• Information
  1. Introduction
  2. Overview of Acid-Base Physiology
  3. Interpreting Acid-Base Disorders
  4. Compensation
  5. Effects on Hemoglobin
  6. Examples

A. Introduction

1. These are common disorders, particularly in critically ill patients
   1. Also occur in patients with volume dysregulation
   2. Suspect in any patient with abnormal bicarbonate (HCO3-) level on serum chemistries
2. Generally rely on use of blood gases
   1. Arterial blood is usually measured
   2. This includes blood pO2, pCO2, pH and calculated HCO3- (bicarbonate)
   3. Normal arterial pH = 7.40 (7.36-7.44)
   4. Normal arterial pCO2 ~40mm Hg (36-44mm)
   5. Normal calculated arterial HCO3- ~25mM
3. Venous blood gases can also be used for monitoring acid-base abnormalities
   1. Normal venous pH ~7.35 (7.31-7.39)
   2. Normal venous pCO2 ~45mm (42-48mm)
   3. Normal calculated venous HCO3- ~25mM
4. Acidosis is present when pH <7.36
5. Alkalosis is present when pH >7.44
6. Acidemia and alkalemia refer to components which enter into the final acid-base balance

B. Overview of Acid-Base Physiology [3]

1. ECF contains about 350 mmol of HCO3- (bicarbonate) buffer
   1. All HCO3- is filtered through glomerulus
   2. Kidney resorbs ~85% of filtered HCO3- in proximal tubule
   3. Thick ascending limb resorbs ~10% of filtered HCO3-
   4. In collecting duct cells regenerate HCO3- (using mainly ammonium buffers)
   5. Thus, all filtered HCO3- is eventually reclaimed or replaced
2. Metabolism produces ~1 mmol/kg (~70 mmol) as nonvolatile acids
   1. ~35% is sulfuric acid
   2. ~60% is non-metabolized organic acids
   3. Remainder is phosphoric and other acids
3. Protons (hydrogen ions, H+) are secreted and buffered in tubule fluid
   1. Rate of H+ secretion is affected by several factors:
   2. Luminal pH - higher tubule lumen pH increases secretion
   3. Systemic pCO2 - higher pCO2 increases secretion
   4. Mineralococorticoids - higher levels increase secretion of H+
   5. Potential difference across collecting duct (normal -30 to -60 mV)
4. Protons are buffered primarily by ammonia
   1. Ammonia is produced by deamination of glutamine in mitochondria of proximal tubule
   2. Rate of ammonia production is increased in high H+ states
   3. Metabolic acidosis, hypokalemia, and glucocorticoids stimulate ammonia production
   4. Hyperkalemia suppresses ammonia production
5. Net acid secreted, HCO3- utilized, ammonia produced and HCO3- regenerated are equal under normal physiological homeostatic conditions
6. Acid production by the body is regulated by pH via a feedback loop [5]
   1. A drop in pH will lead to a reduction in metabolic acid production
   2. An increase in pH will lead to an increase in metabolic acid production
   3. This regulation is in addition to the more acute changes in respiratory compensation

B. Interpreting Acid-Base Disorders

1. Use arterial blood gas to determine whether acidosis or alkalosis are present
2. Determine whether process is primarily respiratory or metabolic
   1. Acidemia is primarily respiratory when pCO2 >44 mm Hg
   2. Acidemia is primarily metabolic when HCO3- <25 mM (25mEq/L)
   3. Acidemia has mixed etiologies when both pCO2 >44 and HCO3- <25 mM
   4. Alkalemia is primarily respiratory when pCO2 <38mm
   5. Alkalemia is primarily metabolic when HCO3- >25mM
   6. Alkalemia has mixed etiologies when both pCO2 <38mm and HCO3- >25mM
3. Determine the Anion Gap (AG) [6]
   1. AG is difference between serum cation and anion electrolytes
   2. Of course, serum is electroneutral, but AG arises due to presence of unmeasured anions
   3. The major unmeasured anion are serum proteins, particularly albumin
   4. Each gram/mL of albumin contributes ~2 units to the AG
   5. AG = [Na+] + [K+] - [Cl-] - [HCO3-] = 7-14 units normally
   6. For AG >14, a metabolic acidosis is present; thus, "extra" unmeasured acids present
   7. For AG >25, a primary metabolic acidosis must be present
   8. AG<7 occurs with hypoalbuminemia (any cause), lithium intoxication, myeloma
4. Consider determining if there is an osmolal gap in paients with anion gap acidosis [6]
   1. Methanol and ethylene glycol acute intoxication lead to osmolol gap
   2. Osmolol gap = measured osmolality - calculated osmolality
   3. Calculated osmolality = (2x[Na+]) + ([BUN mg/dL]/2.8) + ([glucose mg/dL]/18)
   4. If osmolol gap >10mmol/L, then their is a toxic substance present (unmeasured osmoles)
5. These steps permit an initial analysis of acid-base status of patient
6. Physiologic (homeostatic) mechanisms - called compensation - try to maintain normal pH

C. Compensation

1. Body attenuates deviations in pH by activating systems to oppose the initial pH change
   1. This is true when homeostatic systems are intact
   2. In critically ill patients, homeostatic systems are often dysfunctional
   3. Thus, failure of compensatory mechanisms leads to appearance of "mixed" disorders
   4. It is critical to determine when mixed disorders are present in order to optimize therapy
2. When possible, body uses respiratory and metabolic mechansims to maintain pH homostasis
   1. When primary respiratory problem exists, metabolic compensation is activated
   2. When primary metabolic problem exists, respiratory compensation is activated
   3. Compensatory mechanisms never overshoot the initial pH deviation
3. In general, chronic pH deviations are better compensated than acute
   1. Acute changes in respiratory systems are poorly or uncompensated for pH abnormalities
   2. Acute changes in metabolic systems are better compensated by respiratory changes
   3. Chronic changes are generally compensated well if systems are intact
   4. Normal compensation must be understood In order to discover mixed disorders
4. Compensation in Metabolic Acidemia
   1. Simplest method (mainly acute situations) for determining if appropriate respiratory compensation is present is if pCO2 in mmHg is equal to last two digits of pH
   2. Thus, in metabolic acidemia where pH=7.20, appropriate pCO2 compensation is 20mm
   3. More accurately, the decrease (from normal) in pCO2 ~ 1.3 x drop from normal in [HCO3-]
   4. Thus, in metabolic acidemia where HCO3- is 15mM, correct pCO2 is 40-(10x1.3)=27mm
   5. Another equation uses pCO2 level should ~ (1.5 x [HCO3-])+8 using ABG values
   6. If calculated values of pCO2 differ >10% from actual values, mixed disorder is present
   7. If <10% deviations from expected pCO2 are present, then mixed disorder is not present
5. Compensation in Metabolic Alkalemia
   1. Metabolic alkalemia is due to HCO3- retention or to other bases (such as myleoma proteins)
   2. Main homeostatic mechanism here is hypoventilation leading to increase in pCO2
   3. This can be dangerous, particularly in critically ill, because hypoxia often occurs also
   4. Appropriate compensatory increase in pCO2 ~ 0.6 x increase in [HCO3-]
   5. Thus, for metabolic alkalemia where [HCO3-]=35mM, pCO2 increases to (10x0.6)+40=46
   6. If pCO2 >49mm in this example, then a primary respiratory acidosis is also present
   7. If pCO2 <43mm in this example, then a primary respiratory alkalosis is also present
6. Compensation for Respiratory Alkalemia and Acidemia
   1. Again, acute metabolic compensation does not really exist per say
   2. Therefore, uncompensated respiratory deviations are almost always acute
   3. Acute CO2 retention (acidosis) is bufferred by HCO3- already present in blood
   4. However, in acute CO2 retention with normal pH, mixed disorder is present
   5. True metabolic compensation for respiratory disorders requires about 3 days (72 hours)
   6. Chronic CO2 retention with a pH in normal range is fully compensated
   7. Chronic CO2 retention with pH outside of normal range indicates mixed disorder
   8. Chronic hypocarbia with pH outside of normal range indicates mixed disorder
7. Mixed Alkalemia-Acidemia Situations (Delta-Delta)
   1. For every increase in AG, there should be a 1:1 decrease in HCO3- level
   2. This is because HCO3- is the only (normal) homeostatic buffer in the blood
   3. If the change in HCO3- > change in AG (from normal), then a primary acidosis is present
   4. If the change in HCO3- < change in AG (from normal), then a primary alkalosis is present
   5. In other words, if expected HCO3- is more than measured HCO3-, then excess HCO3- was present before acidosis occurred
   6. Likewise, if expected HCO3- is less than the measured HCO3-, then the HCO3- level when the anion gap acidosis began was low (i.e. a non-anion gap acidemia was present)

D. Effects on Hemoglobin [1]

1. Hb Affinity for O2
   [Figure] "O2-Hb Dissociation Curve"
   1. Oxygen, the primary ligand, induces increased affinity for itself (homotropic effector)
   2. There are three major heterotropic effectors
   3. These are hydrogen ion (pH), carbon dioxide (CO2), red-cell 2,3-diphosphoglycerate (DPG)
   4. Hydrogen ions (decreased pH) and CO2 reduces O2 binding of Hb (Boehr Effect)
   5. O2 binding to Hb reduces its affinity for CO2 (Haldane Effect)
   6. Reduction in Hb affinity for O2 shifts O2-Hb Dissociation Curve to the right
   7. In addition, temperature increases reduce O2 affinity (similar to acid)
   8. These concepts explain much of O2 delivery physiology between lung and tissue
2. O2 Delivery to Tissues
   1. Because tissues are more acidic than blood due to increased CO2 and lactate production
   2. Both CO2 and acid leads to reduced affinity of Hb for O2
   3. Thus, O2 is released by Hb in tissues, and CO2 is absorbed onto the Hb
   4. In the lung, high O2 concentrations drive O2 binding by Hb and lead to CO2 release
3. Red Cell DPG
   1. Red blood cells (RBC, erythrocytes) depend solely on glycolysis for energy production
   2. 2,3 DPG is normally a metabolic intermediate derived from 1,3 DPG
   3. The enzyme responsible is 2,3-DPG synthetase
   4. This pathway is normally minor, with most of 1,3 DPG converted to ATP and 3-mono-PG
   5. In RBC, 2,3-DPG is sequestered by deoxyhemoglobin and acumulates at high levels
   6. In other cell types, 2,3 is not sequestered and concentrations are very low
   7. DPG binds to Hb, stabilizes the T conformation, and reduces O2 affinity
   8. In addition, DPG binding also lowers intracellular pH
   9. In chronic acidosis, reduced RBC DPG levels compensate partially for drop in pH
4. Hb and Acid-Base Disorders
   1. Acute acidosis increases P50, favors oxygen unloading from Hb
   2. Chronic acidosis has reduced RBC DPG, leading to essentially normal P50
   3. Acute alkalosis has reduced P50, favors O2 binding and reduces O2 unloading
   4. Chronic alkalosis has essentially normal P50 due to increased RBC DPG
   5. Acute alkalinization in chronic acidosis can cause markedly reduced P50
   6. This is especially problematic in cerebral tissues, where alkali causes vasoconstriction
   7. Therefore, O2 delivery and unloading to cerebral tissues are reduced (may be severe)

References

1. Adrogue HJ and Madias NE. 1998. NEJM. 338(1):26
2. Adrogue HJ and Madias NE. 1998. NEJM. 338(2):107
3. Gluck SL. 1998. Lancet. 352(9126):474
4. Hsia CCW. 1998. NEJM. 338(4):239
5. Hood VL and Tannen RL. 1998. NEJM. 339(12):819
6. Takayesu JK, Bazari H, Linshaw M. 2006. NEJM. 354(10):1065 (Case Record)