect Dis. 2002 Feb;15(1):23-9.
Abstract/Text
Hyperlactatemia associated with use of nucleoside analogue reverse transcriptase inhibitors (NRTIs) is not a single entity but a spectrum of abnormalities. The spectrum reflects varying degrees of derangement in systemic homeostasis in the face of primary drug effects on lactate load. Lactic acidosis, characterized by metabolic acidosis, blood lactate above 5 mmol/l, hepatic steatosis and high mortality, represents the extreme end of this spectrum where there is complete decompensation. Partially compensated states of lactate excess have now been described, ranging from less fulminant symptomatic hyperlactatemia with hepatic steatosis to chronic or intermittent low-grade hyperlactatemia without acidosis, steatosis or any symptoms. At a population level, average venous lactate concentrations do rise following treatment with NRTIs but stabilize long term in the majority of cases. The average increase in systemic lactate turnover that is required to maintain such compensated blood levels is not known and research into this may provide insights into the extent of incipient mitochondrial toxicity associated with chronic NRTI use. At a tissue-specific level, it is not known which tissues or organs (liver, fat, other) are the predominant contributors to an increase in systemic lactate load, nor whether the primary defect is one of increased production, decreased elimination or both.
M H Mokrzycki, C Harris, H May, J Laut, J Palmisano
Lactic acidosis associated with stavudine administration: a report of five cases.
Clin Infect Dis. 2000 Jan;30(1):198-200. doi: 10.1086/313594.
Abstract/Text
Type "B" lactic acidosis has been described in patients receiving the nucleoside analogs zidovudine, didanosine, and fialuridine. Lactic acidosis has also been described in 4 patients receiving combination therapy with stavudine and lamivudine. We describe the development of chronic type "B" lactic acidosis in 3 patients receiving stavudine as a single agent and in 2 patients receiving combination therapy with stavudine and either lamivudine or delavirdine, a nonnucleoside analog. All patients presented with abdominal pain, vomiting, and hepatic steatosis. Other signs of mitochondrial toxicity included pancreatitis and myopathy (2 cases). The mean duration of stavudine therapy was 9.4 months, and the mean observed peak lactate level+/-SD was 10.3+/-5 mmol/L. After discontinuation of stavudine treatment, lactic acidosis improved in 4 patients after 4-60 weeks, and 1 patient died. Evaluations for other causes of lactic acidosis, including hypoxemia, malignancy, sepsis, and cardiogenic shock, were negative.
K D Miller, M Cameron, L V Wood, M C Dalakas, J A Kovacs
Lactic acidosis and hepatic steatosis associated with use of stavudine: report of four cases.
Ann Intern Med. 2000 Aug 1;133(3):192-6.
Abstract/Text
BACKGROUND: An association between use of zidovudine and didanosine and a rare but life-threatening syndrome of hepatic steatosis, lactic acidosis, and myopathy has been reported.
OBJECTIVE: To describe the syndrome of hepatic steatosis, lactic acidosis, and myopathy in four patients taking stavudine.
DESIGN: Case series.
SETTING: A community hospital in Washington, D.C., and National Institutes of Health Clinical Center, Bethesda, Maryland.
PATIENTS: Two men and two women with HIV-1 infection who were taking stavudine presented with lactic acidosis and elevated levels of aminotransferases. All patients required intensive care.
MEASUREMENTS: Levels of lactic acid, alanine aminotransferase, aspartate aminotransferase, amylase, and lipase; computed tomography of the abdomen; liver biopsy (two patients); and muscle biopsy (two patients).
RESULTS: Histologic findings consistent with mitochondrial injury confirmed the diagnosis of hepatic or muscle abnormality.
CONCLUSION: Because hepatic steatosis may be life-threatening, physicians should consider it as a possible cause of elevated hepatic aminotransferase levels among patients taking stavudine.
Vicente Falcó, Dolors Rodríguez, Esteban Ribera, Esteban Martínez, José Maria Miró, Pere Domingo, Ruth Diazaraque, José R Arribas, Juan J González-García, Francesc Montero, Lluis Sánchez, Albert Pahissa
Severe nucleoside-associated lactic acidosis in human immunodeficiency virus-infected patients: report of 12 cases and review of the literature.
Clin Infect Dis. 2002 Mar 15;34(6):838-46. doi: 10.1086/339041. Epub 2002 Feb 13.
Abstract/Text
Lactic acidosis is a rare but often fatal complication reported in some human immunodeficiency virus (HIV)-infected patients treated with nucleoside-analogue reverse-transcriptase inhibitors. We report a series of 12 patients with HIV infection treated with nucleoside analogues who developed unexplained metabolic acidosis. We have also reviewed 60 additional published cases. The aim of the present study is to describe the clinical picture, prognostic factors, and final outcome for nucleoside-associated lactic acidosis. The mortality rate is high: 33% for our patients, and 57% for the patients described in the literature. In the multivariate analysis, a lactate serum level of >10 mM (odds ratio [OR], 13.23; 95% confidence interval [CI], 2.96-59.25) was the only factor associated with higher mortality. The administration of specific therapy with cofactors against acidosis was associated with a lower mortality (OR, 0.17; 95% CI, 0.04-0.73). We conclude that specific therapy with cofactors may improve the outcome for patients with this syndrome.
K Brinkman
Management of hyperlactatemia: no need for routine lactate measurements.
AIDS. 2001 Apr 13;15(6):795-7.
Abstract/Text
E B Marliss, J L Ohman, T T Aoki, G P Kozak
Altered redox state obscuring ketoacidosis in diabetic patients with lactic acidosis.
N Engl J Med. 1970 Oct 29;283(18):978-80. doi: 10.1056/NEJM197010292831807.
Abstract/Text
H J Adrogué, N E Madias
Management of life-threatening acid-base disorders. First of two parts.
N Engl J Med. 1998 Jan 1;338(1):26-34. doi: 10.1056/NEJM199801013380106.
Abstract/Text
R J Velez, B Myers, M S Guber
Severe acute metabolic acidosis (acute beriberi): an avoidable complication of total parenteral nutrition.
JPEN J Parenter Enteral Nutr. 1985 Mar-Apr;9(2):216-9.
Abstract/Text
Total parenteral nutrition is one of the most important recent advances in medicine. The delivery of total parenteral nutrition, however, can be associated with a broad spectrum of complications ranging from mechanical (catheter related) to metabolic. We have recently seen a previously unreported complication of total parenteral nutrition - three patients maintained on total parenteral nutrition, who did not receive vitamins and experienced the acute onset of life-threatening metabolic acidosis with pH values as low as 6.70. All responded promptly and completely to the administration of intravenous thiamine, and thus were probably examples of acute beriberi. Acute beriberi is a well-documented syndrome which usually occurs in nutritionally compromised individuals outside the hospital setting who lack thiamine in their diet. Without thiamine, glucose cannot enter the Krebs cycle in order to be completely oxidized for energy production and therefore, accumulates as lactic acid. This lactic acidosis is refractory to any treatment except thiamine and will result in cardiovascular collapse if the vitamin is not administered.
野村昌哉, 中尾量保, 仲原正明, 荻野信夫, 弓場健義, 宮崎知, 江本節, 黒住和史, 成田匡志. 高カロリー輸液施行中に発症したビタミンB1欠乏による乳酸アシドーシスの1症例. 日消外会誌1997;30:97-101.
足立洋希, 鈴木知子, 日野原千速, 安井玲子, 今井千鶴子, 新島梨恵, 村井聡美, 長井俊道, 近藤純子, 河野公子, 柳内秀勝.ビタミンB1内服中にも関わらずビタミンB1欠乏症による乳酸アシドーシスを発症した摂食障害の一例. 日本病態栄養学会誌2011;14:241-6.
S M Forsythe, G A Schmidt
Sodium bicarbonate for the treatment of lactic acidosis.
Chest. 2000 Jan;117(1):260-7.
Abstract/Text
Lactic acidosis often challenges the intensivist and is associated with a strikingly high mortality. Treatment involves discerning and correcting its underlying cause, ensuring adequate oxygen delivery to tissues, reducing oxygen demand through sedation and mechanical ventilation, and (most controversially) attempting to alkalinize the blood with IV sodium bicarbonate. Here we review the literature to answer the following questions: Is a low pH bad? Can sodium bicarbonate raise the pH in vivo? Does increasing the blood pH with sodium bicarbonate have any salutary effects? Does sodium bicarbonate have negative side effects? We find that the oft-cited rationale for bicarbonate use, that it might ameliorate the hemodynamic depression of metabolic acidemia, has been disproved convincingly. Further, given the lack of evidence supporting its use, we cannot condone bicarbonate administration for patients with lactic acidosis, regardless of the degree of acidemia.
D J Cooper, K R Walley, B R Wiggs, J A Russell
Bicarbonate does not improve hemodynamics in critically ill patients who have lactic acidosis. A prospective, controlled clinical study.
Ann Intern Med. 1990 Apr 1;112(7):492-8.
Abstract/Text
STUDY OBJECTIVE: To determine whether correction of acidemia using bicarbonate improves hemodynamics in patients who have lactic acidosis.
DESIGN: Prospective, randomized, blinded, crossover study. Each patient sequentially received sodium bicarbonate and equimolar sodium chloride. The order of the infusions was randomized.
SETTING: Intensive care unit of a tertiary care hospital.
PATIENTS: Fourteen patients who had metabolic acidosis (bicarbonate less than 17 mmol/L and base excess less than -10) and increased arterial lactate (mean, 7.8 mmol/L). All had pulmonary artery catheters and 13 were receiving catecholamines.
MEASUREMENTS AND MAIN RESULTS: Sodium bicarbonate (2 mmol/kg body weight over 15 minutes) increased arterial pH (7.22 to 7.36, P less than 0.001), serum bicarbonate (12 to 18 mmol/L, P less than 0.001), and partial pressure of CO2 in arterial blood (PaCO2) (35 to 40 mm Hg, P less than 0.001) and decreased plasma ionized calcium (0.95 to 0.87 mmol/L, P less than 0.001). Sodium bicarbonate and sodium chloride both transiently increased pulmonary capillary wedge pressure (15 to 17 mm Hg, and 14 to 17 mm Hg, P less than 0.001) and cardiac output (18% and 16%, P less than 0.01). The mean arterial pressure was unchanged. Hemodynamic responses to sodium bicarbonate and sodium chloride were the same. These data have more than 90% power of detecting a 0.5 L/min (7%) change in mean cardiac output after administration of sodium bicarbonate compared with that after sodium chloride. Even the 7 most acidemic patients (mean pH, 7.13; range, 6.90 to 7.20) had no significant hemodynamic changes after either infusion.
CONCLUSIONS: Correction of acidemia using sodium bicarbonate does not improve hemodynamics in critically ill patients who have metabolic acidosis and increased blood lactate or the cardiovascular response to infused catecholamines in these patients. Sodium bicarbonate decreases plasma ionized calcium and increases PaCO2.
M L Weisfeldt, A D Guerci
Sodium bicarbonate in CPR.
JAMA. 1991 Oct 16;266(15):2129-30.
Abstract/Text
F Kette, M H Weil, M von Planta, R J Gazmuri, E C Rackow
Buffer agents do not reverse intramyocardial acidosis during cardiac resuscitation.
Circulation. 1990 May;81(5):1660-6.
Abstract/Text
We investigated the effects of carbon dioxide-producing and carbon dioxide-consuming buffers on intramyocardial pH and on cardiac resuscitability. In 29 pigs, intramyocardial pH was continuously measured with a glass electrode advanced into the midmyocardium of the posterior left ventricle through a diaphragmatic window. Ventricular fibrillation (VF) was electrically induced by alternating current applied to the epicardium of the left ventricle. After 3 minutes of VF, precordial compression was begun and continued for an interval of 8 minutes. Sodium bicarbonate (a carbon dioxide-generating buffer), Carbicarb (a carbon dioxide-consuming buffer), and hypertonic sodium chloride (control solution) were infused into the right atrium during cardiac resuscitation. Defibrillation was attempted by transthoracic direct-current shock after 11 minutes of VF. Intramyocardial pH progressively decreased from an average value of 7.26 before VF to 6.87 before infusion of buffers. Systemic circulation and great cardiac vein pH significantly increased after administration of the two buffer agents. However, intramyocardial pH continued to decline to an average of 6.62 after 11 minutes of VF, and this decline was not altered by either buffer solution or by the saline control. As in previous studies, resuscitability was closely related to coronary perfusion pressure at the time of direct-current countershock but not to pH. Accordingly, the rationale of reversing acidosis by the administration of these buffer agents is not supported. Even more important, neither carbon dioxide-consuming nor carbon dioxide-producing buffers altered myocardial acidosis or improved myocardial resuscitability under controlled experimental conditions of cardiac arrest.
