Metabolic Acidosis – Causes, Symptoms, Treatment

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Metabolic Acidosis is a serious electrolyte disorder characterized by an imbalance in the body’s acid-base balance. Metabolic acidosis has three main root causes: increased acid production, loss of bicarbonate, and a reduced ability of the kidneys to excrete excess acids.[rx] Metabolic acidosis can lead to acidemia, which is defined as arterial blood pH that is lower than 7.35.[rx] Acidemia and acidosis are not mutually exclusive – pH and hydrogen ion concentrations also depend on the coexistence of other acid-base disorders; therefore, pH levels in people with metabolic acidosis can range from low, normal, to high.

Metabolic acidosis is characterized by an increase in the hydrogen ion concentration in the systemic circulation resulting in a serum HCO3 less than 24 mEq/L. Metabolic acidosis is not a benign condition and signifies an underlying disorder that needs to be corrected to minimize morbidity and mortality. The many etiologies of metabolic acidosis are classified into 4 main mechanisms: increased production of acid, decreased excretion of acid, acid ingestion, and renal or gastrointestinal (GI) bicarbonate losses.

Types of Metabolic Acidosis

Acute metabolic acidosis

Symptoms are not specific, and diagnosis can be difficult unless patients present with clear indications for arterial blood gas sampling. Symptoms may include palpitations, headache, altered mental status such as severe anxiety due to hypoxia, decreased visual acuity, nausea, vomiting, abdominal pain, altered appetite and weight gain, muscle weakness, bone pain, and joint pain. People with acute metabolic acidosis may exhibit deep, rapid breathing called Kussmaul respirations which is classically associated with diabetic ketoacidosis.[rx] Rapid deep breaths increase the amount of carbon dioxide exhaled, thus lowering the serum carbon dioxide levels, resulting in some degree of compensation. Overcompensation via respiratory alkalosis to form an alkalemia does not occur.

Extreme acidemia can also lead to neurological and cardiac complications:

  • Neurological: lethargy, stupor, coma, seizures
  • Cardiac: Abnormal heart rhythms (e.g., ventricular tachycardia) and decreased response to epinephrine, both leading to low blood pressure

Physical examination can occasionally reveal signs of the disease, but is often otherwise normal. Cranial nerve abnormalities are reported in ethylene glycol poisoning, and retinal edema can be a sign of methanol intoxication.

Chronic metabolic acidosis

Chronic metabolic acidosis has non-specific clinical symptoms but can be readily diagnosed by testing serum bicarbonate levels in patients with Chronic Kidney Disease (CKD) as part of a comprehensive metabolic panel. Patients with CKD Stages G3-G5 should be routinely screened for metabolic acidosis.[rx][rx]

Causes of Metabolic Acidosis

Determining the type of metabolic acidosis can help clinicians narrow down the cause of the disturbance. Acidemia refers to a pH less than the normal range of 7.35 to 7.45. In addition, metabolic acidosis requires a bicarbonate value less than 24 mEq/L. Further classification of metabolic acidosis is based on the presence or absence of an anion gap, or concentration of unmeasured serum anions. Plasma neutrality dictates that anions must balance cations to maintain a neutral charge. Therefore, sodium (Na), the primary plasma cation, is balanced by the sum of the anions bicarbonate and chloride in addition to the unmeasured anions, which represent the anion gap.

There are many causes of acute metabolic acidosis, and thus it is helpful to group them by the presence or absence of a normal anion gap.[rx]

Increased anion gap

Causes of increased anion gap include:

  • Lactic acidosis
  • Ketoacidosis (e.g., Alcoholic, diabetic, or starvation)[rx]
  • Chronic kidney failure
  • Transient 5-oxoprolinemia due to long-term ingestion of high-doses of acetaminophen (often seen with sepsis, liver failure, kidney failure, or malnutrition)[rx]
  • Intoxication:
    • Salicylates, methanol, ethylene glycol[rx]
    • Organic acids, paraldehyde, ethanol, formaldehyde[rx]
    • Carbon monoxide, cyanide, ibuprofen, metformin[rx]
  • Propylene glycol (metabolized to L and D-lactate and is often found in infusions for certain intravenous medications used in the intensive care unit)[rx]
  • Massive rhabdomyolysis[rx]
  • Isoniazid, iron, phenelzine, tranylcypromine, valproic acid, verapamil[rx]
  • Topiramate
  • Sulfates[rx]
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Normal anion gap

Causes of normal anion gap include[rx]

  • Inorganic acid addition
    • Infusion/ingestion of HCl, NH
      4Cl
  • Gastrointestinal base loss
    • Diarrhea
    • Small bowel fistula/drainage
    • Surgical diversion of urine into gut loops
  • Renal base loss/acid retention:
    • Proximal renal tubular acidosis
    • Distal renal tubular acidosis
  • Hyperalimentation
  • Addison disease
  • Acetazolamide
  • Spironolactone
  • Saline infusion

Unmeasured anions include lactate and acetoacetate, and these are often some of the main contributors to metabolic acidosis.

  • Anion gap (AG) = [Na] –([Cl] + [HCO3])

Anion gap metabolic acidosis is frequently due to anaerobic metabolism and lactic acid accumulation. While lactate is part of many mnemonics for metabolic acidosis, it is important to distinguish it is not a separate etiology, but rather a consequence of a condition.

Mnemonic for anion gap metabolic acidosis differential: CAT MUDPILES

  • C: Cyanide and carbon monoxide poisoning
  • A: Arsenic
  • T: Toluene
  • M: Methanol, Metformin
  • U: Uremia
  • D: DKA
  • P: Paraldehyde
  • I: Iron, INH
  • L: Lactate
  • E: Ethylene glycol
  • S: Salicylates

Non-gap metabolic acidosis is primarily due to the loss of bicarbonate, and the main causes of this condition are diarrhea and renal tubular acidosis. Additional and rarer etiologies include Addison’s disease, ureterosigmoid or pancreatic fistulas, acetazolamide use, and hyperalimentation through TPN initiation. GI and renal losses of bicarbonate can be distinguished via urine anion gap analysis:

  • Urine AG = Urine Na + Urine K – Urine Cl

A positive value is indicative of renal bicarbonate loss, such as renal tubular acidosis. Negative values are found with non-renal bicarbonate losses, such as diarrhea.

Symptoms of Metabolic Acidosis

Symptoms and signs are primarily those of the cause. Mild acidemia is itself asymptomatic. More severe acidemia (pH < 7.10) may cause nausea, vomiting, and malaise. Symptoms may occur at higher pH if acidosis develops rapidly.

The most characteristic sign is hyperpnea (long, deep breaths at a normal rate), reflecting a compensatory increase in alveolar ventilation; this hyperpnea is not accompanied by a feeling of dyspnea.

Although symptoms can differ, someone with metabolic acidosis will often:

  • Breathe fast
  • Have a fast heartbeat
  • Have a headache
  • Be confused
  • Confusion
  • Fast heartbeat
  • Feeling sick to your stomach
  • Headache
  • Long and deep breaths
  • Not wanting to eat
  • Vomiting
  • Feeling tired
  • Have little desire to eat
  • Feel sick to their stomach
  • Throw up

Severe, acute acidemia predisposes to cardiac dysfunction with hypotension and shock, ventricular arrhythmias, and coma. Chronic acidemia causes bone demineralization disorders (eg, rickets, osteomalacia, osteopenia).

Diagnosis of Metabolic Acidosis

History and Physical

A focused history can elicit potential causes of acid-base disturbances such as vomiting, diarrhea, medications, possible overdoses and chronic conditions with a predisposition to acidosis including diabetes mellitus.

The physical exam reveals signs unique to each cause such as dry mucous membranes in the patient with diabetic ketoacidosis. Hyperventilation may also be present as a compensatory respiratory alkalosis to assist with PCO2 elimination and correction of the acidemia. Compensatory reactions do not completely correct a disturbance to the normal pH range, however.

Interpretation Steps

Acid-base interpretation is crucial to identify and correct disturbances in acid-base equilibrium that have profound consequences on patient health. The following steps use lab values and equations to determine if a patient has metabolic acidosis and any additional acid-base disturbances.

Step 1: pH, determine if the acid-base status is acidemia or alkalemia

Blood pH is maintained within a narrow range for optimization of physiological functions. Acid-base equilibrium is achieved within a pH range of 7.35 to 7.45. Blood pH distinguishes between acidemia (pH less than 7.35) and alkalemia (pH greater than 7.45)

Step 2: CO2, determine if the disturbance is metabolic or respiratory

The pCO2 determines whether an acidosis is respiratory or metabolic in origin. For a respiratory acidosis, the pCO2 is greater than 40 to 45 due to decreased ventilation. Metabolic acidosis is due to alterations in bicarbonate, so the pCO2 is less than 40 since it is not the cause of the primary acid-base disturbance. In metabolic acidosis, the distinguishing lab value is a decreased bicarbonate (normal range 21 to 28 mEq/L).

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Step 3: Determine if there is an anion gap or non-anion gap in metabolic acidosis
  • AG= Na – (Cl + HCO3)

The normal anion gap is 12. Therefore, values greater than 12 define an anion gap metabolic acidosis.

Step 4: CO2, assess if respiratory compensation is appropriate

Respiratory compensation is the physiologic mechanism to help normalize a metabolic acidosis, however, compensation never completely corrects an acidemia. It is important to determine if there is adequate respiratory compensation or if there is another underlying respiratory acid-base disturbance. Winter’s formula is the equation used to determine the expected CO2 for adequate compensation.

  • Winter’s formula: Expected CO2 = (Bicarbonate x 1.5) + 8 +/- 2

If the patient’s pCO2 is within the predicted range, then there is no additional respiratory disturbance. If the pCO2 is greater than expected, this indicates an additional respiratory acidosis. If the pCO2 is less than expected, there is an additional respiratory alkalosis occurring.

Step 5: Evaluate for additional metabolic disturbances

A delta gap must be determined if an anion gap is present.

  • Delta gap = Delta AG – Delta HCO3 = (AG-12) – (24-bicarbonate)

If the gap is less than -6, then a NAGMA is present.

If the gap is greater than 6, then an underlying metabolic alkalosis is present.

If the gap is between -6 and 6 then only an anion gap acidosis exists.

Exams and Tests
  • Anion gap –This test measures the chemical balance in your blood. It compares the numbers of positively and negatively charged particles, including sodium, chloride, and bicarbonate. Certain types of metabolic acidosis have a bigger difference — or “gap” — than others.
  • Arterial blood gases – This test measures the pH of your blood and the levels of oxygen and carbon dioxide in it.
  • Urine tests – can reveal ketoacidosis, kidney problems, and poisoning from alcohol, aspirin, and antifreeze. If you have diabetes, you can test your pee for ketones at home with test strips you can buy over the counter.

These tests can help diagnose acidosis. They can also determine whether the cause is a breathing problem or a metabolic problem. Tests may include:

  • Arterial blood gas
  • Basic metabolic panel, (a group of blood tests that measure your sodium and potassium levels, kidney function, and other chemicals and functions)
  • Blood ketones
  • Lactic acid test
  • Urine ketones
  • Urine pH

Other tests may be needed to determine the cause of the acidosis.

Treatment of Metabolic Acidosis

The management of metabolic acidosis should address the cause of the underlying acid-base derangement. For example, adequate fluid resuscitation and correction of electrolyte abnormalities are necessary for sepsis and diabetic ketoacidosis. Other therapies to consider include antidotes for poisoning, dialysis, antibiotics, and bicarbonate administration in certain situations.

The earlier you’re treated, the better. Common treatments include:

  • Detoxification, if you have drug or alcohol poisoning
  • Insulin, if you have DKA
  • IV fluids, given by needle through a vein in your arm
  • Sodium bicarbonate, by IV

You might have to go to a hospital.

Refer to the specific conditions for a thorough explanation of the appropriate treatment.

Acute Metabolic Acidosis

Bicarbonate therapy is generally administered In patients with severe acute acidemia (pH < 7.11), or with less severe acidemia (pH 7.1-7.2) who have severe acute kidney injury. Bicarbonate therapy is not recommended for people with less severe acidosis (pH ≥ 7.1), unless severe acute kidney injury is present. In the BICAR-ICU trial,[37] bicarbonate therapy for maintaining a pH >7.3 had no overall effect on the composite outcome of all-cause mortality and the presence of at least one organ failure at day 7. However, amongst the sub-group of patients with severe acute kidney injury, bicarbonate therapy significantly decreased the primary composite outcome, and 28-day mortality, along with the need for dialysis.

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Chronic Metabolic Acidosis

For people with Chronic Kidney Disease, treating metabolic acidosis slows the progression of chronic kidney disease.[rx] Dietary interventions for treatment of chronic metabolic acidosis include base-inducing fruits and vegetables that assist with reducing the urine net acid excretion, and increase TCO2. Recent research has also suggested that dietary protein restriction, through ketoanalogue-supplemented vegetarian very low protein diets are also a nutritionally safe option for correction of metabolic acidosis in people with Chronic Kidney Disease.[rx]

Currently, the most commonly used treatment for chronic metabolic acidosis is oral bicarbonate. The NKF/KDOQI guidelines recommend starting treatment when serum bicarbonate levels are <22 mEq/L, in order to maintain levels ≥ 22 mEq/L.[rx][rx] Studies investigating the effects of oral alkali therapy demonstrated improvements in serum bicarbonate levels, resulting in a slower decline in kidney function, and reduction in proteinuria – leading to a reduction in the risk of progressing to kidney failure. However, side effects of oral alkali therapy include gastrointestinal intolerance, worsening edema, and worsening hypertension. Furthermore, large doses of oral alkali are required to treat chronic metabolic acidosis, and the pill burden can limit adherence.[rx]

Veverimer (TRC 101) is a promising investigational drug designed to treat metabolic acidosis by binding with the acid in the gastrointestinal tract and removing it from the body through excretion in the feces, in turn decreasing the amount of acid in the body, and increasing the level of bicarbonate in the blood. Results from a Phase 3, double-blind placebo-controlled 12-week clinical trial in people with CKD and metabolic acidosis demonstrated that Veverimer effectively and safely corrected metabolic acidosis in the short-term,[rx] and a blinded, placebo-controlled, 40-week extension of the trial assessing long-term safety, demonstrated sustained improvements in physical function and a combined endpoint of death, dialysis, or 50% decline in eGFR.[rx]

What are the complications of metabolic acidosis if I have kidney disease or kidney failure?

  • Increased bone loss (osteoporosis) – Metabolic acidosis can lead to a loss of bone in your body. This can lead to a higher chance of fractures in important bones like your hips or backbone.
  • Progression of kidney disease – Metabolic acidosis can make your kidney disease worse.  Exactly how this happens is not clear. As acid builds up, kidney function lowers; and as kidney function lowers, acid builds up. This can lead to the progression of kidney disease.
  • Muscle loss – Albumin is an important protein in your body that helps build and keep muscles healthy. Metabolic acidosis lowers the amount of albumin created in your body, and leads to muscle loss, or what is called “muscle wasting.”
  • Endocrine disorders – Metabolic acidosis interferes with your body’s ability to maintain normal functions of your endocrine system (the collection of glands that produce hormones). This can cause your body to build a resistance to insulin (the hormone in your body that helps keep your blood sugar level from getting too high or too low). If left untreated for too long or not corrected in time, it can lead to diabetes.

References

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