Tufts OpenCourseware
Author: Angie Warner, D.V.M.,D.Sc.

1. Learning Objectives:

  • Understand why [H+], [OH-], and [HCO3-] are NOT independent variables in acid-base physiology.
  • Understand the difference between strong and weak ions.
  • Be able to contrast the role of renal function in the traditional vs. the quantitative approach to acid-base physiology.
  • Be able to explain why you would treat a patient with metabolic alkalosis with intravenous NaCl and a patient with metabolic acidosis with NaHCO3 (think about how much Na or Cl you would be giving).

2. Theoretical Development

2.1. Introduction

  • Recent physiochemical analysis of biological solutions has yielded new understanding of H+ behavior and requires changes in many generally accepted concepts of H+ behavior.
  • The new concepts can best be understood by considering progressively more complex "biological" solutions, beginning with pure water, and adding strong ions, proteins, and finally CO2.
  • The analysis shows there are independent variables in this system; these can be changed from outside the system and will result in changes in dependent variables that are internal to the system.
  • Major point: changes in dependent variables are caused by changes in independent variables, but not by changes in other dependent variables (i.e., dependent variables are not causally related to each other).
  • The Henderson-Hasselbalch equation accurately describes the relationship among H+, PCO2, and HCO3, but does not describe the "control" for the system.

2.2. Pure H2O

  • H2O dissociates slightly into H+ and OH- : [H2O] [H+] + [OH-].
    • the dissociation constant, K'w is essentially a constant, regardless of the degree of dissociation, but is temperature sensitive.
      Kw = [H+] [OH-]

      K'w = [H+] [OH-] = 1x10-14 at 25oC

  • As in all solutions, electroneutrality must be preserved:
    • electroneutrality: sum of positive ions = sum negative ions (ie. [ H+] = [OH-])
    • chemical neutrality: [H+] = [OH-]
    • for pure water: [H+] = [OH-] satisfies both
  • One can use these relationships to calculate [H+] in H2O:
    • [H+] = √K'w = [OH¯ ] = 1x10-7 Eq/L (pH 7.0 at 25oC)
      • therefore, K'w determines the [H+] in pure H2O
  • However, at other temperatures, [H+] will not= 1 x 10-7 eq/L. For example, at 37oC, K'w = 4.4x10-14, and [H+] = 2.1x10-7 Eq/L (pH 6.7).
    • 6.7 is the pH of chemical neutrality at body temperature-ie when [H+]=[OH-]
    • i.e. body fluids are very alkaline (pH = 7.4)

2.3. Strong Ion Solutions

  • Strong electrolytes dissociate essentially completely (i.e., no dissociation equlibrium) in solution.
    • strong ions in mammalian biological fluids are Na+, Cl¯ , K+, SO4, and lactate or keto acids (when present). Ca++ and Mg++ are minor
  • The Gamblegram is a diagram for electroneutrality in solutions with positive and negative ions; the height of the columns represents the sum of positively and negatively charged ions.
    • consider addition of 10 mM HCl or 10 mM NaOH to an NaCL solution. The diagram shows the amount of each ion present and demonstrates electroneutrality
  • Consider H2O at a constant temperature to which HCl and NaOH have been added.
    • to maiintain electroneutrality: [Na+] + [H+] = [Cl¯ ] + [OH¯ ]
    • if [Na+] = [Cl¯ ], then [H+] = [OH¯ ], but if [Na+] [Cl¯ ], then [H+] [OH¯ ]
    • in this system, the difference between [H+] and [OH¯ ] will exactly equal the difference between [Na+] and [Cl¯ ], which can be controlled by how much is added from outside the system
  • Quantitative analysis of this system shows mathematically that [H+] depends on K'w (a constant) and [Na+] and [Cl¯ ], which can be controlled from outside the system.
  • Strong ion difference (SID), the critical factor:
    • it is the difference [Na+] [Cl¯ ], or strong cations in solution not electrically balanced by strong anions that will determine [H+] and [OH¯ ]
    • any other strong ions present in solution (ex. K+) will also affect the calculation of SID, but only inorganic ions are routinely measured
    • SID = sum of all strong cation concentrations minus sum of all strong anion concentrations
    • SID will be balanced by net charge on weak ions to fulfill electroneutrality for that solution
    • in plasma, SID is normally approximately +40 mEq/L; thus [OH¯ ] > [H+] and the solution is alkaline: [H+] + SID = [OH¯ ]
    • if SID is negative, strong anions exceed strong cations; to balance, [H+] will be > [OH¯ ], and the solution will be acidic
  • Any change in SID must change both [H+] and [OH¯ ]; therefore SID is an independent variable, while [H+] and [OH¯ ] are dependent variables.
  • The [H+] now depends on K'w and SID, and only SID is easily changed in body fluids.

2.4. Weak Acids (Plasma Proteins)

  • Weak acids dissociate partially HP H+ + P¯ .
    • Ka = [H+] [P¯ ]
    • the dissociation constant Ka will be part of the quantitative analysis
  • The total amount of "P" per liter is a constant determined by the amount originally present (conservation of mass), regardless of the degree of dissociation:
    • [Ptot] = [HP] + [P¯ ]
  • [Ptot] is a new independent variable, and [H+] and [P¯ ] are dependent variables that change when [Ptot] changes.
  • To satisfy electroneutrality: [H+] + SID = [P¯ ] + [OH¯ ].
  • [H+] now depends on K'w, SID, and [Ptot]; of these, only SID and [Ptot] change in body fluids.

2.5. Addition of CO2

  • Addition of CO2 adds dissolved CO2 and H2CO3 (both negligible), and bicarbonate (HCO3 ) and carbonate (CO3=) anions.
    • H2O + CO2 H2CO3 H+ + HCO3-- H+ + CO3=
      • for quantitative analysis, there are new dissociation constants
  • Electroneutrality statement: [H+] + SID = [P¯ ] + [OH¯ ] + [ HCO3--] + [CO3=].
  • The new independent variable is PCO2, not [ HCO3- ] !.
  • [H+] quantitatively now depends on K'w, SID, [Ptot], and PCO2.
    • [H+] does not depend on [ HCO3-- ], rather [ HCO3-- ] is another dependent variable, like [OH¯], that will change when independent variables are manipulated

2.6. Summary and Conclusions

  • We can now identify the mechanisms by which changes in [H+] are brought about.
  • In biological fluids, we have three independent variables: SID, [Ptot] and PCO2.
    • [H+], [OH¯ ], [HP], [P¯ ], and [ HCO3-- ] are dependent variables that all change when one or more independent variables are changed
    • acid base derangements arise from abnormalities of SID, proteins, and PCO2
    • evaluation of acid base status requires evaluation of SID (serum electrolytes), serum proteins, and PCO2
    • therapeutic efforts to correct acid base derangements will be directed toward correction of SID and PCO2

3. Acid-Base Derangements

3.1. Changes in the Independent Variables

  • PCO2 depends on respiration, and changes occur rapidly (within minutes) and will affect acid base status of plasma and other fluids.
    • increased PCO2 = respiratory acidosis
    • decreased PCO2 = respiratory alkalosis
  • The concentration of strong ions depends on GI absorption and GI and renal loss, both normal and pathological; SID changes occur slowly (over hours).
    • normal SID in plasma is 42 mEq/L
    • increased SID causes metabolic alkalosis (hypochloremic alkalosis)
    • decreased SID causes metabolic acidosis
    • if [H+] PCO2, [Ptot] and inorganic SID are known, the difference between measured inorganic SID and the point on the graph represents the SID component due to any unmeasured strong ions present (ex. keto-acids or lactate)
  • Proteins are the major weak acids in plasma, and their concentration is determined by hepatic synthesis or pathologic losses; changes occur slowly (over days).
    • hyperproteinemia causes metabolic acidosis
    • The [ HCO3-- ] is of minor interest, since it is a dependent variable and does not determine [H+]

3.2. Body Fluid Interactions

  • Interactions across semipermeable membranes depend on changes in independent variables.
    • i.e., to change [H+] in a fluid, one must change SID, [Ptot], or PCO3
    • [H+] is a dependent variable, and moving H+ from one compartment to another cannot explain changes in [H+] of either fluid (the same is true for HCO3-)
  • CO2 is very soluble and most biological membranes are permeable to it; it diffuses rapidly between fluids on the basis of partial pressure gradient.
    • thus, PCO2 changes are a potential mechanism for overall short term changes in acid base status of all body fluids, but not for interactions between fluids in different compartments
  • Most membranes are highly impermeable to protein, and protein movement between fluids is thus not a mechanism of interaction.
  • Biological membranes are selectively permeable to strong ions, and membrane pumps allow movements between compartments.
    • therefore, SID changes are the major mechanism of body fluid interactions among compartments (for example, renal control of Na+, Cl¯ and K+ excretion

3.3. Metabolic Acid Base Control Revisited

  • The kidney does not act to remove H+, it lowers [H+] of plasma by excreting more Cl¯ than Na+, and thus raising the plasma SID.
  • Movement of HCO3-- in or out of plasma or renal tubules does not alter [H+], because both are dependent variables.
  • Thus, renal control of acid base status is via control of SID through selective strong ion excretion, and not through retention or removal of HCO3-.
    • ex. Excretion of CL- in excess of Na+ or K+ will influence plasma SID and [H+]
  • GI absorption and loss of strong ions also contributes to acid base equlibrium through effects on SID
    • for example, gastric pH is lowered by creating a high negative SID (Cl¯ secretion or Na+ absorption), not by pumping H+

4. References

  • Jones NL. Blood Gases and Acid Base Physiology, 2nd ed., Theime Medical Publishers, New York, 1987.
  • Stewart PA. Modern quantitative acid base chemistry. Can J Physiol Pharmacol 61: 1444 1461, 1983.
  • Stewart PA. How to Understand Acid base: A Quantitative Acid base Primer for Biology and Medicine, Elsevier, New York, 1981.
  • Jones NL. Acid-base Physiology. IN: RG Crystal and JB West eds, The Lung: Scientific Foundations. Raven Press, LTd, NY 1991, pp. 1251-1265.