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.
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).
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).
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|
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.
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.
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.