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Annotated References By Category


  1. Stewart PA. Modern quantitative acid-base chemistry. Can J Physiol Pharmacol 61:1444-1461, 1983.

    This is Stewart’s original piece and it’s a classic. It’s not an easy read but try to get through it at least once. It may be easier to understand after you have read through some of the other reviews.

  2. Stewart PA: How to understand acid-base. In A quantitative acid-base primer for biology and medicine. Edited by Stewart PA. Elsevier, New York, 1981:1--286.

    Unfortunately, this is out of print. However, many medical libraries still have it on the shelf.

  3. Kellum JA. Metabolic acidosis in the critically ill: Lessons from physical chemistry. Kidney International 53 (Suppl 66): S81-S86, 1998.

    A concise summary of the major implications of the physical chemical approach to acid-base balance, focusing mainly on the clinical implications. The article probably lacks sufficient detail to allow you to fully understand this business but serves as an introduction.

  4. Kellum JA. Determinants of Blood pH in Health and Disease. Critical Care 2000;4:6-14.

    A bit less concise, but more up to date. Available on line (subscription only) through Critical Care Forum

  5. Current Opinion in Critical Care Vol 5 No. 6 December 1999. Renal System edited by Rinaldo Bellomo and Claudio Ronco.

    The entire issue is devoted to Stewart’s approach to acid-base physiology.

  6. Jones NL: A quantitative physciochemical approach to acid-base physiology. Clin Biochem 1990; 23:89-195.
  7. Fencl V, Leith DE: Stewart’s quantitative acid-base chemistry: Applications in biology and medicine. Resp Physiol 1993, 91:1--16.

Chapters in Textbooks

  1. Critical Care Nephrology. Kluwer Academic Publishers, Dordrecht, The Netherlands, 1998. Ronco C, Bellomo R (eds).

    Section 5; Chapter 1: Leblanc M, Kellum JA. Biochemical and Biophysical Principles of Hydrogen Ion Regulation. pp 261-277.

    Section 5; Chapter 2: Magder S. Pathophysiology of metabolic acid-base disturbances in patients with critical illness. pp 279-296.

  2. Textbook of Critical Care, W.B. Saunders Co, Philadelphia, PA , 1999. Grenvik A, Shoemaker PK, Ayers S, Holbrook (eds).

Chapter 75: Schlichtig R. Acid-Base Balance (Quantitation). pp 828-839

Chapter 76: Kellum JA. Diagnosis and Treatment of Acid-Base Disorders. pp 839-853.    

Unmeasured Anions and Strong Ion Gap (SIG)

  1. Figge J, Mydosh T, Fencl V: Serum proteins and acid-base equilibria: a follow-up. J Lab Clin Med 1992, 120:713--719.
  2. Gilfix BM, Bique M, Magder S: A physical chemical approach to the analysis of acid-base balance in the clinical setting. J Crit Care 1993, 8:187--197.
  3. Kellum JA, Kramer DJ, Pinsky MR: Strong ion gap: A methodology for exploring unexplained anions. J Crit Care 1995,10:51--55.
  4. Kellum JA, Bellomo R, Kramer DJ, Pinksy MR: Hepatic anion flux during acute endotoxemia. J Appl Physiol 1995, 78:2212--2217.

Base Excess vs. SID

  1. Schlichtig R: Base excess vs strong ion difference: Which is more helpful? Adv Exper Med Biol 1997, 411:91--95.

  2. Wooten EW: Analytic calculation of physiological acid-base parameters. J Appl Physiol 1999, 86:326--334.

    This author has translated base-excess, standard bicarbonate and strong ion difference and shown that they are all mathematically equivalent and derived from the same basic principles. The simulations also support the premise that strong ion difference changes as ATOT changes.  

Weak Acids (ATOT)

  1. Jabor A. Kazda A: Modeling of acid-base equilibria. Acta Anaesth Scand 1995, 39: Suppl 107:119--122.

    Classification of acid-base disorders remains controversial. These authors argue for the use of three types of disorders based on the three independent variables identified by Stewart. However, there is little evidence that this approach to classification is logical or helpful (see 3 below and review 4).

  2. Figge J, Jabor A, Kazda A, Fencl V: Anion gap and hypoalbuminemia. Crit Care Med. 1998, 26:1807--10.

    These authors demonstrate how the anion gap must be corrected for changes in albumin concentration. Patients with severe disorders of phosphate will require additional correction not detailed by the authors but available in this review.

  3. Wilkes P: Hypoproteinemia, strong ion difference, and acid-base status in critically ill patients. J Appl Physiol 1998, 84:1740--1748.

    This excellent observational study details the changes in strong ion difference as a function of changes in ATOT. The study provides convincing evidence that the normal physiologic response to hypoalbuminemia is to reduce the strong ion difference, principally by increasing the plasma chloride concentration.

Hyperchloremic Acidosis

  1. Kellum JA, Bellomo R, Kramer DJ, Pinsky MR: Etiology of Metabolic Acidosis During Saline Resuscitation in Endotoxemia. Shock 1998, 9: 364--368.

    Experimental evidence of the effect of saline resuscitation on acid-base parameters in an endotoxic animal model.

  2. Scheingraber S, Rehm M, Sehmisch C, Finsterer U: Rapid saline infusion produces hyperchloremic acidosis in patients undergoing gynecologic surgery. Anesthesiology 1999, 90:1265--1270.

    A clinical study detailing the acidosis associated with saline vs. no change in pH with lactated Ringer’s solution in patient undergoing major abdominal/pelvic surgery.

  3. Waters JH, Miller LR, Clack S, Kim JV. Cause of metabolic acidosis in prolonged surgery. Crit Care Med. 1999; 27:2142-6.

  4. Liskaser FJ, Bellomo R, Hayhoe M, et al: Role of Pump Prime in the Etiology and Pathogenesis of Cardiopulmonary Bypass-associated Acidosis. Anesthesiology 2000; 93:1170-1173

  5. Rehm M, Orth V, Scheingraber S, et al: Acid-Base Changes Caused by 5% Albumin versus 6% Hydroxyethyl Starch Solution in Patients Undergoing Acute Normovolemic Hemodilution: A Randomized Prospective Study. Anesthesiology 2000; 93:1174-1183

  6. Waters JH, Bernstein CA: Dilutional Acidosis following Hetastarch or Albumin in Healthy Volunteers. Anesthesiology 2000; 93:1184-1187

    These three studies published in the November, 2000 issue of the journal Anesthesiology provide conclusive evidence that the Chloride content of volume expanding solutions determines the degree of acidosis. In the study by Lisaker, two types of pump-priming solutions for cardiopulmonary bypass are compared. A hyperchloremic solution and a solution with acetate and gluconate as metabolizable anions are used. As predicted, both cause an acute acidosis but with the acetate/gluconate solution, it resolves quickly while the hyperchloremic solution causes a persistent hyperchloremic acidosis. The next two studies found that normovolumic hemodilution with HES or Albumin in saline (Rhem et al.) produced similar amounts of acidosis while Albumin in a normo-chloremic solution (Waters et al.) produced no acidosis at all. The accompanying editorial seemed to have missed this point.

Other Clinical Studies Using SID

  1. Alfaro V, Torras R, Ibanez J, Palacios L: A physical-chemical analysis of the acid-base response to chronic obstructive pulmonary disease. Can J Physiol Pharmacol 1996, 74:1229--1235.
  2. Hayhoe M. Bellomo R. Liu G. McNicol L. Buxton B. The aetiology and pathogenesis of cardiopulmonary bypass-associated metabolic acidosis using polygeline pump prime. Intens Care Med. 1999;25:680-6855.
  3. Hayhoe M, Bellomo R, Liu G, Kellum JA, McNicol L, Buxton B. The role of the splanchnic circulation in acid-base balance during cardio-pulmonary bypass. Crit Care Med 1999; 27:2671-2677.
  4. Fencl V, Jabor A, Kazda A, Figge J. Diagnosis of metabolic acid-base disturbances in critically ill patients. Am J Respir Crit Care Med 2000 Dec;162(6):2246-51

This observational study argues for a re-classification of metabolic acid-base disorders into those that alter the SID and those that affect the ATOT. The controversy arises when a low ATOT and a low SID coexist with a normal pH and normal BE. This was a common occurrence in this study (1 out of 6 patients) and the authors classify it a mixed disorder.

Other Laboratory Studies Using SID

  1. Lindinger MI, Heigenhauser GJF, McKelvie RS, Jones NL: Blood ion regulation during repeated maximal exercise and recovery in humans. Am J Physiol 1992, 262:R126--136.
  2. Rozenfeld RA, Dishart MK, Tonnessen TI, Schlichtig R: Methods for detecting local intestinal ischemic anaerobic metabolic acidosis by PCO2. J Appl Physiol 1996, 81:1834--1842.
  3. Kellum JA, Bellomo R, Kramer DJ, Pinsky MR: Splanchnic buffering of metabolic acid during early endotoxemia. J Crit Care 1997, 12:7--12.
  4. Morgan TJ, Hall JA: Hyperlactaemia without acidosis-an investigation using an in vitro model. Critical Care and Resuscitation 1999; 1:354-359

Dissenting Opinions

Every new idea has it’s detractors…

  1. Siggard-Andersen O, Foch-Andersen N: Base excess or buffer base (strong ion difference) as measure of a non-respiratory acid-base disturbance. Acta Anaesthiol Scand 1995, 39: Suppl 107:123--128.
  2. Worthley L. Strong Ion Difference: A New Paradigm or New Clothes for the Acid-Base Emperor. Critical Care and Resuscitation 1999;1:211-214