strong ion protein binding and its effect on SID, especially [Ca2+], [Mg+] and [Cl-]


This is still an unresolved issue!

Most of the published clinical studies do not specify how they handle the conversion of calcium and magnesium concentrations in mmol/l to mEq/l, which is the value needed to calculate SID and SIG.

From the data in their tables one can deduce that many use only 1mEq/l for these bivalent ions; one can presume that they do this because about half of their molar quantities are bound to serum proteins.
(examples are references (1) and (2))

Others double the molar values to get the value in mEq/l, but base this on the free ("ionised") calcium concentration.
(examples are references (3) and (4))


Two of the people who worked contemporarily with Stewart and have done much of the basic work extending his approach (the late Vladimir Fencl and James Figge) use the full ionisation values of calcium and magnesium, thus 2mEq/l.
(references (5) and (6))
One of the most prolific groups publishing clinical studies using the "Stewart approach", typically including Dirk Brügger and Markus Rehm, from München, Germany, has recently changed their definition of SIDapp to the one just described, too. (They did not include the bivalent kations at all in earlier publications.)  (references (12) and (13))


Peter Lloyd (he died prematurely, find a little dedication to him via our links page!) even triples the molar values of calcium and magnesium. He assumes a fixed strong anion charge of the otherwise weak acids, assumes an ionic strength of 3mEq/ mmol for the multivalent ions (Ca, Mg and sulfate) and assigns a default value of 0.75mmol/l to [sulphate].
(reference (7))


I can only find one clinical study where Stewart himself is one of the authors - here the plurivalent ions are simply not included in the analysis, restricting the calculation of SID to [Na+]+[K+]-[Cl-]-[lactate-].
(reference (8))


Another source of diverging results is, whether lactate is included in the calculation or not. Fencl and Figge (references (5) and (6)) do not include it, while most others do so.


These different approaches lead, of course, to different normal values for SID and SIG (strong ion gap). They are most probably clinically equally valid, but the diversity of formulae and corresponding normal values are, to put it mildly, confusing for anybody not highly specialising in the topic of Stewart type acid-base analysis!




Chris Anstey takes the discussion even one step further (without drawing further consequences from this in his clinical studies):
He mentions [Cl-] binding to albumin:
"In 1993, Fogh-Andersen et al measured the ionic binding of sodium, potassium, calcium and chloride on human albumin across a pH range of 4.0 to 9.0 using both flame-emission photometry and ionselective electrodes. On average, they found that at a pH of 7.40, one calcium and seven chloride ions were bound per albumin molecule. At physiological concentrations of albumin (≈0.65 mmol/l) this would result in a net extra surface charge of approximately 0.65∗(-7∗1+1∗2)=3.2 mEq/l. Combining this result with the data of Moviat et al virtually accounts for the missing charge. This extra negative charge on albumin is currently unaccounted because the commonly used model of Figge et al is based on native human albumin, stripped of bound ions while contemporary plasma electrolyte measurements use ion selective electrodes. "
(references (9) and (10))
This does not, however, represent the full account (whether anybody can deliver that at all seems doubtful .... ).
What the ion selective electrodes respond to is, at any rate, not the concentrations of the substances in question, but their ionic activity! This ionic activity is also what drives the reactions in the body in general and in acid-base equilibria in particular.
When the ion selective electrodes were introduced as the standard instrument instead of flame photometers in the 1980'es, it was, in order to not confuse clinicians and to maintain compatibility, one had to introduce correction factors. (reference (11))
The normal ionic acitivity of sodium is only about 0.74 its molar value, for instance. (See our own page about this issue: ionic activity of sodium)




We prefer to use Figge's and Fencl's approach to this issue. The argument is that whatever the binding of [Ca2+] and [Mg+] may be, their atoms are virtually sure not to exist in metallic form, and likewise [Cl-] probably does not exist as atomic, unionised chlor either. Their charge may thus be hidden from the view of the ion-sensitive electrodes, but they have to be mathematically balanced with the sum of albumin's own anionic and kationic charges.



the mathematics behind predicting pH changes:
read more!


references:
(1) Mirjam Moviat, Frank van Haren and Hans van der Hoeven
Conventional or physicochemical approach in intensive care unit patients with metabolic acidosis
Critical Care 2003, 7:R41-R45 (DOI 10.1186/cc2184)

(2) Dubin, Arnaldo; Menises, María; Masevicius, Fabio D.; Moseinco, Miriam C.; Kutscherauer, Daniela Olmos; Ventrice, Elizabeth; Laffaire, Enrique; Estenssoro, Elisa
Comparison of three different methods of evaluation of metabolic acid-base disorders
Critical Care, Volume 35(5), May 2007, pp 1264-1270; DOI: 10.1097/01.CCM.0000259536.11943.90

(3) Jan Klaboch, Sylvie Opatrná, Karel Matousovic, Frantisek Sefrna, Jan Havlín, Otto Schück;
Acid-Base Balance in Peritoneal Dialysis Patients: A Stewart-Fencl Analysis
Ren Fail. 2009;31(8):625-32

(4) Alexandre Toledo Maciel, Marcelo Park;
A physicochemical acid-base approach for managing diabetic ketoacidosis
Clinics 2009;64(6):714-8, doi: 10.1590/S1807-59322009000700018

(5) Vladimir Fencl, Antonin Jabor, Antonin Kazda, James Figge;
Diagnosis of Metabolic Acid-Base Disturbances in Critically Ill Patients
Am J Respir Crit Care Med Vol 162. pp 2246-2251, 2000

(6) Figge, James; Jabor, Antonin; Kazda, Antonin; Fencl, Vladimir;
Anion gap and hypoalbuminemia
Critical Care Medicine: Volume 26(11), November 1998, pp 1807-1810

(7) Peter Lloyd
Strong Ion Calculator - A Practical Bedside Application of Modern Quantitative Acid-Base Physiology
Critical Care and Resuscitation 2004; 6: 285-294

(8) Weinstein, Yitzhak; Magazanik, Avraham; Grodjinovsky, Amos; Inbar, Omri; Stewart, Peter A.;
Reexamination of Stewart's quantitative analysis acid-base status
Medicine & Science in Sports & Exercise. 23(11):1270-1275, November 1991

(9) Chris Anstey
An assessment of the population variance of the strong ion gap using Monte Carlo simulation
Anaesth Intensive Care 2009; 37: 983-991

(10) Fogh-Andersen N, Bjerrum PJ, Siggaard-Andersen O.;
Ionic binding, net charge and Donnan effect of human serum albumin as a function of pH
Clin Chem 1993; 39:48-52

(11) Anton H.J.Maas, Ole Siggaard-Andersen, Harry F.Welsberg, Wlllem G.Zjlstra;
Ion-Selective Electrodes for Sodium and Potassium:A New Problem of What Is Measured and What Should Be Reported
Clin Chem 1985; 31/3: 482-485

(12) Dirk Bruegger, Gregor I Kemming, Matthias Jacob, Franz G Meisner, Christoph J Wojtczyk, Kristian B Packert, Peter E Keipert, N Simon Faithfull, Oliver P Habler, Bernhard F Becker and Markus Rehm
Causes of metabolic acidosis in canine hemorrhagic shock: role of unmeasured ions
Critical Care 2007, 11:R130

(13) Bruegger D, Bauer A, Rehm M, Niklas M, Jacob M, Irlbeck M, Becker BF, Christ F
Effect of hypertonic saline dextran on acid-base balance in patients undergoing surgery of abdominal aortic aneurysm
Crit Care Med. 2005 Mar;33(3):556-63




consult the glossary for other aspects of acid-base equilibria and the rules and mathematics behind our website:     Glossary