Approach to the child with metabolic acidosis

INTRODUCTION — Metabolic acidosis is a biochemical abnormality defined by an increase in blood hydrogen ion (H⁺) concentration or a reduction in serum bicarbonate (HCO₃) concentration. It is either an acute or chronic process and is secondary to a wide range of underlying disorders.

The etiology, clinical impact, and diagnostic evaluation of children with metabolic acidosis will be reviewed. Metabolic acidosis in adults is discussed separately. (See "Approach to the adult with metabolic acidosis".)

DEFINITIONS

●Metabolic acidosis is defined as a pathologic process that increases the concentration of hydrogen ions (H⁺) and reduces blood bicarbonate (HCO₃) concentration. It can be acute (minutes to days) or chronic (weeks to months).

●Respiratory acidosis is defined as an elevation in arterial partial pressure of carbon dioxide (CO₂) concentration that reduces arterial pH.

●Acidemia (as opposed to acidosis) is defined as a low arterial pH (<7.35), which can result from a metabolic acidosis, respiratory acidosis, or a combination of both.

●Total CO₂ measured in the electrolyte panel includes measurements of serum HCO₃ (95 percent of total CO₂), dissolved CO₂, and carbonic acid.

ETIOLOGY BASED ON PATHOGENESIS

Pathogenesis — The etiology of metabolic acidosis in children can be separated into three pathogenetic mechanisms (table 1).

●Increase in acid concentration either due to increased acid generation (endogenous production or exogenous ingestion/infusions) or decreased kidney acid excretion.

●Loss of bicarbonate (HCO₃) via the intestine or kidneys.

●Dilution of serum HCO₃ concentrations by nonbicarbonate/acetate/lactate-containing solutions with a resultant rise in blood hydrogen ions (H⁺) concentrations.

Increased acid concentration: High anion gap metabolic acidosis — A high anion gap (AG) metabolic acidosis is due to the overproduction of endogenous acids, excessive intake of exogenous acids (eg, salicylates), or accumulation of acids due to the kidney's inability to excrete acid in sufficient quantities to maintain normal serum HCO₃ concentrations.

A frequently used mnemonic to identify the more common causes of AG metabolic acidosis in children is MUDPILES (where M = methanol; U = uremia; D = diabetic ketoacidosis; P = paraldehyde; I = iron, isoniazid, and inborn metabolic errors; L = lactic acid; E= ethylene glycol; and S = salicylates).

●Methanol, or wood alcohol, when ingested in excessive quantities, causes an increase in serum formaldehyde, which is converted to formate and formic acid. These metabolites inhibit cytochrome oxidation, leading to progressive acidosis due to the rise of blood lactic acid and ketoacid concentrations [1]. The osmolal gap can be useful in detecting the ingestion of methanol. (See "Methanol and ethylene glycol poisoning: Pharmacology, clinical manifestations, and diagnosis" and "Serum osmolal gap".)

●Uremia in patients with acute or chronic kidney failure is associated with reduced acid excretion by the kidneys resulting in an accumulation of lactic acid, hippuric acid, amino acids [2], pyroglutamic acid [2], guanidinosuccinic acid [3], short-chain fatty acids [3], and sulfuric acid.

●Diabetic ketoacidosis (hyperglycemia due to insulin deficiency) results in excess serum levels of acetoacetate (acetoacetic acid), L-lactate/D-lactate, and beta-hydroxybutyrate [4]. Ketosis due to either starvation or ketogenic diet can also cause AG metabolic acidosis. Ketosis results in increased serum levels of acetoacetate (acetoacetic acid) and beta-hydroxybutyrate and ketones in the urine [5-7].

●Paraldehyde administration is reported to increase serum concentrations of lactic acid [8]. The inclusion of paraldehyde is more historical as it is no longer available in the United States.

●Inborn errors of metabolism can present with metabolic acidosis due to accumulation of lactic acid, ketoacids, and methylmalonic acid depending on the underlying etiology (table 2). In particular, metabolic acidosis is a predominant finding of organic acidemias (methylmalonic, propionic, and isovaleric acidemia, glutaric acidemia type 1, 3-methylglutaconic aciduria (table 3)) and also observed in children with maple syrup urine disease and disorders of carbohydrate production (eg, pyruvate carboxylase, pyruvate dehydrogenase, and phosphoenolpyruvate carboxykinase deficiency) (table 4). (See "Metabolic emergencies in suspected inborn errors of metabolism: Presentation, evaluation, and management", section on 'Metabolic acidosis' and "Inborn errors of metabolism: Classification".)

●Iron overdose can cause a high AG metabolic acidosis from accumulation of lactic acid due to the complications of dissociated ferrous or ferric molecules, including intestinal ulceration, fulminant liver failure, and decreased cardiac output [9]. "I" also may refer to other possible ingestions that are associated with metabolic acidosis (table 5). (See "Approach to the child with occult toxic exposure".)

●Isoniazid overdose is characterized by seizures, coma, and metabolic acidosis due to elevated levels of ketoacids [10-12].

●Lactic acidosis occurs when lactate is overproduced or underutilized. In children, causes of lactic acidosis include:

•Conditions associated with shock result in increased lactate acid due to impaired tissue oxygenation, such as sepsis, cardiac failure, and severe hypoxia. Elevated lactate levels >36 mg/dL measured in children with sepsis have been correlated with a high mortality [13] (See "Causes of lactic acidosis", section on 'Type A lactic acidosis'.)

•Underlying mitochondrial dysfunction, either congenital (table 6) or acquired due to fasting [14]. (See "Inborn errors of metabolism: Classification", section on 'Mitochondrial disorders' and "Causes of lactic acidosis", section on 'Mitochondrial dysfunction'.)

•Severe crush injury resulting in rhabdomyolysis resulting in lactic acidosis due to muscle ischemia. (See "Rhabdomyolysis: Clinical manifestations and diagnosis", section on 'Fluid and electrolyte abnormalities'.)

●Ethylene glycol poisoning causes increased levels of lactic acid and ketoacids [15]. The osmolal gap is useful in detecting ingestion of ethylene glycol as well as methanol and ethanol. (See "Serum osmolal gap" and "Methanol and ethylene glycol poisoning: Pharmacology, clinical manifestations, and diagnosis".)

●Salicylate toxicity in children produce elevated levels of salicylic acid, ketoacids, and lactic acid [16]. (See "Salicylate (aspirin) poisoning: Clinical manifestations and evaluation".)

Loss of bicarbonate: Normal anion gap metabolic acidosis — Normal AG (also referred to as non-AG) metabolic acidosis occurs with a loss of serum HCO₃, which is matched with a concomitant rise in serum chloride (hyperchloremic metabolic acidosis).

The following causes should be considered in a child who presents with normal AG metabolic acidosis:

●Gastrointestinal losses of HCO₃ due to diarrhea, small bowel, or pancreatic drainage cause a significant reduction in serum HCO₃ concentrations.

●Kidney losses of HCO₃ or the inability to acidify the urine, as is seen with renal tubular acidosis (RTA), leads to a hyperchloremic metabolic acidosis. (See "Etiology and clinical manifestations of renal tubular acidosis in infants and children".)

Carbonic anhydrase inhibitors, like acetazolamide, decrease conversion of carbonic acid to water and carbon dioxide (CO₂) at the renal tubule brush border resulting in HCO₃ loss and, subsequently, metabolic acidosis. (See "Mechanism of action of diuretics", section on 'Carbonic anhydrase inhibitors (acetazolamide)'.)

Mixed high anion and normal gap acidosis — Occasionally, there are pediatric patients who have mixed causes of metabolic acidosis, where both high and normal AG causes coexist. (See 'Mixed anion gap' below.)

●In certain situations, children with chronic kidney disease (CKD) can have both accumulated acids (high AG acidosis due to uremia) and RTA (normal gap acidosis with the inability to excrete adequate H⁺ and/or the loss of HCO₃) occur at the same time.

●Children recovering from ketoacidosis may still have elevated serum ketoacids that are converted back to HCO₃. However, if ketoacid anions are lost in urine before they can be metabolized (as sodium or potassium salts), they represent lost potential HCO₃. The effect of these urinary losses is that most patients with diabetic ketoacidosis with initial high AG acidosis develop a normal AG metabolic acidosis during their recovery phase.

●Children with severe diarrhea have a normal AG due to loss of HCO₃, but, if severe hypovolemia develops, high AG metabolic acidosis may develop due to increased lactic acid production (poor tissue perfusion) and impaired acid excretion by the kidney. These patients with hypovolemic shock require fluid resuscitation to restore tissue perfusion. (See "Shock in children in resource-abundant settings: Initial management", section on 'Volume and rate'.)

Dilutional metabolic acidosis — Dilutional acidosis refers to a fall in serum HCO₃ concentration that is due to expansion of the intravascular fluid volume with large volumes of intravenous (IV) fluids containing neither HCO₃ nor the sodium salts of organic anions that can be metabolized to HCO₃ (such as lactate or acetate). Dilutional metabolic acidosis has been reported in children who receive parenteral fluids following trauma or those undergoing surgery [17-20]. Dilution-induced metabolic acidosis is usually mild and often associated with clinical signs of fluid overload (periorbital or pretibial edema, pleural effusions, ascites), fluid intake greatly in excess of urine output, and increases in patient weight. Laboratory studies that support a diagnosis of dilutional-induced acidosis include a low serum chloride, low serum uric acid, low blood urea nitrogen, low serum osmolality, and high beta-type natriuretic peptide.

The underlying mechanism of dilutional acidosis remains unknown as the dilution of both serum HCO₃ and H⁺ with normal saline is proportional. Proposed mechanisms include [21,22]:

●CO₂ from the lungs equilibrates with lower CO₂ in the diluted blood and becomes hydrated to carbonic acid

●Normal cellular metabolism contributes to the H⁺

CLINICAL MANIFESTATIONS — There are no distinguishing clinical features of pediatric metabolic acidosis. Findings are nonspecific and vary between the acute and chronic disorders.

Acute metabolic acidosis — Children with acute metabolic acidosis typically present with symptoms related to the underlying condition and may also have signs/symptoms of compensatory respiratory alkalosis.

●Tachypnea and hypernea – The most common manifestations of acute metabolic acidosis in children are tachypnea and/or hyperpnea due to compensatory respiratory compensation. Older children can exhibit an increase in respiratory rate (tachypnea) and depth of respiration (eg, Kussmaul respirations). In young children and infants, the increase in depth of respiration, as observed in classic Kussmaul breathing, may not be as apparent and tachypnea may be the only response to metabolic acidosis. An inability to generate an appropriate hyperventilatory response may be indicative of significant underlying neurologic and/or respiratory disorder.

●Neurologic findings – Mental confusion and lethargy have been observed in patients with severe acute metabolic acidosis, despite minor changes in cerebrospinal and brain pH [23]. As an example, children with severe metabolic acidosis due to diabetic ketoacidosis generally present with lethargy, altered mental status, seizures, ataxia, hypotonia, muscle weakness, and developmental delay, as well as vision and hearing impairments [24].

●Laboratory findings

•Partial pressure of carbon dioxide (PCO₂) – The respiratory alkalotic compensation results in a decrease in the PCO₂ concentrations, which raise the blood pH toward normal, although usually never complete and never overcompensated. The respiratory compensation for metabolic acidosis generates a relatively linear relationship between the arterial PCO₂ and bicarbonate (HCO₃) concentration, with a decreased of PCO₂ of 1.2 mmHg for every 1 mmol/L decrease in serum HCO₃. This respiratory response to metabolic acidosis begins within 30 minutes and is complete by 12 to 24 hours. (See "Approach to the adult with metabolic acidosis", section on 'Determination of whether respiratory compensation is appropriate'.)

•Hyperkalemia – Acute metabolic acidosis can precipitate hyperkalemia, which, if severe, is associated with life-threatening cardiac conduction abnormalities. (See 'Effect of acidemia on potassium and ionized calcium and magnesium levels' below and "Causes, clinical manifestations, diagnosis, and evaluation of hyperkalemia in children", section on 'Cardiac conduction abnormalities'.)

●Cardiac effects – Data from animal and tissue studies showed myocardial depression and arrhythmias when the pH falls below 7.1 [25,26]. A study of critically ill adults demonstrated diminished cardiac function when blood pH was less than 7.28 [27].

Chronic metabolic acidosis — Children with chronic metabolic acidosis can be asymptomatic or present with multiple-system manifestations depending on the duration and severity of the underlying disorder. For children with long-standing uncorrected metabolic acidosis (eg, renal tubular acidosis [RTA]), findings include:

●Poor growth and skeletal muscle wasting ‒ Poor growth and skeletal muscle wasting are attributed to aberrant growth hormone secretion and resistance to insulin-like growth factors as well as rickets due to bone abnormalities [28]. Growth impairment is commonly seen in children with uncorrected acidosis due to RTA; however, adequate treatment can prevent poor growth and, in some young children, can result in catchup growth [29]. (See "Etiology and clinical manifestations of renal tubular acidosis in infants and children" and "Growth failure in children with chronic kidney disease: Risk factors, evaluation, and diagnosis", section on 'Metabolic acidosis'.)

●Decreased bone mineral content ‒ Rickets is observed in children with chronic acidosis due to bone biochemistry abnormalities. Bone buffering of some of the excess hydrogen ions (H⁺) is associated with the release of calcium and phosphate from bone, resulting in a decrease in bone mineral content. Chronic acidosis decreases osteoblast activity and increases osteoclastic activity [30]. Treatment of chronic metabolic acidosis improves bone mineral density and rickets, as well as linear growth in these children [29,31]. (See "Pathogenesis, consequences, and treatment of metabolic acidosis in chronic kidney disease", section on 'Prevention of bone buffering'.)

●Nephrolithiasis and nephrocalcinosis ‒ Hypercalciuria in children with chronic metabolic acidosis increases the risk of nephrolithiasis and nephrocalcinosis. For example, children with distal (type 1) RTA have an increased risk of nephrolithiasis and nephrocalcinosis. Calcium is mobilized from the bone, resulting in increased calcium excretion by the kidney [32]. In addition, the hypocitraturia that occurs in response to metabolic acidosis enhances proximal tubular citrate reabsorption, which limits tubular calcium reabsorption, leading to kidney calculi (stone) formation [33]. (See "Kidney stones in children: Epidemiology and risk factors", section on 'Hypocitraturia' and "Nephrocalcinosis in neonates", section on 'Hypocitraturia' and "Etiology and clinical manifestations of renal tubular acidosis in infants and children", section on 'Clinical manifestations'.)

Neonates — Newborns and infants are more vulnerable to developing metabolic acidosis than are older children and adults as they have a lower kidney capacity for net acid excretion [34].

Infants with perinatal asphyxia are at risk for metabolic acidosis due to increased blood lactic acid concentrations, which can be detected in umbilical cord samples [35,36]. (See "Perinatal asphyxia in term and late preterm infants", section on 'Basic laboratory tests'.)

The clinical determination of a (serum) chloride:sodium ratio (<0.75) has been reported to be useful in identifying these infants as they have a normal chloride or hypochloremic metabolic acidosis due to an anion gap (AG) metabolic acidosis [37]. (See 'Dilutional metabolic acidosis' above.)

LABORATORY TESTS

Detection: Electrolyte panel and blood gas measurements — Metabolic acidosis is typically detected by a low serum total carbon dioxide (CO₂) in an electrolyte panel and, less commonly, by a low bicarbonate (HCO₃) concentration in a blood gas sample. The total serum CO₂, which is routinely reported in serum electrolyte panels, includes measurements of serum HCO₃ (95 percent of total CO₂), dissolved CO₂, and carbonic acid. In contrast, arterial and venous blood gas measurements separately report total HCO₃ values and the partial pressure of CO₂ (PCO₂). In some clinical settings, the diagnosis may be apparent without a blood gas measurement of pH (eg, diabetic ketoacidosis). As a rule of thumb, serum total CO₂ concentrations lower than 14 mmol/L are due to metabolic acidosis, not as compensation for a respiratory alkalosis. (See 'Confirmation of primary metabolic acidosis' below.)

Normative total carbon dioxide and bicarbonate levels by age — Serum total CO₂ and HCO₃ concentrations vary with age [38].

●18 to 40 years of age – 23 to 30 mmol/L [39]

●>2 to 18 years – 22 to 26 mmol/L [40,41]

●Infants to 2 years – 16 to 24 mmol/L

Newborn infants normally have lower serum HCO₃ concentrations compared with older infants and children. The lower normal values are due to their lower renal plasma HCO₃ threshold with increased urinary losses and their lower capacity to excrete an acid load, resulting in a greater risk to develop metabolic acidosis and a reduced regeneration and reabsorption of HCO₃ in the proximal renal tubule. Both HCO₃ reabsorption and kidney acid excretion improve rapidly during the first few days to weeks of life, resulting in higher levels of HCO₃ [34,42]. (See "Neonatal acute kidney injury: Evaluation, management, and prognosis", section on 'Metabolic acidosis'.)

Effect of acidemia on potassium and ionized calcium and magnesium levels — Metabolic acidosis can affect the following:

●Serum/plasma potassium (K⁺) – Serum/plasma K⁺ increases with increasing acidemia (decreasing pH). For every decrease in the blood pH by 0.1, the serum potassium increases by 0.6 mEq/L.

There is a diffusion-based equilibration of hydrogen ions (H⁺) between extracellular and intracellular spaces so that when serum H⁺ concentrations are high, there is a net influx of H⁺ into the cells. Serum/plasma K⁺ concentrations rise due to the exchange of intracellular K⁺ for extracellular H⁺. Sodium is incapable of moving intracellularly in response to the H⁺ diffusion due to the presence of the sodium-potassium ATPase (Na⁺/K⁺-ATPase) [43]. (See "Causes, clinical manifestations, diagnosis, and evaluation of hyperkalemia in children", section on 'Metabolic acidosis'.)

●Ionized calcium and magnesium – Ionized calcium and magnesium increase with increasing acidemia [44]. When H⁺ competes with calcium and magnesium for binding sites on albumin and other serum proteins, calcium and magnesium are displaced from their protein binding sites, resulting in an increase in ionized (free) calcium and magnesium ions in the serum/plasma. Ionized magnesium changes 0.12 mmol/L per pH unit, and ionized calcium changes 0.36 mmol/L per pH unit [44]. Conversely, correction of the acidosis (eg, HCO₃ therapy) may lead to clinically significant decreases in ionized calcium and magnesium levels. (See "Relation between total and ionized serum calcium concentrations", section on 'Acid-base disorders'.)

DIAGNOSTIC EVALUATION — A diagnostic evaluation that includes serum or plasma electrolytes, calculation of the anion gap (AG), and elements from the history and physical examination are usually sufficient to determine the cause of the metabolic acidosis and guide therapy (algorithm 1). In some cases, a blood gas measurement is needed to confirm primary metabolic acidosis from compensated respiratory alkalosis.

Confirmation of primary metabolic acidosis — If metabolic acidosis is tentatively identified by a low total carbon dioxide (CO₂) on an electrolyte panel measurement, an arterial or venous blood gas sample may be needed to differentiate metabolic acidosis from compensated respiratory alkalosis as a low bicarbonate (HCO₃) level may be observed in both conditions. If the patient has a simple metabolic acidosis, then the patient will be acidemic with a pH <7.35. If the patient has a primary respiratory alkalosis with compensated metabolic acidosis, the patient is alkalemic with a pH >7.42. (See 'Detection: Electrolyte panel and blood gas measurements' above and "Simple and mixed acid-base disorders".)

In the following two examples, the HCO₃ level is 18 mmol/L and the pH from a blood gas example differentiates between the two processes.

●Primary metabolic acidosis with an incomplete compensatory respiratory alkalosis – pH 7.34, partial pressure of CO₂ (PCO₂) 35 mmHg, HCO₃ 18 mmol/L

●Primary acute respiratory alkalosis with an incomplete compensatory metabolic acidosis – pH 7.46, PCO₂ 29 mmHg, HCO₃ 18 mmol/L

Blood gas PCO₂ values can assist in determining the primary acid-base derangement:

●If the primary acid-base perturbation is metabolic acidosis, then the PCO₂ should drop by 1.2 mmHg for every 1 mmol/L drop in serum total CO₂ concentration.

●If the primary acid-base perturbation is respiratory alkalosis, then the serum total CO₂ concentration should decrease by 5 mmol/L for every 10 mmHg decrease in PCO₂.

Anion gap — Once a metabolic acidosis diagnosis has been confirmed, serum electrolyte values are used to determine the serum AG (algorithm 1). The serum AG is defined as the difference between measured cations and measured anions. (See "Approach to the adult with metabolic acidosis", section on 'Assessment of the serum anion gap'.)

Several equations may be used:

●Because sodium (Na) is the primary measured cation and chloride (Cl) and HCO₃ are the primary measured anions, most institutions, including our center, use the following formula to determine the AG (calculator 1):

The normal value of the serum AG depends on the specific chemical analyzers used to measure each analyte and, therefore, will vary from laboratory to laboratory and over time. In general, the normal AG range using this formula is approximately 4 to 12 mEq/L. However, it is best for each laboratory to determine its own local normative range.

●Other centers, particularly outside of the United States, include the potassium (K) as a measured cation and use the following formula:

The normal range for this formula is 4 mEq/L higher than in the preceding formula because the normal value of K used in this formula is 4 mEq/L.

Interpretation of the serum AG is most helpful when an individual's usual, or baseline, AG is known and serial measurements are available from the same laboratory. As an example, if a patient's baseline AG is 4 mEq/L and a subsequent measurement is 12 mEq/L, then the 8 mEq/L increase in AG is probably clinically significant despite the fact that the AG is still within the "normal" range.

For children with hypoalbuminemia, use of the above equations can underestimate the AG. To adjust for hypoalbuminemia, the following equation is used:

High anion gap — For patients with a high AG, the etiology of their metabolic acidosis is caused by an increased acid concentration due to the presence of unmeasured anions. (See 'Increased acid concentration: High anion gap metabolic acidosis' above.)

Results from the initial basic metabolic tests, history, and physical examination are typically helpful in determining the underlying cause and, in some circumstances, guide further diagnostic evaluation:

●Diabetes – Elevated blood glucose and a history of polyuria with or without weight loss, abdominal pain, and vomiting suggests diabetic ketoacidosis. Patients with diabetic ketoacidosis will also have elevated urine ketones. (See "Diabetic ketoacidosis in children: Clinical features and diagnosis", section on 'Diagnosis'.)

●Kidney disease – Elevated blood urea nitrogen and serum creatinine are observed in children with uremia and impaired kidney acid excretion. (See "Acute kidney injury in children: Clinical features, etiology, evaluation, and diagnosis", section on 'Other laboratory findings' and "Chronic kidney disease in children: Complications", section on 'Metabolic acidosis'.)

●Ingestion – History of accidental or intentional ingestion (table 5). If the type of ingestion is unknown, determination of the serum osmolal gap might help distinguish between different types of ingestions. First, measure the serum osmolality and electrolytes. Next, determine the calculated serum osmolality, using a calculator (calculator 2 and calculator 3) or the following formula (using conventional units):

Then, calculate the osmolal gap, which is the difference between measured and calculated serum osmolalities.

In the presence of a high AG metabolic acidosis, a high osmolal gap (eg, >10 to 15 mOsm/L) suggests ethylene glycol, ethanol, or methanol ingestion (table 7) (see "Methanol and ethylene glycol poisoning: Pharmacology, clinical manifestations, and diagnosis"). By contrast, a normal osmolal gap (<10 mOsm/L) suggests elevated levels of iron, cyanide, carboxyhemoglobin, salicylates, cocaine, or amphetamine. These toxicities can be confirmed by laboratory testing and, in some cases, rapid drug screening. (See "Acute iron poisoning" and "Approach to the child with occult toxic exposure", section on 'Diagnosis of poisoning' and "Salicylate (aspirin) poisoning: Clinical manifestations and evaluation", section on 'Serum salicylate concentration'.)

●Evidence of poor tissue perfusion (shock) ‒ Blood lactic acid is elevated in patients with poor tissue perfusion (eg, sepsis, cardiac failure, severe hypoxia) and severe crush injuries. (See "Septic shock in children in resource-abundant settings: Rapid recognition and initial resuscitation (first hour)" and "Rhabdomyolysis: Clinical manifestations and diagnosis", section on 'Clinical manifestations'.)

●Inborn error of metabolism – Neurologic signs and symptoms including a history of severe hypotonia, seizures, developmental delay, or apnea in a newborn infant suggests the possibility of an inborn error of metabolism. Elevated lactic acid is observed in patients with mitochondrial disorders and organic acidurias. A serum ammonia level and a lactic acid:pyruvic acid ratio may be helpful in the determining the specific metabolic disorder. (See "Inborn errors of metabolism: Identifying the specific disorder".)

Normal anion gap — Patients with metabolic acidosis and normal AG generally have an underlying disorder that results from a loss of HCO₃. Most pediatric cases of metabolic acidosis with a normal AG are due to losses of HCO₃ from the gastrointestinal tract and are typically diagnosed based on a history of diarrhea or abnormal drainage from the small bowel or pancreas.

Determination of the urine AG may be useful if the etiology of the normal AG remains unclear. The urine AG is calculated from the following formula:

In the presence of metabolic acidosis, a positive urine AG value indicates impaired ammonium excretion, such as is seen in distal (type 1) and hypoaldosteronism (type 4) renal tubular acidosis (RTA). Conversely, a negative urine AG is consistent with intact urinary ammonium excretion as seen in children with metabolic acidosis due to proximal (type 2) RTA (with a very low serum total CO₂ concentration) and gastrointestinal losses [45]. (See "Urine anion and osmolal gaps in metabolic acidosis".)

Mixed anion gap — The delta gap ratio may be helpful to confirm mixed metabolic acidosis when both high and normal AG causes coexist. However, the use of this tool assumes that the baseline serum AG and HCO₃ concentration are known or can be accurately estimated and that all buffering is provided by HCO₃ and is extracellular. (See "The delta anion gap/delta HCO3 ratio in patients with a high anion gap metabolic acidosis".)

The calculated delta gap ratio may be used to distinguish the various forms of metabolic acidosis:

●<0.4 – Normal AG metabolic acidosis

●0.4 to 0.99 – Mixed high AG and normal AG metabolic acidosis

●1.0 to 1.6 – High AG metabolic acidosis

●>1.6 – Mixed high AG metabolic acidosis with metabolic alkalosis

In a study of adult trauma patients with measured lactic acid and HCO₃ values prior to intravenous (IV) hydration, the delta gap ratio was 1.86 [46]. The higher-than-expected delta gap of 1.0 was attributed to unmeasured anions.

TREATMENT — Whenever possible, the primary focus of therapy for metabolic acidosis should be directed at reversing the underlying pathophysiologic process. Directed treatment of the acidosis is based on whether the metabolic acidosis is acute or chronic and the severity of acidosis.

Acute metabolic acidosis — Acute metabolic acidosis is generally well tolerated, but extreme acidemia can be life-threatening. The best management strategy is to treat the underlying disorder, such as septic shock or diabetic ketoacidosis.

Intravenous bicarbonate therapy

Patient selection — The use of intravenous (IV) sodium bicarbonate (HCO₃) therapy or other buffering agents in critically ill patients with severe acidemia remains controversial. In most cases, sodium HCO₃ therapy may temporarily improve or may even correct the acidemia but does not alter the underlying metabolic acidosis cause. If the underlying cause is not treated, the metabolic acidosis persists and results in subsequent reaccumulation of hydrogen ions (H⁺).

Our approach depends on the cause of the acidosis:

●Acute kidney injury or chronic kidney failure – There may be a role for IV sodium HCO₃ therapy in selected patients with acute kidney injury and chronic kidney failure. In our practice, we reserve the use of IV sodium HCO₃ for patients with impaired kidney acid excretion (with renal tubular acidosis [RTA; if oral administration of HCO₃ is not possible], acute kidney injury, or chronic kidney disease [CKD]) when their blood pH <7.2 or when urine alkalization is needed. This is based on indirect evidence from a randomized trial of critically ill adults who had a pH of 7.2 or less, in which sodium HCO₃ decreased the risk of death for patients with kidney injury but not for the entire cohort [47]. (See "Prevention and treatment of heme pigment-induced acute kidney injury (including rhabdomyolysis)", section on 'Bicarbonate in selected patients'.)

●Resuscitation – By contrast, IV sodium HCO₃ is generally not recommended for pediatric resuscitation, except for a few specific conditions, as discussed separately. (See "Primary drugs in pediatric resuscitation", section on 'Sodium bicarbonate'.)

Adverse effects of IV HCO₃ therapy can include (see "Primary drugs in pediatric resuscitation", section on 'Sodium bicarbonate' and "Approach to the adult with metabolic acidosis", section on 'Acute metabolic acidosis'):

●Hypertonicity and hypernatremia – This is caused by the high sodium load in the sodium HCO₃. The 8.4 percent sodium HCO₃ solution has sodium concentration of 1 mEq/mL (or 1000 mEq/L). In the rare cases where large quantities of IV sodium HCO₃ are used, sodium HCO₃ should be mixed in D5 IV fluid to a concentration of 150 mEq/L to avoid hypernatremia.

●Hypokalemia – This is caused by rapid correction of a metabolic acidosis. An increase of 0.1 unit rise in pH can cause a decrease of serum/plasma potassium of 0.4 mEq/L as potassium moves intracellularly to maintain electroneutrality. (See "Hypokalemia in children", section on 'Increased intracellular uptake' and "Potassium balance in acid-base disorders".)

●Hypocalcemia – Ionized calcium can decrease rapidly in response to sodium HCO₃ administration because the binding of calcium to albumin is pH dependent. For example, if a child's blood pH increases from 7.05 to 7.3 with HCO₃ administration or dialysis, the ionized calcium would be expected to fall from 1.0 mmol/L to 0.87 mmol/L.

●In patients with diabetic ketoacidosis, HCO₃ administration is not recommended, because it has been associated with cerebral injury (cerebral edema) and hypokalemia and also may delay resolution of ketosis. (See "Diabetic ketoacidosis in children: Treatment and complications", section on 'Metabolic acidosis'.)

●Rapid infusion of sodium HCO₃ may be associated with adverse cardiovascular effects, based on studies in animal models.

Preadministration considerations — If the decision is made to administer IV sodium HCO₃, the clinician needs to consider the following prior to administration:

●Steps to avoid hypocalcemia – Ionized calcium values decrease when sodium HCO₃ is infused or when a patient is receiving hemodialysis with a dialysate with a high HCO₃ concentration. Ionized calcium levels can be quickly obtained with a blood gas measurement. Pretreatment with IV calcium is advised if:

•The corrected total calcium is <8.0 mg/dL (2 mmol/L)

•The ionized calcium is <1.0 mmol/L

The pretreatment consists of IV calcium gluconate (preferred) 100 mg/kg or IV calcium chloride 10 mg/kg. This is slowly infused via a central catheter or a large vein prior to infusing sodium HCO₃. Failure to correct the calcium prior to the sodium HCO₃ infusion can lead to acute hypocalcemia due to enhanced binding of ionized calcium to serum proteins including albumin as the blood pH increases. An acute decrease in the ionized calcium concentration below 0.75 mmol/L (3 mg/dL) or a corrected calcium <7 to 7.5 mg/dL can cause cardiac dysrhythmias, seizures, and/or even tetany.

●Compatibility with other IV mediations – Due to its higher pH, sodium HCO₃ can cause compatibility problems with medications that are concurrently infused. For example, precipitation of calcium carbonate can occur when IV administration of calcium chloride/calcium gluconate is mixed with sodium HCO₃. If there is a medication compatibility issue due to IV fluid pH, use of sodium acetate instead of sodium HCO₃ is a good option.

Administration and dosing

●Emergency setting – In an emergency, either 4.2 or 8.4 percent sodium HCO₃ solution is administered at a dose of 1 mEq/kg up to a maximum dose of 50 mEq, as an IV slow push. Five to 15 minutes after administration, blood gas, ionized calcium, and serum electrolytes are obtained to determine therapy effectiveness and/or if there has been an adverse effect of HCO₃ therapy (ie, low ionized calcium and hypokalemia).

●Nonemergency setting repletion – In a nonemergent setting, the dosing of sodium HCO₃ is determined by the calculated estimated HCO₃ deficit using the following formula:

One-half of the estimated HCO₃ deficit is infused IV over two to four hours. The remaining one-half of the HCO₃ deficit is infused over the following 6 to 24 hours. A longer course of infusion should be prescribed when the sodium HCO₃ deficit is large (>3 mEq/kg).

During and after repletion of the HCO₃ deficit, blood gas, ionized calcium, and serum electrolytes are obtained to determine whether additional HCO₃ therapy is required and to detect any adverse effect of HCO₃ therapy (low ionized calcium and hypokalemia).

●Ongoing replacement therapy directed at HCO₃ loss or H⁺ accumulation – To achieve a goal of normalizing serum HCO₃, the total dose of sodium HCO₃ delivered over the course of a day should include not only the amount for repletion but also the maintenance dose of sodium HCO₃ needed to replace ongoing HCO₃ loss or buffer new H⁺ accumulation. For example, patients with acute metabolic acidosis due to advanced CKD or distal RTA may require an additional 1 to 2 mEq/kg/day of sodium HCO₃ to maintain normal serum total carbon dioxide (CO₂) concentrations.

When the patient can tolerate oral medications, maintenance administration should be changed to an oral alkali (table 8).

Kidney replacement therapy — Dialysis and/or continuous kidney replacement therapy may be needed for treatment of severe, life-threatening metabolic acidosis unresponsive to medical therapy, especially if it is associated with other electrolyte abnormalities including hyperkalemia. (See "Pediatric acute kidney injury: Indications, timing, and choice of modality for kidney replacement therapy".)

Chronic metabolic acidosis — Children with chronic acidosis typically require consistent administration of exogenous oral alkali preparations to correct the acidosis, thereby preventing the clinical manifestations of chronic acidosis. We begin alkali therapy in children with a primary renal non-anion gap (AG) metabolic acidosis (CKD and RTA) and a persistent serum total CO₂ <21 mmol/L.

Alkali therapy includes a number of formulations of sodium HCO₃, sodium citrate/citric acid, potassium citrate/citric acid, and combination of sodium citric acid and potassium citrate and citric acid (table 8). The choice of therapy is dependent on the underlying cause of chronic metabolic acidosis, availability and cost of the specific medication, and experience of the prescribing clinician.

In our practice, the choice of alkali therapy and dosing are based on the underlying etiology:

●Distal or proximal RTA without hypokalemia – RTA can be effectively treated with sodium citrate-citric acid therapy. Sodium HCO₃ can also be used but is less preferred because of the risk of nephrocalcinosis. The amount of HCO₃ equivalent needed in children with distal RTA is normally 1 to 2 mEq/kg/day. Children with proximal RTA need a much higher oral alkali dose (5 to 10 mEq/kg/day) due to the increased urinary HCO₃ loss, which increases with therapy. Oral alkali treatment doses are typically divided three or four times daily in infants and two to three times daily in older children. (See "Treatment of distal (type 1) and proximal (type 2) renal tubular acidosis".)

●RTA with hypokalemia – This condition requires potassium supplementation. For most children, we use an oral liquid formulation of sodium citrate-potassium citrate-citric acid, which delivers 1 mEq K, 1 mEq Na, and citrate equivalent to 2 mEq HCO₃ per mL. The initial dose varies depending on the type of RTA: For distal RTA, we use 2 mEq/kg HCO₃ equivalent, and, for proximal RDA, we use 4 mEq/kg HCO₃ equivalent [48]. Children with more severe hypokalemia may require potassium citrate-citric acid therapy, which delivers 2 mEq K and citrate equivalent to 2 mEq HCO₃ per mL. Some clinicians use a combination of sodium citrate-citric acid and potassium citrate-citric acid therapy to allow the separate adjustment of alkali and potassium dosing in children who cannot be successfully treated with a single formulation of oral alkali. (See "Treatment of distal (type 1) and proximal (type 2) renal tubular acidosis".)

●Nephrolithiasis – Children who have nephrolithiasis due to hypocitraturia are best treated with either oral liquid citric acid potassium citrate or potassium citrate tablet therapy, with an initial starting dose of approximately 1 mEq/kg/day. Urine pH and serum potassium and total CO₂ concentrations should be monitored to ensure that urine pH does not rise to the point where calcium- and phosphate-based calculi formation increases and the patient develops a metabolic alkalosis or hyperkalemia.

To maintain relatively stable acid-base control, oral potassium-based alkali treatment doses are typically divided three or four times daily in infants and two to three times daily in older children.

●Chronic kidney failure – For children with metabolic acidosis in association with chronic kidney failure, the goal of therapy is to maintain a total CO₂ at or above 22 mEq/L. We initially begin sodium HCO₃ therapy at 1 mEq/kg per day divided into two to three doses, and the dose is increased until the clinical target is reached. Citrate preparations should be used with caution in children with CKD because they may promote aluminum absorption. Potassium-based alkali therapy should be generally avoided due to the risk of developing hyperkalemia. (See "Chronic kidney disease in children: Complications", section on 'Metabolic acidosis'.)

When alkali therapy is initiated, the smallest dose should be used and increased in a stepwise fashion until the targeted total CO₂ level is reached. Ongoing testing includes monitoring acid-base status (blood gas sample), serum sodium, calcium, potassium, and urine calcium/urine creatinine ratios. The additional sodium load with sodium-based oral alkali can increase urinary calcium excretion, which may worsen the nephrocalcinosis frequently seen in children with distal RTA.

For children with chronic metabolic acidosis, consistent administration of exogenous oral alkali preparations to correct acidosis can help prevent the clinical manifestations of chronic acidosis, including poor growth, bone abnormalities, and nephrolithiasis. The effect of metabolic acidosis on height was shown in an observational study in children with CKD in which metabolic acidosis was associated with lower height Z-score and persistent alkali therapy use was associated with better height Z-scores [49]. In children with glomerular disease, low HCO₃ concentrations have been linked to a higher risk of CKD progression and resolution of low HCO₃ was associated with a lower risk of CKD progression [50].

The Mediterranean diet may help to prevent and correct metabolic acidosis in the early stages of CKD, while the low-protein diet and the vegan low-protein diet are more effective in the advanced stages of CKD [51].

For infants and young children, sodium HCO₃ and sodium citrate-citric acid are normally provided as oral liquids. However, administration can be challenging due to poor palatability and burping is a common side effect due to the rapid conversion of HCO₃ into water and CO₂ in the acidic environment of the stomach. If these problems occur, oral alkali can be mixed into formula or food to improve palatability and reduce burping. When alkali is mixed into formula, it is essential to ensure that the entire volume of formula has been consumed, otherwise the infant will not receive the full alkali dose.

Finally, it is important to recognize that administering oral alkali three or more times per day to a child can be extremely challenging. Before making an oral alkali dose adjustment based on a laboratory result, it is important to ask the family or caregivers, in a noncritical manner, whether they have been able to adhere to the prescribed dosing. If the serum total CO₂ is low and reported dosing by the family falls short of the prescribed amount, encourage the family to give the appropriate dose and repeat the laboratory testing rather than increase the oral alkali dose.

SUMMARY AND RECOMMENDATIONS

●Causes – Metabolic acidosis is a biochemical abnormality resulting in an increase in hydrogen ions (H⁺) in the serum or plasma. It can be either an acute or chronic process and is secondary to a wide range of underlying disorders.

The etiology of metabolic acidosis in children can be classified based on pathogenesis (table 1):

•Accumulation of H⁺ – Increased acid concentration (H⁺) can be caused by overproduction of endogenous acids, excessive intake of exogenous acids, or accumulation of acids due to the kidney's inability to excrete acid in sufficient quantities. This causes metabolic acidosis with a high anion gap (AG). (See 'Increased acid concentration: High anion gap metabolic acidosis' above.)

•Loss of bicarbonate (HCO₃) – Loss of HCO₃ from the gastrointestinal tract or kidneys causes metabolic acidosis with a normal AG. (See 'Loss of bicarbonate: Normal anion gap metabolic acidosis' above.)

•Mixed mechanisms – A mixed metabolic acidosis occurs when children have coexisting conditions with high and normal AG. (See 'Mixed high anion and normal gap acidosis' above.)

•Dilutional – Dilutional metabolic acidosis is caused by a fall in serum HCO₃ concentration due to expansion of the intravascular fluid volume, with large volumes of intravenous (IV) fluids that do not contain HCO₃. (See 'Dilutional metabolic acidosis' above.)

●Clinical manifestations – There are no typical distinguishing clinical features of pediatric metabolic acidosis. Infants and children with acute metabolic acidosis can present with symptoms related to the underlying condition and may present with tachypnea and/or hyperpnea as signs of compensatory respiratory alkalosis. Children with chronic metabolic acidosis may have nonspecific findings including poor growth, bony abnormalities, and nephrolithiasis. Neonates are more vulnerable to developing metabolic acidosis due to their lower kidney capacity for net acid excretion. (See 'Clinical manifestations' above.)

●Laboratory findings

•Metabolic acidosis is typically detected by a low serum total carbon dioxide (CO₂) in the electrolyte panel and, less commonly, by a low HCO₃ level in a blood gas sample.

Measurement of the serum total CO₂ in the electrolyte panel may not be sufficient, because a low concentration can be seen in metabolic acidosis or as a compensatory response to a primary respiratory alkalosis (increased respiratory effort with lowering partial pressure of CO₂ [PCO₂]). To distinguish between the two, a blood gas may be needed to determine the pH. If the patient has a simple metabolic acidosis, then the patient will have a low (acidic) pH and, if the patient has respiratory alkalosis with compensated metabolic acidosis, the pH should be elevated (alkalotic). (See 'Detection: Electrolyte panel and blood gas measurements' above.)

•Normative HCO₃ levels vary and increase from birth through late adolescence. (See 'Normative total carbon dioxide and bicarbonate levels by age' above.)

•Metabolic acidosis increases serum/plasma potassium and ionized (free) calcium and magnesium.

●Diagnostic evaluation – After confirmation of metabolic acidosis, a diagnostic evaluation that includes serum or plasma electrolytes, calculation of the AG, and elements from the history and physical examination is usually sufficient to determine the cause of the metabolic acidosis and guide therapy (algorithm 1). (See 'Diagnostic evaluation' above.)

●Treatment – Whenever possible, the primary focus of therapy for metabolic acidosis should be directed at reversing the underlying pathophysiologic process. Directed treatment of the acidosis is based on whether the metabolic acidosis is acute or chronic and the severity of acidosis.

•IV HCO₃ – We generally avoid routine administration of IV sodium HCO₃ to hospitalized children with metabolic acidosis and also avoid it during pediatric cardiopulmonary resuscitation. For children with acute or chronic kidney disease (CKD), IV HCO₃ therapy can be considered in cases of severe acidosis (pH <7.2), recognizing that this is only a temporary intervention. (See 'Intravenous bicarbonate therapy' above.)

•Kidney replacement therapy – Dialysis and/or continuous kidney replacement therapy may be needed for life-threatening conditions associated with metabolic acidosis, especially if it is associated with other electrolyte abnormalities such as hyperkalemia. (See 'Kidney replacement therapy' above and "Pediatric acute kidney injury: Indications, timing, and choice of modality for kidney replacement therapy".)

•Oral alkali – Children with chronic metabolic acidosis typically require consistent administration of exogenous oral alkali preparations to correct acidosis, thereby preventing the clinical manifestations of chronic acidosis (eg, poor growth, bone abnormalities, and nephrolithiasis). (See 'Chronic metabolic acidosis' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Kanwal Kher, MD, MBA, Matthew Sharron, MD, Mahesh Sharman, MD, FAAP, and Ashok Sarnaik, MD, FAAP, FCCM, who contributed to earlier versions of this topic review.