| Editor:
John
Kellum, MD
 The
purpose of the this web page is to provide clinicians, researchers,
students and other interested parties access to current information
about acid-base physiology,focusing in particular on modern physical
chemical principles. It is our intention to serve both as a source
for useful information and software as well as a forum (or pHorum
if you like) for debate and discussion.
This site is dedicated to the memory
and work of the late Peter A. Stewart, Ph.D whose novel thinking
has revolutionized the modern understanding of acid-base homeostasis.
The importance of Dr. Stewart's contribution is only now, nearly
20 years after it's first publication, being fully realized. If
you are not familiar with the work of Stewart, the following summary
may be useful. But of course, you are advised to look at the numerous
reviews and primary studies available in the literature (see references).
In much the same way that Copernicus provided
us with an alternative view of the solar system, a view in which
the Earth rather than the Sun moves, Stewart has provided us with
an alternative view of the acid-base universe. While conceptually
new, this analysis is based on the same underlying fundamental principles
used in more traditional treatments of acid-base. When properly
translated, all approaches are mathematically interchangeable. The
difference however, is that the Stewart approach emphasizes mathematically
independent and dependent variables. By this definition, bicarbonate
and hydrogen ions are dependent variables and thus represent the
effects rather than the causes of acid-base derangements. Neither
bicarbonate nor pH can be regulated directly. Rather, they are controlled
by the independent variables. In blood plasma there are three independent
variables, PCO2, weak acids, and the strong ion difference
(SID). SID is the difference between completely dissociated cations
(e.g. Na+) and completely dissociated anions (e.g. Cl-)
The Stewart approach has now been validated in
a wide variety of patient types and experimental conditions. Recently,
it has been shown that quantitatively, this approach is compatible
with the more traditional approaches such as base excess and analysis
of bicarbonate and PCO2. The difference between these
approaches and Stewart, lies in the understanding of the mechanisms
involved in acid-base regulation. The observation that metabolic
acidosis is associated with a decrease in plasma bicarbonate and
base excess remains valid. However, the implication that these changes
cause the acidosis is not. Some might argue that such a change makes
little difference. If one can measure the size and origin (respiratory
vs. metabolic) of a change in acid-base status, does the average
clinician really need to understand how it occurs? Of course, this
is the same argument facing Galileo when he insisted that the Earth
was not the center of the universe. Even without Copernicus's theory
it was still quite possible to "understand" the universe and it
is very unlikely that the life of the average person living in those
times was altered in any way by this new knowledge. The argument
obviously evaporates when considered in these terms. The understanding
that bicarbonate (HCO3-) and hydrogen ions
(H+) are not at the center of the acid-base universe
produces as violent a change in our concepts of physiology as did
Copernicus change our concepts of astronomy.
Biochemistry of
Aqueous Solutions
In order to understand how the body regulates
plasma H+ concentration, we must first understand the
physical-chemical determinants of H+ concentration. Virtually
all solutions in human biology contain water and aqueous solutions
provide a virtually inexhaustible source of H+. In these
solutions, H+ concentration is determined by the dissociation
of water into H+ and OH- ions. Said another
way, changes in H+ concentration occur not as a result
of how much H+ is added or removed but as a consequence
of water dissociation. The factors that determine the dissociation
of water are the laws of physical chemistry. Two in particular apply
here, electroneutrality (which dictates that, in aqueous solutions,
the sum of all positively charged ions must equal the sum of all
negatively charged ions) and conservation of mass (which means that
the amount of a substance remains constant unless it is added or
generated, or removed or destroyed). In pure water, according to
the principle of electroneutrality, the concentration of H+
must always equal the concentration of OH-. In more complex
solutions, we have to consider other determinants of water dissociation,
but still, the source of H+ remains water. Fortunately,
even in a solution as complex as blood plasma, the determinants
of H+ concentration can be reduced to three. If we know
the value of these three determinants, the H+ concentration
can be predicted under any condition. These three determinants are
the strong ion difference (SID), pCO2, and total weak
acid concentration (ATOT).
SID, pCO2
and ATOT
The SID is the net charge balance of all strong
ions present where a "strong" ion is one that is completely (or
near-completely) dissociated. For practical purposes this means
(NA+ + K+ + Ca++ + Mg++)
- (CL + lactate-). This is often referred to as the "apparent"
SID (SIDa) with the understanding that some "unmeasured" ions might
also be present. In healthy humans, this value is 40-42 mEq/L, although
it often quite different in critically ill patients. Of note, neither
H+ nor HCO3- are strong ions. The
pCO2 is an independent variable assuming that the system
is open (i.e. ventilation is present). Finally, the total weak acid
concentration (ATOT) which are mostly proteins and phosphates,
is the third independent variable because its concnetration is not
determined by any other variable. The essence of the Stewart approach
(and indeed what is revolutionary) is the understanding that only
these three variables are important. Neither H+ nor HCO3-
can change unless one or more of these three variables change. The
principle of conservation of mass makes this point more than semantics.
Strong ions cannot be created or destroyed to satisfy electroneutrality
but H+'s are generated or consumed by changes in water
dissociation. Hence, in order to understand how the body regulates
pH we need only ask how it regulates these three independent variables
(SID, pCO2 and ATOT).
Examples
Case 1: The
patient is a 60 y.o. white male with a past medical history of hypertension,
chronic obstructive lung disease and a remote history of cholecystectomy
for acute cholecystitis. His outpatient medications include nifedipine,
albuterol and atrovent inhalers. He is involved in a motor vehicle
accident and sustains injuries to his right anterior chest and upper
abdomen. He is diagnosed with rib fractures, pulmonary contusion
and a grade III liver laceration. He undergoes surgery for his liver
laceration. The surgical team finds extensive adhesions and there
is a very large blood loss during the operation. The patient is
resuscitated with lactated Ringers and blood products in the trauma
bay as well as in the operating room. Arterial blood obtained in
the operating room reveals a pH of 7.10, a PaCO2 of 30 mm Hg and
a SBE of -19 mEq/L. The plasma lactate concentration is 11.5 mE/L
and additional blood products are given for resuscitation as well
as 120 mEq of NaHCO3. On arrival to the ICU, the patient's blood
gas analysis reveals a pH of 7.35, PaCO2 of 35 mm Hg and a SBE of
-5 mEq/L, but the lactate concentration is still 8.0 mEq/L. His
hematocrit is 29% and he is given more blood and colloid. After
6 hours in the ICU his pH increases to 7.60, PaCO2 of 33 mm Hg and
SBE of +10 mEq/L; the lactate concentration is now 2.0 mEq/L. At
this point, the patient has a fairly straight forward metabolic
alkalosis as seen by an increased SBE and a mild respiratory alkalosis
by the PaCO2 of 33 mm Hg. The metabolic component is due to a combination
of lactate clearance, massive blood transfusion (citrate) and NaHCO3
administration. The respiratory component is due to ventilator settings,
ordered to adjust for a metabolic acidosis which has now cleared.
The ventilator is reduced allowing the PaCO2 to increase to 55 mm
Hg to normalize the pH to 7.40.
On the third postoperative day the patient develops
fever and hypotension. An arterial blood gas is obtained and reveals
a pH of 7.31 and an SBE of -9. The AG is calculated at 19 mEq/L
and phosphate and albumin concentrations are within normal limits
(making the normal AG value for this patient ~12). An arterial lactate
is checked and it is 5.8. The patient is resuscitated with 0.9%
normal saline and started on a norepinephrine infusion. His central
venous pressures remain low however and so he continues to receive
saline and a total of 10L is given in the next 24 hrs. Despite,
the resuscitation, his urine output was only 200cc over this time
period. The next morning his plasma HCO3- concentration 13mEq/L.
An arterial blood gas analysis reveals a pH of 7.28 PCO2 of 30 mm
Hg and an SBE of -12 mEq/L although the lactate has come down to
4.3. These values are summarized in the table below.
The patient's serum electrolyte pattern and blood
gases are shown below.
| Blood chemistries |
6am POD3 |
10am POD4 |
6am POD5 |
| NA |
140 |
142 |
143 |
| K |
3.1 |
3.5 |
4 |
| CL |
108 |
117 |
116 |
| HCO3 |
16 |
13 |
19 |
| PH |
7.31 |
7.28 |
7.36 |
| PCO2 (torr) |
32 |
30 |
34 |
| SBE |
-9 |
-12 |
-5 |
| Lactate |
5.8 |
4.3 |
2.1 |
The advantage of the Stewart approach is that
it allows us to understand what has happened here in completely
organized, mathematical way. The changes in NA and CL are predictable
given the volumes of solution administered and known compositions
of the solutions. Note that CL and NA are effected differently even
though saline contains equal quantities of each ion. This is because
the starting values in the plasma are different for these two ions
and CL is increased proportionally more than NA As this happens,
the SID is decreased and the pH falls.
Over the next 24 hrs the patient requires
additional fluids but this time lactated Ringers is given (4L).
Urine output begins to improve as well but there is an ATN and urine
concentrating ability and tubular function is impaired. However,
the patients acid-base status is improved this time by lowering
the CL with solutions that have a lower CL content compared to NA
Thus the SID increases and the pH increases.
Case 2: This
patient is a 55 y.o. female who returned from the operating room
6 hours ago after having undergone orthotopic liver transplantation.
The allograft has been slow to function and there is evidence of
significant preservation injury. The arterial lactate concentration
is 16 mEq/L and rising. An arterial blood gas reveals a pH of 7.16,
PCO2 of 32 mm Hg and an SBE of -16 mEq/L. Thus, the patient has
a pure metabolic acidosis secondary to lactic acid. The ventilation
is also inadequate and since the patient is heavily sedated she
is not able to compensate normally. The respiratory rate on the
mechanical ventilator is increased from 14 to 18 in an effort to
decrease the PCO2 to 25-28 mm Hg. The lactic acid is entirely responsible
for the acidosis since the negative SBE value is exactly equal to
the lactate concentration, i.e. there is no mixed acidosis present.
The source of the lactic acidosis is almost certainly delayed hepatic
function with little or no uptake of lactate by the liver. In such
situations the liver may actually produce additional lactate. However,
the pulmonary capillary wedge pressure is 14 mm Hg and the right
ventricular end-diastolic volume is 120 ml. Additional fluids are
given to reduce the likelihood that anaerobic lactate production
may also be present. Colloids are chosen for this indication because
the patient's albumin is 2.0 g/dl (secondary to her underlying liver
disease) and because saline may worsen the acidosis by further decreasing
the SID. Even lactated Ringers may transiently worsen the SID in
this case because of the severe hepatic dysfunction. A liter of
5% albumin solution is given intravenously. In addition, the patient's
urine output is poor and the serum NA+ and CL concentrations are
130 and 105 mEq/L respectively. Accordingly, she is also given 120
mEq of NaHCO3.
With these treatments a repeat arterial blood
gas analysis reveals the following: pH of 7.32, PCO2 of 25 mm Hg
and an SBE of -12 mEq/L. The lactate concentration is still 16 mEq/L.
Over the course of the next 12 hours the lactate concentration decreases
to 10 mEq/L, the liver is making bile, the patient is waking up
and the urine output has improved considerably. The mechanical ventilator
has been adjusted multiple times to keep the PCO2 in the appropriate
range for the resolving acidosis and is now set at 12 breaths/min.
Repeat arterial blood gas analysis reveals a pH of 7.40, PCO2 of
35 mm Hg and an SBE of -1 mEq/L. At first glance, the complete correction
of the acidosis seems to contrast with the persisting hyperlacticemia.
Indeed, the lactate concentration of 10 mEq/L should produce a SBE
in a corresponding range. The lactic acid still in the patient's
blood stream is no less "acidic" than it was twelve hours earlier.
Examination of the patient's electrolytes reveals
what has changed. The patient's serum NA+ and CL concentrations
are now 132 and 102 mEq/L respectively. This, seemingly small, change
from 130 and 105 mEq/L earlier has enormous importance. Twelve hours
ago the patient's SID was 18 mEq/L. By increasing the serum NA+
by 2 and by decreasing the serum CL by 3 and lactate by 6 mEq/L,
the SID has increased by 11 mEq/L and is now 29 mEq/L. The patient's
intact renal function as well as intercompartmental shifts have
allowed for the decrease in serum CL concentration. The serum NA+
concentration increased as a result of exogenous NA+ administration
(both as NaHCO3 and as 5% albumin solution) and the lactate decreased
as the allograft function improved. This patient's "baseline" SID
is low (30 mEq/L) because the ATOT is low (albumin is
2 g/dl, phosphate is 3 mg/dl). As the remaining lactate clears over
the next few hours, the SID will increase to near 40 mEq/L and the
patient will become alkalemic unless steps are taken to reduce minute
ventilation further. By allowing the PCO2 to increase to 45 mm Hg,
the pH will remain less than 7.50 and over the next several hours
the kidneys will restore the SID to the baseline concentration by
retaining CL Over the next few weeks to months, the new liver will
increase the albumin concentration and as the ATOT improves
the kidneys will slowly adjust the SID upward until a new steady-state
is reached.
Conclusions
In order understand the causes of the acid-base
derangements, many of which are common in the ICU, we need only
look at three independent variables (SID, pCO2 and ATOT).
Metabolic acidemia results from a decrease in the plasma SID usually
brought about by the addition of strong anions (lactate, CL, other
"unknown" anions). Conversely, metabolic alkalemia occurs when the
plasma SID is increased either as a result of the addition of strong
cations without strong anions (e.g. NaHCO3) or by the
removal of strong anions without strong cations (e.g. gastric suctioning).
This "new" understanding has considerable impact on how we think
about gastric suction alkalosis, dilutional acidosis and lactic
acidosis as well as how we approach the treatment of these disorders.
Our understanding of many other medical conditions (e.g. renal tubular
acidosis) relies on a paradigm of acid-base regulation that is inconsistent
with established physical-chemical principles. In this "post-Copernican"
era, we will need to rethink our approach to these areas in light
of this fact.
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