Metabolic acidosis is an acid-base disorder characterized by a decrease in serum pH that results from either a primary decrease in plasma bicarbonate concentration ([HCO3-]) or an increase in hydrogen ion concentration ([H+]).[1] It is not a disease but rather a biochemical abnormality. The clinical manifestations of a metabolic acidosis are nonspecific, and its differential diagnoses include common and rare diseases. (See Etiology.)
Metabolic acidosis induces an increase in the excretion of urinary calcium. The increased urinary calcium excretion results mainly from the increased mobilization of calcium out of bone and the inhibition of calcium transport processes within the renal tubule.[2]
The underlying disorder usually produces most of the signs and symptoms in children with a mild or moderate metabolic acidosis. (See History.)
The image below depicts a flowchart for evaluating metabolic acidosis.
View Image
Approach for evaluating metabolic acidosis.
Complications
Untreated, severe metabolic acidosis can lead to myocardial depression, seizures, shock, and multiorgan failure. (See Pathophysiology.)
Bicarbonate administration during treatment for diabetic ketoacidosis has been associated with an increased risk of cerebral edema.[3] (See Treatment.)
Go to Metabolic Acidosis in Emergency Medicine and Metabolic Acidosis for complete information on these topics.
A primary metabolic acidosis is a pathophysiologic state characterized by an arterial pH of less than 7.35 in the absence of an elevated PaCO2. It is created by one of three mechanisms: (1) increased production of acids, (2) decreased excretion of acids, or (3) loss of alkali.
Acutely, medullary chemoreceptors compensate for a metabolic acidosis through increases in alveolar ventilation. The resulting tachypnea and hyperpnea reduces the PaCO2 in an attempt to increase the pH back toward normal. In a primary metabolic acidosis, the degree of acute respiratory compensation can be predicted by the following relationship:
Expected PaCO2 = (1.5 X [HCO3-]) + 8 ± 2
If the measured PaCO2 is higher than the expected PaCO2, a concomitant respiratory acidosis is also present. The development of normocapnia or hypercapnia when a severe metabolic acidosis is present often signals respiratory muscle fatigue, impending respiratory failure, and the possible need for initiating mechanical ventilation.
The kidneys are responsible for reclaiming filtered bicarbonate (HCO3-) and eliminating the daily acid load generated from nitrogen (protein) metabolism. Normally, the kidneys excrete hydrogen ions (H+) through the formation of titratable acids and ammonium. The ability of the kidney to excrete an increased acid load generally begins 12-24 hours after the compensatory hyperventilation begins and continues for 1-3 days. Over time, the kidneys attempt to increase reabsorption of HCO3- to compensate for the acidosis. The severity of the acidosis depends on the rapidity of bicarbonate loss and the ability of the kidney to replenish bicarbonate.
Anion gap
To achieve electrochemical balance, ionic elements in the extracellular fluid must equal a net charge of zero. Therefore, the number of negatively charged ions (anions) should equal the number of positively charged ions (cations). Measured serum anions are chloride and bicarbonate, and the unmeasured anions include phosphates, sulfates, and proteins (eg, albumin). The primary measured serum cation is sodium, but other cations are noted, such as calcium, potassium, and magnesium.
Under typical conditions, unmeasured anions exceed unmeasured cations; this is referred to as the anion gap and can be represented by the following formulas:
Practically, a metabolic acidosis is divided into processes that are associated with a normal anion gap (8-12 mEq/L) or an elevated anion gap (>12 mEq/L). A normal anion gap metabolic acidosis involves no gain of unmeasured anions; however, because of the need for electrical neutrality, serum chloride replaces the depleted bicarbonate, and hyperchloremia develops. In contrast, an elevated anion gap metabolic acidosis is caused when extra unmeasured anions are added to the blood.
General physiologic and metabolic effects
The clinical manifestations of a metabolic acidosis are related to the degree of acidemia. Initially, patients with a metabolic acidosis develop a compensatory tachypnea and hyperpnea; if the acidemia is severe, the child can present with significant work of breathing and distress. An increase in serum hydrogen ion concentration results in pulmonary vasoconstriction, which raises pulmonary artery pressure and pulmonary vascular resistance. An increase in right ventricular afterload and, potentially, right ventricular dysfunction can then occur. This is especially problematic in newborn infants with persistent pulmonary hypertension.
Tachycardia is the most common cardiovascular effect seen with a mild metabolic acidosis. As the serum pH continues to fall below 7.2, myocardial depression occurs because hydrogen ions act as a negative inotrope and peripheral vasodilation occurs. Also, with acidemia, cardiovascular response to endogenous and exogenous catecholamines can decrease, which can possibly exacerbate hypotension in children with volume depletion or shock.
Central nervous system (CNS) manifestations can include headache, lethargy, confusion, or any change in mental status secondary to a decrease in intracerebral pH. Cerebral vasodilation occurs as a result of a metabolic acidosis and may contribute to an increase in intracranial pressure.
Acidosis shifts the oxygen-hemoglobin dissociation curve to the right, decreasing hemoglobin’s affinity for oxygen and thus promoting release into body tissues.
During a metabolic acidosis, excess hydrogen ions move toward the intracellular compartment and potassium moves out of the cell into the extracellular space (serum). For every decrease in the serum pH by 0.1, a concomitant increase in the serum potassium level by 0.5 mEq occurs. As a result, hyperkalemic arrhythmias (peaked T waves and QRS widening) and ventricular fibrillation may occur. Other acute metabolic effects of acidemia include insulin resistance, increased protein degradation, and reduced adenosine triphosphate (ATP) synthesis. During acidemia, the oxyhemoglobin dissociation curve shifts to the right; oxygen has a lower affinity for hemoglobin, but hemoglobin more readily releases oxygen. Also, nonspecific GI complaints, such as abdominal pain, nausea, or vomiting, may be present.
The causes of a metabolic acidosis can be classified on the basis of a normal or elevated anion gap.
An elevated anion gap is created by inorganic (eg, phosphate or sulfate), organic (eg, ketoacids or lactate), or exogenous (eg, salicylate) acids incompletely neutralized by bicarbonate. Frequent causes of an elevated anion gap metabolic acidosis are represented by the mnemonic MUDPILES:
Methanol
Uremia
Diabetic ketoacidosis
Paraldehyde
Iron, isoniazid (INH)
Lactic acid
Ethanol, ethylene glycol
Salicylates
A normal anion gap metabolic acidosis occurs when loss of bicarbonate from the GI tract or kidneys is excessive or when hydrogen ions cannot be secreted because of renal failure. The causes can be represented by the mnemonic USEDCARP:
Infants are more likely to develop a normal anion gap metabolic acidosis secondary to significant losses of bicarbonate in diarrheal stools. The stool output can contain as much as 70-80 mEq/L of bicarbonate.
Patients with an ureterosigmoidostomy may lose bicarbonate in exchange for the reabsorption of chloride and ammonium as urine accumulates in the sigmoid colon.
Children with congenital or acquired renal tubular acidosis can lose large amounts of bicarbonate, with or without concomitant potassium loss.
Inborn errors of metabolism may result in a metabolic acidosis, with or without hypoglycemia or hyperammonemia.
In children, metabolic acidosis is frequently caused by lactate. Lactate is the end product of anaerobic glycolysis, which can be represented by the following equation:
Glucose + 2 ATP + 2 H2 PO4 → 2 Lactate + 2 ADP + 2 H2 O
Hydrogen ions generated by the hydrolysis of ATP convert lactate to lactic acid. Under normal conditions, the liver rapidly converts these small amounts of lactic acid to pyruvic acid, which is then metabolized to carbon dioxide and water. Under conditions of oxygen deprivation and decreased oxygen delivery to the tissues, anaerobic metabolism produces excessive amounts of lactic acid. Most disease processes that result in decreased oxygen delivery also frequently lead to diminished hepatic function, further compounding lactic acid accumulation. Conditions that frequently lead to lactic acidosis include shock, sepsis, thiamine deficiency, diabetic ketoacidosis, and cellular poisoning (eg, cyanide toxicity).
Metabolic acidosis is a biochemical derangement occurring as part of certain disease states and conditions. No statistics are available on its frequency.
Race, sex, and age predilection
No race predilection is noted in metabolic acidosis, and the prevalence rates for the condition are equal in males and females.
Patient outcome depends on the nature of the disease process that led to metabolic acidosis. Children with an inherited metabolic disease require long-term, specialized management and a special diet.
Those with diabetic ketoacidosis need lifelong insulin administration and an appropriate diet.
Patients who develop a metabolic acidosis secondary to a toxic ingestion or poisoning have the potential to recover without long-standing consequences.
Guidelines regarding metabolic acidosis and growth in children have been established.[5]
Mortality and morbidity
Untreated severe metabolic acidosis may be associated with life-threatening arrhythmias, myocardial depression, and respiratory muscle fatigue but is not generally the ultimate cause of morbidity and mortality.
Perinatal metabolic acidosis in very low birthweight infants is associated with higher mortality and neurodevelopmental impairment.[6]
The etiology of a metabolic acidosis is often apparent from the patient’s history and physical examination. The following factors are assessed in a complete investigation of the patient's history:
Anorexia, nausea, vomiting, or diarrhea - In pediatric patients, diarrhea is the most common cause of a metabolic acidosis
Metabolic acidosis associated with seizures, a depressed sensorium, or both in a neonate - This warrants consideration of an inborn error of metabolism, or neonatal sepsis
History of depressed mental status, lethargy, and poor feeding in a neonate - Left-sided, obstructive cardiac lesions should be considered (eg, aortic coarctation or hypoplastic left heart syndrome)
Failure to thrive suggestive of chronic metabolic acidosis - This can be seen in renal insufficiency or RTA
New onset of polyuria, polydipsia, and weight loss - This could signify undiagnosed diabetes mellitus and diabetic ketoacidosis in a child
Possible ingestion of a toxin or other form of intoxication - Inquire as to what medications are in the home; suspect a poisoning in a healthy child who quickly develops a metabolic acidosis; possible agents are ethanol, ethylene glycol, salicylates, and methanol
History of trauma, hives, or fever
History of states associated with a lactic acidosis secondary to shock from hypovolemia, sepsis, cardiac failure, anaphylaxis, or spinal shock
Chronic medical or surgical issue - Examples to be concerned with include chronic renal failure, presence of a ureterosigmoidostomy, or diabetes mellitus
Clinical findings generally depend on the etiology and severity of the metabolic acidosis.
Hyperventilation or Kussmaul breathing may often be the first sign of a metabolic acidosis in a child. Breath sounds are often clear to auscultation (“quiet tachypnea”).
Patients with metabolic acidosis secondary to shock may have signs reflective of single- or multiple-organ dysfunction, as follows:
CNS manifestations may include lethargy, coma, and seizures
Respiratory manifestations may include tachypnea, respiratory distress, and hypoxemia
Cardiovascular signs may include poor perfusion, weak pulses, tachycardia, hypotension, murmurs, or a gallop
Nonspecific abdominal symptoms and signs may be present such as nausea, pain, vomiting, and altered appetite
Signs of dehydration may include tachycardia, dry mucous membranes, and delayed capillary refill
Patients with diabetic ketoacidosis may present with fruity odor to their breath
An arterial blood gas (ABG) measurement reveals the acidemia.
Basic laboratory tests for a child with metabolic acidosis should include measurements of electrolytes, BUN, creatinine, and serum glucose levels, as well as a urinalysis.
Echocardiography is performed if a left-sided, obstructive lesion in a neonate or a new occurrence of a cardiomyopathy presenting with a lactic acidosis is suggested.
Computed tomography (CT) scans for an infectious source or ischemic bowel should be performed, if indicated.
Go to Metabolic Acidosis in Emergency Medicine and Metabolic Acidosis for complete information on these topics.
Imaging studies may be required depending on the presumed underlying etiology for the acidosis.
Echocardiography is performed if a left-sided, obstructive lesion in a neonate or a new occurrence of a cardiomyopathy presenting with a lactic acidosis is suggested.
CT scans for an infectious source or ischemic bowel should be performed, if indicated.
As previously mentioned, an ABG measurement reveals the acidemia. In addition, it shows the degree of respiratory compensation. To determine whether respiratory compensation is adequate or a mixed metabolic and respiratory acidosis is present, the Winter formula can be applied:
Expected PaCO2 = (1.5 X [HCO3-]) + 8 ± 2
A PaCO2 that is significantly higher than the level indicated by the Winter formula indicates that the patient is unable to compensate appropriately. This condition may be caused by a depressed mental state, airway obstruction, or fatigue. The inability to compensate may be especially important in patients with diabetic ketoacidosis who are at risk for cerebral edema.
Basic laboratory tests for a child with a metabolic acidosis should include measurements of electrolytes, blood urea nitrogen (BUN), creatinine, and serum glucose levels, as well as a urinalysis.
Calculate the anion gap from the electrolyte levels. This guides the initial diagnostic approach (ie, for a normal or elevated anion gap).
The serum potassium level is often abnormal. Patients with a metabolic acidosis may have a low serum potassium level due to excessive body losses of potassium or an elevated serum potassium level secondary to renal insufficiency, tissue breakdown, and shift of potassium from the intracellular space to the extracellular space as a result of acidemia.
Patients with renal insufficiency have elevated BUN and creatinine levels. A BUN-to-creatinine ratio greater than 20:1 supports the diagnosis of prerenal azotemia and hypovolemia.
Hypoglycemia associated with a metabolic acidosis can be caused by adrenal insufficiency or liver failure.
Hyperglycemia, glycosuria, ketonuria, and a metabolic acidosis support the diagnosis of diabetic ketoacidosis.[7] Less commonly, this combination of findings can be secondary to an inborn error of metabolism.
Normoglycemia, glycosuria, and a metabolic acidosis can occur in children with type II renal tubular acidosis (Fanconi syndrome).
Starvation causes ketosis, but a metabolic acidosis may be absent or mild (bicarbonate level >18).
The serum lactate level can be monitored as an adjunct to evaluate the response to therapy.
The osmole gap may be helpful in diagnosing a suspected ingestion of a toxic substance. An elevated osmole gap (>20 mOsm/L) with a metabolic acidosis can suggest the presence of osmotically active agents such as methanol, ethylene glycol, or ethanol. The osmole gap and serum osmolality can be measured as follows:
Osmole Gap = Measured Serum Osmolality - Estimated Serum Osmolality
Hypoalbuminemia is the most common cause of a low anion gap. Albumin represents about half of the total unmeasured anion pool; for every decrease of 1 g/dL of the serum albumin level, the serum anion gap decreases by 2.5 mEq/L.
Inability to recognize the etiology of metabolic acidosis can lead to failure to treat the basic disease process. For example, a child who ingests windshield-wiper fluid containing ethylene glycol may present with severe metabolic acidosis, hypoglycemia, and coma. Failure to be adequately suspicious regarding this symptom complex would prevent the physician from obtaining immediate treatment (hemodialysis) for this patient.
Insulin administration is necessary in cases of diabetic ketoacidosis, and restoration of adequate perfusion with crystalloid administration is necessary in cases of dehydration.[8, 9] The same holds true for other diseases, such as renal failure and shock, that lead to metabolic acidosis.
In a retrospective chart review study, Cohen et al found evidence that subcutaneous regular insulin administered every 4 hours is a safe and effective alternative for the insulin treatment of pediatric diabetic ketoacidosis (DKA) with pH > 7.0. In the 76 DKA episodes in 52 patients included in the study, the investigators’ protocol resulted in recovery from DKA with a median time to DKA resolution of 10.3 (5.5, 14.2) hours. No incidents of cerebral edema, cardiac arrhythmias, or mortality occurred.[10]
Further inpatient management, including critical care, depends on the underlying etiology. Children with inherited metabolic abnormalities, poisoning, or renal failure may require hemodialysis. Children with lactic acidosis caused by circulatory failure, thiamine deficiency, or septic shock require appropriate supportive care that first addresses the ABCs and potentially includes fluid resuscitation, inotropic support, and antibiotics. Children with diabetic ketoacidosis must be treated with appropriate fluid and electrolyte therapy and insulin.
The underlying disease state (eg, diabetes, renal failure) may require diet modification.
A 2009 study concluded that albumin was not more effective than normal saline in initial hydration of dehydrated term infants with metabolic acidosis due to acute diarrhea.[11]
Go to Metabolic Acidosis in Emergency Medicine and Metabolic Acidosis for complete information on these topics.
Consultations depend on the underlying etiology of metabolic acidosis and include the following:
Critical care specialist: in cases of metabolic acidosis with shock
Nephrologist: in cases of children with renal failure, who may or may not require dialysis
Geneticist: in cases of inborn errors of metabolism
Surgeon: in cases where the underlying cause of metabolic acidosis is surgical in nature (necrotizing enterocolitis, malrotation, volvulus, ruptured appendicitis)
Endocrinologist: in cases of children whose metabolic acidosis is caused by diabetic ketoacidosis
In instances in which the serum bicarbonate level is only mildly to moderately depressed (>10-12 mEq/L), bicarbonate replacement may not be necessary. If the underlying disease is treated appropriately, the kidneys are able to replenish bicarbonate stores within 3-4 days, unless significant renal dysfunction is present.
In some disease states, the use of bicarbonate therapy is clearly indicated. For patients with chronic renal failure or renal tubular acidosis (RTA), bicarbonate replacement is necessary because of known, ongoing bicarbonate losses. In salicylate intoxication, short-term therapy with bicarbonate to create an alkalemic environment enhances toxin elimination.
Emergent bicarbonate therapy may be warranted in decompensated shock states in patients with a pH of less than 7.15. Studies of human lactic acidosis have generally failed to demonstrate a hemodynamic benefit to bicarbonate therapy.[12] Patients with lactic acidosis from severe asthma exacerbations, however, may benefit from bicarbonate therapy.[13] A survey of pediatric acute care physicians published in 2013 showed that there is a range of opinions regarding the use of emergency bicarbonate therapy in shock and cardiac arrest.[14]
Calculating the amount of bicarbonate replacement necessary must take into account the effect of nonbicarbonate buffers on exogenously administered bicarbonate. Multiply the desired increase in plasma bicarbonate concentration by the apparent volume of distribution and weight. The bicarbonate deficit can be calculated as follows:
(Desired Bicarbonate - Measured Bicarbonate) x Weight (kg) x 0.6
The general recommendation is to replace only half of the total bicarbonate deficit during the first few hours of therapy.
Do not overestimate or overcorrect the bicarbonate deficit. Rapid infusion of bicarbonate for chronic conditions and overcorrection of the metabolic acidosis can lead to complications such as tetany, seizures, and hypokalemia by worsening the preexisting hypocalcemia and hypokalemia.
Doses of bicarbonate exceeding 1 mEq/kg per dose may lead to an alkaline overshoot. For each 0.1 increase in pH, oxygen availability may decrease by 10% because of the shift of the oxygen-hemoglobin dissociation curve to the left.
Parenteral forms of sodium bicarbonate are available as 4% (half strength) or 8% solutions. The sodium load can be significant when multiple bolus doses are administered.
If hypernatremia is a concern, consider continuous infusion of sodium bicarbonate as part of the maintenance intravenous solution. For example, 34 mEq/L of sodium bicarbonate can be added to a 0.22% sodium chloride solution to make up a 0.45% salt solution for maintenance intravenous therapy.
The use of sodium bicarbonate therapy in cases of diabetic ketoacidosis is controversial. A report by Glaser et al stated that patients with diabetic ketoacidosis who were treated with sodium bicarbonate were at increased risk for cerebral edema.[3]
In newborns, frequent administration of hypertonic solutions, such as sodium bicarbonate, have led to intracranial hemorrhage resulting from hyperosmolality and resultant fluid shifts from the intracellular space.
Rapid infusion of sodium bicarbonate to correct metabolic acidosis has led to paradoxical CNS acidosis in animal studies. The cause is believed to be sodium bicarbonate dissociating into carbon dioxide and water; carbon dioxide rapidly crosses the blood-brain barrier, but bicarbonate does not, leading to CNS acidosis.
Thiamine deficiency is a very rare cause of severe lactic acidosis and shock, which is often resistant to inotropic agents and volume resuscitation. Thiamine deficiency should be considered for patients with lactic acidosis and shock on long-term total parenteral nutrition without multivitamins for 2 or more weeks. Thiamine administration rapidly corrects the clinical symptomatology.
Tromethamine (also called THAM or tris [hydroxymethyl]-aminomethane) is a buffer that can be used to treat acidosis when concerns exist regarding carbon dioxide accumulation from the metabolism of administered sodium bicarbonate. THAM increases serum bicarbonate predictably:
Hemodialysis is an option for correcting a severe metabolic acidosis associated with renal failure or intoxication with methanol or ethylene glycol.[15]
Surgical care
Surgical care may be indicated based on the etiology of metabolic acidosis. Tissue ischemia or necrosis from bowel obstruction or necrotizing enterocolitis, with or without peritonitis, may lead to metabolic acidosis.
Especially in newborns with necrotizing enterocolitis, metabolic acidosis may be the first laboratory abnormality associated with a surgical abdomen.
Specific therapies are directed at the underlying disease process that causes metabolic acidosis. However, sodium bicarbonate and tromethamine (also called THAM or tris [hydroxymethyl]-aminomethane) are used to address the acidosis itself.
Clinical Context:
THAM combines with hydrogen ions to form bicarbonate buffer. It is used to prevent and correct systemic acidosis. It is available as 0.3-mol/L IV solution containing 18 g (150 mEq) per 500 mL (0.3 mEq/mL).
Sodium bicarbonate is used as a gastric, systemic, and urinary alkalinizer and has been used in the treatment of acidosis resulting from metabolic and respiratory causes, including, diarrhea, kidney disturbances, and shock. Alternatively, THAM is a buffering agent that increases pH without increasing levels of PaCO2. It may be used to correct metabolic acidosis if sodium bicarbonate is contraindicated.
Clinical Context:
Thiamine is an essential coenzyme that combines with ATP to form thiamine pyrophosphate. The dosage forms include a parenteral injection (100 mg/mL) and tablets. Thiamine administration rapidly corrects the clinical symptomatology in metabolic acidosis.
Lennox H Huang, MD, FAAP, Chief Medical Officer, The Hospital for Sick Children; Associate Professor of Pediatrics, University of Toronto Faculty of Medicine; Associate Clinical Professor of Pediatrics, McMaster University School of Medicine, Canada
Disclosure: Nothing to disclose.
Coauthor(s)
Margaret A Priestley, MD, Associate Professor of Clinical Anesthesiology and Critical Care, Perelman School of Medicine at the University of Pennsylvania; Clinical Director, Pediatric Intensive Care Unit, The Children's Hospital of Philadelphia
Disclosure: Nothing to disclose.
Chief Editor
Timothy E Corden, MD, Associate Professor of Pediatrics, Co-Director, Policy Core, Injury Research Center, Medical College of Wisconsin; Associate Director, PICU, Children's Hospital of Wisconsin
Disclosure: Nothing to disclose.
Acknowledgements
G Patricia Cantwell, MD, FCCM Professor of Clinical Pediatrics, Chief, Division of Pediatric Critical Care Medicine, University of Miami, Leonard M Miller School of Medicine; Medical Director, Palliative Care Team, Director, Pediatric Critical Care Transport, Holtz Children's Hospital, Jackson Memorial Medical Center; Medical Manager, FEMA, Urban Search and Rescue, South Florida, Task Force 2; Pediatric Medical Director, Tilli Kids – Pediatric Initiative, Division of Hospice Care Southeast Florida, Inc
G Patricia Cantwell, MD, FCCM is a member of the following medical societies: American Academy of Hospice and Palliative Medicine, American Academy of Pediatrics, American Heart Association, American Trauma Society, National Association of EMS Physicians, Society of Critical Care Medicine, and Wilderness Medical Society
Disclosure: Nothing to disclose.
Barry J Evans, MD Assistant Professor of Pediatrics, Temple University Medical School; Director of Pediatric Critical Care and Pulmonology, Associate Chair for Pediatric Education, Temple University Children's Medical Center
Barry J Evans, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Chest Physicians, American Thoracic Society, and Society of Critical Care Medicine
Disclosure: Nothing to disclose.
Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
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