INTRODUCTION — Metabolic acidosis is a biochemical abnormality defined by an increase in blood hydrogen ion 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 (<22 mmol/L). 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 (PaCO2) 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 bicarbonate (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 renal acid excretion.
●Loss of bicarbonate via the intestine or kidneys.
●Dilution of serum bicarbonate concentrations by nonbicarbonate/acetate/lactate-containing solutions with a resultant rise in blood H+ concentrations.
Increased acid concentration: High anion gap metabolic acidosis — A high anion gap metabolic acidosis is due to the 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 to maintain normal serum bicarbonate concentrations.
A frequently used mnemonic to identify the more common causes of anion gap 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 is 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 renal acid excretion 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].
●Paraldehyde administration is reported to increase serum concentrations of lactic acid [5]. The inclusion of paraldehyde is more historical as it is no longer available in the United States.
●Inborn errors of metabolism [IEM] 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 anion gap 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 [6]. "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 [7-9].
●Lactic acidosis occurs when lactate is overproduced or underutilized. In children, causes of lactic acidosis include:
•Conditions associated with shock resulting 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 [10] (See "Causes of lactic acidosis", section on 'Type A lactic acidosis'.)
•Underlying mitochondrial dysfunction, either congenital (table 6) or acquired due to fasting [11]. (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".)
●Ethylene glycol poisoning causes increased levels of lactic acid and ketoacids [12]. 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 [13]. (See "Salicylate poisoning in children and adolescents".)
●Ketosis due to either starvation or ketogenic diet is another cause of anion gap metabolic. Ketosis results in increased serum levels of acetoacetate (acetoacetic acid) and beta-hydroxybutyrate and ketones in the urine [14-16].
Loss of bicarbonate: Normal anion gap metabolic acidosis — Normal anion (also referred to as nonanion) gap metabolic acidosis occurs with a loss of serum bicarbonate, 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 anion gap metabolic acidosis:
●Gastrointestinal losses of bicarbonate due to diarrhea, small bowel, or pancreatic drainage cause a significant reduction in serum bicarbonate concentrations.
●Kidney losses of bicarbonate 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 at the renal tubule brush border resulting in bicarbonate 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 anion gap causes coexist. (See 'Mixed anion gap' below.)
●In certain situations, children with chronic kidney disease can have both accumulated acids (high anion gap acidosis due to uremia) and RTA (normal gap acidosis with the inability to excrete adequate H+ and/or the loss of bicarbonate) occur at the same time.
●Children recovering from ketoacidosis may still have elevated serum ketoacids that are converted back to bicarbonate. However, if ketoacid anions are lost in urine before they can be metabolized (as sodium or potassium salts), they represent lost potential bicarbonate. The effect of these urinary losses is that most patients with diabetic ketoacidosis with initial high anion gap acidosis develop a normal anion gap metabolic acidosis during their recovery phase.
●Children with severe diarrhea have a normal anion gap due to loss of HCO3, and if severe hypovolemia develops, high anion gap 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 "Initial management of shock in children", section on 'Volume and rate'.)
Dilutional metabolic acidosis — Dilutional acidosis refers to a fall in serum bicarbonate concentration that is due to expansion of the intravascular fluid volume with large volumes of intravenous fluids containing neither bicarbonate nor the sodium salts of organic anions that can be metabolized to bicarbonate (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 (BUN), low serum osmolality, and a high beta-type natriuretic peptide (BNP).
The underlying mechanism of dilutional acidosis remains unknown, as the dilution of both serum bicarbonate and H+ ion with normal saline is proportional. Proposed mechanisms include [21,22]:
●Carbon dioxide (CO2) from the lungs equilibrates with lower CO2 in the diluted blood and becomes hydrated to carbonic acid.
●Normal cellular metabolism contributes the H+ ions.
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 the only response to metabolic acidosis maybe tachypnea. An inability to generate an appropriate hyperventilatory response may be indicative of significant underlying neurologic and/or respiratory disorder.
●Laboratory findings
•Partial pressure of carbon dioxide – The respiratory alkalotic compensation results in a decreased in the partial pressure of carbon dioxide (PCO2) concentrations, which raises the blood pH towards normal, although usually never complete, and never overcompensated. The respiratory compensation for metabolic acidosis generates a reproducible and relatively linear relationship between the arterial PCO2 and bicarbonate concentration with a decreased of PCO2 of 1.2 mmHg for every 1 mmol/L decrease in serum bicarbonate. 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'.)
●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 DKA generally present with lethargy, altered mental status, seizures, ataxia, hypotonia, muscle weakness, and developmental delay, as well as vision and hearing impairments [24].
●Unknown cardiac effects – The impact of acute acidemia on cardiac function remains unclear. Data from animal and tissue studies have shown myocardial depression and arrhythmias when the pH falls below 7.1 [25,26]. However, clinical studies in humans have not reported the same effect on cardiac function, as observed transient decreases in pH to 6.8 in individuals with diabetic ketoacidosis were not associated with depressed cardiac function [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), 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 renal tubular acidosis; however, adequate treatment can prevent poor growth and in some young children can result in catch-up growth [29]. (See "Etiology and clinical manifestations of renal tubular acidosis in infants and children" and "Growth failure in children with chronic kidney disease (CKD): Risk factors, evaluation, and diagnosis", section on 'Metabolic acidosis'.)
●Rickets ‒ Rickets is observed in children with chronic acidosis due to bone biochemistry abnormalities. Bone buffering of some of the excess hydrogen ions is associated with the release of calcium and phosphate from bone resulting in a decrease in bone mineral content. Treatment of chronic metabolic acidosis improves bone mineral density and rickets, as well as linear growth in these children [29,30]. (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. In these patients, there is mobilization of calcium out of the bone resulting in an increased renal load of calcium [31]. In addition, hypocitraturia occurs in response to metabolic acidosis with enhanced proximal tubular citrate reabsorption, which limits the ability to reabsorb tubular calcium leading to stone formation [32]. Distal (type 1) renal tubular acidosis is also associated with an increased risk of nephrolithiasis and nephrocalcinosis. (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 older children and adults as they have a lower renal capacity for net acid excretion [33].
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 [34,35]. (See "Perinatal asphyxia in term and late preterm infants", section on 'Basic laboratory tests'.)
Neonates who require parenteral fluids are at-risk for dilutional metabolic acidosis due to the infusion of normal saline. The use of (serum) chloride-sodium ratio (<0.75) has been reported to be useful in identifying these infants as they have hypochloremic metabolic acidosis [36]. (See 'Dilutional metabolic acidosis' above.)
LABORATORY TESTS
Detection: Electrolyte panel and blood gas measurements — Metabolic acidosis is typically detected by a low serum total CO2 in an electrolyte panel and less commonly by a low bicarbonate level within a blood gas sample. The total serum CO2, which is routinely reported in serum electrolyte panels, includes measurements of serum bicarbonate (95 percent of total CO2), dissolved CO2, and carbonic acid. In contrast, arterial and venous blood gas measurements separately report total bicarbonate values and the partial pressure of carbon dioxide (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 CO2 and bicarbonate levels by age — Serum total CO2 and bicarbonate concentrations vary with age [37].
●18 to 40 years of age – 23 to 30 mmol/L [38]
●>2 to 18 years – 22 to 26 mmol/L [39,40]
●Infants to 2 years – 16 to 24 mmol/L
Newborn infants normally have lower serum bicarbonate concentrations compared with older infants and children. The lower normal values are due to a lower capacity to excrete an acid load during the neonatal period, resulting in a greater risk to develop metabolic acidosis, and a reduced regeneration and reabsorption of bicarbonate in the proximal renal tubule. Both bicarbonate reabsorption and renal acid excretion improve rapidly during the first few days to weeks of life, resulting in higher levels of bicarbonate [33,41]. (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 – Serum/plasma potassium (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 H+ ions 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+ ions. Sodium is incapable of moving intracellularly in response to the H+ diffusion due to the presence of the sodium-potassium ATPase (Na+/K+-ATPase). (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 [42]. When H+ ions compete 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 [42]. Of note, when acidosis is corrected (eg, bicarbonate therapy), ionized calcium and magnesium levels will fall and may have clinical application. (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, 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 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 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, and if the patient has 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 bicarbonate level is 18 mmol/L and the pH from a blood gas example differentiates between the two processes.
●Primary metabolic acidosis (with incomplete compensatory respiratory alkalosis) will have a pH: 7.34, PCO2: 35 mmHg, HCO3: 18 mmol/L.
●Primary acute respiratory alkalosis with 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 the diagnosis of a metabolic acidosis has been confirmed, serum electrolyte values are used to determinate the serum anion gap (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'.)
Since sodium (Na) is the primary measured cation and chloride (Cl) and bicarbonate (HCO3) are the primary measured anions, most institutions, including our center, use the following formula to determine the anion gap (calculator 1).
Serum AG = Na – (Cl + HCO3)
The normal value of the serum anion gap is dependent 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 range is approximately 4 to 12 mEq/L. However, it is best for each laboratory to determine its own local normal range.
Other centers, particularly outside the United States, will also use the potassium (K) as a measured cation and the following formula.
Serum AG = (Na + K) – (Cl + HCO3)
The normal range for this formula will be 4 mEq/L higher than above as the normal value of K used in this formula is 4 mEq/L.
Interpretation of the serum anion gap is most helpful when an individual's usual, or baseline, anion gap is known and serial measurements are available from the same laboratory. As an example, if a patient's baseline anion gap is 4 mEq/L and is found to be 12 mEq/L, then this 8 mEq/L increase in the anion gap is probably clinically significant despite the fact that the anion gap is still within the "normal" range. Unfortunately, baseline data are often unavailable.
The anion gap can be underestimated in children with hypoalbuminemia. To adjust for hypoalbuminemia the following equation is used:
Corrected anion gap = Anion gap + (0.25 x (4 – albumin in g/dL))
High anion gap — For patients with a high anion gap, 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 and the history and physical examination are typically helpful in determining the underlying cause and in some circumstances, guide further diagnostic evaluation:
●Elevated blood glucose and a history of polyuria with or without weight loss, abdominal pain, and vomiting is suggestive of diabetic ketoacidosis. Patients with diabetic ketoacidosis will also have elevated urine ketones. (See "Diabetic ketoacidosis in children: Clinical features and diagnosis", section on 'Diagnosis'.)
●Elevated blood urea nitrogen (BUN) and serum creatinine are observed in children with uremia and impaired renal 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'.)
●History of accidental or intentional ingestion (table 5):
•Ethylene glycol, ethanol, or methanol ingestion results in both a serum high anion gap and an osmolal gap (table 7). (See "Methanol and ethylene glycol poisoning: Pharmacology, clinical manifestations, and diagnosis".)
•Elevated levels of iron, cyanide, carboxyhemoglobin, salicylates, cocaine, or amphetamines are associated with high anion gap metabolic acidosis but with a normal osmolal gap. They can be confirmed by laboratory testing and in some cases, rapid drug screening. (See "Acute iron poisoning" and "Salicylate poisoning in children and adolescents" and "Approach to the child with occult toxic exposure", section on 'Diagnosis of poisoning'.)
Serum osmolal gap greater than 10 to 15 mOsm/L is consistent with the presence of ethylene glycol, ethanol, or methanol. The serum osmolal gap is the difference between measured serum osmolalities and is calculated using the following formula based on the normal solutes (urea, sodium, and glucose) (calculator 2 and calculator 3).
Calculated serum osmolality = (2 x Na) + (BUN in mg/dL/2.8) + serum glucose in mg/dL/18.
●Evidence of poor tissue perfusion (shock) ‒ Blood lactic acid is elevated in patients with poor tissue perfusion (eg, sepsis, cardiac failure, and severe hypoxia) and severe crush injuries. (See "Septic shock in children: Rapid recognition and initial resuscitation (first hour)" and "Rhabdomyolysis: Clinical manifestations and diagnosis", section on 'Clinical manifestations'.)
●Neurologic signs and symptoms ‒ A history of severe hypotonia, seizures, developmental delay, or apnea in a newborn infant may be suggestive of an inborn error of metabolism (IEM). Elevated lactic acid is observed in patients with mitochondrial disorders and organic acidurias. A serum ammonia level and a lactic acid and pyruvic acid ratio may be helpful in the differentiation of the IEM. (See "Inborn errors of metabolism: Identifying the specific disorder".)
Normal anion gap — Patients with metabolic acidosis and normal anion gap generally have an underlying disorder that results from a loss of bicarbonate. Most pediatric cases with normal anion gap are due to losses of bicarbonate from the gastrointestinal tract and are typically diagnosed based on a history of diarrhea or abnormal drainage from the small bowel or pancreas.
If the etiology of the normal anion gap remains unclear, a urine anion gap may be useful. In the presence of metabolic acidosis, a positive value for urine anion gap is indicative of impaired ammonium excretion (NH4+), such as is seen in distal (type 1) and hypoaldosteronism (type 4) renal tubular acidosis. Conversely, a negative value is consistent with intact urinary ammonium excretion as seen in children with metabolic acidosis due to proximal (type 2) renal tubular acidosis and gastrointestinal losses [43]. (See "Urine anion and osmolal gaps in metabolic acidosis".)
Urine anion gap = (Urine sodium + urine potassium) – urine chloride
Mixed anion gap — The delta gap ratio may helpful to confirm mixed metabolic acidosis when both high and normal anion gap causes coexist. However, the use of this tool assumes that the baseline serum anion gap (AG) and HCO3 concentration are known or can be accurately estimated and that all buffering is provided by bicarbonate and is extracellular. (See "The delta anion gap/delta HCO3 ratio in patients with a high anion gap metabolic acidosis".)
The Delta gap ratio = Change in anion gap (from a normal of 12 mmol/L)/change in bicarbonate (from normal of 24 mmol/L).
The calculated delta gap ratio may be used to separate the various forms of metabolic acidosis based on the delta gap ratio:
●<0.4 – Normal anion gap metabolic acidosis
●0.4 to 0.99 – Mixed high and normal anion gap metabolic acidosis
●1.0 to 1.6 – High anion metabolic acidosis
●>1.6 – High anion metabolic acidosis mixed with metabolic alkalosis
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 (DKA).
Intravenous bicarbonate therapy — It is controversial whether sodium bicarbonate or other buffering agents should be used. In most cases, sodium bicarbonate therapy temporarily improves or may even correct the acidemia, but will not alter the cause of the metabolic acidosis. If the underlying cause is not treated, the metabolic acidosis remains persistent and results in subsequent re-accumulation of H+. In our practice, administration of intravenous (IV) sodium bicarbonate is not routinely administrated. We reserve the use of IV sodium bicarbonate for cases of extreme acidosis, when the blood pH <7.0 or for patients with impaired renal acid excretion (with renal tubular acidosis, acute kidney injury, or chronic kidney disease) when their blood pH <7.2 or when urine alkalization is needed. However, other centers rarely use bicarbonate in the setting of cardiac arrest due to hyperkalemia or when urine alkalinization is required therapeutically (severe rhabdomyolysis). (See "Prevention and treatment of heme pigment-induced acute kidney injury (including rhabdomyolysis)", section on 'Bicarbonate in selected patients'.).
Outcome data have not shown that bicarbonate therapy during neonatal resuscitation improves survival or near-term neurologic outcomes [44]. Similar results was also observed in adults with no proven benefit in reducing mortality or end-organ failure for those receiving IV sodium bicarbonate compared with placebo. (See "Approach to the adult with metabolic acidosis", section on 'Acute metabolic acidosis'.)
In addition, adverse effects of bicarbonate therapy have been observed. (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 due to excessive administration of sodium bicarbonate. The 8.4 percent sodium bicarbonate solution has sodium concentration of 1 mEq/mL (or 1000 mEq/L). When large quantities of IV sodium bicarbonate are used, sodium bicarbonate should be mixed in D5 IV fluid to a concentration of 150 mEq/L to avoid hypernatremia.
●Hypokalemia can occur with the 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".)
●In patients with diabetic ketoacidosis, the routine use of bicarbonate administration is not recommended as it has been associated with the development of cerebral edema, hypokalemia, and delaying the resolution of ketosis. (See "Diabetic ketoacidosis in children: Treatment and complications", section on 'Metabolic acidosis'.)
●Animal data demonstrated that rapid infusion of sodium bicarbonate was associated with adverse cardiovascular effects.
Preadministration considerations — When it is decided that IV sodium bicarbonate will be used, the clinician needs to consider the following prior to administration:
●Effect of sodium bicarbonate on the level of serum/plasma ionized calcium – Ionized calcium concentrations change 0.36 mmol/L for every pH unit, so ionized calcium values decrease when sodium bicarbonate is infused. Ionized calcium levels can be quickly obtained with a blood gas measurement. Pre-treatment with IV calcium is advised if:
•The corrected calcium is <8 mg/dL
•The ionized calcium is <1 mmol/L
IV calcium gluconate (preferred) 100 mg/kg, or IV calcium chloride 10 mg/kg, can be slowly infused via a central catheter or a large vein prior to infusing sodium bicarbonate. Failure to correct the calcium prior to the sodium bicarbonate 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 – Sodium bicarbonate can cause compatibility problems with medications that are concurrently infused due to its higher pH. For example, precipitation of calcium carbonate can occur when IV administration of calcium chloride/calcium gluconate is mixed with sodium bicarbonate. If there is a medication compatibility issue due to IV fluid pH, use of sodium acetate instead of sodium bicarbonate can be a good option.
Administration and dosing
●Emergency setting – In an emergency, 8.4 percent sodium bicarbonate 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 bicarbonate therapy (low ionized calcium and hypokalemia).
●Non-emergency setting repletion – In a nonemergent setting, the dosing of sodium bicarbonate is determined by the calculated estimated bicarbonate deficit using the following formula:
Estimated bicarbonate deficit = (Target bicarbonate – current bicarbonate) x weight (in kg) x 0.4 – 0.5
Half of the estimated bicarbonate deficit is infused intravenously over 2 to 4 hours. The remaining half of the bicarbonate deficit is infused over the following 6 to 24 hours. A longer course of infusion should be prescribed when the sodium bicarbonate deficit is large (>3 mEq/kg).
During and after repletion of the bicarbonate deficit, blood gas, ionized calcium, and serum electrolytes are obtained to determine whether additional bicarbonate therapy is required and to detect any adverse effect of bicarbonate therapy (low ionized calcium and hypokalemia).
●Ongoing replacement therapy directed at bicarbonate loss or H+ accumulation – To achieve a goal of normalizing serum bicarbonate, the total dose of sodium bicarbonate delivered over the course of a day should include not only the amount for repletion but also the maintenance dose of sodium bicarbonate needed to replace ongoing bicarbonate loss or buffer new H+ accumulation. For example, patients with acute metabolic acidosis who also have advanced chronic kidney disease or distal renal tubular acidosis may require an additional 1 to 2 mEq/kg/day of sodium bicarbonate to maintain normal total CO2 concentrations from their chronic condition.
When the patient can tolerate oral medications, maintenance administration should be changed to an oral alkali (table 8).
Renal replacement therapy — Dialysis and/or continuous renal 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 such as hyperkalemia. (See "Pediatric acute kidney injury (AKI): Indications, timing, and choice of modality for kidney replacement therapy (KRT)".)
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 metabolic acidosis (chronic kidney disease [CKD] and renal tubular acidosis [RTA]) and a persistent serum total CO2 <21 mmol/L.
Alkali therapy includes a number of formulations of sodium bicarbonate, 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 the experience of the prescribing clinician.
In our practice, the choice of alkali therapy and dosing is based on the underlying etiology:
●Proximal or distal RTA can be effectively treated with sodium bicarbonate or sodium citrate-citric acid therapy. The amount of bicarbonate 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 bicarbonate 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".)
●Hypokalemic distal renal tubular acidosis requires potassium supplementation. In most of our pediatric cases, combination of potassium citric acid/citrate and sodium citrate oral liquid, which contains per mL 1 mEq K, 1 mEq Na, and 2 mEq citrate, is prescribed with an initial dose of 2 to 4 mEq of bicarbonate equivalent [45]. Some children, who have more severe hypokalemia, require citric acid potassium citrate therapy, which is formulated with 2 mEq K and 2 mEq citrate/mL. Some clinicians use a combination sodium citrate-citric acid and citric acid-potassium citrate therapy to allow the separate adjustment of alkali and potassium dosing in children who cannot be successfully treated with a single form of oral alkali.
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 doses around 1 mEq/kg/day.
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.
●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 bicarbonate therapy at 1 to 2 mEq/kg per day divided into two to three doses, and the dose is increased until the clinical target is reached. Citrate preparations are not suggested to be used in children with CKD as it may enhance aluminum absorption. In addition, potassium-based therapy should be 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 does should be used and increased in a stepwise fashion until the targeted total CO2/bicarbonate 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 infants and young children, oral liquid sodium bicarbonate and sodium citrate-citric acid are normally provided. However, there can be challenges in administration due to poor palatability and burping is a common side effect due to the rapid conversion of bicarbonate into water and carbon dioxide 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 remember how challenging giving oral alkali three or more times per day to a child can be for families. Before making an oral alkali dose adjustment based on a laboratory result, it is important to verify with the family, in a non-threatening manner, compliance with 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
●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):
•Increased acid concentration (H+) results in high anion gap metabolic acidosis due to the 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. (See 'Increased acid concentration: High anion gap metabolic acidosis' above.)
•Loss of bicarbonate results in normal anion gap metabolic acidosis due to losses from the gastrointestinal tract and kidneys. (See 'Loss of bicarbonate: Normal anion gap metabolic acidosis' above.)
•Mixed high and normal gap metabolic acidosis occurs when children have coexisting conditions with high and normal anion gap. (See 'Mixed high anion and normal gap acidosis' above.)
•Dilutional metabolic acidosis is caused by a fall in serum bicarbonate concentration due to expansion of the intravascular fluid volume with large volumes of intravenous fluids that do not contain bicarbonate. (See 'Dilutional metabolic acidosis' above.)
●There are no distinguishing clinical features of pediatric metabolic acidosis. Typically, infants and children with acute metabolic acidosis 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 renal capacity for net acid excretion. (See 'Clinical manifestations' above.)
●Metabolic acidosis is typically detected by a low serum total CO2 in the electrolyte panel and less commonly by a low bicarbonate level within a blood gas sample. Measurement of the serum total CO2 in the electrolyte panel may not be sufficient, as 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 carbon dioxide [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 bicarbonate levels vary and decrease from late adolescent to neonates. (See 'Normative total CO2 and bicarbonate levels by age' above.)
●Metabolic acidosis increases serum/plasma potassium and ionized (free) calcium and magnesium.
●After confirmation of metabolic acidosis, a diagnostic evaluation that includes serum or plasma electrolytes, calculation of the anion gap, 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.)
●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.
•We suggest not to routinely administer sodium bicarbonate to children with metabolic acidosis (Grade 2C). Intravenous bicarbonate therapy can be considered in cases of severe acidosis (pH <7.0), recognizing that this is only a temporary intervention. Dialysis and/or continuous renal 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 'Acute metabolic acidosis' above and "Pediatric acute kidney injury (AKI): Indications, timing, and choice of modality for kidney replacement therapy (KRT)", section on 'Indication and timing for KRT'.)
•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)
ACKNOWLEDGMENTS — The editorial staff at UpToDate acknowledge Kanwal Kher, MD, MBA; Matthew Sharron, MD; Mahesh Sharman, MD, FAAP; and Ashok Sarnaik, MD, FAAP, FCCM, who contributed to an earlier version of this topic review.
