The Anion Gap: Oxygen Pressure Field Theory VII

OPFT Part VII:  The Anion Gap

The anion gap is the difference in the measured cations and the measured anions in serum, plasma, or urine. The magnitude of this difference (i.e. “gap”) in the serum is often calculated in medicine when attempting to identify the cause of metabolic acidosis. If the gap is greater than normal, then high anion gap metabolic acidosis is diagnosed.

The term “anion gap” usually implies “serum anion gap”, but the urine anion gap is also a clinically useful measure.


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Authored by:  Gary Grist,  BS, RN, CCP, LCP   

To View all of Gary Grist”s Posts Regarding OPFT-  click here

Mr Gary Grist delivered a seminar on this topic at The Missouri Perfusion Society 16th Annual Meeting titled “Beyond The Fick Equation”  on June 10-12, 2011

The Anion Gap

Up to this point the discussion has concerned the theory of oxygen pressure fields.  Now we will deal with known facts in order to find the practical application of the theory in perfusion.Oxygen pressure fields have been measured and mapped.  The range of tissue pO2 values range from as high as the arterial pO2 to as low as zero.  The median tissue pO2 is about 20 mmHg in the normal air breathing human.  This means that 50% of the tissues have a pO2 above 20 mmHg and 50%  have tissue pO2 values of 20 or less.  This differs from the average (mean) tissue pO2 of about 55 mmHg.  This is because the upper 50% of  tissue values have a wide range while the lower 50% of tissue values range from only 20 to zero mmHg.  So the average tissue pO2 value is skewed above the median value.

This can lead to some confusion when researching the subject because some investigators reportaverage values and some report median values.  Tissue pO2 values are measured in various ways.  Specialized probes which can measure individual cell values allow the investigator to make multiple measurements to see how many 100’s mmHg, 50’s mmHg, 20’s mmHg, 0’s mmHg pO2 values, etc., occur in a selected tissue sample.

From this the median values can be ascertained.  A tonometer, on the other hand, is a permeable tube placed through a selected tissue.  The gas or fluid within the tube equilibrates with the surrounding tissue to yield a pO2 value which is the average of all the cells within the area (this is the type of value obtained from urine pO2’s).  (The use of tissue pO2 measuring systems is a moot question for perfusionists since these measuring systems are not available on the open market for clinical use.) Approximately 5% of all the tissues have a pO2 value of 5 to 0 mmHg.  It is these tissues which are thought to be in the area where the lethal corner would first appear and are at greatest risk for hypoxia/anoxia and CO2 retention.

It is obvious that the microvascular redistribution  (MR) system is constantly practicing brinkmanship,  making sure that the tissues get the minimum amount of oxygen necessary and shuffling resources to maximize energy conservation.  During a disease state or when the body ends-up on extracorporeal support the MR system balance is going to be difficult to maintain.  The probability of the development of a lethal corner is not only possible but likely.  So how can a perfusionist know if a lethal corner is present in a patient?

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Keeping the previous thought in mind

Oxygen Pressure Field Theory suggests that mechanisms that we currently use to assess oxygenation of tissues are incomplete at best and self-deceiving at worst because blood pO2 measurements are only an indirect measurement of tissue oxygenation.  This was recognized years ago.  Consider this quote from Dr. Michael J. Miller MD, PhD in 1982 from his excellent review article;  “None of the commonly utilized indices of tissue oxygenation will reliably reflect tissue oxygenation in all clinical settings,  owing, principally, to problems arising from circulatory redistribution in disease.  Low values of oxygen delivery, consumable oxygen, or mixed venous pO2 can usually be interpreted as compatible with tissue hypoxia, particularly in the presence of shock or when signs of frank tissue anaerobiosis (lactic acidosis) exist.

Normal or high values of oxygen delivery or consumable oxygen alone do not ensure adequate tissue oxygenation, even in the absence or circulatory redistribution, as they may be inappropriate to tissue oxygen demand.”  In other words, intracapillary velocity may be too slow and /or perfused capillary density may be poor in relation to the actual oxygen  NEED of the tissue.  For example, take the blood gases of an accidental hypothermia patient (Tyndal et al, Perfusion 1996; 11:57-60).  They are ABG 7.04/40/317/BE-19.9 and VBG 6.96/62/53/BE-18.3 .

According to the pvO2, tissue oxygenation is more than adequate, but it doesn’t take a rocket scientist to figure out that the pH says  that perfused capillary density is poor.  In addition the p(V-A)CO2 is a very high value indicating that intracapillary velocity is very poor. Using the formula; Cardiac Index = 12.9 / p(v-a)CO2 = 12.9 / 22 mmHg =  0.5 L/min/M2, the cardiac index is a lethal value.  This is an extreme example.  If the paO2 and pvO2 fail to properly indicate tissue oxygenation in this patient, then they can fail when the perfusion deficit is much more subtle.

What about the base balance?  It is very high in the example given above. Isn’t it always a reliable indicator of acidosis?The base balance is an important marker for adequacy of perfusion.  However, it too may be deceptive. Consider the blood gas of a status post repair of Tetrology Of  Fallot after 135 hours of ECMO because of cardiac failure post-op; ABG 7.43/37/394 BE+1, VBG 7.37/49/37 BE+4.  This is hardly representative of a patient in multiple organ failure;  no urine output, elevated liver enzymes, no bowel sounds and in a coma.

The pump is supporting the compensation mechanisms well enough to make the numbers look good, but intracellularly the patient is dying.  The increased p(v-a)CO2 is a dead giveaway that things are not right, but the p(v-a)CO2 is not a traditionally accepted marker.  Despite what the blood gases indicate, this patient has a serious perfusion defect involving reduced intracapillary velocity.  So how come there is a  base excess?  This is one of my cases before I knew anything about OPFT.

So guess what we did.  We weaned, of course.  At the end of 374 ECMO hours our blood gases looked like this: ABG 7.36/37/138 BE -4, VBG 7.28/60/36 BE 0.  The intracellular pH from the retained CO2 [the p(v-a)CO2 at this point was  23 mmHg] must have been very high  making tissue pH very low.  The ability of the tissues to heal would be very difficult if not impossible.  The patient died soon thereafter. As perfusionists,  in long-term perfusion applications we cannot rely too much on blood gas  and mixed venous saturation interpretation to guide our actions because the indices they convey are incomplete and sometimes deceptive.

Since the measurements of oxygen supply and consumption may not be reliable there is need to look elsewhere for a marker to indicate adequacy of perfusion.  In order to do this we must review the basic cell function for a clue.   In the healthy cell, oxygen and glucose enter the cell where they are converted by the cell process of aerobic metabolism to make energy (ATP) and the waste products of  CO2 and water.  None of these four components is a charged molecule.  As they enter and leave the cell the net charge on the cell remains neutral.

In the anoxic cell, oxygen is unavailable.  Glucose enters the cell and the process of anaerobic metabolism makes energy (ATP in lesser amounts) and the waste products of CO2, water and lactic acid.  The lactic acid ionizes within the cell.  The hydronium ion is buffered within the cell, much of it complexing with cell protein buffers.  However, as the lactate builds up it migrates outside the cell.  This leaves the cell with a positive charge. Outside of the cell, in the extracellular space there are two main anions; chloride [Cl] and bicarbonate [HCO3] in the ratio of approximately 4 to 1.

For simplicity sake, let’s suppose that the Cl concentration is  100 mEq/L and the HCO3 is 25 mEq/L, extracellularly.  As the lactate leaves the cell it must be replaced by another anion in order to maintain a neutral cell charge.  So, if 5 lactate anions exit the cell, 5 extracellular anions must enter the cell.  Because the Cl and HCO3 are present in a ratio of about 4 to 1, four Cl anions will enter the cell for every HCO3 anion that enters the cell.  The Cl will drop to 96 mEq/L as 4 Cl anions enter the cell and the HCO3 will drop to 24 mEq/L as one HCO3 anion enters the cell. Another 5 lactate anions exit the cell.  The Cl drops to 92 mEq/L and the HCO3 drops to 23 mEq/L.  Still, another 5 lactate anions leave the cell.  The Cl drops to 88 mEq/L and the HCO3 drops to 22 mEq/L.

Remember that the hydronium ions are buffered within the cell by the proteins, with very little acid leaving the cell until the intracellular buffers are close to depletion.  Up to this point 15 mEq/L of lactic acid (at lot) has been generated by the cell, but a major extracellular buffer has only dropped from 25 mEq/L to 22 mEq/L.  In this compensated system the major change has been in the concentration of the extracellular Cl anion, dropping from 100 to 88 mEq/L.

This change in the concentration of extracellular anions is measured as an “anion gap”.  In the classical measurement all of the known measured anions are added up and subtracted from all of the  cations in the blood serum. The difference is the anion gap.  However, this is an impractical method and two abbreviated methods are now clinically used.  In the first, the measured serum Cl and serum HCO3 anions are added together. Their sum is then subtracted from the major cation; serum sodium [Na].  The formula looks like this: Na – [Cl + HCO3] =  anion gap.  If the electrolytes are Na = 135 mEq/L, Cl = 100 mEq/L and HCO3 = 25 mEq/L, the anion gap would be 135 – [100 + 25] = 10 mEq/L.

The other formula simply uses total CO2  [TCO2] instead of HCO3.  These two values are close enough that the difference is negligable.  For example, if the Na = 135, Cl = 100, TCO2 = 25.5, the anion gap would be 135 – [100 + 25.5] = 9.5 mEq/L rounded to 10 mEq/L.

The anion gap is better at assessing an ongoing metabolic acidosis than blood gases or base deficits 

Because it is not effected by the use of NaHCO3.  For example, consider the following anion gap; Na 135 – [Cl 90 + HCO3 15] = 30 mEq/L.  Suppose that 10 mEq/L of NaHCO3 is given to correct the buffer base with the resulting anion gap; Na 145 – [Cl 90 + HCO3 25] = 30 mEq/L.The HCO3 base has been returned to normal, but the metabolic acidosis is ongoing because the anion gap hasn’t changed. In other words, all the buffer base did was make the numbers “look” better without actually correcting the ongoing intracellular metabolic acidosis.

In reality the anion gap is a non-specific indicator of abnormal metabolism. That is, it doesn’t change just with anaerobic metabolism. For example, if oxygen is plentiful but glucose cannot be utilized (as in diabetes) the cells burn fatty acids.  Ketones are the result of this abnormal metabolism and they exchange with the extracellular anions in the same way that lactate does.  This results in ketoacidosis and an increase in the anion gap.  In uremia, the adult body produces about 60 mEq/L per day of organic acids that can only be removed by the kidneys.

As the anions of these organic acids build up intracellularly they also exchange with the major extracellular anions and the anion gap increases.  In cyanide poisoning where the enzymes responsible for oxygen utilization are destroyed, abnormal metabolites build up intracellularly.  These also exchange with the major extracellular anions and the anion gap increases. In other words, abnormal cellular metabolisim usually generates some type of weird organic acid as a waste product.  The hydronium cation is mostly buffered within the cell, but the anion migrates outside the cell and exchanges for CL and HCO3.  The change is gradual in a compensated system. Of course, in sudden and complete cardiovascular collapse there is no time for compensatory tactics on the part of the body, so intracellular buffers are quickly depleted and acid cations and organic anions  flood the extracellular space resulting in severe pH changes.

What all these aberrations have in common is that they all cause the anion gap to increase.  It doesn’t matter what causes the anion gap to increase, if it goes high enough and stays elevated long enough, the patient dies. Because a patient in multiple organ failure has a wide array of abnormal metabolic mechanisms the anion gap is a good overall tool to assess the adequacy of perfusion and the magnitude of abnormal metabolism.  If the anion gap goes up things will not go well.  However, if interventions bring the anion gap down, chances are the patient will get better, regardless of what the blood gases indicate.

Getting back to the relevancy of the lethal corner, if a lethal corner begins to develope in the 5% of tissue cells with the lowest O2 concentration and the highest CO2 concentration the blood gas may not change. However, the anion gap will increase as organic anions exchange for extracellular anions.As the lethal corner gets larger the anion gap gets higher.  So relative changes in the anion gap can be used to assess relative changes in the lethal corner even when compensation mechanisms make the blood gases look normal. The next posting will discuss the interpretation of anion gaps.