Correspondence
Acid–Base Disorders
N Engl J Med 1998; 338:1626-1629May 28, 1998
- Article
To the Editor:
We respectfully disagree with Adrogué and Madias (Jan. 1 and Jan. 8 issues)1 on a number of issues in their review of acid–base disturbances. The authors fail to emphasize that, except in specific circumstances, such as methanol or ethylene glycol poisoning, there is no scientific evidence to support treating a metabolic or respiratory acidosis with sodium bicarbonate. Furthermore, it is the intracellular pH that is important in determining cellular function.2 The intracellular buffering system is much more effective than the extracellular buffers in restoring pH to normal.2 Consequently, patients have tolerated a pH as low as 7.0 during sustained hypercapnia, without obvious adverse effects.3
In addition, the authors imply that the dissociation of lactate is responsible for the acidosis seen in patients with tissue hypoxia. Krebs et al. first noted that the acidosis that occurs during increased glycolysis caused by inadequate cellular oxygen delivery is produced by ATP that is continually being hydrolyzed.4 The hydrolysis of ATP releases protons (H+) that are responsible for the metabolic acidosis that accompanies hypoxia. The increase in ATP-producing protons drives the equilibrium reaction from pyruvate to lactic acid, causing the lactic acid:pyruvate ratio to shift from the normal ratio of approximately 10:1 to a higher ratio. Furthermore, it is important to note that increased glycolysis leads to the production of lactic acid, not lactate. Because of the low pK a of lactic acid (3.86), dissociation to lactate and H+ occurs only when the pH is less than 6, which is far below the pH encountered in clinical medicine.
The authors state that in patients with lactic acidosis, “drugs causing vasoconstriction (such as norepinephrine) should be avoided, since they can worsen tissue hypoxia.” This statement is incorrect. Numerous studies have demonstrated that in patients with sepsis, norepinephrine improves hemodynamics, as well as local and global indexes of tissue oxygenation.5,6
With respect to the management of metabolic alkalosis, we believe that the authors overemphasize the role of hydrochloric acid. We have reported that acetazolamide is safe and efficacious in this setting.7
7 ReferencesPaul Marik, M.D.
St. Vincent Hospital, Worcester, MA 01640Joseph Varon, M.D.
Methodist Hospital, Houston, TX 770301
Adrogue HJ ,Madias NE . Management of life-threatening acid-base disorders. N Engl J Med 1998;338:26-34, 107
Full Text | Web of Science | Medline2
Siesjo BK . Quantification of pH regulation in hypercapnia and hypocapnia. Scand J Lab Invest 1971;28:113-119
CrossRef | Web of Science | Medline3
Hickling KG ,Henderson SJ ,Jackson R . Low mortality associated with low volume pressure limited ventilation with permissive hypercapnia in severe adult respiratory distress syndrome. Intensive Care Med 1990;16:372-377
CrossRef | Web of Science | Medline4
Krebs HA ,Woods HF ,Alberti KGMM . Hyperlactataemia and lactic acidosis. Essays Med Biochem 1970;1:81-1035
Marik PE ,Mohedin M . The contrasting effects of dopamine and norepinephrine on systemic and splanchnic oxygen utilization in hyperdynamic sepsis. JAMA 1994;272:1354-1357
CrossRef | Web of Science | Medline6
Levy B ,Bollaert PE ,Charpentier C , et al. Comparison of norepinephrine and dobutamine to epinephrine for hemodynamics, lactate metabolism, and gastric tonometric variables in septic shock: a prospective, randomized study. Intensive Care Med 1997;23:282-287
CrossRef | Web of Science | Medline7
Marik PE ,Kussman BD ,Lipman J ,Kraus P . Acetazolamide in the treatment of metabolic alkalosis in critically ill patients. Heart Lung 1991;20:455-459
Web of Science | Medline
To the Editor:
We commend Adrogué and Madias on their excellent review of life-threatening acid–base disorders. However, some points regarding the management of ethylene glycol and methanol poisoning merit clarification. First, although it is a benign therapy, activated charcoal is unlikely to bind such small and rapidly absorbed molecules in vivo.1 Clearly, the use of activated charcoal is indicated if there is a concern about coingestants.
The authors correctly note, “Large amounts of alkali are often required to combat the severe acidemia.” Further evidence suggests additional benefits of bicarbonate therapy in patients with methanol poisoning. Urinary alkalinization enhances the elimination of formate, the toxic metabolite. The concentration gradient created limits the accumulation of formate in the brain and eyes.2
The data supporting the use of forced diuresis to prevent the acute tubular necrosis that occurs in severe ethylene glycol poisoning are extremely limited.3 Furthermore, severe fluid and electrolyte abnormalities may result from attempts at forced diuresis. More beneficial measures include the prevention of dehydration and blockade of alcohol dehydrogenase, the enzyme required for the formation of toxic metabolites. The blockade of alcohol dehydrogenase has traditionally been accomplished with the use of ethanol, a competitive alcohol dehydrogenase inhibitor. As of early December 1997, however, the Food and Drug Administration had approved the use of fomepizole (4-methylpyrazole) for the management of ethylene glycol poisoning. Its use for the treatment of methanol poisoning is currently being evaluated.
Ultimately, hemodialysis may be required for patients with severe ethylene glycol or methanol poisoning. Methanol may be redistributed from tissues after dialysis, and a second hemodialysis procedure may be required.4 Therefore, techniques used to inhibit alcohol dehydrogenase and enhance elimination should be continued until post-hemodialysis levels are determined.
4 ReferencesRama B. Rao, M.D.
Robert S. Hoffman, M.D.
New York City Poison Control Center, New York, NY 100161
Neuvonen PJ ,Olkkola KT . Oral activated charcoal in the treatment of intoxications: role of single and repeated doses. Med Toxicol Adverse Drug Exp 1988;3:33-58
Medline2
Jacobsen D ,McMartin KE . Methanol and ethylene glycol poisonings: mechanism of toxicity, clinical course, diagnosis and treatment. Med Toxicol 1986;1:309-334
Medline3
Cheng JT ,Beysolow TD ,Kaul B ,Weisman R ,Feinfeld DA . Clearance of ethylene glycol by kidneys and hemodialysis. J Toxicol Clin Toxicol 1987;25:95-108
CrossRef | Medline4
Swartz RD ,Millman RP ,Billi JE , et al. Epidemic methanol poisoning: clinical and biochemical analysis of a recent episode. Medicine (Baltimore) 1981;60:373-382
CrossRef | Web of Science | Medline
To the Editor:
Drs. Adrogué and Madias use A– to denote “unmeasured plasma anions.” The value given for this variable in Figure 1 and Figure 2 is 10 mmol per liter. This leads to confusion between the terms “unmeasured anions” and “anion gap.” The anion gap usually refers to the numerical difference between the “unmeasured” anions (or, more precisely, those not included in the calculation — namely, negative charges on albumin, sulfate, phosphate, and other anions) and the “unmeasured” cations (again, more precisely, those not included in the calculation, such as potassium, calcium, and magnesium). Under normal circumstances, this difference is approximately 10 to 12 mmol per liter and is referred to as the anion gap.1 The actual value for the concentration of “unmeasured anions” is greater (16 to 18 mmol per liter). Accuracy in the use of terminology is important in the diagnosis of disorders that can modify the anion gap, through alterations in the concentrations of either the unmeasured anions or the unmeasured cations, without necessarily being associated with an acid–base disorder.
1 ReferencesKarl Skorecki, M.D.
Rambam Medical Center, Haifa 31096, Israel1
Gabow PA . Disorders associated with an altered anion gap. Kidney Int 1985;27:472-483
CrossRef | Web of Science | Medline
To the Editor:
Adrogué and Madias recommend the use of intravenous hydrochloric acid for the accelerated correction of severe metabolic alkalosis. We agree that this is a safe and effective method, with hydrochloric acid infused in standard solutions or in parenteral nutrient mixtures containing amino acids, dextrose, electrolytes, and vitamins. However, the concentration recommended as the upper limit, 0.2 N (200 mmol per liter), or any higher concentration, has been shown to cause degradation of central catheters.1 Clinically significant concentrations of 0.1 N (100 mmol per liter) were not injurious and have been widely used by us2,3 and others.
A second concern is that hydrochloric acid is contraindicated in total nutrient mixtures containing amino acids, dextrose, and fat, because the low pH induced by even 0.1 N solutions destabilizes the three-in-one emulsion.2 This can lead to embolic pneumonia from very large fat particles, with potentially serious clinical consequences. Peripheral administration of hydrochloric acid mixed with amino acids and coinfused with fat emulsion,4 which the authors refer to as an alternative to central administration, is potentially hazardous for the same reason, given the low measured pH in the study cited, even when the duration of exposure of fat emulsion to hydrochloric acid is minimized by the branch connection used. Furthermore, the data in this study 4 were limited to two patients, in one of whom there was evidence of the development of thrombi in the peripheral vein used for infusion. We recommend not using this technique for peripheral administration of hydrochloric acid.
4 ReferencesBruce R. Bistrian, M.D., Ph.D.
Karen C. McCowen, M.D.
David Driscoll, Ph.D.
Beth Israel Deaconess Medical Center, Boston, MA 022151
Kopel RF ,Durbin CG Jr . Pulmonary artery catheter deterioration during hydrochloric acid infusion for the treatment of metabolic alkalosis. Crit Care Med 1989;17:688-689
CrossRef | Web of Science | Medline2
Driscoll DF ,Blackburn GL . Total parenteral nutrition 1990: a review of its current status in hospitalised patients, and the need for patient-specific feeding. Drugs 1990;40:346-363
CrossRef | Web of Science | Medline3
Daley BJ, Cahill S, Driscoll DF, Bistrian BR. Parenteral and enteral nutrition. In: Wolfe MM, ed. Gastrointestinal pharmacotherapy. Philadelphia: W.B. Saunders, 1993:302.
4
Knutsen OH . New method for administration of hydrochloric acid in metabolic alkalosis. Lancet 1983;1:953-956
CrossRef | Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: Contrary to the views of Drs. Marik and Varon, extensive experimental and clinical evidence indicates that bicarbonate therapy in patients with severe metabolic acidemia caused by one of several entities (cholera and other diarrheal states, renal tubular acidosis, renal failure, or various intoxications) can be lifesaving. The rationale for the salutary effects of alkali is addressed in our article.1 Furthermore, we2 and others3,4 have previously provided a detailed defense of the thesis that severe metabolic acidemia caused by lactic acidosis warrants the judicious administration of bicarbonate, as specified in our article.1 Similarly, having weighed the available knowledge, we consider it prudent to administer alkali for severe acidemia in patients with permissive hypercapnia.1 The origin of the proton excess during hyperlactatemia was beyond the scope of our article. We have addressed this issue in detail elsewhere.2
We stand by our recommendation that vasoconstrictors, such as norepinephrine, should be avoided in patients with lactic acidosis. Neither of the studies cited by Drs. Marik and Varon involved patients with lactic acidosis, and one of the studies actually investigated the effects of the combination of norepinephrine and dobutamine, not norepinephrine itself. Finally, acetazolamide is not a substitute for hydrochloric acid in the management of severe metabolic alkalosis; the indications for these agents and their limitations, efficacy, and side effects differ considerably.1
We agree with Drs. Rao and Hoffman about the limited value of activated charcoal in the management of methanol and ethylene glycol intoxication. Also, we concur that the evidence supporting forced diuresis to prevent acute renal failure in severe ethylene glycol poisoning is limited. Nonetheless, forced diuresis may augment the elimination of the toxin, since its renal clearance can reach a level of 28 ml per minute.5
It has been a long-standing practice to use the expressions “unmeasured anion concentration” and “anion gap” interchangeably to denote the term [Na+–(Cl–+HCO3–)]. However, as Dr. Skorecki points out, the anion gap can also be defined as the difference between the “unmeasured anions” (UA–; i.e., all plasma anions other than Cl– and HCO3–) and the “unmeasured cations” (UC+; i.e., all plasma cations other than Na+), as follows:
or
As indicated, the two definitions of the anion gap denote an identical numerical term. Despite the time-honored practice, Dr. Skorecki's suggestion that “unmeasured anion concentration” and “anion gap” not be used synonymously is appropriate.
The safety and efficacy of infusing hydrochloric acid as a 0.1 to 0.2 N solution through a central catheter is based on numerous reports and extensive personal experience. We agree with Bistrian et al. that the data on peripheral administration of hydrochloric acid mixed with amino acids and coinfused with a fat emulsion are scanty, and we appreciate their recommendation not to use this method of infusion.
5 ReferencesHoracio J. Adrogué, M.D.
Veterans Affairs Medical Center, Houston, TX 77030Nicolaos E. Madias, M.D.
New England Medical Center, Boston, MA 021111
Adrogue HJ ,Madias NE . Management of life-threatening acid-base disorders. N Engl J Med 1998;338:26-34, 107
Full Text | Web of Science | Medline2
Madias NE . Lactic acidosis. Kidney Int 1986;29:752-774
CrossRef | Web of Science | Medline3
Narins RG ,Cohen JJ . Bicarbonate therapy for organic acidosis: the case for its continued use. Ann Intern Med 1987;106:615-618
Web of Science | Medline4
Hindman BJ . Sodium bicarbonate in the treatment of subtypes of acute lactic acidosis: physiologic considerations. Anesthesiology 1990;72:1064-1076
CrossRef | Web of Science | Medline5
Cheng JT ,Beysolow TD ,Kaul B ,Weisman R ,Feinfeld DA . Clearance of ethylene glycol by kidneys and hemodialysis. J Toxicol Clin Toxicol 1987;25:95-108
CrossRef | Medline
