Metabolic Acidosis

Metabolic Acidosis
Acid-base balance is maintained by pulmonary and renal excretion of carbon dioxide and nonvolatile acid, respectively.
Renal excretion of acid involves the combination of hydrogen ions with urinary titratable acids, particularly phosphate (HPO42- + H+   —>   H2PO4-), or with ammonia to form ammonium (NH3 + H+   —>   NH4+). The latter is the primary adaptive response since ammonia production from the metabolism of glutamine can be appropriately increased in response to an acid load.
Definition and Pathogenesis: 
  • Acidemia (as opposed to acidosis) is defined as a low arterial pH (<7.35), which can result from a metabolic acidosis, respiratory acidosis, or both.
  • Metabolic acidosis can be produced by three major mechanisms. The most important individual etiologies are discussed in detail elsewhere: 
    • Increased acid generation (MUDPILES)
    • Loss of bicarbonate ( Diarrhea, RTA , urethral diversion, acetazolamide)
    • Diminished renal acid excretion ( CKD)
    • Dilution Acidosis
The normal anion gap metabolic acidosis must, by definition, manifest hyperchloremia (relative to the sodium concentration). Thus, the two groups can also be labeled high anion gap metabolic acidosis and hyperchloremic metabolic acidosis.
Increased acid generation: 
  • Lactic acidosis
  • Ketoacidosis due to uncontrolled diabetes mellitus, excess alcohol intake (generally in a malnourished patient), or fasting. There is a shift in metabolism from carbohydrates to free fatty acids, which are metabolized into ketoacids (acetoacetate and β-hydroxybutyrate).
  • Ingestions or infusions like Methanol, ethylene glycol, diethylene glycol, or propylene glycol
  • Aspirin / salicylate poisoning.
  • Chronic acetaminophen ingestion, especially in malnourished women.
  • D-lactic acid is generated from carbohydrates by gastrointestinal bacteria. In some patients, especially those with a short gastrointestinal tract, this acid is absorbed, accumulates, and produces a metabolic acidosis.
  • Toluene ( "Inhalant abuse in children and adolescents") 
Loss of bicarbonate : 
  • Severe diarrhea
  • When urine is exposed to gastrointestinal mucosa, which occurs after ureteral implantation into the sigmoid colon or the creation of replacement urinary bladder using a short loop of ileum (There is a chloride- Bicarb ion exchange in colon and hence, the more flow through colon, the more Bicarb is lost).
  • Proximal (type 2) renal tubular acidosis, in which proximal bicarbonate reabsorption is impaired
In addition, among patients with ketoacidosis, the excretion of ketoacid anions in the urine with sodium or potassium represents the loss of "potential bicarbonate." With the onset of ketoacidosis, bicarbonate levels fall and ketoacid anion concentrations increase. As ketoacidosis resolves, metabolism of the ketoacid anions results in regeneration of the bicarbonate which was lost in the initial buffering reaction. Thus, if these ketoacid anions are lost into the urine before they can be metabolized, they represent lost potential bicarbonate. The effect of these urinary losses is that most patients with diabetic ketoacidosis develop a normal anion gap metabolic acidosis following insulin therapy.  Eg: In ketoacidosis, ketoacid anions (beta-hydroxybutyrate and acetoacetate) are lost in the urine as the sodium and potassium salts.
In skeletal muscles and other tissues, these ketone bodies are converted back to acetyl-CoA, which is oxidized in the TCA cycle with generation of ATP. Acetone is produced by spontaneous decarboxylation of acetoacetate, meaning this ketone body will break down in five hours, if it is not used for energy and be removed as waste, or converted to Pyruvate
Diminished renal acid excretion: 
  • Reduced acid excretion that occurs in conjunction with a reduction in glomerular filtration rate (ie, the acidosis of renal failure). With progression of CKD, there are lesser functional nephrons.
  • Distal (type 1) renal tubular acidosis in which tubular dysfunction is the primary problem and glomerular filtration is initially preserved.
  • In progressive loss of renal function, GFR of 20–50 mL/min is associated with hyperchloremic acidosis and when the GFR decreases to < 20 mL/min, uremic acidosis with a high AG ensues.
Dilution acidosis:
Dilution acidosis refers to a fall in serum bicarbonate concentration that is solely due to expansion of the extracellular fluid volume with large volumes of intravenous fluids that contain neither bicarbonate nor another anion (such as lactate) which can be metabolized to bicarbonate.
Compensatory respiratory response — the development of metabolic acidosis will normally generate a compensatory respiratory response. The reduction in the serum bicarbonate and pH caused by the metabolic acidosis results in hyperventilation and a reduction of the pCO2.
In all simple acid-base disorders, the primary abnormality will cause a compensatory response such that the HCO3 concentration and pCO2 will move in the same direction (either both will increase or both will decrease). These directional changes will always act to return the pH toward the normal range.
This respiratory response to metabolic acidosis begins within the first 30 minutes and is complete by 12 to 24 hours.
However, of the mathematical rules that are acceptable for clinical use, the two that are easiest to remember are:
  • pCO2 = HCO3 + 15
  • pCO2 = 1.5 x HCO3 + 8 +- 2
  • The pCO2 should approximate the decimal digits of the arterial pH (for example, if the pH is 7.25, then the pCO2 should be about 25 mmHg)
  • Ph: HCO3+ 15 will give last 2 digits of PH. Eg: 24+15 is a Ph of 7.39
EVALUATION — Evaluation of a patient with a low serum bicarbonate concentration requires the following:
  • Measurement of the arterial pH and pCO2 
  • Determination of whether respiratory compensation is appropriate ―
  • Assessment of the serum anion gap 
  • Calculation of the Δanion gap/ΔHCO3 ratio in patients who have an elevated anion gap 
Serum anion gap and differential diagnosis: 
  Normal Anion Gap=2.5 (Albumin) + 0.5 (Phosphate)
  Serum anion gap = Measured cations – Measured anions
  Serum anion gap = Na – (Cl + HCO3)
The normal value for the serum anion gap is now about 3 to 10 meq/L (averaging 6 meq/L). However, it is always best for each laboratory to determine its own normal range for the serum anion gap. In normal subjects, the major unmeasured anion responsible for the serum anion gap is albumin, which has a net negative charge in the physiologic pH range. As a result, the expected "normal" value for the anion gap must be adjusted downward in patients with hypoalbuminemia. The serum anion gap falls by 2.5 mEq/L for every 1 g/dL reduction in the serum albumin concentration. 
Corrected serum anion gap = (serum anion gap measured) + (2.5 x [4.5 – observed serum albumin])
In addition to hypoalbuminemia, marked hyperkalemia may affect the interpretation of the anion gap. Potassium is an "unmeasured" cation using the equation that does not include the serum K. Thus, a serum K of 6 meq/L will reduce the anion gap by 2 meq/L. Hypercalcemia and/or hypermagnesemia will similarly reduce the anion gap.
First, in any solution (eg, plasma):  All anions = All cations
  •  Measured anions + Unmeasured anions = Measured cations + Unmeasured cations
This equation can also be expressed as:
  • Unmeasured anions – Unmeasured cations = Measured cations – Measured anions
Then, since the anion gap is the difference between measured cations and measured anions:
  • Serum anion gap = Unmeasured anions – Unmeasured cations
When the anion gap is elevated — An increased serum anion gap metabolic acidosis develops when the accumulating acid is any strong acid other than HCl since the bicarbonate concentration falls and the concentration of chloride, the only other "measured" anion, remains relatively unchanged. As an example, when lactic acidosis develops, the following reaction occurs:
   HLactate  +  NaHCO3  —>  NaLactate  +  H2CO3  —>  CO2  +  H2O
The acidosis, due to the retained hydrogen ion, reduces the bicarbonate concentration while the increase in lactate (an "unmeasured" anion) will raise the serum anion gap. Note that, in this oversimplified schema, the magnitude of decrease in HCO3 matches the magnitude of increase in the lactate concentration and the anion gap. However, this 1:1 relationship between the fall in HCO3 and increase in serum anion gap does not always occur; The H+ is also buffered by bone phosphate, Hb and creatinine.
Two major additional factors influence the ΔAG/ΔHCO3 ratio:
  • The buffering reaction is not limited to the extracellular fluid, and the space of distribution of hydrogen ions is different from that of lactate or ketoacid anions. Most of the anions remain in the extracellular space, thereby raising the AG. In contrast, more than 50 percent of the excess hydrogen ions are buffered in the cells and in bone, a proportion that increases as the serum HCO3 falls. Buffering hydrogen ions outside the extracellular fluid will not lower the serum bicarbonate concentration. Thus, the serum AG will increase more than the HCO3 concentration will fall, raising the ΔAG/ΔHCO3 ratio above 1:1.
  • The renal excretion of the anions and hydrogen ions occur at different rates. This applies more to ketoacidosis than hypoperfusion-induced lactic acidosis in which there is typically little or no renal function. To the extent that ketoacid anions are excreted with sodium or potassium, the serum AG will fall without a concomitant increase in serum HCO3, lowering the ΔAG/ΔHCO3 ratio below 1:1 and resulting in the development of a hyperchloremic (ie, normal AG) acidosis after insulin therapy is initiated and extracellular volume repletion has been achieved.
Causes of elevated anion gap metabolic acidosis:
  • Lactic acidosis – Lactic acidosis
  • Ketoacidosis – Ketoacidosis results from DKA, alcohol or starvation
  • Acute or chronic kidney disease – Patients with severe renal failure may develop a high anion gap acidosis, resulting from the retention of both hydrogen ions and anions such as sulfate, phosphate, and urate.
  • Toxic alcohol ingestion – Ingestion of methanol or ethylene glycol produces high anion gap metabolic acidosis. These alcohols are metabolized to various organic acids; methanol is metabolized to formic acid, and ethylene glycol to glycolic and oxalic acid.
  • Salicylate (aspirin) poisoning – Salicylate poisoning impairs oxidative phosphorylation and causes the accumulation of multiple acids including lactic acid and ketoacids.
  • Acetaminophen – Chronic acetaminophen use (at therapeutic doses rather than in the setting of an overdose) can result in an elevated anion gap metabolic acidosis. The accumulating acid is pyroglutamic acid (also called 5-oxoproline). Affected patients are usually women with chronic illness and malnutrition. The pathogenesis is probably related to chronic glutathione deficiency.
  • D-lactic acidosis – D-lactic acid is generated by bacterial fermentation of ingested, but unabsorbed, carbohydrates. D-lactic acidosis results from excessive absorption of D-lactic acid from the lumen of the gastrointestinal tract, usually in patients with jejunoileal bypass or short bowel syndrome.
Diabetic ketoacidosis
This condition is caused by increased fatty acid metabolism and the accumulation of ketoacids (acetoacetate and -hydroxybutyrate). DKA usually occurs in insulin-dependent diabetes mellitus in association with cessation of insulin or an intercurrent illness, which increases insulin requirements temporarily and acutely.
The accumulation of ketoacids accounts for the increment in the AG and is accompanied most often by hyperglycemia. The relationship between the AG and HCO3– is ~1:1 in DKA but may decrease in the well-hydrated patient with preservation of renal function. Ketoacid excretion in the urine reduces the anion gap in this situation. It should be noted that since insulin prevents production of ketones, bicarbonate therapy is rarely needed except with extreme acidemia (pH < 7.1). Patients with DKA are typically volume depleted and require fluid resuscitation with isotonic saline. Volume overexpansion is not uncommon after IV fluid administration, and contributes to the development of a hyperchloremic acidosis during treatment of DKA because volume expansion increases urinary ketoacid anion excretion (loss of potential bicarbonate). The mainstay for treatment of this condition is IV regular Insulin therapy.
The intial ketoacid in DKA is beta- hydroxybutyrate, which converts into acetone. However, for beta- hydroxybutyrate to get converted into acetone, insulin is required. Hence, in acute DKA, intial acetone may be negative and only after starting insulin drip, acetone appears in blood. Also, with adequate hydration, ketoacids get cleared in the blood and gets washed away in the urine. Hence, late appearance of ketones in urine doesn’t necessarily mean worsening DKA.
In DKA, bicarb therapy markedly increases the blood ketone levels and cause delayed clearance of ketonemia. 
In both ketoacidosis and lactic acidosis, the unmeasured anion represents "potential bicarbonate" because these anions can be metabolized to bicarbonate once the underlying abnormality is corrected (eg, restoration of tissue perfusion in lactic acidosis, and insulin therapy in diabetic ketoacidosis). However, these disorders differ in the following way:
  • In patients with ketoacidosis, some of this potential bicarbonate is excreted in the urine as sodium or potassium salts. The renal loss of ketoacids becomes much more pronounced during therapy in the hospital because volume expansion with intravenous saline restores the extracellular fluid volume, improves renal function, and thereby exacerbates the renal loss of potential bicarbonate. The net effect is that almost all patients with diabetic ketoacidosis develop a normal anion gap (hyperchloremic) acidosis during successful therapy
  • In patients with hypoperfusion-induced lactic acidosis, renal loss of potential bicarbonate generally does not occur since renal function is typically reduced or absent. Thus, lactate anions are not excreted and, after adequate perfusion is restored, a normal anion gap acidosis does not develop.
When the anion gap is normal — Normal anion gap (hyperchloremic) metabolic acidoses are caused by loss of bicarbonate or the combination of a relatively normal glomerular filtration rate with diminished renal acid excretion.
When HCl is added to the extracellular fluid space, bicarbonate is replaced on an equimolar basis by chloride. Thus, there is no change in the serum anion gap. The terms "normal anion gap metabolic acidosis" and "hyperchloremic metabolic acidosis" are therefore interchangeable names for this disorder.
Causes of hyperchloremic metabolic acidosis — 
Loss of bicarbonate-rich fluid can occur in several clinical settings including:
  • Diarrhea
  • Prolonged exposure of urine to colonic or ileal mucosa (in patients who have had ureteral implants into the colon or have a malfunctioning ileal loop bladder)
  • Proximal (type 2) renal tubular acidosis
Serum anion gap without overt metabolic acidosis — Much less commonly, the AG elevation is due to increased levels of anions which are not acids. For example, hyperalbuminemia, hyperphosphatemia, or, rarely, an anionic paraprotein (usually an IgA monoclonal immunoglobulin) can increase the AG.
Overview of Threapy— 
First, whenever possible, the primary focus of therapy for metabolic acidosis should be directed at reversing the underlying pathophysiologic process. Second, it is important to consider acute and chronic forms of metabolic acidosis separately:
  • Acute metabolic acidosis ― Severe acidemia can be treated by the intravenous administration of sodium bicarbonate. When the pH falls below 7.2, the acidemia itself can have major adverse consequences (such as catecholamine-resistant hypotension). Thus, the initial aim of sodium bicarbonate therapy in such patients is to raise the systemic pH above 7.2.
  • Chronic metabolic acidosis ― The most common causes of chronic metabolic acidosis are diarrhea, advanced chronic kidney disease, and the various forms of renal tubular acidosis.
  • Generally, if more normal acid-base parameters can be achieved with exogenous alkali (eg, sodium or potassium bicarbonate or citrate) without creating other difficulties (such as potassium wasting in disorders such as type 2 or proximal renal tubular acidosis), then such treatment may be helpful. The rational for alkali therapy is :
    •  Increasing the bicarbonate concentration reduces or eliminates the need for compensatory hyperventilation and can alleviate the dyspnea experienced by some patients.
    •  Chronic metabolic acidosis may have adverse effects on muscle function and metabolism, skeletal integrity, hormone levels, and other physiologic parameters.
    •  Patients with chronic distal (type 1) renal tubular acidosis are likely to develop nephrocalcinosis and calcium-containing kidney stones. This defect can be reversed with adequate bicarbonate replacement.
    •  Chronic metabolic acidosis in patients with kidney dysfunction may accelerate the progression of their kidney damage, and reversal of the acidosis can slow this process.
Treatment with alkali
Giving bicarb in non-anion gap acidosis like diarrhea where there is a true bicarb deficit is not controversial. Controversy arises when bicarb decreases due to its conversion into another base, which given sufficient time, can be converted back to bicarbonate, such as in DKA and lactic acidosis. There is no benefit of alkali administration in patients with a pure AG acidosis, owing to accumulation of a metabolizable organic acid anion (ketoacidosis or lactic acidosis). It must be determined if the acid anion in plasma is metabolizable (i.e., – hydroxybutyrate, acetoacetate, and lactate) or nonmetabolizable (anions that accumulate in chronic renal failure and after toxin ingestion). The latter requires return of renal function to replenish the [HCO3–] deficit, a slow and often unpredictable process. Consequently, patients with an AG attributable to a nonmetabolizable anion as in the face of renal failure should receive alkali therapy, either PO or IV, in an amount necessary to slowly increase the plasma [HCO3–] into the 20–22 mmol/L range. Sodium bicarbonate (NaHCO3) therapy may paradoxically depress cardiac performance and exacerbate acidosis by enhancing lactate production.
Dosing of alkali therapy (when given) — 
From a practical clinical perspective, the dose of bicarbonate to be administered is determined empirically. If the virtual bicarbonate space is roughly 50 percent of lean body weight, then one vial will raise the serum HCO3 concentration by about 1.3 to 1.5 meq/L in a 70 kg patient. Most physiologists recommend giving just enough bicarb to raise the Ph >7.1
The virtual bicarbonate distribution space — after the infusion of sodium bicarbonate into the intravascular space, it will rapidly distribute throughout the extracellular fluid space. Some will enter the intracellular fluid space, some will be titrated by hydrogen ions released from a variety of body acid-base buffers, and some will be titrated by organic acids that can be produced both as a part of the original pathologic process and in response to the bicarbonate load and increase of pH. In short, the volume of distribution of bicarb roughly equal to that of total body water. 
Together, the physical distribution of the bicarbonate into these spaces and the disappearance of some bicarbonate as a result of its titration with hydrogen ions can be considered a virtual "space" into which the infused HCO3 load distributes. If the bicarbonate distribution space can be determined, then the quantity of bicarbonate required to elevate the serum bicarbonate concentration by any given amount can be estimated from the bicarbonate deficit:
 HCO3 deficit    =    HCO3 space   x   HCO3 deficit per liter
When the serum bicarbonate concentration is normal to moderately reduced, the apparent bicarbonate space is approximately 55 percent of lean body weight. Bicarb space increases with the degree of acidemia. In severe acidemia, it can go as high as 90%. 
 HCO3 space   =   [0.4 + (2.6 ÷ [HCO3])] x lean body weight (in kg)
It is recommended that 50% of total deficit be given over 3 to 4 hours, and the remainder replaced over 8-24 hours. The usual initial target (desired HCO3– concentration): 10 – 12 mEq/L, which should bring the blood pH to ~7.20. The subsequent  goal is to increase the bicarbonate level to 15 meq/L over the next 24 hours.
Eg: if the weight is 100kg, the Bicarb space, if assumed to be 50%, is 50 liters. Hence, if we give 1 amp of Bicarb, that 50meq will get distributed among 50 liters and hence, Bicarb value increases by 1 meq/L.
Summary and Recommendations: 
  • In patients with metabolic acidosis, the excretion of NH4, usually with Cl, increases the urine Cl concentration. In such settings, urine Cl usually exceeds the sum of urine Na and urine K, resulting in a negative UAG. The value of the UAG can provide an indirect estimate of urinary NH4 excretion in these patients.
  • A positive UAG is consistent with low or normal NH4 excretion. As an example, patients who have metabolic acidosis associated with impaired NH4 excretion (such as a distal renal tubular acidosis) will have a positive UAG.
  • A negative UAG is consistent with increased NH4 excretion (ie, greater than 80 meq/L). As an example, the UAG generally falls to a range between -20 and -50meq/L in patients who develop metabolic acidosis as a result of diarrhea
  • Compensatory mechanisms:
    1. Metabolic acidosis: for every 1 unit change in bicarbonate, PCO2 changes by 1.25 times
    2. Metabolic alkalosis: for every 1 unit change in bicarbonate, PCO2 changes by 0.75 times
    3. Acute Respiratory acidosis: for every 1 unit change in PCO2, HCO3 changes by 0.1 times
    4. Chronic Respiratory acidosis: for every 1 unit change in PCO2, HCO3 changes by 0.3-0.4 times
    5. Acute Respiratory alkalosis: for every 1 unit change in PCO2, HCO3 changes by 0.2 times
    6. Chronic Respiratory alkalosis: for every 1 unit change in PCO2, HCO3 changes by 0.4-0.5 times
  • Osmolarity = 2xNa+Glucose/18+ BUN/2.8+ EtoH/4.6
  • Osmolar gap with narrow anion gap is seen in lithium toxicity, mannitol, pseudohyponatremia and hypertriglyceridemia, ethylene glycol and isopropyl alcohol.
  • All toxic alcohols can increase osmolarity.
  • Isopropyl alcohol causes osmolar gap but no anion gap. It gets metabolized into acetone.
  • Propylene glycol contained in ativan drip causes anion gap but no osmolar gap.
  • Bicarb therapy in lactic acidosis: Sodium bicarbonate is clearly effective in raising the arterial pH in critically ill patients with lactic acidosis. However, it doesn’t change the intracellular PH. Despite the correction of acidemia, it doesn’t have any favorable effects on hemodynamics as was widely believed before.
  • Bicarb raises intracellular PH by shifting of CO2 into cells.
  • Remember admin of bicarb increases CO2. So, only give if intubated or patient has compensatory reserve to blow off excess
  • While H+ and HCO3-, as charged ions, do not readily diffuse across cell membranes, CO2 does readily diffuse. In the intracellular compartment, the high CO2 concentration will drive this same equation in reverse and generate intracellular H+. Thus, bicarbonate administration will cause intracellular acidosis unless PCO2 can be controlled by increased ventilation.
  • D5W and Bicarb gets distributed throughout the TBW (ICF+ECF). NS gets distributed only in ECF.

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