the anion gap: taking it to the next level

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The Anion Gap: Taking it to

the Next Level

Benjamin Abelow, M.D.

Preface. I wrote this article for students and clinicians who already have a strong grasp of the fundamentals of clinical acid-base, including the anion gap. I had in mind especially those who have read my book The Painless Guide to Mastering Clinical Acid-Base, but anyone is welcome to read or circulate the article. Readers may wish to periodically visit the website www.AcidBaseMadeClear.com to see whether a revision of this article has been issued, or whether any additional free educational materials have been posted. For those who don’t already have a good understanding of acid-base fundamentals, I invite you to read The Painless Guide to Mastering Clinical Acid-Base before proceeding. You can “look inside” the book and read endorsements at Amazon.

Acknowledgements. This article benefited greatly from the generous input of three individuals: Dr. Nicolaos E. Madias, who commented on an early draft and shared his clinical insights on a number of key topics; Dr. Asghar Rastegar, who described to me his clinical teaching on the “dynamic” assessment of serial anion gap measurements in hospitalized patients; and Dr. Steven Coca, who provided thoughtful comments and suggestions on a late draft and discussed a number of clinical and pedagogical issues with me. Responsibility for any shortcomings or errors is mine alone.

Comments. I welcome comments and suggestions for future editions of this article. Please write to [email protected], with the words acid-base in the subject line. I may not be able to respond to emails personally or in detail, but please be assured that I will carefully read everything I receive.

Permissions. Permission is granted to freely circulate this article in print, dig-itally, or in any other form, so long as the article is circulated unaltered and in its entirety, including with this introductory material and copyright information.

Copyright. Copyright © 2016 Benjamin Abelow, M.D. All rights reserved.

Disclaimer. This article is intended for educational purposes. It is not intended to provide authoritative clinical guidelines. Careful efforts have been made to ensure that the information is accurate. However, because human error can occur, and because progress in medical science is sometimes rapid, no guarantee can

The Painless Guide to Mastering Clinical Acid-Base

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be offered about the accuracy of everything contained herein. When making management decisions for particular patients, readers are encouraged to refer to current therapeutic manuals, recent journal publications, guides to toxicology and other frequently updated sources, and to consult with clinical experts who have a full knowledge of each case.

Last Revised. August 26, 2016

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Contents

This article covers three broad topics:

I. The Anion Gap: It’s Not Always What You ExpectII. Improving the Gap’s Screening Ability: The Anion Gap Tool BoxIII. The Ups & Downs of Gap Acidosis: R/F Analysis (a.k.a. Delta/Delta)

I. The Anion Gap: It’s Not Always What You Expect

The anion gap is an extremely useful tool, but interpreting the gap is sometimes less clear-cut than it first appears. Here we’ll consider five important situations where the anion gap may not be what you expect. Keeping these situations in mind can help you avoid errors in diagnosis.

1. Simple Metabolic Alkalosis

Simple (i.e. not mixed) metabolic alkalosis, especially when severe and due to vomiting or diuretics, can itself raise the anion gap by up to about 6 meq/l above its baseline. The gap may still fall within the normal range, or it may be frankly elevated (i.e., above the normal range), depending on where within the gap’s nor-mal range the patient’s usual set point lies. For example, a patient who, in health, has an anion gap whose value lies in the upper part of the normal range is more likely to have a frankly elevated anion gap during a simple metabolic alkalosis. If you’re not aware that simple metabolic alkalosis can raise the anion gap, you might automatically interpret a slightly elevated gap that occurs in the context of a high venous [HCO

3−] as a mixed disturbance—that is, as an anion gap metabolic aci-

dosis plus either metabolic alkalosis or chronic [compensated] respiratory acidosis.*

The rise in the anion gap during simple metabolic alkalosis is due to several factors. One factor is volume depletion, which usually accompanies metabolic alkalosis. With volume depletion, ECF (extracellular fluid) and plasma volume decrease but the total quantity of unmeasured anions remains relatively constant, so the concentration of unmeasured anions increases. Since the anion gap assesses the concentration of unmeasured anions (measured in meq/l), the anion gap increases. The increase in plasma albumin concentration that occurs during volume depletion is especially important, since the negative charges on albumin make up a large portion of the unmeasured anions. Another factor that contributes to the rise in the anion gap is alkalemia (high pH, low [H+]), which accompanies simple metabolic alkalosis.

* Reminders. First, the term “anion gap metabolic acidosis” is sometimes shortened to either “gap metabolic acidosis” or “gap acidosis,” and some writers abbreviate it as AGMA. Second, venous [HCO3

−] is often measured by a variable known as Total CO2. In general, Total CO2 is slightly higher (about 5 percent higher) than actual venous [HCO

3−], but as a practical matter

the two terms can be, and often are, used interchangeably. The precise relationship between venous [HCO3

−] and Total CO2 is discussed in The Painless Guide to Mastering Clinical Acid-Base, Chapter 12, section on venous [HCO3

−] (pp. 137−138 in the print edition).

Chapter 1 / The Chemical Foundation: The Bicarbonate Buffer System


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Alkalemia shifts the albumin buffer equilibrium (HX ⇋ X− + H+) to the right; this shift increases the level of unprotonated albumin (X−), thus elevating the gap irrespective of the increase in total albumin concentration.

2. Diarrhea

Diarrhea, which is a classic cause of non-gap (a.k.a. hyperchloremic) metabolic acidosis, can sometimes raise the anion gap modestly through indirect mecha-nisms. These mechanisms include the following: (a) volume depletion raises the gap for the same reason just described for simple metabolic alkalosis; (b) anorexia, which may accompany diarrhea, can lead to mild starvation ketoacidosis; (c) fluid loss with resulting volume depletion can lower GFR and thereby hinder the excre-tion of unmeasured anions; (d) in patients with severe or protracted diarrhea, ECF volume and tissue perfusion may decrease to the point where lactic acidosis devel-ops (depending on the severity of the volume depletion, this lactic acidosis may be clinically important). Technically, (b), (c), and (d) represent mixed disturbances: a non-gap acidosis from diarrhea plus ketoacidosis in (b), renal failure (pre-renal) in (c), and lactic acidosis in (d).

3. Lactic Acidosis

Lactic acidosis of mild or even moderate severity can present with a normal anion gap. There is still an increased quantity of lactate anions in the blood, but this quantity can “hide” within the normal range of the gap, raising the gap above its baseline but not to a level that exceeds the top of the normal range. (This possibility was mentioned when discussing Patient 8 in Chapter 13 of The Painless Guide to Mastering Clinical Acid-Base; here I am explaining the point in more detail.) Given the fairly wide normal range of the anion gap, lactate levels up to about 10 mmol/l can potentially present with a normal gap. The risk that a hidden (normal-range gap) lactic acidosis is present may be greatest when the anion gap is in the high-nor-mal range, but the risk exists even with lower gap levels. Because you can’t rely on the anion gap to rule out lactic acidosis, you should measure plasma lactate directly whenever the clinical situation warrants it.

A further complication pertains to the bicarbonate level. The normal range for plasma bicarbonate can span 6 or more mmol/l between the low and high cutoffs, depending on the lab’s normal range. For example, in some labs, the normal range for Total CO

2 is 23 –29 mmol/l. If you assume that each mmol of lactic acid

titrates one mmol of bicarbonate (a 1:1 ratio), a decrease of plasma [bicarbonate] from high normal to low normal can theoretically be associated with a clinically significant lactic acidosis. To give an extreme example, a decrease in bicarbonate from 29 to 23, with a 1:1 titration, can be associated with a plasma lactate concen-tration of 6 mmol liter. Confusing things even further is the fact that in lactic aci-dosis the increase in plasma [lactate] is often somewhat greater than the decrease in plasma [bicarbonate], due in part to the movement of some bicarbonate from inside cells into the ECF; this movement of bicarbonate tends to raise the plasma bicarbonate level without affecting the lactate level. The result is that a decrease of Total CO

2 from very high normal to very low normal can potentially be associated

with a rise in plasma [lactate] of even greater than 6 mmol/l.

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Thus, even when both the anion gap and plasma bicarbonate are in their normal ranges, a significant lactic acidosis may be present. The risk of this problem is great-est when the anion gap is in the upper part of its normal range and the plasma bicar-bonate (whether arterial or venous—the two values will track each other) is in the lower part of its normal range, but the problem can occur even with values elsewhere in their normal ranges. The key point is to measure plasma lactate whenever the clinical situation warrants it, regardless of either the anion gap, plasma bicarbonate level, or both.

4. Diabetic Ketoacidosis

Diabetic ketoacidosis (DKA) is a classic cause of anion gap metabolic acidosis. However, when the patient is being treated with volume-expanding fluids, which leads to an increase in urine output and thus to a more rapid loss of ketoanions in the urine, the anion gap often drops toward normal. Once insulin is given and the remaining (non-excreted) ketoanions undergo hepatic conversion to bicarbonate, the anion gap may normalize completely at a time when hypobicarbonatemia is still present. In other words, the gap metabolic acidosis may convert into a non-gap (hyperchloremic) metabolic acidosis. (Notwithstanding the creation of new bicarbonate following administration of insulin, a degree of hypobicarbonatemia often persists because some ketoanions had previously been excreted; thus, bicarbonate that was lost buffering the ketoacids will not be fully replaced.)

In fact, a non-gap acidosis may occasionally exist even at presentation if the patient was able to maintain good hydration and volume status from the onset of the DKA episode. In well-hydrated patients, the urinary loss of ketoanions may be rapid enough to keep the anion gap within the normal range, even if it is elevated above its normal set point. The excretion of a lesser quantity of unmeasured anions can result in an anion gap that is elevated only slightly.*

Thus, the issue of an elevated anion gap’s “hiding” in the normal range, which we discussed for lactate, applies for ketoanions as well. Once again, the solution is awareness: to recognize that the anion gap is a useful but imperfect screening device. Thus, whenever the clinical situation raises concern, test for the specific substance of interest (in this case ketones).

5. Methanol and Ethylene Glycol Intoxications

Methanol and ethylene glycol intoxications are classic causes of anion gap meta-bolic acidosis. However, the situation is complex because the metabolic acidosis

* Clinical Note. In patients with well-maintained plasma volume, the BUN (urea), hema-tocrit, and albumin levels will tend to be normal, all else being equal. In contrast, patients with volume depletion usually present with a BUN that is frankly high (as a result of in-creased renal reabsorption of filtered urea), as well as a hematocrit and albumin level that are elevated above their normal baseline values; these elevations from baseline are due to a contraction of plasma volume around fixed quantities of red blood cells and albumin. In this situation, hematocrit and albumin levels often will still be within the lab’s normal range, though they may be frankly high, depending on the patient’s baseline values and the extent of the volume depletion.



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does not develop immediately. Instead, the acidosis develops only after the meth-anol or ethylene glycol is metabolized to its acid end-products. (Recall that meth-anol and ethylene glycol are neutral molecules.) This metabolism is gradual and can be especially slow if the patient also ingested ethanol, since ethanol inhibits the metabolism of the methanol and ethylene glycol. The result is that when the os-molar gap (reflecting the unmetabolized, neutral substances) is highest, the anion gap (reflecting the dissociated acid anions) may be normal, and by the time the an-ion gap is elevated, the osmolar gap may be normal. You can think of the situation as involving a gradual transition from elevated osmolar gap to elevated anion gap.

The situation is further complicated by the fact that a normal osmolar gap never rules out methanol or ethylene glycol, even when they are in their un-metabolized forms. This last point is discussed in The Painless Guide to Mastering Clinical Acid-Base, Chapter 6, subsection on the Osmolar Gap (pp. 81-83 of the print edition). In addition, even assuming that the methanol and ethylene glycol are fully metab-olized to their acid end products, smaller ingestions can potentially present with normal anion gaps due, once again, to the acid anions’ “hiding” within the gap’s normal range—yet another reason to assay for the specific toxins when the clinical situation warrants a reliable rule out.

Summary

• An anion gap in the normal range (and even a bicarbonate level in the normal range) does not rule out a significant lactic acidosis. Plasma lactate should be measured based on clinical suspicion.

• Some gap acidoses can have completely normal anion gaps at particular periods during the pathophysiologic time course. An important example is DKA either during treatment or at presentation in an especially well-hydrated patient. Another important example is ethylene glycol or methanol intoxication soon after ingestion, or when ethanol has been ingested along with these toxins, or when the ingestion is relatively small.

• Some seemingly “non-gap” situations can present with a mildly elevated anion gap. Prominent examples are simple metabolic alkalosis, especially from vomiting or diuretics, and simple metabolic acidosis from diarrhea.

II. Improving the Gap’s Screening Ability: The Anion Gap Tool Box

One problem with relying on the anion gap as a screening device for metabolic acidosis is that its wide normal range leaves ample room for a clinically meaning-ful accumulation of unmeasured anions to hide within the normal range and thus go undetected. This is best documented for lactic acidosis but may be a problem also in ketoacidosis and in intoxication with substances such as methanol and ethylene glycol. No refinements in using the gap can completely overcome this problem, so it remains essential to assay for specific substances when the clinical situation warrants it. However, there are four techniques that may increase the


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sensitivity of the anion gap as a screening tool. For simplicity, you can think of techniques as tools in a toolbox. I list the tools here, numbering them 1-4 for convenience.

1. Know Your Lab’s Normal Range. This first tool is one you must always use; in this sense, it is not simply a tool but rather an absolute requirement. I discuss it in The Painless Guide To Mastering Acid-Base but I repeat it here, in a bit more detail, for the sake of completeness and because it is so important. Laboratory normal ranges for the anion gap can vary markedly, depending on the type of analyzer used and how it is calibrated. It is therefore essential to know your own lab’s normal range. This is doubly important since newer lab technologies are in-creasingly available. These newer technologies, which use ion-selective electrodes, tend to generate lower normal ranges for the anion gap, largely because they tend to give higher values for plasma chloride. (Looking at the formula for the gap, [Na+] – ([Cl−] + [HCO

3−]), you can see that the higher the measured [Cl−] value,

the lower will be the value of the anion gap.) You don’t need to know what kind of analyzer your lab uses or how it is calibrated, because these technological factors are ultimately reflected in the lab’s normal range for the anion gap; thus, simply knowing your lab’s normal range will tell you what you need to know.

2. Correct the Anion Gap in Patients with Low Plasma Albumin Levels. Scan the following figure, which I’ve copied from The Painless Guide to Mastering Clin-ical Acid-Base. Focus especially on the top part of the anion column, where the components relevant to unmeasured anions are indicated.

As you can see, proteins make up a large part of the unmeasured anions and, hence, a large part of the anion gap. Among the proteins, albumin provides the majority of charges. It follows that a low plasma [albumin], a condition referred to as hypoalbuminemia, will tend to reduce the anion gap. The amount of the reduction in the gap is roughly 2.5 meq/l for each 1 g/dl reduction in albumin. Thus, if a patient’s [albumin] is 2 g/dl below his or her baseline, the anion gap


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will be reduced by about 5 meq/l (that is, 2.5 x 2 = 5). If this patient’s anion gap would normally be 20, the observed gap will instead be 15. Nonetheless—and this a key point—the unmeasured anions other than albumin, including the anions that raise concern about the presence of a gap metabolic acidosis (e.g., ketoacid anions, lactate, and sulfate and other anions associated with kidney fail-ure)—will still be present at levels you would usually see when the gap is 20. To correct for this fact, when you encounter hypoalbuminemia, you should adjust the patient’s observed anion gap upward. By doing so, you are in effect saying: “The value of the anion gap is abnormally suppressed, leading to an underesti-mation of the anions I am most concerned about. To compensate for this, I’ll pretend the gap is higher than it really is, by an amount that is required to make the anion gap better reflect the level of those anions of concern.” The correction process is summarized in this box:

For each 1 gram per deciliter (g/dl) that albumin is low, add 2.5 to the anion gap.

Upwardly adjusting the observed value of the anion gap in this manner gives you an “albumin-corrected anion gap,” which many clinicians refer to simply as a “corrected anion gap.” The albumin-corrected gap provides a best-guess estimate of what the anion gap would have been had plasma [albumin] been normal. To avoid confusion, when you record the anion gap in the patient’s chart or describe it verbally, it is useful to give both the uncorrected gap (calculated as usual) and the albumin-corrected gap. (Some sources recommend using 2.3 instead of 2.5 as the adjustment factor; the difference is trivial and either number can be used.)

There are different ways of implementing this correction and I am unaware of any evidence that one is superior to the others. Therefore, it is generally best to use the approach that conforms to your hospital’s norms, so that other clinicians will more easily recognize what you have done. I will describe here two of the possible ap-proaches, so you can get a sense of the major differences. For ease of identification in this discussion, I’ll refer to these as Approach 1 and Approach 2.

In Approach 1, you pick a point within the lower portion of the albumin normal range and do the calculation whenever albumin falls below that point. For example, assume that your lab’s normal range is 3.5–5.0 and that you use 4.0 as the cutoff. If the patient’s albumin is 3.0, you would subtract 3.0 from 4.0, giving a difference of 1.0. You would then multiply 1.0 times 2.5, giving 2.5, and add that 2.5 to the patient’s gap. Thus, if the gap as normally calculated is 13, the corrected gap will be 15.5, which you could round to 16.

In Approach 2, which is probably more common, you do the correction only when plasma albumin is frankly low (i.e., beneath the bottom cutoff of the normal range). So if the lab’s normal range for albumin is 3.5–5.0, you do the calculation only if [albumin] is 3.4 g/dl or lower. Using this approach, if [al-bumin] is low, you subtract the measured albumin value from the mid-point of your lab’s normal range for albumin (4.25 in this example), then multiply the difference by 2.5 and adjust the gap accordingly. In estimating the amount by

Chapter 2 / Overview of Acid-Base: A Balancing Act

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which albumin is reduced, the midpoint of albumin’s normal range, rather than the lower cutoff of the range, is used because the midpoint is, statistically, the most common baseline value, assuming a normal bell-curve distribution of lab values in the population.

For example, assume that your lab’s normal range for albumin is 3.5-5.0 g/dl and that your patient’s [albumin] is 1.9 g/dl. The mid-point of the normal range is 4.25 (i.e., (3.5 + 5.0)/ 2 = 4.25), which you can round to 4.3. Subtracting 1.9 from 4.3 gives you 2.4 (i.e., 4.3 −1.9 = 2.4). Multiplying 2.4 x 2.5 gives you an adjustment value of 6 (2.4 x 2.5 = 6). Adding 6 to your patient’s anion gap gives you the corrected gap. If, say, the uncorrected anion gap is 13, the corrected gap is 19.*∗

Notice that in Approach 2, you are using the lower cutoff of the normal range as the “trigger” for the calculation, but you are estimating the decrement in the anion gap based on the midpoint of the normal range, which you are taking as the patient’s assumed baseline. This contrasts with the procedure in Approach 1, where you are using some value in the lower portion of the normal range as both the trigger for the calculation and the assumed baseline from which to work the calculation. Other variants of the correction procedure are possible, but these two approaches give you a sense of the options and the relevant differences between them (trigger vs. assumed baseline). If there is no established norm in your hos-pital or other clinical setting, it makes sense to use Approach 2, simply because it is probably more common and thus the one more people are likely to be familiar with. As an added benefit, the lower trigger value in Approach 2 means you will need to do the correction in fewer patients, thus saving you time. In any case, the corrected gap values produced by the two approaches correspond fairly well with each other, so it should not matter much one way or the other.**∗

* Going further. In patients with severe hypoalbuminemia, the anion gap itself may be sub-normal (below the normal range). In fact, among those patients with a frankly low anion gap (about 1 percent of all patients have a sub-normal anion gap), hypoalbuminemia is the most common cause. The next most common cause, by far, of a sub-normal anion gap is laboratory error in measuring the electrolytes. Therefore, if you can’t account for a frankly low anion gap by hypoalbuminemia, repeat the labs. If the gap is still low, consider rarer causes. Most of these rare causes involve elevated levels of unmeasured cations (i.e, cations other than Na+). The most common of these are multiple myeloma (which can produce cationic IgG immunoglobulins), lithium (Li+) overdose, and some combination of markedly elevated plasma K+, Ca2+, Mg2, and Mn2+.

** Clinical Note. Let me add one qualification, in case you do use Approach 2. In this approach, you are adopting a convenient and not-too-disruptive fiction. You are acting as if plasma albumin is reduced only when it is beneath the cutoff of the normal range. However, on a statistical basis, if a patient’s albumin is anywhere near the lower cutoff of normal (say, in the lower third of the normal range), then the albumin value is actually somewhat lower than the typical value used by labs to establish the normal range for the anion gap. Thus, it is useful to remain aware that a low-normal albumin level may indicate a level of unmeasured anions that is slightly higher than the anion gap would suggest. (Recall that the anion gap tracks unmeasured anion concentration but does not equal it.) Keeping this fact in mind may give you a bit more relevant information in a borderline case when you are trying to weigh the possibility that the anion gap is elevated.


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Chapter 2 / Overview of Acid-Base: A Balancing Act

A final note: hypoalbuminemia is much more common than hyperalbuminemia (high blood [albumin]). This is especially true in hospitalized patients, because hypoalbuminemia often develops in response to acute illness; it may also reflect underlying malnutrition, which itself is common in acutely ill individuals. However, in those rare situations where hyperalbuminemia is present, a greater-than-normal fraction of the anion gap represents albumin (to see why, look again at the above figure). Thus, in patients with frank hyperalbuminemia you should reverse the above method and adjust the patient’s anion gap value downward. For example, if the patient’s albumin is 6.0, with a normal range of 3.5–5.0, subtract 4.25 (the midpoint of albumin’s normal range) from 6.0, giving a difference of 1.75. Multiply 1.75 by 2.5, giving 4.375, which you can round to 4.4, and subtract this value from the normally calculated anion gap. Thus, if the patient’s gap is 17, the corrected gap would be 12.6, which you could round to 13. Again, this situation is not one you will often encounter, and as a practical matter you may not want to spend mental energy thinking about it, but I include the point for completeness.

3. Compare Gap Values Across Time. To use this “tool,” you compare the anion gap not only against the lab’s normal range (which is based on the average for a large number of patients) but also against the patient’s own previous anion gap levels. Doing this second comparison can increase your ability to detect potentially meaningful increases in the anion gap even while the gap remains in the normal range. We’ll consider three distinct ways of applying this general approach, which I’ll follow with some clarifying comments.

First, you can compare the current gap against the patient’s healthy base-line value, as obtained from old clinical notes or lab reports during a pe-riod of health (or at least during a period when there clearly was no gap acidosis). This approach is typically most useful when first assessing an acute illness, for example, when interpreting the initial ED or admission blood tests. In any given case, a healthy baseline gap value may or may not be available in a timely manner, but when it is, it is worth doing the comparison. If two or more healthy baseline gaps are available for the same patient, you can take their average as the starting point. Or if you happen to have a handful of baseline values available, and you think that the highest and lowest truly represent normal variations in the patient’s healthy baseline, you can consider these two values as defining the top and bottom of that patient’s own individual normal range (which you can think of as the patient’s “set point normal range”) and then work all calculations relative to that patient-specific range. (As a practical matter, this last scenario may not occur very often.) If you can’t find or calculate the patient’s actual baseline, it’s generally best to assume that the patient’s normal value is the mid-point of the normal range (once again because, given a normal bell-curve distribution, the mid-point of the normal range will statistically be the most likely set-point for any given patient).

Second, for a hospitalized patient, you can—and should— compare each new anion gap against the previous anion gaps measured during the same

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hospitalization. In other words, you track the movements of the anion gap serially. Doing so helps you rapidly detect potentially meaningful changes within the anion gap’s normal range during a period of acute illness. As an example, consider a hospital where the anion gap’s normal range is 8-16. If a patient’s gap on admission is 9, and a day later is found to be 14, it is important to recognize this fact and to seek to understand its origin. This “normal” value of 14, which may indicate the onset of a fulminant metabolic acidosis, may actually be much more clinically meaningful and ominous than an elevated gap value of, say, 18 that is stable over a pe-riod of days. This approach to assessing serial measurements of the gap can be described as dynamic (or diachronic), in contrast to the static (or synchronic) approach of comparing a single gap measurement against the normal range. In the acutely ill patient, both approaches (dynamic and static) must be used, and if anything, the dynamic approach is more important. Finally, when dynamically assessing the gap, it is important to correct the gap for hypoalbuminemia, if present, as described earlier in this “toolbox” section; because plasma [albumin] often falls rapidly in severely ill patients, a stable, uncorrected anion gap may actually reflect a clinically meaningful increase in unmeasured anions that is being nu-merically offset by a decrease in the negative charges on plasma albumin.

Third, in the two approaches just described, you calculate the change in the gap from its healthy baseline, or tracked serial changes in the gap during the same acute illness, as part of a diagnostic screening strategy de-signed to better identify a clinically meaningful increase in the anion gap. In this third approach, you compare gaps over time during treatment, or even as part of a specific treatment protocol, especially during treatment of an organic acidosis (e.g. ketoacidosis or lactic acidosis). Here you are looking for a rapid decrease in the gap, reflecting the metabolism of or-ganic anions in the ECF. In the context of effective treatment, a clear-cut decrease in the gap, accompanied by an increase in the plasma bicarbon-ate level, can be taken as a semi-quantitative marker for a decrease in the relevant organic anion; and this marker is at times used as a surrogate for measuring the specific anions of interest (e.g., ketoanions in DKA, lactate in lactic acidosis). For instance, in DKA, after the initial ketone measure-ments are made, serial measurements of the anion gap are sometimes used to track the reduction in ketoanions, rather than repeatedly measuring ketones.

Thinking about randomness. The anion gap, like other lab values, shows some nor-mal variation within the same patient over time. In fact, because the anion gap is derived from three different lab measurements (Na+, Cl−, HCO3

−), variations in which can be cumulative, the anion gap may show a greater random variation than a single, directly measured lab value (though, at other times, the random varia-tions in the three underlying measurements may offset each other). The random variation in the anion gap can result from either random changes in the patient’s electrolytes over time, or from random variations in the lab’s assays, or both. You need to keep the possibility of these random changes in mind when evaluating


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changes in the gap. If you don’t, you risk interpreting every little change as clini-cally important.

So, how do you decide whether a change in the gap is meaningful? There is no hard and fast answer, but the general and best rule is: the greater the change in the gap, and the more rapidly that change occurs, the greater should be your level of suspi-cion and concern. This rule is appropriate because it reflects the continuous nature of risk, which is not an either/or proposition; rather, the level of risk tracks the degree of change. The emphasis on the rate of change (which applies when assess-ing serial gaps dynamically in acutely ill patients, but is usually not relevant when comparing an initial gap against a previously healthy baseline) reflects the fact that relatively small but rapidly evolving changes in the gap may indicate the onset of a fulminant metabolic acidosis.

Let’s continue this discussion by focusing on the two main diagnostic situations given above.

Assessing an initial anion gap relative to a healthy baseline. When comparing an initial anion gap of an acutely ill patient (for instance, an ED or admission gap) with a previous, healthy baseline from the patient, you may wish to keep some threshold value in mind, above which you start to pay more attention. Below the threshold value, you won’t give much weight to a difference between the two anion gaps, on the assumption that it likely is due to chance. This makes sense because a lot of time may have elapsed since the baseline measurement (weeks, months, or possibly even years), and this time lag increases the likelihood that the difference between the two anion gap values is due to random or clinically irrelevant causes. The goal of using a threshold is to avoid worrying about small, clinically meaning-less differences between the two gaps.*

Although there is no firm validation for the best threshold, some experienced cli-nicians use 5 meq/l . For example, using this threshold, an ED anion gap of 13, compared to a baseline measurement of 10 from two months ago, would probably not raise much concern. However, thresholds are by their nature arbitrary, because they represent nothing more than a best-guess about how to eliminate much of the random noise without losing a great deal of sensitivity in detecting clinically meaningful changes. That is, the threshold represents a best-guess estimate about how to optimize the balance between specificity and sensitivity. For this reason,

* Going further. In doing this comparison, you must keep in mind the possibility that the two anion gaps were measured in different labs with different normal ranges. If you don’t know whether the normal ranges are the same, and you can’t reasonably infer that they are, you cannot compare the two anion gaps. If you know that the normal ranges are not the same, but you know the normal ranges in both cases, you can still compare the gaps, though not directly. Rather, you’ll need to make an adjustment of some sort, or to compare a derived variable. One approach is to determine how far and in which direction each gap measurement is from the mid-point of its own normal range, and then compare those deviations-from-midpoint with each other. For example, if the healthy baseline gap is 2 meq/l below the midpoint of its normal range, and the current (ED or admission) gap is 4 meq/l above the midpoint of its normal range, you could assume that the gap has increased by 6 meq/l.

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the threshold value (regardless of whether you use 5 or decide on some other num-ber) should be used flexibly and interpreted in light of the overall clinical picture and other lab values. Keep the threshold value in mind as a general guide, but don’t treat it as an absolute cutoff.

A number of times in this discussion, I used phrases such as “the change in the anion gap from its baseline.” Because this phrase is somewhat unwieldy, the terms “delta gap” or “delta AG” (with AG standing for “anion gap”) are often used as a verbal shortcut. This shortcut, which makes use of the fact that the Greek letter delta rep-resents the change in a mathematical variable, is intended to indicate the numerical difference between the current gap and baseline gap. Sometimes these shortcuts are written with the actual Greek letter delta, as in “∆ gap.” Using this terminology, we can translate our discussion of threshold values into this concise piece of advice: “When the delta gap is greater than 5, make sure you are aware of it and trying to decide if it is clinically meaningful.”*

Assessing the anion gap “dynamically.” In contrast to situations where you are com-paring an ED or admission gap with a previous healthy baseline, you should not use a threshold value when tracking serial gaps within a single hospitalization. In this setting, even a change of a couple of meq/l, especially if the change occurs rapidly, should raise your level of suspicion and may lead you to examine the patient more carefully and to order assays for specific substances, such as lactate or ketones. This heightened caution is appropriate because a small rise in the anion gap might po-tentially be signaling the onset of a rapidly progressive, severe gap acidosis. For in-stance, it could indicate the onset of sepsis, or of clinically meaningful hypoxemia, or of tissue hypoxia from bowel or limb ischemia. Because such conditions can have a rapid and catastrophic clinical course, it is crucial to identify them as early as possible, even at the cost of what may eventually prove to be unnecessary venous or capillary blood assays and heightened clinical surveillance. Here, the need for sensitivity trumps the value of specificity.

It is worth recognizing that, beyond the major causes of gap acidosis, a number of clinical scenarios that are common in hospitalized patients can cause small in-creases in the gap. These include acute kidney injury, which is relatively common in seriously ill patients; mild lactic acidosis from volume depletion, which usually is easily reversed with volume expanding fluids; and evolving starvation ketoacido-sis in patients who are being kept NPO. Assessing the anion gap dynamically can increase your awareness of these possibilities.

* Going further. In general, the presumption when calculating the delta gap is that, if the two gaps are meaningfully different, the current (admission or ED) gap will be higher than the previous (healthy baseline) gap. For this reason, the delta gap is commonly determined by subtracting the baseline gap from the current one. The result is that the delta gap, when not zero, is presumed to be a positive number. In principle, one could refer to the reverse situation (i.e., when the baseline gap is higher) by using a negative value for the delta gap. For example, a delta gap of −4 would mean that the current gap is 4 meq/l lower than the previous one. However, this use of negative values is not frequently or conventionally done and thus could easily cause confusion. In the end, what is most important is not the name or the sign, but understanding the concepts and communicating clearly, including with others who may be less facile with the detla gap terminology.


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When assessing the anion gap dynamically, you need to recognize that when the increase in the gap is small, the assays for specific anions will also show only a small increase. For instance, in mild lactic acidosis (sometimes defined as a lactate level <5 meq/l), the lactate level, though elevated above its baseline, may still be within the normal range. Complicating things further, in gap acidosis in general, the increment in the specific anion (lactate, ketoacid anions, etc.) is usually somewhat smaller than the increment in the anion gap itself. This discrepancy is typical because, even in a gap acidosis caused purely by a single cause, the increment in unmeasured anions is due largely, but not entirely, to the signal anion (e.g. lactate or ketoanions); at least a fraction of the increase is usually due to other, poorly defined unmeasured anions. For example, even in a pure lactic acidosis, an increase in the gap from, say, 9 to 12 may be accompanied by an increase in lactate of 2 meq/l. In such cases, the patient may have a high-normal lactate value whose importance is not immediately clear. The bottom line here is that even when you decide to test for specific anions, you still may not get a definitive answer; and you will have to rely on the overall clinical picture and other lab values for guidance. To ensure that you are getting as much value as possible from assessing the gap dynamically, it is important, as mentioned previously, to correct the gap if hypoalbuminemia is present.

4. Correct the Gap for Markedly Abnormal Levels of Plasma Potassium. As with the correction for albumin, this “tool” is considered only in a specific circum-stance—in this case, when plasma potassium is markedly abnormal. Glance back to the above illustration of the ionic makeup of blood, this time focusing your attention on the cation (+) column. Notice that one of the minor constituents in this column is the inorganic cations (K+, Mg2+, and Ca2+). The most widely used anion gap formula, [Na+] – ([Cl−] + [HCO

3−]), uses Na+ as the only cation.

The other cations are not usually included, and in most cases this doesn’t matter because the normal ranges that labs set for the anion gap are based on more-or-less normal level of these cations. However, when the sum of these other cations is markedly abnormal, the anion gap’s normal range is no longer quite as accurate.

The “other” cations at the top of the column consist largely of positively charged proteins, which are not routinely measured. Of the inorganic cations (K+, Mg2+, and Ca2+) in the figure, only potassium is routinely measured—thus our focus on potassium. The cations other than K+ are still important in theory, because marked abnormalities in their levels will affect the accuracy of the anion gap’s normal range. But since they are not routinely measured and you therefore won’t know their concentrations, the statistically best assumption is that their concen-trations are normal.

When plasma [K+] is markedly elevated, the level of unmeasured anions will be higher than the anion gap suggests, with the difference being quantitatively equal to the increment of potassium above its normal level. To adjust for this, you simply add the excess level of potassium to the calculated gap. That is, unlike for albumin, whose adjustment requires a multiplication factor of 2.5 because there is more than one exposed anionic site per albumin molecule, here you are dealing with a substance that has one charge unit per ion. In most cases, the lack of a multiplication factor means the adjustment will be small and therefore need

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not be bothered with. But in a situation where [K+] is very high, you should do the correction. For example, if [K+] is 6.25, and the normal range is 3.5 to 5.0 mmol/l, you can calculate the difference between the 6.25 and the mid-point of the normal range (4.25), giving a value of 2.0. (As with albumin, the midpoint can be used because it is, statistically, the most likely normal value for any given patient, assuming a normal bell-curve distribution.) Add that 2.0 to the anion gap. So if the gap is calculated as 14, the potassium-corrected gap is 16. If the [K+] is very low, you can reverse the procedure, adjusting the anion gap down-ward by the amount equal to the difference between the midpoint of the K+ normal range and the current value.

In situations where you also have the levels of Mg2+, Ca2+, or both, you can modify the above procedure by taking the cumulative excess of as many of the values as you have. Just be sure that Mg2+ and Ca2+ are measured in meq/l (i.e, in charge, rather than particle, concentration), since the anion gap reflects charges, not particles and is itself measured in meq/l. (If your lab provides the values in mmo/l, you can convert these to meq/l simply by multiplying the excess above the midpoint by 2, since the ions have a charge valence of 2.) As an extreme example, if the concen-tration of each of these three cations is 3 meq/l above the midpoint of its normal range, you would add 9.0 to the anion gap. But if [K+] is elevated by 3.0 above the midpoint of its normal range, and both Ca2+ and Mg2+ are both 1.5 meq/l below the midpoints of their normal ranges, then the cumulative excess is zero: 3.0 − 1.5 − 1.5 = 0. In this case, no correction would be needed. Finally, if you know just one of these other cations (say, [Ca2+]), take its elevation above the midpoint of its normal range, add it to the elevation of [K+] above the midpoint of its normal range, and use that sum to make the adjustment (notice that, because you don’t have any evidence to the contrary, you continue to assume [Mg2+] is normal, and therefore you don’t worry about it).

The Anion Gap Tool Box: A Final Caveat

Returning our focus now to the “tool box” as a whole, we need to end with a ca-veat, which repeats a point from the start of the discussion. It is essential to keep in mind that even when you use the tool box assiduously and appropriately, the anion gap remains an imperfect screening device. It simply does not have the sen-sitivity to do its job perfectly. Thus, you still need to measure lactate or other spe-cific substances (e.g. toxic alcohols, ketones) when the clinical scenario warrants it. The main value of the tool box is that it makes the anion gap a better screen for problems you might not otherwise suspect.

Summary of the Anion Gap Toolbox

• Always know and use your particular lab’s normal range for the anion gap.

• In hypoalbuminemia, adjust the gap upward using a correction factor of 2.5. The most common approach is to use the lower cutoff of the normal range for albumin as the trigger for the calculation, and then to use the mid-point of the albumin normal range as the baseline from which to calculate how much albumin is reduced.


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• Compare the anion gap over time. There are three main applications. First, compare an initial (e.g., ER or admission) anion gap against a previous, healthy baseline, when available (“delta gap”). Second, for all acutely ill and hospitalized patients, track the anion gap serially to help detect poten-tially meaningful changes in the gap within its normal range (“dynamic” assessment of the gap). Third, tracking serial gaps during the treatment of DKA or lactic acidosis can provide a semi-quantitative marker for treat-ment progress without your having to repeatedly check ketone or lactate levels; in this situation, a decreasing gap indicates that circulating organic anions are being metabolized to bicarbonate.

• In patients with frank hyperkalemia, subtract the midpoint of the [K+] nor-mal range from the current [K+] value, then add the difference to the anion gap. Reverse the procedure for severe hypokalemia. Values for Mg2+ and Ca2+ can also be taken into account, as described above, when available.

III. The Ups & Downs of Gap Acidosis: R/F Analysis(a.k.a. Delta/Delta)

This topic was introduced in the final clinical problem of Chapter 13 in The Pain-less Guide to Mastering Clinical Acid-Base. Here I present the topic in depth. I’ll start this explanation at the beginning, both for completeness and for any readers of this article who have not read my book.

When looking at a venous chemistry report, you typically will examine the venous [HCO3

−] (most commonly measured as Total CO2) and calculate the anion gap. If [HCO3

−] is decreased and the anion gap is increased, you will rightly suspect a gap metabolic acidosis. If you want to extract additional information, you can do the following three-step procedure: (1) determine how much the anion gap has risen from its baseline, (2) determine how much [HCO3

−] has fallen from its baseline, and (3) compare these two changes. We can describe this process as one of comparing the increment or “rise” in the anion gap with the decrement or “fall” in bicarbonate. As I’ll explain in a moment, doing this comparison can sometimes tip you off to the presence of a mixed acid-base disturbance that you might other-wise have missed. As an added benefit, the comparison can give you insight into a number of physiological and pathophysiological processes affecting the patient.

There are various ways you can compare the increment or rise in the anion gap with the decrement or fall in bicarbonate, but the most common one is to set up a fractional ratio in which the rise in the gap is placed in the numerator and the fall in [HCO3

−] is placed in the denominator. For example, if the gap has risen from its baseline by 10 (say, from 12 to 22) and [HCO3

−] has fallen from its baseline by 10 (say, from 24 to 14), you set up the ratio like this:

Rise in anion gap / Fall in [HCO3−] = 10/10 = 1

Or, if the gap rises from 12 to 34 (an increase of 22) and bicarbonate falls from 24 to 13 (a decrease of 11), the ratio looks like this:

Rise in anion gap / Fall in [HCO3−] = 22/11 = 2

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You can call this number the Rise/Fall ratio — or R/F, for short. Thus, in the first example, R/F = 1. In the second example, R/F = 2. As you may have noticed, the R term is identical to the “delta gap” discussed earlier in this article; R and delta gap are simply two ways of describing the same thing.

When calculating R and F, it is best to use the patient’s actual, pre-acidosis baseline values for [HCO3

−] and the gap, assuming you have timely access to previous lab reports or chart notes. Using true baseline values, rather than the population aver-ages contained in the lab’s normal ranges, lets you determine more accurately how much the numbers have actually changed. If you have multiple baselines, take the average. If relevant baselines are not available on a timely basis, use the mid-point of the normal range as your assumed baseline.

A Brief Digression On Terminology:“Rise/Fall” versus “Delta/Delta”

The R/F ratio has traditionally been called the delta/delta (sometimes writ-ten ∆/∆). This name literally means “change/change,” since the Greek letter delta (∆) is used in math to represent the change in a variable. I prefer to call the ratio R/F because this name reminds you how to set up the fraction: the Rise in the anion gap goes in the numerator and the Fall in bicarbonate goes in the denominator. Using the name delta/delta, it’s easy to forget which “change” goes in the numerator and which goes in the denominator. Or you can get really mixed up and use the ratio (entirely incorrectly) in a situation where both the anion gap and bicarbonate are increased (after all, both the gap and [HCO3

−] have still “changed”), such as during a mixed metabolic alkalosis and gap metabolic acidosis in which the alkalosis predominates. In reality, the ratio should be calculated only in situations that fit a Rise/Fall pattern that is broadly consistent with a gap metabolic acidosis: an elevated anion gap and a decreased [HCO3

−]. Further adding to the mischief that the delta/delta terminology can create, the symbol ∆ is sometimes used as a shorthand notation to indicate the anion gap itself, that is, the actual value of the gap, rather than the increment in the gap. This dual meaning of the delta symbol can lead to additional confusion. Calling the ratio R/F auto-matically helps you avoid all these common missteps. Even if your clinical environment continues to use the delta/delta terminology, keeping in mind that delta/delta actually means Rise/Fall can help you stay on track. If you want a mnemonic that leaves little room for error when setting up the ratio, the inelegant but serviceable “RAG OR FIB” lays it out practically word for word: Rise in Anion Gap OveR Fall In Bicarbonate.

The clinical use of the R/F ratio is best validated, and is most often calculated, for ketoacidosis (especially DKA) and lactic acidosis. For this reason, the rest of this discussion is about these two conditions. To understand how R/F works in


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these conditions, let’s start by tracking the R/F of a hypothetical patient with gap acidosis. In doing so, I’ll simplify things somewhat by (1) focusing on the most important physiologic and pathophysiologic processes and (2) artificially breaking the time course into three discrete steps or phases, though in reality there is some overlap among these.

Phase 1. In gap metabolic acidosis, the offending acid (say, a ketoacid) enters the ECF, where it dissociates and deposits an anion (thus raising the anion gap) and, through buffering of the released protons, consumes an equivalent amount of bicar-bonate (thus reducing [HCO3

−]). This buffering sequence leads to an R/F of 1/1, or 1, since each bicarbonate that is lost is replaced by an unmeasured anion. This ratio of 1 does, in fact, exist early in the course of most gap metabolic acidoses, including both DKA and lactic acidosis.

Phase 2. Within an hour or two from the onset of acidosis, the ratio can start to change markedly. One process responsible for this change is that some bicarbon-ate moves out of cells and into the ECF. This movement occurs because the fall in extracellular [HCO3

−] creates a “downhill” concentration (and electrochemical) gradient, so the bicarbonate moves naturally out of the cells, that is, it moves from the ICF (intracellular fluid) into the ECF. This movement tends to raise the plasma [HCO3

−] and thus to reduce the value of F. The result is that R/F tends to rise. As a rough approximation, we can say that the movement of bicarbonate usually raises R/F to about 1.5, though there is quite a bit of variation. In fact, clinical studies have shown that the mean R/F among patients with lactic acidosis actually does equal 1.5. Though nobody has plotted it, it seems likely that for lactic acidosis there is actually a normal bell curve distribution of values, with the top of the curve (the most common value statistically) falling at 1.5. However, the distribution of values (the base of the bell curve) is not narrow enough to let you “expect” a value of 1.5. In other words, the variance, which is sometimes measured by the size of the SD (standard deviation), is pretty large.

Phase 3. The same movement of bicarbonate from ICF to ECF occurs in both lactic acidosis and ketoacidosis. Thus, there is some tendency for the mean R/F in both conditions to rise to about 1.5. However, something often happens in DKA that keeps R/F close to 1.0—the initial level that we saw in Phase 1— or that causes R/F to fall back down towards 1.0 if it already has risen above that point. That “something” is the excretion of ketoanions in the urine. In fact, the mean R/F among DKA patients actually is about 1.0, indicating that in many patients, some significant quantity of unmeasured anions is lost. Unlike ketoan-ions, which are freely excreted by the kidney, lactate does not leave the body in the urine because the kidney has a high reabsorptive threshold for lactate. That is, even when plasma [lactate] is markedly elevated, almost all lactate that is filtered from the blood at the glomerulus is reabsorbed back into the blood by the renal tubules and thus is retained in the ECF. In contrast, ketoanions that are filtered at the glomerulus do not undergo reabsorption, so they appear in the urine instead. This difference in the renal handling of lactate vs. ketoanions largely accounts for the difference in mean R/F between these two conditions. However, in DKA, as in lactic acidosis, a normal bell curve distribution of R/F is likely, and the width of the curve is great enough that you should not “expect” to see an R/F of 1.0.

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In fact, the R/F bell curves for lactic acidosis and DKA overlap to a substantial degree, making it a mistake to rely heavily on the R/F to differentiate between lactic acidosis and DKA.

Phase 3, continued. Here I need to offer a clarification. Although at least some ketoanions are consistently excreted in DKA, the quantity is highly sensitive to renal function, which itself depends on both volume status and the patient’s baseline chronic kidney function.* In DKA, both volume status and baseline kidney function are important to be aware of because the osmotic diuresis often induces volume depletion and diabetes itself frequently leads to chronic kidney disease. In patients with either marked volume depletion or chronic renal impairment, or both, the excretion of ketoanions is reduced, typically causing R and hence R/F to remain elevated above the 1.0 starting point. In other words, in patients with substantial renal impairment, whether temporary due to volume depletion or permanent due to chronic kidney disease, mean R/F values are especially likely to overlap with those seen in lactic acidosis.

To summarize a key point about the mean R/F values in DKA and lactic acidosis: although 1.0 (DKA) and 1.5 (lactic acidosis) probably do represent the mean or classic R/F values for these conditions, marked variations around those means, based in part on differences in volume status and chronic kidney function in DKA patients, makes it unreliable to differentiate lactic and ketoacidosis based on R/F values. Further, even in the same patient over time, R/F may change markedly, especially in response to changes in volume status in DKA patients.**

It follows from all this that scrutinizing R and F, while not letting you differentiate diagnostically between lactic acidosis and DKA, can provide a window into many aspects of the patient’s physiology and pathophysiology. Grappling with R/F and trying to make sense of the value can thus force you to think through a number of clinically important aspects of the patient’s condition. However, the single most important reason to consider R/F is that it can alert you to the presence of a mixed disturbance you might otherwise not have considered. We turn to that subject now.

Detecting Mixed Disturbances With R/F

As a starting point, recognize that the presence of a second acid-base disturbance (in addition to a gap acidosis) influences the R/F ratio almost purely by affecting F, that is, through its effect on the bicarbonate level. (The one exception occurs when a second anion gap metabolic acidosis is superimposed on the first.) So let’s

* Reminder. Recall that volume depletion impairs renal blood flow, decreasing filtration and hence impairing the kidney’s ability to excrete wastes in the urine.

** Going Further. Yet another factor that can variably affect R/F in both DKA and lactic acidosis patients is the metabolism of circulating anions, which occurs primarily during the treatment phase. By converting organic anions to bicarbonate, this metabolism tends to reduce both R and F, but the changes in these two need not be entirely symmetrical in relative terms, depending on what the starting points are. Thus, the metabolism of the anions may or may not itself alter R/F.


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consider what happens to F in the four primary acid based disturbances that might be superimposed on the underlying gap acidosis. Non-gap metabolic acidosis and compensated respiratory alkalosis both lower plasma [HCO3

−], and thus tend to increase the value of F. Because these disturbances do not affect R, they have the effect of lowering R/F. Thus, if R/F is abnormally low, you should consider the possibility of a mixed disturbance consisting of a gap acidosis plus either a non-gap acidosis or a compensated respiratory alkalosis. Conversely, metabolic alkalosis and compensated respiratory acidosis raise the bicarbonate level and hence de-crease the value of F without affecting R. These disturbances thus raise R/F. Thus, if R/F is abnormally high, you should consider the possibility of a mixed distur-bance consisting of a gap acidosis plus either metabolic alkalosis or compensated respiratory acidosis.

Given that a range of factors can influence R and F, including mixed disturbances, how do you know when a mixed disturbance is actually present? To address this question, it is useful to focus separately on situations where R/F is markedly ele-vated (much higher than 1) and markedly decreased (much lower than 1).

R/F Much Greater Than 1. The most important guideline here is that the higher the R/F is, the more likely it is that a mixed disturbance is present—that is, a gap acidosis plus either a metabolic alkalosis or a compensated respiratory acidosis. By the time R/F reaches a value of 2 (i.e., when the increment of the anion gap is twice that of the decrement in bicarbonate), a mixed disturbance is likely, and at R/F values much greater than 2, a mixed disturbance become increasingly certain.

R/F Much Lower Than 1. Let’s say R/F = 0.3, which means that the increase in the anion gap is only 3/10ths the size of the decrease in plasma [HCO3

−]. The most common situation where the anion gap is thus lowered involves an especially well-hydrated ketoacidosis patient with good baseline renal function, a combination that results in the rapid urinary excretion of ketoanions. In some of these patients, the gap may actually fall to normal (R = 0) even while [HCO3

−] is still quite low, resulting in an R/F of 0. As described earlier in this article, these patients now have, by definition, a non-gap (a.k.a. hyperchloremic) metabolic acidosis. How about factors that lower the bicarbonate level, and thus increase F? As mentioned, you must consider the possibility that a non-gap metabolic acidosis or compensated respiratory alkalosis is superimposed on the underlying gap acidosis. Thus, in contrast to patients with very high R/F values, which almost certainly indicate a mixed disturbance, very low R/F values can occur without a mixed disturbance at all: a low R/F may be due to either the loss of anions in the urine (this possibility is relevant only in ketoacidosis; recall that lactate is retained by the kidney regardless of volume status) or a mixed disturbance with a bicarbonate-lowering process, or some combination of these.

As the above comments suggest, calculating the R/F ratio usually does not provide hard and fast answers about whether a mixed disturbance is present, except when R/F is clearly above 2, in which case a mixed disturbance is very likely. But regard-less whether a mixed disturbance is present, calculating R/F often raises important questions and presents you with pathophysiologic puzzles that are worth trying to solve. If you can explain the R/F pathophysiologically, regardless whether a mixed

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disturbance is present or not, you may gain a deeper understanding of the patient’s overall condition.

R/F and Bicarbonate Therapy in DKA Patients

In addition to the above diagnostic uses of R/F, the ratio can also be of some help during the treatment of ketoacidosis. Specifically, R/F can help you predict how completely plasma [HCO3

−] will normalize once you begin treatment. An R/F of 1 or greater suggests that the metabolism of organic anions may produce enough bicarbonate to increase plasma [HCO

3−] to normal, since each anion that

is metabolized replaces one bicarbonate ion. In contrast, an R/F much below 1 suggests that metabolism of organic anions likely will be insufficient to completely replace the bicarbonate deficit. This latter scenario, as discussed above, is most likely in well-hydrated DKA patients with good renal function who have lost large quantities of organic anions in the urine. You can think of this urinary excretion of organic anions as causing a loss of “potential bicarbonate” (i.e., a loss of substances that, had they remained in the body, could have been metabolically converted into bicarbonate). This lost potential bicarbonate must be replaced by the clinician or be gradually regenerated by the kidney over a period of days. The bottom line here is that in DKA, a low R/F may slightly increase your willingness to give bicarbonate as part of the treatment, assuming no contraindications exist. That said, studies have not demonstrated a benefit to giving bicarbonate in DKA, and most experts recommend not even considering giving bicarbonate in DKA unless acidemia is very severe.

Summary Points on R/F

• R/F is calculated in patients with gap metabolic acidosis, especially lactic acidosis and diabetic ketoacidosis.

• On average, R/F is higher in lactic acidosis (mean = 1.5) than DKA (mean = 1.0), with the higher value in lactic acidosis usually accounted for partly by the renal retention of lactate anions. However, as a result of large variations in R/F among patients, and in the same patient over time, these mean values usually cannot be relied upon to differentiate DKA from lactic acidosis.

• When possible, calculate R and F using the patient’s actual healthy base-lines for [HCO3

−] and the gap, rather than using the lab’s normal ranges (which are population averages). When actual baseline values are not available, use the midpoints of the lab’s normal ranges.

• A very high R/F (2 or greater) usually indicates a mixed disturbance with a bicarbonate-raising process (i.e., a gap acidosis plus either metabolic al-kalosis or compensated respiratory acidosis). In contrast, a very low R/F (even as low as 0) is much less diagnostic, as it can indicate either a mixed disturbance with a bicarbonate-lowering process (a gap acidosis plus either non-gap acidosis or compensated respiratory alkalosis) or, simply, a rapid excretion of unmeasured anions, especially in DKA.

• Therapeutically, an R/F of 1 or greater suggests that enough unmeasured


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organic anions are circulating to replace the bicarbonate deficit once these anions are metabolized to bicarbonate by the liver. In a patient with a low R/F, the metabolism of circulating anions may not be sufficient to replace lost bicarbonate, and thus may slightly increase your willingness to give bicarbonate, assuming no contraindications; though as noted above, bi-carbonate administration would be considered only rarely in any case.

* * *

For readers who wish to explore the anion gap even further, the following detailed and thorough review is an excellent next step: Jeffrey A. Kraut & Nicolaos E. Madias, Serum Anion Gap: Its Uses and Limitations in Clinical Medicine, Clin Am J Soc Nephrol (2007) 2: 162−174. Additional valuable readings include Jeffrey A. Kraut and Glenn T. Nagami, The Serum Anion Gap in the Evaluation of Acid-Base Disorders: What Are Its Limitations and Can Its effectiveness Be Improved? Clin J Am Soc Nephrol (2013) 8: 2018−2024; and Alfred A. Vichot and Asghar Rastergar, Use of Anion Gap in the Evaluation of a Patient With Metabolic Acidosis, Am J Kidney Dis (2014) 64(4):653-657.

Finally, if you’ve made it this far but, along the way, realized that your grasp of the fundamentals is not as strong as you would like, consider reading The Painless Guide to Mastering Clinical Acid-Base. You can “look inside” the book and read endorse-ments at Amazon.

the anion gap: taking it to the next level

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