I. Problem/Condition.

Non-gap metabolic acidosis, or hyperchloremic metabolic acidosis, are a group of disorders characterized by a low bicarbonate, hyperchloremia and a normal anion gap (10-12). A non-gapped metabolic acidosis fall into three categories:

1) loss of base (bicarbonate) from the gastrointestinal (GI) tract or

2) loss of base (bicarbonate) from the kidneys,

Continue Reading

3) intravenous administration of sodium chloride solution.

Bicarbonate can be lost from the GI tract (diarrhea) or from the kidneys (renal tubular acidosis) or displaced by chloride.

II. Diagnostic Approach.

A. What is the differential diagnosis for this problem?

I. Gastrointestinal bicarbonate loss

  • Diarrhea (low potassium [K+])

  • Colostomy (low K+)

  • Enteric fistulas (low K+)

  • Ileostomy (low K+)

II. Urologic procedures

  • Uretero-sigmoidostomy (low K+)

  • Uretero-ileostomy (low K+)

III. Renal bicarbonate loss

  • Tubulointerstitial disease

  • Proximal renal tubular acidosis: (low K+)

  • Distal renal tubular acidosis: (low or high K+)

IV. Drugs

  • Acetazolamide

  • Calcium chloride (high K+)

  • Magnesium sulfate

  • Spironolactone (high K+)

  • Triamterene (high K+)

  • Amiloride (high K+)

  • Trimethoprim (high K+)

  • Pentamidine (high K+)

  • Prostaglandin Inhibitors, (aspirin, nonsteroidal anti-inflammatory drugs, cyclooxygenase 2 inhibitors)

  • Toluene

V. Adrenal disorders

  • Adrenal insufficiency (primary or secondary) (high K+)

  • Pseudoaldosteronism, type 1

  • Pseudoaldosteronism, type 2 (Gordon’s syndrome)

B. Describe a diagnostic approach/method to the patient with this problem.

Metabolic acidosis can be divided into two groups based on anion gap. If an anion gap is elevated (usually greater than 12), see gapped metabolic acidosis. Diagnosis of the cause of non-gapped metabolic acidosis is usually clinically evident – as it can be attributed to diarrhea, intravenous saline or by default, renal tubular acidosis. Occasionally, it may not be clear whether loss of base occurs due to the kidney or bowel. In such a case, one should calculate the urinary anion gap. The urinary anion gap (UAG) = sodium (Na+)+K+– chloride (Cl). Caution if ketonuria or drug anions are in the urine as it would invalidate the calculation.

Diarrhea: UAG is a negative value.

Renal tubular acidosis: UAG is positive value.

As an aid, UAG is neGUTive when associated with bowel causes.

Non-gapped metabolic acidosis can further be divided into two categories:

1) High or normal serum potassium,

2) Low serum potassium.

1. Historical information important in the diagnosis of this problem.

The urinary anion gap is key to determining if the non-gapped metabolic acidosis is GI or renal. The urinary anion gap provides an estimate of the urinary ammonium (NH4+) excretion. The urinary anion gap is defined as UAG = Unmeasured Anion (UA) – Unmeasured Cation (UC). As seen in diarrhea, bicarbonate is excreted via the gut triggering urinary ammonium excretion to maintain electroneutrality. This causes an increased UC (urinary NH4+) and results in a negative UAG. On the other hand, renal tubular acidosis involve the inability of the kidney to resorb bicarbonate. This causes an increased UA (urinary HCO3) and results in a positive UAG.

It is worthy to understand how the urinary anion gap was derived. The cations present in urine include: Na+, K+, Ca2+, Mg. The anions in urine include: Cl, HCO3, sulfate, phosphate and some organic acids. Only Na+, K+, Cl are typically measured in urine.

By law of electroneutrality we have the equation: Na+ + K+ + UC = Cl + UA; UC: unmeasured cations; UA: unmeasured anions.

Rewriting the equation, Urine anion gap = UA – UC = Na+ + K+ – Cl

If acidosis is due to loss of bicarbonate from the bowel, the kidney excretes more urinary NH4+ or Unmeasured Cation (UC). Thus, the UAG will be less or negative.

If acidosis is due to loss of bicarbonate from the kidney, the kidney excretes more urinary HCO3 or Unmeasured Anion (UA). Thus, the UAG will be greater or positive.

2. Physical Examination maneuvers that are likely to be useful in diagnosing the cause of this problem.


3. Laboratory, radiographic and other tests that are likely to be useful in diagnosing the cause of this problem.

  • Serum potassium

  • Urine anion gap

  • Urine osmolal gap

  • Urine pH

C. Criteria for Diagnosing Each Diagnosis in the Method Above.

I. Gastrointestinal bicarbonate loss:

  • Diarrhea

– For acid-base disorders to arise, the amount of enteric fluid must be significant enough to overwhelm the kidney’s ability to maintain acid-base balance. The acid-base abnormality that develops is a function of the electrolyte content (sodium, chloride, and bicarbonate) that is lost. All diarrhea types result in a non-gap metabolic acidosis except for congenital chloridorrhea which causes a metabolic alkalosis. Congenital chloridorrhea is a genetic disorder which results in a fetus having persistent secretory diarrhea, severe electrolyte disorders, abdominal distension and failure to thrive.

  • Laxative abuse (low K+)

– Acid-base abnormalities tend to be mild and can range from metabolic alkalosis to metabolic acidosis depending on the amount of stool bicarbonate losses. The most prominent electrolyte disorder is hypokalemia. Hypokalemia may actually be protective from development of metabolic acidosis as H+ moves into the cells as potassium leaves cells to buffer the stool potassium losses. However, if stool loss is large, metabolic acidosis may ensue.

  • Enteric fistulas (low K+)

– Biliary and pancreatic fluid is extremely rich in bicarbonate. However, the volume of drainage is generally low thus limiting the degree of metabolic acidosis. In the setting of biliary or pancreatic fistulas or external drains, there may be massive loss of bicarbonate fluids leading to non-gap metabolic acidosis and volume depletion.

  • Ileostomy (low K+)

– This is a surgical opening created where a loop of small intestine (ileum) is brought out onto the skin. This is needed in the case the colon is partially or completely removed. Typical losses from the ileostomy are 200-1,000ml of fluid. However, patients may develop metabolic acidosis if the ileostomy output increases or if dietary intake is disrupted.

  • Colostomy (low K+)

– In general, ileostomies are at higher risk for fluid-electrolyte imbalance than colostomies.

II. Urologic Procedures:

  • Uretero-sigmoidostomy (low K+)

– This is a surgical procedure where the ureters are diverted into the sigmoid colon. It is usually done as a treatment for bladder cancer. This procedure often results in an increased risk of kidney infections and thus require patients to take prophylactic antibiotics. In addition, urine containing salts, Na+ and Cl, travel through the sigmoid colon are exchanged for K+ and HCO3 resulting in metabolic acidosis and hypokalemia. This procedure is no longer popular in most developed countries due to the aforementioned complications.

  • Uretero-ileostomy/ ileal conduit (low K+)

– In developed countries uretero-ileostomy (or ileal conduit) is employed, where the ureter is connected to a detached portion of ileum. The end of the ileum is then brought through an opening in the abdomen for which a bag is attached to collect urine. The incidence of metabolic acidosis in ileal conduit (2-20%) is much less than uretero-sigmoidostomy (30-80%). This is because of much shorter dwell time in the ileal conduit allows for minimal Chloride-Bicarbonate exchange.

III. Renal bicarbonate loss:

  • Tubulointerstitial disease (acute interstitial nephritis and chronic interstitial nephritis)

  • Proximal type 2 renal tubular acidosis: (low K+)

– This is a proximal tubular disorder where the proximal tubules are unable to resorb solutes: bicarbonate, phosphate, glucose, uric acid, and amino acids.

  • Distal Type 1 Renal Tubular Acidosis (low or high K+)

– This is an inability to maximally acidify the urine. Typically urine pH remains > 5.5 despite severe acidemia ([HCO3] < 15 millimoles/Liter).

  • Hypoaldosteronism type 4 renal tubular acidosis

IV. Drugs:

  • Acetazolamide

  • Calcium chloride (high K+)

  • Magnesium sulfate

  • Spironolactone (high K+)

  • Triamterene (high K+)

  • Amiloride (high K+)

  • Trimethoprim (high K+)

  • Pentamidine (high K+)

  • Prostaglandin inhibitors, (aspirin, nonsteroidal anti-inflammatory drugs, cyclooxygenase 2 inhibitors)

  • Toluene

V. Adrenal disorders:

  • Adrenal insufficiency (primary or secondary) (high K+)

  • Pseudoaldosteronism, type 1

  • Pseudoaldosteronism, type 2 (Gordon’s syndrome)

D. Over-utilized or “wasted” diagnostic tests associated with the evaluation of this problem.


III. Management while the Diagnostic Process is Proceeding.

A. Management of Clinical Problem Non-gapped Metabolic Acidosis.

Management of this disorder, in general, involves:

1. Identifying and correcting the underlying disease.

2. Metabolic acidosis (Acute process), i.e. sepsis, diabetic ketoacidosis. The goal of giving bicarbonate is to try and restore normal extracellular pH to allow for optimal functioning of cells.

  • If arterial pH>7.20, one can consider holding off on giving bicarbonate if patient is asymptomatic and the underlying process (i.e. diarrhea) can be controlled.

  • If arterial pH is <7.20, consider administering sodium bicarbonate to avert major consequences of severe acidemia except in cases of diabetic ketoacidosis and lactic acidosis.

  • If arterial pH is <7.15 (in lactic acidosis), consider administering sodium bicarbonate.

  • If arterial pH is <7.00 (in diabetic ketoacidosis), consider administering sodium bicarbonate.

  • Estimate bicarbonate deficiency using the following formula. HCO3 milliequivalents (mEq) = 0.5 x weight (kilograms [kg]) x ( 24 – serum HCO3 (mEq/L).

  • Administer 1/2 dose initially and 1/2 dose over next 24 hours. Monitor serum pH and serum HCO3. These equations only provide an estimate.

  • Sodium bicarbonate is given in ampules.

– For example, 1 ampule is 50 mEq. Therefore, one may give 3 ampules or 150 mEq in dextrose 5%. Caution that when giving sodium bicarbonate, one should account for the tonicity of the solution. Therefore, do not give 3 ampules of sodium bicarbonate in normal saline. This would result in a significantly hypertonic solution.

3. Metabolic acidosis (chronic process)

  • Chronic kidney disease (CKD)

– Acidosis can be associated with muscle wasting, bone disease, hypoalbuminemia, inflammation, progression of CKD and increased mortality.

– Start oral bicarbonate therapy when HCO3 < 22 mEq/L. Start with 20-36 mEq/day in divided doses. Titrate to bicarbonate levels 22 or greater mEq/L. However the target bicarbonate level is unclear. Serum bicarbonate levels >24 mEq/L maybe associated with higher cardiovascular mortality.

  • Distal renal tubular acidosis

– 0.5-2 mEq/kg/day in 4-5 divided doses.

  • Proximal Renal tubular acidosis

– Initial 5-10 mEq/kg/day; Increase as required to maintain serum HCO3 in normal range.

  • Sodium bicarbonate tablets

– Tablets are available from 325 milligram (mg) to 650 mg. Each 1 gram of sodium bicarbonate equals approximately 12 mEq of sodium and bicarbonate. The usual adult dose can range from 325 mg to 2 grams orally 4 times per day.

B. Common Pitfalls and Side-Effects of Management of this Clinical Problem.

  • Precaution needs to be taken in patients with congestive heart failure who are given sodium bicarbonate and the possibility of causing volume overload.

  • Sodium bicarbonate may cause stomach cramps, flatulence, vomiting and case reports of stomach rupture.

  • Sodium bicarbonate may also affect the metabolism of numerous drugs because of its effect on stomach acidity and systemic pH.

– The packet insert should be consulted to ensure that drug disposition is not affected.

  • Treating with intravenous sodium bicarbonate

– Administer in dextrose 5% water.