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review article
Disorders of Fluids and Electrolytes
Julie R. Ingelfinger, M.D., Editor

Integration of AcidBase and Electrolyte


Disorders
Julian L. Seifter, M.D.

T
his review describes a method of analyzing acidbase disorders From the Department of Medicine, Renal
Division, Brigham and Womens Hospital
that incorporates insights from the traditional, bicarbonate-centered model and Harvard Medical School both in
and the Stewart (or strong ion) model (Table 1).1-6 Acidbase balance and Boston. Address reprint requests to Dr.
electrolyte homeostasis are intricately connected at the cellular level and in clinical Seifter at the Renal Division, Department
of Medicine, Brigham and Womens Hos
disorders. This article emphasizes the integration of the principles of mass balance pital, 75 Francis St., Boston, MA 02482,
and electroneutrality which are prominently featured in the strong ion model or at jseifter@partners.org.
(also known as the physicochemical model) for interpretation of acidbase N Engl J Med 2014;371:1821-31.
phenomena. Most acidbase abnormalities can be diagnosed and interpreted with DOI: 10.1056/NEJMra1215672
the use of the traditional approach. Why, then, should the strong ion theory be in- Copyright 2014 Massachusetts Medical Society.

corporated into teaching about acidbase balance? Although the Stewart model is
not primarily a mathematical expression of a confirmed reality, it is relevant be-
cause it is a powerful construct that can shed light on an important biologic system.
Included in this article are several case vignettes that show the explanatory
power of the strong ion approach in clinical practice. Some of these examples have
been presented in a companion article on the physiological approach to acidbase
balance by Berend et al.7 Other cases that are interpreted with a strong ion ap-
proach are included in the Supplementary Appendix, available with the full text of
this article at NEJM.org. The more complex chemistry of the hydrogen-ion concen-
tration in intracellular and extracellular fluid compartments is beyond the scope
of this article.

Bic a r bonate- Cen ter ed a nd S t rong Ion A pproache s

The traditional model uses easily measured concentrations of blood carbon diox-
ide [CO2] and bicarbonate [HCO3].6 It is the basis of the HendersonHasselbalch
equation:

pH=pK+log10
( [HCO3] ,
0.03 (Paco2) ) (1)

where pK is the acid dissociation constant, Paco2 the partial pressure of arterial
carbon dioxide, and 0.03 the solubility of CO2 in blood.
The overall equilibrium between carbon dioxide and bicarbonate is shown
below:

CO2+H2O H2CO3 H++HCO3, (2)

where H2CO3 denotes carbonic acid, and H+ hydrogen.


In a teaching model, this relationship shows how alterations in the partial pres-
sure of carbon dioxide (Pco2) or levels of hydrogen or bicarbonate affect the
other variables through mass balance. The fact that the hydrogen ion concentra-

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The n e w e ng l a n d j o u r na l of m e dic i n e

Table 1. Comparison of the Key Elements Associated with Two Models of AcidBase Balance.*

Traditional Approach Based on BicarbonateCarbon Dioxide Physicochemical (Stewart) Approach


CO2/HCO3 equilibrium: CO2/HCO3 equilibrium:
CO2+H2O H2CO3 H++HCO3 CO2+H2O H2CO3 H++HCO3
and for [CO32] and for [CO32]
2[HCO3] [CO32]+[H2O] 2[HCO3] [CO32]+[H2O]+[CO2]
HendersonHasselbalch equation: [H+][OH ]
pH=pK+log10
( [HCO3]
0.03 (Paco2) ) Water dissociation: Kw=
H2O
Weak acid (HA) dissociation:
[H+] [A]=KA [HA];
weak acid conservation:
[Atot]=[HA]+[A]
Anion gap=[Na+]([Cl]+[HCO3]) mmol per liter Strong ion difference (mmol per liter)=[Na+]+[K+]+[Ca2+]+[Mg2+][Cl];
[strong ion difference][A]=[HCO3]+[CO32]+[(OH)][H+];
or,
strong ion difference[A][HCO3]
(anion gap12)
Delta/delta =
(25[HCO3])

Example of expected compensation: Example of expected compensation:


Pco2=1.5 [HCO3]+82 Pco2=1.5 [HCO3]+82
The Winters formula for respiratory compensation of metabolic The Winters formula for respiratory compensation of metabolic
acidosis, in which Pco2 is dependent on the decrease in acidosis, in which Pco2 is dependent on the decrease in
bicarbonate bicarbonate

* The traditional approach is based on bicarbonatecarbon dioxide. The physicochemical (Stewart) approach is dependent on the strong ion
difference and Atot, the total content of albumin, phosphate, and circulating nonvolatile weak acids and their dissociated anions. H2CO3 de
notes carbonic acid, and Paco2 partial pressure of arterial carbon dioxide.
Relationships featuring electroneutrality are emphasized in the Stewart model. The equation for strong ion difference[A] can be reduced
to approximately [HCO3] because [HCO3] is much greater than [H+], [OH], and [CO32]. Stewarts equation (not shown), based on the re
lationships above, has been mathematically reduced to the HendersonHasselbalch equation (bicarbonate/CO2 method).2

tion is more than a million times lower than the all unmeasured charged species (predominantly
bicarbonate level indicates that other forces are albumin) in plasma, is calculated below as
at work in the regulation of pH.
As in any chemical reaction in equilibrium, a anion gap=[Na+]([Cl]+[HCO3]). (3)
change in the concentration of the reactant or
product will move the reaction in the direction The anion gap is used in the differential diagno-
that would reestablish equilibrium (Le Chteliers sis of metabolic acidosis.8-10 It can suggest a
principle). If this principle is applied to equation cause for unmeasured anions. Possible causes
2, metabolic acidosis may be attributed to either include lactic acidosis, ketoacidosis, and uremic
the addition of hydrogen, with the consumption acidosis; ingestion of salicylate, methanol, ethyl-
of bicarbonate as the reaction shifts to the left, ene glycol, or propylene glycol; and many inborn
or the removal of bicarbonate from the body, errors of metabolism. It is assumed that the
resulting in increased hydrogen as the reaction unmeasured anion is added as the protonated
shifts to the right (from carbon dioxide) to re- acid (such as lactic acid). However, a severe form
place lost bicarbonate. The observed relation be- of metabolic acidosis results from treatment
tween arterial PCO2 (PaCO2) and bicarbonate with sodium thiosulfate, a compound that has
effectively predicts the direction but not the no hydrogen.11
magnitude or time course of respiratory and re- In contrast to the anion gap shown in equa-
nal compensations. Only empirical observations tion 3 above, the physicochemical model empha-
can determine the appropriate degree of com- sizes that all cation and anion concentrations
pensation. must balance, according to the laws of electro-
The anion gap, consisting of the sum total of neutrality.3 The independent balance of each ion,

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Integr ation of Acid Base and Electrolyte Disorders

when disrupted, provides a mechanism for the a very minimal strong ion difference, since large
acidbase condition. In their classic article, Pe- charge separations are not possible. We can as-
ters and Van Slyke defined acidbase balance in sume that electrostatic forces come into play until
the blood as the chemical state resulting from changes in bicarbonate concentrations match
the balance between cations and anions.12 Car- the charge separations among other ionic spe-
rying this idea to the extreme, one could view cies. Clearly, electroneutrality in the macroenvi-
metabolic acidbase disorders as the predicted ronment always exists.
consequences of primary fluid and electrolyte One drawback of using equation 6 in a clini-
imbalance. cal calculation of the hydrogen concentration is
Strong ions such as sodium and chloride are that the error in measurements of electrolytes in
assumed to be completely dissociated in body the millimolar range cannot allow for an accu-
water but can be lost or gained disproportion- rate determination of the hydrogen level in nano-
ately. When the sum of all negatively charged molar concentrations.
ions (predominantly chloride) is subtracted from As shown in Table 1, the Stewart (or physico-
the sum of all positively charged strong ions, a chemical) model of acidbase balance is quanti-
value known as the strong ion difference (in tatively based on the view that the hydrogen and
millimoles per liter) is introduced. The strong bicarbonate concentrations are not independently
ion difference is calculated as shown below: determined. Instead, they are dependent on the
following: carbon dioxide (Paco2) and its spon-
strong ion difference= (4) taneous relationship with hydrogen and bicar-
[Na+]+[K+]+[Ca2+]+[Mg2+][Cl], bonate, the dissociation of water (the abundant
source of hydrogen within body fluids), the dis-
where Ca2+ denotes calcium, and Mg2+ mag solved strong ions, the strong ion difference,
nesium. and Atot, which is the sum of all buffer pairs
As shown in equation 5 below, the total con- (mostly weak acids) that move toward equilibrium
tent of albumin, phosphate, and circulating with a dissociated anion [A] according to the
nonvolatile weak acids [HA] and their dissoci- dissociation constant for each (e.g., albumin
ated anions [A] is referred to as [Atot] in the with its net negative charge under physiological
Stewart model: conditions).13
In keeping with the laws of electroneutrality,
[Atot]=[HA]+[A]. (5) all charged species must balance. This requires
that any change in the concentration of one of
As shown in equation 6 below, in which the charged variables (the strong ion difference)
CO32 denotes carbonate and OH hydroxide, an must be matched by a change in the concentra-
expression for remaining charged species, con- tion of another charged species. According to
sidered to be the dependent variables, is constraints in this internal system, the hydrogen
and bicarbonate concentrations are dependent
[strong ion difference][A]= (6) on the other variables, the total mass of which
[HCO3]+[CO32]+[(OH)][H+], is conserved.
The simultaneous mathematical solution of
in which the levels of carbonate, hydroxide, and these reactions is complex and is not required to
hydrogen are much lower than the levels of bi- diagnose acidbase disorders. Furthermore, both
carbonate. Any developed difference in the ionic experimental and clinical observations can be ex-
charge, or strong ion difference, determines the plained with the use of either model. Yet the
bicarbonate concentration. Essential to this ar- physicochemical model is useful in revealing in-
gument is that any difference in an unbalanced dividual processes in the development of an acid
charge will immediately result in the appearance base disturbance because it associates the abnor-
or disappearance of bicarbonate formed from mality with specific electrolyte disturbances. The
ubiquitous and neutral carbon dioxide and wa- traditional model uses the calculated, and useful,
ter. It is also expected that the changes in the anion gap to elucidate the pathophysiology of
bicarbonate concentration will begin to occur at metabolic disorders. The usual calculation for the

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The n e w e ng l a n d j o u r na l of m e dic i n e

anion gap is shown in equation 3. For this


Table 2. AcidBase Disorders and Their Causes According to
the Relationship between Gains and Losses of Circulating equality to hold true, for electroneutrality pur-
Cations or Anions.* poses, the anion gap must be the net value for
a complex mixture of all ionic species not in-
Metabolic alkalosis
cluded in the calculation, such as albumin,
Decrease (loss) of anion other proteins, calcium, magnesium, potassium,
Hypochloremic and phosphate, plus any additional anions such
Gastrointestinal as lactate or acetoacetate. To illustrate the use-
Vomiting fulness of a more inclusive approach in separat-
Chloridorrhea (villous adenoma, some ing out various components of the anion gap,
chloride secretory diarrheas)
an anion gap hypothetically could be calculated
Renal
as simply [Na+][HCO3]. From a charge point
Chloruretic agents (loop diuretics, thiazides)
of view, it works out, but obviously, hyperchlo-
Chloride channelopathies (e.g., the Bartter
syndrome, the Gitelman syndrome) remic acidosis could not be distinguished from
Hypokalemia leading to loss of chloride an anion gap acidosis.
Sweat
The anion-gap equation could be rearranged
Cystic fibrosis
to solve for the bicarbonate concentration in-
Hypoalbuminemic state13: malnutrition
stead of unmeasured anions:
Increase (gain) of cation
[Na+]([Cl]+[AG])=[HCO3],
Sodium citrate, sodium lactate, sodium bicarbonate,
sodium acetate
Hypernatremic where AG denotes the anion gap.
Hyperaldosteronism This is analogous to the strong ion differ-
Hypercalcemic ence. The anion gap, which is usually calculated
Milk alkali syndrome, calcium carbonate with the use of plasma bicarbonate, is useful
Metabolic acidosis clinically. If every charged species were known
Increase (gain) of anion and measured, the equation could be rearranged
Hyperchloremic (potassium chloride, calcium chloride, to calculate the bicarbonate concentration, but
hydrogen chloride, sodium chloride, often the unmeasured ion is unknown. How,
arginine hydrochloride, lysine hydro then, does the strong ion difference increase or
chloride, ammonium chloride)
decrease? The answer lies in specific gains or
Anion-gap acidosis
losses of electrolytes such as sodium and chlo-
Lactic acidosis
ride in a different proportion to each other than
Diabetic ketoacidosis
the proportion in the normal extracellular fluid.
Other unmeasured anions The first step in understanding how an acid
Thiosulfate base disorder develops is to know or assume the
Hyperphosphatemic specific electrolyte content of any gained fluids
Decrease (loss) of cation (sodium and potassium) (e.g., intravenous fluids) or lost fluids (e.g., gas-
Renal trointestinal fluids, sweat, or urinary fluids).
Renal tubular acidosis Since the normal concentration ratio of so-
Natriuretic agents (e.g., amiloride, triamterene) dium to chloride in extracellular fluid is ap-
Sodium with anions in urine: ketoacids, d-lactate, proximately 140:100, an increase in the sodium
hippurate
level, a decrease in the chloride level, or both
Hypoaldosteronism
will increase the strong ion difference and the
Gastrointestinal
bicarbonate concentration will increase (meta-
Diarrhea with bicarbonate or bacterial organic
anions in stool
bolic alkalosis), according to electroneutrality
Vomiting pancreatic secretions
requirements.3 When the strong ion difference
decreases, pH and the bicarbonate level will de-
* All metabolic acidbase disorders can be viewed in the crease (metabolic acidosis). The electroneutrality
context of the relative losses or gains of cations or anions relationship in equation 6 can be useful in diag-
in body fluids. Hypophosphatemia is not listed because
the plasma phosphate level is normally low.
nosing the causes of metabolic alkalosis and
metabolic acidosis shown in Table 2.

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Integr ation of Acid Base and Electrolyte Disorders

ing to life-threatening volume and potassium


Me ta bol ic Dis t ur b a nce s depletion.
a nd S t rong Ions
The traditional acidbase approach tacitly
Acidbase balance is dependent on strong ions in overlaps with aspects of the strong ion theory
the macroscopic sense because the same cellular (Table 1). Consider the familiar concept known
mechanisms regulate acidbase homeostasis and as the delta-delta (-), the increase () in the
electrolyte homeostasis. The following case vi- anion gap versus the decrease () in the bicar
gnette illustrates this point: bonate level.8,9
All metabolic acidbase disorders are associ-
A 31-year-old woman with gastroenteritis ated with either a change in the concentration of
had been vomiting for 2 days. She was weak sodium, potassium, calcium, chloride, hydrogen
and hypotensive. Laboratory tests revealed phosphate, or albumin or a change in the anion
a sodium concentration of 125 mmol per gap. The normal anion gap can be adjusted for
liter, potassium 2.6 mmol per liter, chlo- hypoalbuminemia by allowing for 2.5 mmol per
ride 72 mmol per liter, and bicarbonate liter of negative charge for each 1 g per deciliter
40 mmol per liter. The arterial pH was of albumin concentration.13 The relative change
7.54, the Paco2 48 mm Hg, and the uri- in the bicarbonate level and the anion gap (-)
nary pH 5.0. is only part of the electroneutrality requirement.
The net sum of all cation and anion electrolyte
Depletion of the extracellular fluid from vom- charge gaps must cancel out. In the search for a
iting creates profound needs to conserve sodium -----, clues about any acidbase disor-
and water and preserve potassium balance; these der will emerge.
mechanisms are clearly obstacles to maintaining A finding of an increase in the anion gap
a normal blood pH and bicarbonate concentra- above the normal concentration (the anion
tion. With volume and potassium depletion, gap) that exceeds the decrease in the bicarbonate
metabolic alkalosis is maintained, not corrected, concentration ( bicarbonate) may indicate mixed
by the kidneys.14,15 Low extracellular fluid vol- metabolic acidosis and metabolic alkalosis. The
ume and low blood pressure increase angioten- following case shows that a ratio other than
sin II and aldosterone levels. Increased sodium 1:1 is not pathognomonic for a mixed acidbase
reabsorption through proximal tubular sodium disturbance:
hydrogen exchange and the collecting-duct
sodium channel, accompanied by hydrogen secre- Before a cardiac arrest, a 67-year-old man
tion by the hydrogen ATPase and the potassium with an acute myocardial infarction had
hydrogen ATPase, in turn increases bicarbonate normal levels of serum electrolytes (level
reabsorption until the urinary pH decreases as it of sodium 140 mmol per liter, potassium
becomes free of bicarbonate. This paradoxical 4.0 mmol per liter, chloride 103 mmol per
aciduria in the midst of alkalemia is evidence liter, and bicarbonate 25 mmol per liter).
that blood pH depends on strong ion balance. While he was anuric after the cardiac ar-
The alkalemia will be corrected only with suffi- rest, his laboratory tests showed a sodium
cient replacement of sodium, chloride, and po- level of 140 mmol per liter, potassium
tassium. In this patient, after the administration 5.0 mmol per liter, chloride 62 mmol per
of 0.9% normal saline with potassium chloride, liter, and bicarbonate 5 mmol per liter. The
the electrolyte status improved, and the urinary arterial pH was 7.10, and the Paco2 was
pH increased to 8.0 with the prompt excretion of 16 mm Hg. The lactate level was 60 mmol
sodium, potassium, and bicarbonate. In this per liter, and the anion gap was 73 mmol per
clinical situation, the interdependency of acid liter.
base and electrolyte balance is self-evident. If
this were not the case, and kidney function in- This patient had severe anion-gap metabolic
stead focused on maintaining a normal acidbase acidosis due to lactate overproduction from tis-
balance, the bicarbonate generated by vomiting sue hypoperfusion. Since lactate production can
would result in the urinary loss of even larger result in blood lactate concentrations greater
quantities of sodium, potassium, and water, lead- than a normal bicarbonate concentration, what

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The n e w e ng l a n d j o u r na l of m e dic i n e

happens when the bicarbonate concentration with changes in each of these strong ions con-
decreases almost to zero? Hydrogen might be tributing to the alkalosis.
preferentially reactive with other tissue buffer sys- Treatment of the alkalosis in this patient with
tems, but a decrease in the chloride level is often hyperaldosteronism will require replacement with
observed, yielding a hypochloremic anion-gap potassium chloride. Administering chloride in
acidosis.16,17 With lactate acting as a strong ion, the form of saline would worsen the hypokale-
the strong ion difference [Na+][Cl][lactate] mia, and administering potassium without chlo-
is decreased and the bicarbonate concentration ride would not correct it; thus, the term saline
decreases to achieve electroneutrality. Chloride unresponsive is more accurate than chloride
moves into cells, probably in exchange for lac- unresponsive as a description of this type of
tate or bicarbonate. In this case, there was no alkalosis.
clinical evidence of superimposed metabolic alka- Hypercalcemia will increase the strong ion
losis: difference and is associated with metabolic alka-
losis.20 The milk alkali syndrome, which is often
[HCO3]+ [Cl]= [AG]=[lactate]. caused by excessive ingestion of calcium-con-
taining antacids, is characterized by alkalosis
Also, consider examples of metabolic alkalosis and hypercalcemia. In contrast, hypercalcemia
in which the increase in a strong cation is bal- in primary hyperparathyroidism is associated
anced by an increase in the bicarbonate concen- with a proximal renal tubular metabolic acidosis
tration, as in the following case, which was also rather than metabolic alkalosis. This observa-
described by Berend et al.7: tion may be explained by the decrease in the
strong ion difference due to losses of urinary
A 50-year-old woman with a recent onset sodium resulting from inhibition of proximal
of hypertension had the following labora- tubular sodiumhydrogen exchange by parathy-
tory results: sodium level 150 mmol per roid hormone.21
liter, potassium 2.2 mmol per liter, chlo-
ride 103 mmol per liter, and bicarbonate G a s t roin te s t ina l L osse s
32 mmol per liter. The arterial pH was of S t rong Ions
7.50, and the Paco2 was 43 mm Hg. She
was found to have an aldosterone-secreting Losses of ions due to diarrhea are associated
adrenal adenoma. with the development of metabolic acidosis22 or
metabolic alkalosis. Since depletion of extracel-
In this case, the change in the bicarbonate lular volume can occur in cases of acidosis or
level was associated with an increased sodium alkalosis and may be initiated by losses of sodi-
concentration, which is often seen in primary um and chloride in any ratio, the term contrac-
hyperaldosteronism and is attributable to in- tion alkalosis is a misnomer. As shown in the
creased function of epithelial sodium channels following case, the relative content of the strong
in renal cortical collecting-duct principal cells. ions lost (sodium and potassium vs. chloride),23
Mild hypernatremia probably occurred as a re- not the site of the loss, determines the acidbase
sult of extracellular fluid expansion that de- disorder:
creased vasopressin release, with a consequent
decrease in renal reabsorption of water. The A 40-year-old woman who underwent a
plasma chloride level was not increased in pro- colonic resection for ulcerative colitis had
portion to the sodium level, which is consistent excessive liquid drainage from an ileostomy.
with less chloride than sodium retention in pri- Her laboratory results revealed a plasma so-
mary hyperaldosteronism.18 Loss of chloride, a dium level of 138 mmol per liter, potassium
feature of aldosterone escape from edema, is 5.0 mmol per liter, chloride 110 mmol per
linked to decreased sodiumchloride cotrans- liter, and bicarbonate 15 mmol per liter.
port in the distal renal tubule.19 Hypokalemia in The arterial pH was 7.30, and the Paco2
turn is associated with increased loss of urinary was 32 mm Hg.
chloride. Thus,
In this case, the loss of watery small-intestinal
[HCO3]= [Na+]+ [K+] [Cl], and pancreatic secretions, which have high sodi-

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Integr ation of Acid Base and Electrolyte Disorders

um and bicarbonate levels and very low chloride compensation, since the very process of excret-
levels, would result in the relative retention of ing acid in this way has an alkalinizing effect on
more chloride than sodium in the extracellular body fluids. The loss of net acid in the form of
fluid, causing hyperchloremic acidosis. In cases ammonium chloride is a normal renal response
of colonic diarrhea, hyperchloremic acidosis to nonrenal causes of metabolic acidosis, such as
may develop because of loss of sodium and po- severe watery diarrhea. The losses of urinary
tassium with organic anions of bacterial origin, chloride result in an increased plasma strong ion
such as acetate, rather than bicarbonate per se.23 difference, which in turn permits the formation
When diarrhea is the cause of metabolic alka- of more bicarbonate.
losis, rather than acidosis, the mechanism is However, in a patient with metabolic alkalo-
determined by measuring the electrolyte content sis, a relative excess of chloride in the urine
in stool. Large losses of chloride may occur in strongly suggests that the losses of urinary chlo-
patients who have villous adenomas or other ride cause the metabolic alkalosis by increasing
secretory diarrheas that cause depletion of chlo- the plasma strong ion difference. In the follow-
ride, as shown in the following case, described ing case, such losses of urinary chloride led to
by Berend et al.7: hypochloremic alkalosis:

Large volumes of watery diarrhea from in- An 80-year-old man with congestive heart
fectious gastroenteritis developed in a 22- failure received furosemide until all pe-
year-old man. Laboratory tests revealed a ripheral edema disappeared. Laboratory
plasma sodium concentration of 140 mmol tests revealed a sodium level of 130 mmol
per liter, potassium 3.0 mmol per liter, per liter, potassium 2.5 mmol per liter,
chloride 86 mmol per liter, and bicarbon- chloride 80 mmol per liter, and bicarbon-
ate 38 mmol per liter. The arterial pH was ate 40 mmol per liter. The arterial pH was
7.60, and the Paco2 was 40 mm Hg. 7.50, and the Paco2 was 53 mm Hg.

In this case, the electrolyte concentrations in In this patient, the sodiumpotassiumchlo-


liquid stool, if measured, would probably show a ride cotransporter was inhibited by furosemide
charge gap, in which (Na++K+)Cl would be (in the thick ascending limb of the loop of
less than the normal plasma bicarbonate con- Henle). Under these circumstances, the stoichio-
centration. High losses of chloride in stool, like metric balance of sodium, potassium, and chlo-
losses of chloride from vomiting or after the use ride was 1:1:2, and proportionately more chlo-
of loop diuretics, cause hypochloremic alkalosis. ride than sodium was lost in the urine. Thus,
there is a direct explanation for the hypochlore-
mic metabolic alkalosis in this patient. Inhibi-
Ur ina r y Ch a rge G a p
a nd S t rong Ions tion of the sodiumchloride cotransporter of the
distal tubule by thiazides (stoichiometric balance
Measurements of urinary electrolyte concentra- between sodium and chloride, 1:1) is also pre-
tions and flow rate indicate renal acidbase func- dictive of metabolic alkalosis because of the
tion even without measurement of urinary bicar- greater loss of chloride than sodium from the ex-
bonate. As shown in equation 7, the urinary net tracellular fluid. In addition to chloride-wasting
charge compares the loss of measured strong diuretics, many hereditary disorders of sodium
cations (sodium and potassium) with the loss of and chloride transport by the renal tubules (so-
chloride24: called channelopathies) may cause acidbase dis-
orders, as shown in Table 2.
Urinary net charge gap=[UNa+]+[UK+][UCl]. (7)
Positive Urinary Charge Gap
Negative Urinary Charge Gap A positive value for the urinary net charge gap
A negative value for the urinary net charge gap indicates excretion of an unmeasured anion. The
indicates the presence of the unmeasured cation, lost, unmeasured anion may be bicarbonate or
ammonium (excretion of ammonium chloride). nonbicarbonate anions such as ketones, lactate,
The loss of ammonium chloride in the urine of a l-lactate, d-lactate, and hippurate in persons
patient with metabolic acidosis is an appropriate who sniff glue. Such loss of anions will decrease

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The n e w e ng l a n d j o u r na l of m e dic i n e

the plasma strong ion difference and acidify the


Figure 1 (facing page). Renal Tubular Cells with Trans
extracellular fluid as the process returns chloride porters That Are Targets of Hormones, Diuretics,
to the circulation.10,25 If the urinary clearance of and Mutations Affecting AcidBase Balance.
these nonchloride anions is high enough that Similar transporters in the gastrointestinal tract that
they do not accumulate as a plasma anion gap, are associated with disease are not shown. All cell trans
then the hyperchloremia may be mistaken for porters on the blood side interface with interstitial fluid
(not shown) before transport into blood. AE1 denotes
renal tubular acidosis.24 Without those nonbicar-
anion exchanger 1, ENaC epithelial sodium channel,
bonate anions, metabolic acidosis with the loss NBC sodium bicarbonate cotransporter, NCC sodium
of urinary sodium and potassium and retention chloride cotransporter, NHE3 sodiumhydrogen ex
of chloride (the positive-charge gap) will result in change, and NKCC sodiumpotassium 2-chloride co
a decreased plasma strong ion difference, consti- transporter.
tuting a renal cause of acidosis (e.g., carbonic
anhydrase inhibition or renal tubular acidosis).
If metabolic alkalosis is present, a positive values. The hyperchloremic renal compensation
urinary gap suggests that the renal loss of for respiratory alkalosis is the excretion of fil-
strong cations (sodium and potassium) and con- tered sodium and potassium with bicarbonate,
servation of chloride will acidify the extracellu- because low Paco2 decreases proximal and distal
lar fluid because of a decrease in the plasma hydrogen secretion. As the plasma strong ion
strong ion difference and in the bicarbonate difference decreases, the plasma bicarbonate
concentration. concentration will decrease.
The excretion patterns of urinary electrolytes In respiratory acidosis, high Paco2 increases
reflect the ability of the kidney to counteract production of ammonia by the kidney, and the
nonrenal acidbase disorders. The capacity of excretion of ammonium chloride with a negative
the kidney to excrete ammonium chloride in urinary net charge, shown in equation 7, results
acidosis allows for elimination of anions with in hypochloremia, an increased plasma strong
conservation of sodium for volume and potassi- ion difference, and an elevated plasma bicarbon-
um for potassium balance. This potassium- ate concentration. The elevated Paco2 increases
sparing effect of urinary ammonium is evident the renal reabsorption of sodium and bicarbon-
in hypokalemic stimulation of ammoniagenesis. ate, so the compensation is maintained. If the
The traditional physiological approach inter- Paco2 is abruptly lowered by means of a ventila-
prets the urine electrolytes to deduce the pres- tor, the compensatory response transitions to
ence of ammonium and bicarbonate with less posthypercapnic hypochloremic metabolic alka-
emphasis on the strong ion pathogenesis of losis, which will not resolve until the chloride that
acidbase disorders. The physicochemical model is lost as ammonium chloride is replenished.
emphasizes the relative losses of the actual mea-
sured quantities to determine the cause of the
In t r av enous Fluids
disturbance. Both perspectives are enlightening. a nd C on ten t of S t rong Ions
The gain of fluids containing strong ions in ra-
C ompens at ion for R e spir at or y
Disor der s a nd Ur ina r y tios dissimilar to those in the extracellular fluid
S t rong Ions also affects acidbase balance, as shown in the
following case, which was also described by
The ratio of bicarbonate to Paco2 in the Hender- Berend et al.7 in their article about the physiolog-
sonHasselbalch equation (equation 1) is a sim- ical approach:
ple way to illustrate the initial disturbance and
then the modulating effect of the compensatory A 22-year-old woman who had been injured
response on pH. In respiratory conditions, the in an accident received 6 liters of isotonic
Paco2 is the initial abnormality leading to sharp, saline, after which the level of sodium was
sudden changes in pH, with little change in 135 mmol per liter, potassium 3.8 mmol
strong ion concentrations. Over time, however, per liter, chloride 115 mmol per liter, and
the change in the level of chloride and reciprocal bicarbonate 18 mmol per liter. The arterial
changes in the level of bicarbonate are the major pH was 7.28, and the Paco2 was 39 mm
factors that allow pH to return toward normal Hg. The urinary sodium level was 65 mmol

1828 n engl j med 371;19nejm.orgnovember 6, 2014

The New England Journal of Medicine


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Integr ation of Acid Base and Electrolyte Disorders

A Proximal tubular cell


Blood Lumen
K+
Na+
The stoichiometric balance of three HCO3 ions
per one Na+ ion is 3HCO3. Disorders of Na+H+
3HCO3 Na+ exchange (NHE3), Na+, 3HCO3 (NBC), and
H+ carbonic anhydrase cause proximal renal tubular
Na+
Carbonic acidosis.
anhydrase

B Thick ascending limb cell of the loop of Henle


Blood Na+
K+ Mutations in NKCC, K+, or the Cl channels
K+ cause the Bartter syndrome, with hypokalemic,
2Cl
Na+ NKCC hypochloremic metabolic alkalosis and
ATPase extracellular fluid volume depletion. This
Cl K+
syndrome can also be caused by the use of
K+ channel Lumen furosemide and NKCC inhibition.
Cl channel

C Cortical distal tubular cell


Blood
Inhibition of NaCl cotransport (NCC) by thiazide
Na+ or an inactivating mutation in Gitelmans
Cl syndrome causes hypochloremic, hypokalemic
K+ NCC metabolic alkalosis, whereas increased function,
Na+ pseudohypoaldosteronism type 2, results in
ATPase Lumen hyperkalemic metabolic acidosis.

D Principal cell, cortical collecting duct


Blood
K+ Increased ENaC, the luminal Na+ channel (Liddles
K + syndrome), and hyperaldosteronism cause
K+ channel hypertension and hypokalemic metabolic alkalosis.
Na+ Lumen
Decreased ENaC, mineralocorticoid-receptor
ATPase
Na +
blockade, and hypoaldosteronism cause
Mineralocorticoid ENaC hypovolemia and hyperkalemic metabolic acidosis.
receptor

E Type A (acid-secreting) intercalated cell, cortical collecting duct

Blood
H+ The type A cell mutations of luminal
Lumen H+ATPase subunits and mutations in AE1
ATPase
Cl with decreased ClHCO3 activity cause
HCO3 H+ distal renal tubular acidosis. K+H+ ATPase
Carbonic K+ in type A cells couples H+ secretion with K+
anhydrase ATPase reabsorption.

F Type B (HCO3 -secreting) intercalated cell, cortical collecting duct

Blood
HCO3
Cl Decreased function of the type B cell ClHCO3
H+ Pendrin exchanger, pendrin, is a cause of chloride-wasting
metabolic alkalosis.
ATPase Lumen
Carbonic
anhydrase

COLOR FIGURE

n engl j med 371;19 nejm.org november 6, 2014 Draft 8


1829
10/22/14
Author Seifter
The New England Journal of Medicine
Fig # 1
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Title Integration of Acid-Base Disorders
Copyright 2014 Massachusetts Medical Society. All rights reserved. with Electrolyte Balance
ME
The n e w e ng l a n d j o u r na l of m e dic i n e

per liter, potassium 15 mmol per liter, and bicarbonate-centered approach to provide an op-
chloride 110 mmol per liter. timal understanding of acidbase disorders.
Electrolyte concentrations of plasma may be al-
This is an example of saline-induced acido- tered by the gains and losses associated with in-
sis,26 which develops because the infusion of a travenous fluids and with urinary, intestinal, or
proportionately high sodium chloridecontain- sweat-gland secretions. An understanding of the
ing solution, one with a sodium-to-chloride ratio consequences of these disturbances helps in the
of less than 140:100, will decrease the plasma diagnosis and treatment of the associated acid
strong ion difference and the bicarbonate con- base disorders.
centration. The insufficient urinary excretion of The evidence connecting acidbase balance
the extra chloride as ammonium chloride leads with electrolyte balance is apparent at the cel-
to metabolic acidosis. The infusion of saline lular level (i.e., ion transporters, their stoichio-
with its 1:1 sodium-to-chloride ratio, resulting metric balance, and the hormones that regulate
in hyperchloremic acidosis, is the converse of them) (Fig. 1) and in clinical practice. The fact
inhibition of the 1:1 sodium-to-chloride trans- that transporters often couple a strong ion such
port ratio in thiazide-induced diuresis and hypo- as sodium or potassium with hydrogen, or chlo-
chloremic metabolic alkalosis. ride with bicarbonate,28-30 suggests an ultimate
Even Ringers lactate, with a level of sodium coherence between the two approaches (Fig. 1).
of 130 mmol per liter, chloride 109 mmol per As more is learned about the molecular nature
liter, and lactate 28 mmol per liter, can cause of disorders of epithelial-cell transport as well as
hyperchloremic acidosis because the ratio of about intracellular pH, it will become more im-
sodium to chloride is smaller than the ratio of portant to understand interactions between car-
sodium to chloride in the normal extracellular bon dioxide and bicarbonate with strong ions
fluid.26,27 Thus, what matters is the content and and cellular buffers in the body.31
amount of infused fluids.
No potential conflict of interest relevant to this article was
reported.
C onclusions Disclosure forms provided by the author are available with the
full text of this article at NEJM.org.
Clinical evidence can be interpreted with the use
of both the strong ion theory and the traditional

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