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Diagnosis and treatment of severe metabolic acidosis
SYMPOSIUM: METABOLIC MEDICINE
Diagnosis and treatment of severe metabolic acidosis
Definition and aetiology Metabolic acidosis, defined as the accumulation of non-carbonic acid equivalents, may be due to excessive production or inadequate excretion of hydrogen ions or from an increased loss of bicarbonate. Changes are compensated for acutely by increased excretion of carbon dioxide by the lungs, and more chronically by renal tubular reabsorption of bicarbonate. Metabolic acidosis is evident from low plasma bicarbonate, low PaCO2 and low arterial pH. Understanding of this process has evolved over the last 100 years, beginning with the Henderson–Hasselbalch equation in 1916 and moving through the base excess, the anion gap and finally the strong ion approach of the 1980s. This latter hypothesis proposes that H+ and bicarbonate are dependent variables and that the ‘cause’ of non-respiratory acidosis is either an imbalance of strong ions (electrolytes that are fully dissociated in water, such as sodium, chloride and lactate) or changes in the concentration of weak acid buffers (e.g. albumin, globulins, inorganic phosphate).1,2 There remains controversy regarding the usefulness of this physiochemical approach to acid–base balance. While the ‘strong ion difference method’ is probably more accurate concerning the aetiology of metabolic acidosis (e.g. it explains why acidosis can result from the infusion of sodium chloride solution), it involves more complex equations and does not necessarily offer a substantial advantage in terms of affecting management over simpler methods such as the calculation of the anion gap, particularly if the latter is adjusted for changes in serum albumin. Because of this, in the immediate management of metabolic acidosis, the authors suggest using the adjusted anion gap if the plasma albumin concentration is known, or the unadjusted anion gap if it is not (Table 1).
S A Jones J H Walter
Abstract Severe non-respiratory acidosis is a frequent biochemical finding in sick children. While treatment is usually straightforward and comprises managing the underlying illness and giving supportive care, in some cases the acidosis itself requires specific therapy. The authors provide an approach to the diagnosis, investigation and management of children with severe metabolic acidosis, using the anion gap (adjusted for serum albumin) as a guide to the aetiology. Lactic acidosis, ketosis and organic acids are discussed, as are specific treatments and the general use of sodium bicarbonate as a base.
Keywords ketoacidosis; lactic acidosis; metabolic acidosis; organic acidaemias
Introduction Severe metabolic acidosis is a common acid–base abnormality in sick children; management is usually relatively straightforward and comprises providing adequate oxygenation and circulating volume, and treating the underlying cause. In certain cases of refractory acidosis or a very sick child, the treatment must also be aimed at the acid–base imbalance itself. While the diagnosis of metabolic acidosis is straightforward (requiring simple blood gas analysis), understanding the aetiology may be more complex. In this article we present the basic physiology, an algorithm to aid understanding of the disease process and some treatment options, both general and specific. For the purposes of this review, severe metabolic acidosis is classified as ‘non-respiratory acidosis causing significant clinical effects’, rather than by attaching abstract numerical limits to this concept. The review deals to some extent with all causes of severe metabolic acidosis, but focuses on the rapid identification and treatment of inborn errors of metabolism (IEM). IEM often present with metabolic acidosis, and the initial clinical and laboratory parameters are often non-specific. Early diagnosis is important to the clinical outcome, as treatments may be disease specific.
Effects of severe metabolic acidosis Metabolic acidosis in itself is rarely a cause of death, but it can contribute significantly to morbidity and has many unwanted physiological effects. These include increased energy expenditure resulting from compensatory measures such as tachypnoea, pulmonary vasoconstriction, cerebral vasodilatation and hyperkalaemia. As the acidosis progresses, respiratory distress, pulmonary hypertension and cerebral oedema develop. Myocardial depression with a significant decline in cardiac output results in poor tissue perfusion with exacerbation of the acidosis from hypoxia and lactate under-utilisation, and leads to arrhythmias and circulatory collapse. Clinically, tachypnoea and tachycardia are seen, along with more non-specific effects such as sweating, vomiting and abdominal pain.
Investigations In most severely ill children, an infection screen, arterial blood gas, blood glucose, plasma electrolytes, blood ammonia and liver function tests are indicated (Table 2). Metabolic acidosis is evident from low plasma bicarbonate, low PaCO2 and low arterial pH, and the (corrected) anion gap can be calculated from the plasma electrolytes (and albumin) (Table 1). The history and clinical examination are normally sufficient to determine the cause or to indicate which additional investigations are necessary.
S A Jones MBChB BSc MRCPCH is a Specialist Registrar in Paediatric Metabolic Medicine at the Willink Biochemical Genetics Unit, Royal Manchester Children’s Hospital, Pendlebury, Manchester M27 4HA, UK. J H Walter MBBS MSc MD FRCP FRCPCH DCH is a Consultant Paediatrician at the Willink Biochemical Genetics Unit, Royal Manchester Children’s Hospital, Pendlebury, Manchester M27 4HA, UK.
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Calculation of the anion gap and the ‘adjusted’ anion gap. Anion gap ¼ (Na++K+) – (HCO 3 +Cl ) Anion gap (adjusted) ¼ anion gap+0.25 (normal plasma albumin – measured plasma albumin)
A normal anion gap is 10–18 mmol/litre and is due to the presence of unmeasured anions such as lactate, sulphate and ketoacids.
Table 1
First-line investigations in severe metabolic acidosis. Blood gas Infection screen Glucose (bedside test and formal venous glucose) Urea and electrolytes (including chloride) Liver function tests Blood ammonia Urine dipstick for ketones and glucose Blood gases are ideally measured from arterial blood, but in much paediatric practice this is not the initial means of assessing patients and in many scenarios involving metabolic acidosis with no significant respiratory involvement, all of the information required can be gained from a free-flowing venous sample or an arterialized capillary sample. It must be remembered that if the result from a capillary gas sample obtained in this manner does not seem appropriate for the child’s clinical condition, it should be repeated, as samples from a cold or shut-down child may not represent the true state.
Table 2
Normal anion gap
GI loss of HCO3
Keto-acids
Diabetic ketoacidosis, ketotic hypoglycaemia, IEM e.g. Maple Syrup Urine Disease (MSUD), disorders of ketone body utilisation
Metabolic acidosis
Raised anion gap
Renal loss of HCO3
Lactic acid
Sepsis, Hypoxia, Hypovolaemia, IEM e.g. Glycogen storage disease, disorders of gluconeogenesis, mitochondrial disorders, pyruvate dehydrogenase deficiency
Organic acids
Drugs
IEM e.g. propionic acidaemia, methylmalonic acidaemia
Salicylate, ethylene glycol (anti-freeze) poisoning
Figure 1 Algorithm to aid understanding of the aetiology of metabolic acidosis based on the anion gap. This algorithm is clearly a simplification; some disorders present with a mixture of acid–base disturbances, with pyruvate carboxylase deficiency being perhaps the best example of this (see case history). IEM, inborn errors of metabolism.
Acidosis with a normal anion gap Acidosis with a normal anion gap, as a result of loss of base from the gut as part of severe enteropathy or from the renal tubules as part of renal tubular acidosis must be further clarified (e.g. by urinary pH and subsequent second-line investigations). Although
The algorithm shown in Figure 1 divides acidoses into those with a normal and those with an increased anion gap. An increased anion gap suggests an excess of unmeasured anions (e.g. lactate, ketones), while a normal anion gap indicates a deficiency of base (i.e. loss of bicarbonate).
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IEM are usually associated with an increased anion gap, in some disorders tubulopathy is a prominent feature (cystinosis, galactosaemia, tyrosinaemia type 1 and mitochondrial disease). Significant bicarbonate loss can also occur in patients with a ureterostomy or small bowel fistula. Intoxication with drugs often increases the anion gap, though it can be normal in ammonium chloride or acetazolamide toxicity.
Inborn errors of metabolism presenting with lactic acidosis as a main feature. Pyruvate dehydrogenase deficiency Pyruvate carboxylase deficiency Respiratory chain defects/mitochondrial disease Fructose-1,6-bisphosphatase deficiency Multiple carboxylase deficiency (as biotinidase or holocarboxylase synthetase deficiency)
Acidosis with an increased anion gap With the exception of diabetic ketoacidosis (DKA), increased anion gap acidosis requires further tests. However, it must be noted that not all cases of ketoacidosis are diabetic in origin. The most common form of increased anion gap acidosis is lactic acidosis, and this can be determined by the measurement of blood lactate as a second-line investigation (Table 3). Diagnosis of an organic acidaemia requires specialist investigations (urinary organic acid analysis by gas chromatography/mass spectrometry and/or blood acylcarnitine analysis by tandem mass spectrometry). Third-line investigations for IEM are for diagnostic confirmation and usually involve enzyme assays or molecular analysis.
Table 4
mia. In contrast to lactic acidosis secondary to tissue hypoxia, ketosis is most often present and the acidosis persists even when there is adequate cardiac output and tissue perfusion, and seems disproportionate to the degree of illness of the child.3 Caveats to this include children with cardiomyopathy or an obstructed cardiac outflow tract (hypoplastic left heart, coarctation of the aorta or interrupted aortic arch) who have very increased lactate due to profound tissue hypoxia but whose condition may be mistaken for congenital lactic acidaemia. The lactate:pyruvate ratio is another way of elucidating the cause of increased lactate; it is elevated in disorders of the respiratory chain due to an altered redox state, and normal or even low in disorders of pyruvate metabolism. Pyruvate is difficult to assay accurately, however, and most UK laboratories do not offer this service. Furthermore, the above rule is not absolute, as mitochondrial disorders that are less severe and do not alter the redox state of the cell can have a normal lactate:pyruvate ratio.4
Lactic acidosis Secondary lactic acidosis An increased blood lactate concentration is often found in very ill children. In contrast to some other metabolites (e.g. ammonia), lactate is not toxic, but it usually reflects severe pathological processes affecting tissue perfusion or oxygenation. A very high lactate concentration in this situation is often associated with a poor prognosis. ‘Hidden’ tissue ischaemia can occur in patients with compromised bowel. As the liver is the site of much lactate oxidation, liver failure can result in lactic acidosis. Primary lactic acidosis Hyperlactataemia may be caused by various IEM, particularly those affecting oxidative phosphorylation (disorders of pyruvate metabolism and the mitochondrial respiratory chain), which are often termed primary or congenital lactic acidaemias. It is also found in inherited disorders of hepatic gluconeogenesis (glucose6–phosphatase deficiency, glucose-6–phosphate translocase deficiency and fructose-1,6–bisphosphatase deficiency) and organic acidaemias (Table 4). It can be difficult to know when to suspect an IEM in sick children with an increased blood lactate. In congenital lactic acidaemias, symptoms may be apparent from birth, the blood lactate is usually above 5 mmol/litre and an anion gap is present that may be attributed to the hyperlactate-
Other causes of lactic acidosis Other causes of increased lactate include drugs and toxins (metformin, alcohol, salicylate, isoniazid, ethylene glycol, cyanide stimulants and nucleoside analogues in antiretroviral treatment), and vitamin deficiencies such as thiamine and biotin deficiency.
Ketosis Ketone production results primarily from beta-oxidation of fatty acids within mitochondria. However, a catabolic stress such as fasting or ‘illness’ should not cause significant acidosis; if this is seen, a pathological cause should be sought. Significant ketosis in the neonate is almost always pathological.3 In DKA, ketones are produced due to a lack of glucose entry into cells. In addition to DKA, significant ketoacidosis is seen in organic acidaemias, fructose-1,6–bisphosphatase deficiency, primary lactic acidosis and respiratory chain defects. It can be the sole presentation in inherited disorders of ketolysis in which episodes of recurrent severe ketoacidosis occur, generally at times of intercurrent illness. Maple syrup urine disease (keto acid branched-chain decarboxylase deficiency) presents with encephalopathy in which ketosis occurs, but this is not usually severe enough to cause a significant acid–base disturbance.
Second-line investigations. Blood lactate Blood spot for acylcarnitine profile Urine for toxicology Urine for amino and organic acids Not all tests will be needed, and should be guided by the history, examination and other investigation results.
Table 3
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tase, electron transfer protein (ETF) or ETF:ubiquinone oxoreductase, succinyl CoA:3–ketoacid CoA transferase, and glutathione synthetase. Most organic acidaemias present in the neonatal period after an initial symptom-free interval of a few days. The onset of illness is not necessarily related to the start of feeding but triggered by endogenous protein catabolism. Characteristically, there is a rapid deterioration beginning with poor feeding, irritability and lethargy and proceeding to apnoea and coma. On examination, there may be dehydration, respiratory distress, central hypotonia and limb hypertonia. Initial investigations show severe metabolic acidosis, ketosis, and usually hyperammonaemia and hypocalcaemia. Neutropenia, thrombocytopenia and hypoglycaemia or hyperglycaemia are often found. Although usual, significant acidosis is not always present in newborn infants with organic acidaemias with hyperammonaemia, in whom respiratory alkalosis may be present. Occasionally, organic acidaemias, particularly those with residual enzyme activity, first present outside the newborn period with profound acidosis and/or encephalopathy, usually provoked by an intercurrent infection. Pancreatitis and cardiomyopathy are recognised complications in older children. In methylmalonic acidaemia, progressive renal involvement can lead to acidosis without a significant increase in the anion gap because of bicarbonate wasting and dehydration from renal tubular disease, though the strong anion gap is abnormal due to an excess of methylmalonic acid. As in other inherited metabolic disorders associated with acute biochemical disturbances, the diagnosis must be made and specific treatment (where available) started as soon as possible to limit long-term morbidity. For this reason a collection of urine for organic acids and a blood spot for acylcarnitine analysis should be routine for all infants with unexplained metabolic acidosis.
Case history A female neonate (first child to distantly consanguineous parents) presents at 8 hours of age, after a normal pregnancy and delivery, with tachypnoea and poor feeding. Initial investigations are as follows: pH pCO2 pO2 Bicarbonate Base deficit Glucose
7.010 2.3 kPa 7.0 kPa 5.0 mmol/litre 26.0 mmol/litre 3.1 mmol/litre
In view of this severe metabolic acidosis, blood is taken for a septic screen and electrolytes, lactate and ammonia, and urine is collected for dipstick and organic and amino acids. Sodium Potassium Chloride Albumin Lactate Ammonia Urine dip Liver function tests
136 mmol/litre 4.2 mmol/litre 105 mmol/litre 35 g/litre 20 mmol/litre 199 mmol/litre Ketones +++ Normal
Her anion gap is thus increased at 30 mmol/litre and the cause appears to be mixed with at least lactic acidosis and ketoacidosis, with a contribution as yet undefined from organic acids. This highly raised lactate is unusual, however, in organic acidaemias and more likely to occur in primary lactic acidosis. Pyruvate carboxylase deficiency typically presents with a very raised lactate and mildly elevated ammonia, and plasma amino acids can sometimes show a typical pattern, as in this case. The acidosis here is due to a combination of hyperlactatemia, ketosis and renal tubular acidosis. Initial management is with general supportive care such as intravenous 10% dextrose and correction of the acidosis with intravenous bicarbonate therapy. While this can maintain normal pH for a time, it does not deal with the underlying defect. Pyruvate carboxylase provides oxaloacetate to the Krebs cycle and aspartate to the urea cycle. This disorder of gluconeogenesis is essentially untreatable, though there have been attempts to use a 7-carbon fatty acid (triheptanoin) with varying degrees of success.
Other inherited metabolic disorders Other inherited metabolic disorders may be associated with acidosis; for example, salt-losing forms of congenital adrenal hyperplasia (21–hydroxylase, 3b-hydroxysteroid dehydrogenase and 20,22–desmolase deficiency). Metabolic acidosis may be found in galactosaemia (as a consequence of renal tubular acidosis), but liver failure is likely to be predominant. Urea cycle disorders are often initially associated with respiratory alkalosis; however, acidosis may develop as the infant deteriorates.
Management Principles of treatment At the start of treatment, the diagnosis may be unclear. Basic supportive care must be provided, adopting the ABC approach.5 Treatment of hypovolaemia, hypoxia and electrolyte disturbances usually correct metabolic acidosis secondary to asphyxia or poor tissue perfusion. Sepsis should be assumed and intravenous antibiotics should be given until this has been excluded. In many cases, these measures correct the acidosis, obviating the need for alkali therapy, assuming parallel treatment of the underlying problem (e.g. antibiotics in sepsis). Other diagnoses may emerge at this stage (e.g. DKA, cardiac lesion) that have specific management strategies. Correct diagnosis, aided by the
Organic acidaemias Organic acids are the least easily measured of the endogenous acids, requiring specialist assays for their identification. The biochemical defects are primarily in amino acid metabolism and most commonly in the catabolism of branched-chain amino acids (propionic, methylmalonic and isovaleric acidaemia). Other, rarer organic acidaemias in which metabolic acidosis may occur include deficiencies of 3–methylcrotonyl CoA carboxylase, 3–hydroxy-3–methylglutaryl CoA lyase, holocarboxylase synthe-
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Specific medications for inborn errors of metabolism associated with metabolic acidosis. Organic acidaemias
Congenital lactic acidosis Biotinidase deficiency and holocarboxylase synthase deficiency
L-carnitine 100–200 mg/kg/day; if associated with hyperammonaemia, consider sodium benzoate 250 mg/kg/day or carbamoyl glutamate 250 mg/kg; single dose Hydroxocobalamin 1 mg i.m. daily in responsive variants of methylmalonic acidaemia Sodium dichloroacetate 50 mg/kg/day; effective at lowering lactate levels but of unproven clinical benefit; Thiamine 200 mg/day in some forms of pyruvate dehydrogenase deficiency Biotin 10 mg daily
Table 5
Treatment of inborn errors of metabolism
algorithm in Figure 1, is essential for management beyond the initial supportive stage.
In IEM with continued production of acid despite normal tissue perfusion and oxygenation (e.g. disorders of ketolysis, organic acidaemias, disorders of gluconeogenesis, congenital lactic acidosis), bicarbonate is usually an essential part of the treatment of metabolic acidosis. These conditions are in addition to those disorders with an element of renal tubular dysfunction such as methylmalonic acidaemia, some mitochondrial diseases, GLUT2 defect (Fanconi–Bickel syndrome) and pyruvate carboxylase deficiency. Glucose infused at a rate of up to 10 mg/kg/minute may inhibit protein catabolism and consequently limit the production of toxic compounds. This effect can be further augmented by adding a continuous infusion of insulin, starting at 0.01 U/kg/hour, provided that the blood glucose concentration is satisfactory. To give sufficient glucose, but to prevent over-hydration, particularly when there is renal impairment, concentrations in excess of 10% may be necessary. These are irritant to peripheral veins and should, if possible, be given via a central venous catheter. However, there are limitations on the quantity of fluid that can be given safely, and hypernatraemia may result from the infusion of large quantities of sodium bicarbonate. Some specific therapies used in the treatment of IEM associated with acidosis are given in Table 5. As the diagnostic and treatment modalities are complex and specialised, these children should be discussed with a specialist centre early in the course of their illness, and transferred if needed.
Sodium bicarbonate Administration of base, usually in the form of sodium bicarbonate, has been used in the management of acidosis for some time; however, its role remains controversial. Intravenous bicarbonate improves the pH and blood gases, and in some circumstances (e.g. bicarbonate-losing states) is a logical treatment. In DKA, there is some evidence against the use of bicarbonate therapy;6,7 other situations are less clear. Bicarbonate therapy aims to correct acidosis and thereby prevent dysfunction of the myocardium, brain (including the blood–brain barrier) and kidney, but may contribute to a paradoxical worsening of intracellular and intracranial acidosis. Electrolyte disturbances such as hypokalaemia and hypernatraemia can also occur, along with hypercapnia. In severe or refractory acidosis, despite aggressive treatment of hypoxia and hypovolaemia, bicarbonate may be used to temporarily improve the pH, thereby potentially aiding cardiac output, until resolution of the cause of the acidosis can be achieved. Advanced paediatric life support guidelines recommend giving a single dose of 1–2 mmol/kg of 8.4% sodium bicarbonate if the pH remains below 7.15 despite adequate resuscitation.5 Based on repeat blood gas analysis, further bicarbonate over a more prolonged period of time may be necessary, particularly if there is continued bicarbonate loss or ongoing acid production from an IEM (see below). Most commonly, the amount of bicarbonate given is that required to half correct the acidosis (full correction theoretically returns the base deficit to zero). This can be calculated according to the following formula:
Intensive care management When the acidosis is severe or refractory, early ventilation is beneficial, not only to maintain a secure airway but also because of the reduction of the metabolic demand from compensatory hyperventilation. This is particularly the case in children with IEM in whom energy production may be compromised. Intensive care support is also usually required for children requiring inotropic support. Extracorporeal techniques such as haemodialysis or haemofiltration may be required to remove toxic metabolites and correct ~ acidosis and hypernatraemia.
Half correction of bicarbonate ðmmolÞ ¼ 0:3 weight ðkgÞ base deficit ðmmol=litreÞ: When given through a peripheral vein, 8.4% bicarbonate is diluted to avoid phlebitis. THAM (tris-hydroxymethylaminomethane) has been used as an alternative to sodium bicarbonate, especially in the presence of severe hypernatraemia and in the very premature. It has the advantage of not increasing the sodium or the carbon dioxide level, but is a less effective base and still contributes to the hyperosmolar state. In hyperchloraemic acidosis secondary to parenteral nutrition, chloride salts can be exchanged for acetate, thereby reducing the chloride load, and the acetate can also act as a buffer.
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REFERENCES 1 Stewart PA. How to understand acid–base – a quantitative acid–base primer for biology and medicine. New York: Elsevier, 1980.
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2 Rinaldi S, De Gaudio AR. Strong ion difference and strong ion gap: the Stewart approach to acid base disturbance. Curr Anaesth Crit Care 2005; 16: 395–402. 3 Robinson BH. Lactic acidemia and mitochondrial disease. Mol Genet Metab 2006; 89: 3–13. 4 Fernandes J, Saudubray J-M, Van Bergeh G, (eds.). Inborn metabolic diseases. 4th Edn. Berlin: Springer; 2006. 5 Advanced Life Support Group. Advanced paediatric life support, the practical approach. Oxford: Blackwell, 2005. 6 Morris LR, Murphy MB, Kitabchi AE. Bicarbonate therapy in severe diabetic ketoacidosis. Ann Intern Med 1986; 105: 836–40. 7 Edge J, Hawkins MM, Winter DL, Dunger DB. The risk and outcome of cerebral edema developing during diabetic ketoacidosis. Arch Dis Child 2001; 85: 16–22.
PAEDIATRICS AND CHILD HEALTH 17:7
Practice points Severe metabolic acidosis is common in sick children Use of the anion gap (adjusted for albumin) can help in understanding the aetiology of the acidosis Lactic acidosis is usually secondary to poor perfusion but with ketosis is more likely to be an inborn error of metabolism Severe ketosis in the neonate is always pathological Use of sodium bicarbonate therapy is indicated in severe refractory acidosis, bicarbonate loss and a number of inborn errors
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Diagnosis and treatment of severe metabolic acidosis
Definition and aetiology Metabolic acidosis, defined as the accumulation of non-carbonic acid equivalents, may be due to excessive production or inadequate excretion of hydrogen ions or from an increased loss of bicarbonate. Changes are compensated for acutely by increased excretion of carbon dioxide by the lungs, and more chronically by renal tubular reabsorption of bicarbonate. Metabolic acidosis is evident from low plasma bicarbonate, low PaCO2 and low arterial pH. Understanding of this process has evolved over the last 100 years, beginning with the Henderson–Hasselbalch equation in 1916 and moving through the base excess, the anion gap and finally the strong ion approach of the 1980s. This latter hypothesis proposes that H+ and bicarbonate are dependent variables and that the ‘cause’ of non-respiratory acidosis is either an imbalance of strong ions (electrolytes that are fully dissociated in water, such as sodium, chloride and lactate) or changes in the concentration of weak acid buffers (e.g. albumin, globulins, inorganic phosphate).1,2 There remains controversy regarding the usefulness of this physiochemical approach to acid–base balance. While the ‘strong ion difference method’ is probably more accurate concerning the aetiology of metabolic acidosis (e.g. it explains why acidosis can result from the infusion of sodium chloride solution), it involves more complex equations and does not necessarily offer a substantial advantage in terms of affecting management over simpler methods such as the calculation of the anion gap, particularly if the latter is adjusted for changes in serum albumin. Because of this, in the immediate management of metabolic acidosis, the authors suggest using the adjusted anion gap if the plasma albumin concentration is known, or the unadjusted anion gap if it is not (Table 1).
S A Jones J H Walter
Abstract Severe non-respiratory acidosis is a frequent biochemical finding in sick children. While treatment is usually straightforward and comprises managing the underlying illness and giving supportive care, in some cases the acidosis itself requires specific therapy. The authors provide an approach to the diagnosis, investigation and management of children with severe metabolic acidosis, using the anion gap (adjusted for serum albumin) as a guide to the aetiology. Lactic acidosis, ketosis and organic acids are discussed, as are specific treatments and the general use of sodium bicarbonate as a base.
Keywords ketoacidosis; lactic acidosis; metabolic acidosis; organic acidaemias
Introduction Severe metabolic acidosis is a common acid–base abnormality in sick children; management is usually relatively straightforward and comprises providing adequate oxygenation and circulating volume, and treating the underlying cause. In certain cases of refractory acidosis or a very sick child, the treatment must also be aimed at the acid–base imbalance itself. While the diagnosis of metabolic acidosis is straightforward (requiring simple blood gas analysis), understanding the aetiology may be more complex. In this article we present the basic physiology, an algorithm to aid understanding of the disease process and some treatment options, both general and specific. For the purposes of this review, severe metabolic acidosis is classified as ‘non-respiratory acidosis causing significant clinical effects’, rather than by attaching abstract numerical limits to this concept. The review deals to some extent with all causes of severe metabolic acidosis, but focuses on the rapid identification and treatment of inborn errors of metabolism (IEM). IEM often present with metabolic acidosis, and the initial clinical and laboratory parameters are often non-specific. Early diagnosis is important to the clinical outcome, as treatments may be disease specific.
Effects of severe metabolic acidosis Metabolic acidosis in itself is rarely a cause of death, but it can contribute significantly to morbidity and has many unwanted physiological effects. These include increased energy expenditure resulting from compensatory measures such as tachypnoea, pulmonary vasoconstriction, cerebral vasodilatation and hyperkalaemia. As the acidosis progresses, respiratory distress, pulmonary hypertension and cerebral oedema develop. Myocardial depression with a significant decline in cardiac output results in poor tissue perfusion with exacerbation of the acidosis from hypoxia and lactate under-utilisation, and leads to arrhythmias and circulatory collapse. Clinically, tachypnoea and tachycardia are seen, along with more non-specific effects such as sweating, vomiting and abdominal pain.
Investigations In most severely ill children, an infection screen, arterial blood gas, blood glucose, plasma electrolytes, blood ammonia and liver function tests are indicated (Table 2). Metabolic acidosis is evident from low plasma bicarbonate, low PaCO2 and low arterial pH, and the (corrected) anion gap can be calculated from the plasma electrolytes (and albumin) (Table 1). The history and clinical examination are normally sufficient to determine the cause or to indicate which additional investigations are necessary.
S A Jones MBChB BSc MRCPCH is a Specialist Registrar in Paediatric Metabolic Medicine at the Willink Biochemical Genetics Unit, Royal Manchester Children’s Hospital, Pendlebury, Manchester M27 4HA, UK. J H Walter MBBS MSc MD FRCP FRCPCH DCH is a Consultant Paediatrician at the Willink Biochemical Genetics Unit, Royal Manchester Children’s Hospital, Pendlebury, Manchester M27 4HA, UK.
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Calculation of the anion gap and the ‘adjusted’ anion gap. Anion gap ¼ (Na++K+) – (HCO 3 +Cl ) Anion gap (adjusted) ¼ anion gap+0.25 (normal plasma albumin – measured plasma albumin)
A normal anion gap is 10–18 mmol/litre and is due to the presence of unmeasured anions such as lactate, sulphate and ketoacids.
Table 1
First-line investigations in severe metabolic acidosis. Blood gas Infection screen Glucose (bedside test and formal venous glucose) Urea and electrolytes (including chloride) Liver function tests Blood ammonia Urine dipstick for ketones and glucose Blood gases are ideally measured from arterial blood, but in much paediatric practice this is not the initial means of assessing patients and in many scenarios involving metabolic acidosis with no significant respiratory involvement, all of the information required can be gained from a free-flowing venous sample or an arterialized capillary sample. It must be remembered that if the result from a capillary gas sample obtained in this manner does not seem appropriate for the child’s clinical condition, it should be repeated, as samples from a cold or shut-down child may not represent the true state.
Table 2
Normal anion gap
GI loss of HCO3
Keto-acids
Diabetic ketoacidosis, ketotic hypoglycaemia, IEM e.g. Maple Syrup Urine Disease (MSUD), disorders of ketone body utilisation
Metabolic acidosis
Raised anion gap
Renal loss of HCO3
Lactic acid
Sepsis, Hypoxia, Hypovolaemia, IEM e.g. Glycogen storage disease, disorders of gluconeogenesis, mitochondrial disorders, pyruvate dehydrogenase deficiency
Organic acids
Drugs
IEM e.g. propionic acidaemia, methylmalonic acidaemia
Salicylate, ethylene glycol (anti-freeze) poisoning
Figure 1 Algorithm to aid understanding of the aetiology of metabolic acidosis based on the anion gap. This algorithm is clearly a simplification; some disorders present with a mixture of acid–base disturbances, with pyruvate carboxylase deficiency being perhaps the best example of this (see case history). IEM, inborn errors of metabolism.
Acidosis with a normal anion gap Acidosis with a normal anion gap, as a result of loss of base from the gut as part of severe enteropathy or from the renal tubules as part of renal tubular acidosis must be further clarified (e.g. by urinary pH and subsequent second-line investigations). Although
The algorithm shown in Figure 1 divides acidoses into those with a normal and those with an increased anion gap. An increased anion gap suggests an excess of unmeasured anions (e.g. lactate, ketones), while a normal anion gap indicates a deficiency of base (i.e. loss of bicarbonate).
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IEM are usually associated with an increased anion gap, in some disorders tubulopathy is a prominent feature (cystinosis, galactosaemia, tyrosinaemia type 1 and mitochondrial disease). Significant bicarbonate loss can also occur in patients with a ureterostomy or small bowel fistula. Intoxication with drugs often increases the anion gap, though it can be normal in ammonium chloride or acetazolamide toxicity.
Inborn errors of metabolism presenting with lactic acidosis as a main feature. Pyruvate dehydrogenase deficiency Pyruvate carboxylase deficiency Respiratory chain defects/mitochondrial disease Fructose-1,6-bisphosphatase deficiency Multiple carboxylase deficiency (as biotinidase or holocarboxylase synthetase deficiency)
Acidosis with an increased anion gap With the exception of diabetic ketoacidosis (DKA), increased anion gap acidosis requires further tests. However, it must be noted that not all cases of ketoacidosis are diabetic in origin. The most common form of increased anion gap acidosis is lactic acidosis, and this can be determined by the measurement of blood lactate as a second-line investigation (Table 3). Diagnosis of an organic acidaemia requires specialist investigations (urinary organic acid analysis by gas chromatography/mass spectrometry and/or blood acylcarnitine analysis by tandem mass spectrometry). Third-line investigations for IEM are for diagnostic confirmation and usually involve enzyme assays or molecular analysis.
Table 4
mia. In contrast to lactic acidosis secondary to tissue hypoxia, ketosis is most often present and the acidosis persists even when there is adequate cardiac output and tissue perfusion, and seems disproportionate to the degree of illness of the child.3 Caveats to this include children with cardiomyopathy or an obstructed cardiac outflow tract (hypoplastic left heart, coarctation of the aorta or interrupted aortic arch) who have very increased lactate due to profound tissue hypoxia but whose condition may be mistaken for congenital lactic acidaemia. The lactate:pyruvate ratio is another way of elucidating the cause of increased lactate; it is elevated in disorders of the respiratory chain due to an altered redox state, and normal or even low in disorders of pyruvate metabolism. Pyruvate is difficult to assay accurately, however, and most UK laboratories do not offer this service. Furthermore, the above rule is not absolute, as mitochondrial disorders that are less severe and do not alter the redox state of the cell can have a normal lactate:pyruvate ratio.4
Lactic acidosis Secondary lactic acidosis An increased blood lactate concentration is often found in very ill children. In contrast to some other metabolites (e.g. ammonia), lactate is not toxic, but it usually reflects severe pathological processes affecting tissue perfusion or oxygenation. A very high lactate concentration in this situation is often associated with a poor prognosis. ‘Hidden’ tissue ischaemia can occur in patients with compromised bowel. As the liver is the site of much lactate oxidation, liver failure can result in lactic acidosis. Primary lactic acidosis Hyperlactataemia may be caused by various IEM, particularly those affecting oxidative phosphorylation (disorders of pyruvate metabolism and the mitochondrial respiratory chain), which are often termed primary or congenital lactic acidaemias. It is also found in inherited disorders of hepatic gluconeogenesis (glucose6–phosphatase deficiency, glucose-6–phosphate translocase deficiency and fructose-1,6–bisphosphatase deficiency) and organic acidaemias (Table 4). It can be difficult to know when to suspect an IEM in sick children with an increased blood lactate. In congenital lactic acidaemias, symptoms may be apparent from birth, the blood lactate is usually above 5 mmol/litre and an anion gap is present that may be attributed to the hyperlactate-
Other causes of lactic acidosis Other causes of increased lactate include drugs and toxins (metformin, alcohol, salicylate, isoniazid, ethylene glycol, cyanide stimulants and nucleoside analogues in antiretroviral treatment), and vitamin deficiencies such as thiamine and biotin deficiency.
Ketosis Ketone production results primarily from beta-oxidation of fatty acids within mitochondria. However, a catabolic stress such as fasting or ‘illness’ should not cause significant acidosis; if this is seen, a pathological cause should be sought. Significant ketosis in the neonate is almost always pathological.3 In DKA, ketones are produced due to a lack of glucose entry into cells. In addition to DKA, significant ketoacidosis is seen in organic acidaemias, fructose-1,6–bisphosphatase deficiency, primary lactic acidosis and respiratory chain defects. It can be the sole presentation in inherited disorders of ketolysis in which episodes of recurrent severe ketoacidosis occur, generally at times of intercurrent illness. Maple syrup urine disease (keto acid branched-chain decarboxylase deficiency) presents with encephalopathy in which ketosis occurs, but this is not usually severe enough to cause a significant acid–base disturbance.
Second-line investigations. Blood lactate Blood spot for acylcarnitine profile Urine for toxicology Urine for amino and organic acids Not all tests will be needed, and should be guided by the history, examination and other investigation results.
Table 3
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tase, electron transfer protein (ETF) or ETF:ubiquinone oxoreductase, succinyl CoA:3–ketoacid CoA transferase, and glutathione synthetase. Most organic acidaemias present in the neonatal period after an initial symptom-free interval of a few days. The onset of illness is not necessarily related to the start of feeding but triggered by endogenous protein catabolism. Characteristically, there is a rapid deterioration beginning with poor feeding, irritability and lethargy and proceeding to apnoea and coma. On examination, there may be dehydration, respiratory distress, central hypotonia and limb hypertonia. Initial investigations show severe metabolic acidosis, ketosis, and usually hyperammonaemia and hypocalcaemia. Neutropenia, thrombocytopenia and hypoglycaemia or hyperglycaemia are often found. Although usual, significant acidosis is not always present in newborn infants with organic acidaemias with hyperammonaemia, in whom respiratory alkalosis may be present. Occasionally, organic acidaemias, particularly those with residual enzyme activity, first present outside the newborn period with profound acidosis and/or encephalopathy, usually provoked by an intercurrent infection. Pancreatitis and cardiomyopathy are recognised complications in older children. In methylmalonic acidaemia, progressive renal involvement can lead to acidosis without a significant increase in the anion gap because of bicarbonate wasting and dehydration from renal tubular disease, though the strong anion gap is abnormal due to an excess of methylmalonic acid. As in other inherited metabolic disorders associated with acute biochemical disturbances, the diagnosis must be made and specific treatment (where available) started as soon as possible to limit long-term morbidity. For this reason a collection of urine for organic acids and a blood spot for acylcarnitine analysis should be routine for all infants with unexplained metabolic acidosis.
Case history A female neonate (first child to distantly consanguineous parents) presents at 8 hours of age, after a normal pregnancy and delivery, with tachypnoea and poor feeding. Initial investigations are as follows: pH pCO2 pO2 Bicarbonate Base deficit Glucose
7.010 2.3 kPa 7.0 kPa 5.0 mmol/litre 26.0 mmol/litre 3.1 mmol/litre
In view of this severe metabolic acidosis, blood is taken for a septic screen and electrolytes, lactate and ammonia, and urine is collected for dipstick and organic and amino acids. Sodium Potassium Chloride Albumin Lactate Ammonia Urine dip Liver function tests
136 mmol/litre 4.2 mmol/litre 105 mmol/litre 35 g/litre 20 mmol/litre 199 mmol/litre Ketones +++ Normal
Her anion gap is thus increased at 30 mmol/litre and the cause appears to be mixed with at least lactic acidosis and ketoacidosis, with a contribution as yet undefined from organic acids. This highly raised lactate is unusual, however, in organic acidaemias and more likely to occur in primary lactic acidosis. Pyruvate carboxylase deficiency typically presents with a very raised lactate and mildly elevated ammonia, and plasma amino acids can sometimes show a typical pattern, as in this case. The acidosis here is due to a combination of hyperlactatemia, ketosis and renal tubular acidosis. Initial management is with general supportive care such as intravenous 10% dextrose and correction of the acidosis with intravenous bicarbonate therapy. While this can maintain normal pH for a time, it does not deal with the underlying defect. Pyruvate carboxylase provides oxaloacetate to the Krebs cycle and aspartate to the urea cycle. This disorder of gluconeogenesis is essentially untreatable, though there have been attempts to use a 7-carbon fatty acid (triheptanoin) with varying degrees of success.
Other inherited metabolic disorders Other inherited metabolic disorders may be associated with acidosis; for example, salt-losing forms of congenital adrenal hyperplasia (21–hydroxylase, 3b-hydroxysteroid dehydrogenase and 20,22–desmolase deficiency). Metabolic acidosis may be found in galactosaemia (as a consequence of renal tubular acidosis), but liver failure is likely to be predominant. Urea cycle disorders are often initially associated with respiratory alkalosis; however, acidosis may develop as the infant deteriorates.
Management Principles of treatment At the start of treatment, the diagnosis may be unclear. Basic supportive care must be provided, adopting the ABC approach.5 Treatment of hypovolaemia, hypoxia and electrolyte disturbances usually correct metabolic acidosis secondary to asphyxia or poor tissue perfusion. Sepsis should be assumed and intravenous antibiotics should be given until this has been excluded. In many cases, these measures correct the acidosis, obviating the need for alkali therapy, assuming parallel treatment of the underlying problem (e.g. antibiotics in sepsis). Other diagnoses may emerge at this stage (e.g. DKA, cardiac lesion) that have specific management strategies. Correct diagnosis, aided by the
Organic acidaemias Organic acids are the least easily measured of the endogenous acids, requiring specialist assays for their identification. The biochemical defects are primarily in amino acid metabolism and most commonly in the catabolism of branched-chain amino acids (propionic, methylmalonic and isovaleric acidaemia). Other, rarer organic acidaemias in which metabolic acidosis may occur include deficiencies of 3–methylcrotonyl CoA carboxylase, 3–hydroxy-3–methylglutaryl CoA lyase, holocarboxylase synthe-
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Specific medications for inborn errors of metabolism associated with metabolic acidosis. Organic acidaemias
Congenital lactic acidosis Biotinidase deficiency and holocarboxylase synthase deficiency
L-carnitine 100–200 mg/kg/day; if associated with hyperammonaemia, consider sodium benzoate 250 mg/kg/day or carbamoyl glutamate 250 mg/kg; single dose Hydroxocobalamin 1 mg i.m. daily in responsive variants of methylmalonic acidaemia Sodium dichloroacetate 50 mg/kg/day; effective at lowering lactate levels but of unproven clinical benefit; Thiamine 200 mg/day in some forms of pyruvate dehydrogenase deficiency Biotin 10 mg daily
Table 5
Treatment of inborn errors of metabolism
algorithm in Figure 1, is essential for management beyond the initial supportive stage.
In IEM with continued production of acid despite normal tissue perfusion and oxygenation (e.g. disorders of ketolysis, organic acidaemias, disorders of gluconeogenesis, congenital lactic acidosis), bicarbonate is usually an essential part of the treatment of metabolic acidosis. These conditions are in addition to those disorders with an element of renal tubular dysfunction such as methylmalonic acidaemia, some mitochondrial diseases, GLUT2 defect (Fanconi–Bickel syndrome) and pyruvate carboxylase deficiency. Glucose infused at a rate of up to 10 mg/kg/minute may inhibit protein catabolism and consequently limit the production of toxic compounds. This effect can be further augmented by adding a continuous infusion of insulin, starting at 0.01 U/kg/hour, provided that the blood glucose concentration is satisfactory. To give sufficient glucose, but to prevent over-hydration, particularly when there is renal impairment, concentrations in excess of 10% may be necessary. These are irritant to peripheral veins and should, if possible, be given via a central venous catheter. However, there are limitations on the quantity of fluid that can be given safely, and hypernatraemia may result from the infusion of large quantities of sodium bicarbonate. Some specific therapies used in the treatment of IEM associated with acidosis are given in Table 5. As the diagnostic and treatment modalities are complex and specialised, these children should be discussed with a specialist centre early in the course of their illness, and transferred if needed.
Sodium bicarbonate Administration of base, usually in the form of sodium bicarbonate, has been used in the management of acidosis for some time; however, its role remains controversial. Intravenous bicarbonate improves the pH and blood gases, and in some circumstances (e.g. bicarbonate-losing states) is a logical treatment. In DKA, there is some evidence against the use of bicarbonate therapy;6,7 other situations are less clear. Bicarbonate therapy aims to correct acidosis and thereby prevent dysfunction of the myocardium, brain (including the blood–brain barrier) and kidney, but may contribute to a paradoxical worsening of intracellular and intracranial acidosis. Electrolyte disturbances such as hypokalaemia and hypernatraemia can also occur, along with hypercapnia. In severe or refractory acidosis, despite aggressive treatment of hypoxia and hypovolaemia, bicarbonate may be used to temporarily improve the pH, thereby potentially aiding cardiac output, until resolution of the cause of the acidosis can be achieved. Advanced paediatric life support guidelines recommend giving a single dose of 1–2 mmol/kg of 8.4% sodium bicarbonate if the pH remains below 7.15 despite adequate resuscitation.5 Based on repeat blood gas analysis, further bicarbonate over a more prolonged period of time may be necessary, particularly if there is continued bicarbonate loss or ongoing acid production from an IEM (see below). Most commonly, the amount of bicarbonate given is that required to half correct the acidosis (full correction theoretically returns the base deficit to zero). This can be calculated according to the following formula:
Intensive care management When the acidosis is severe or refractory, early ventilation is beneficial, not only to maintain a secure airway but also because of the reduction of the metabolic demand from compensatory hyperventilation. This is particularly the case in children with IEM in whom energy production may be compromised. Intensive care support is also usually required for children requiring inotropic support. Extracorporeal techniques such as haemodialysis or haemofiltration may be required to remove toxic metabolites and correct ~ acidosis and hypernatraemia.
Half correction of bicarbonate ðmmolÞ ¼ 0:3 weight ðkgÞ base deficit ðmmol=litreÞ: When given through a peripheral vein, 8.4% bicarbonate is diluted to avoid phlebitis. THAM (tris-hydroxymethylaminomethane) has been used as an alternative to sodium bicarbonate, especially in the presence of severe hypernatraemia and in the very premature. It has the advantage of not increasing the sodium or the carbon dioxide level, but is a less effective base and still contributes to the hyperosmolar state. In hyperchloraemic acidosis secondary to parenteral nutrition, chloride salts can be exchanged for acetate, thereby reducing the chloride load, and the acetate can also act as a buffer.
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REFERENCES 1 Stewart PA. How to understand acid–base – a quantitative acid–base primer for biology and medicine. New York: Elsevier, 1980.
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2 Rinaldi S, De Gaudio AR. Strong ion difference and strong ion gap: the Stewart approach to acid base disturbance. Curr Anaesth Crit Care 2005; 16: 395–402. 3 Robinson BH. Lactic acidemia and mitochondrial disease. Mol Genet Metab 2006; 89: 3–13. 4 Fernandes J, Saudubray J-M, Van Bergeh G, (eds.). Inborn metabolic diseases. 4th Edn. Berlin: Springer; 2006. 5 Advanced Life Support Group. Advanced paediatric life support, the practical approach. Oxford: Blackwell, 2005. 6 Morris LR, Murphy MB, Kitabchi AE. Bicarbonate therapy in severe diabetic ketoacidosis. Ann Intern Med 1986; 105: 836–40. 7 Edge J, Hawkins MM, Winter DL, Dunger DB. The risk and outcome of cerebral edema developing during diabetic ketoacidosis. Arch Dis Child 2001; 85: 16–22.
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Practice points Severe metabolic acidosis is common in sick children Use of the anion gap (adjusted for albumin) can help in understanding the aetiology of the acidosis Lactic acidosis is usually secondary to poor perfusion but with ketosis is more likely to be an inborn error of metabolism Severe ketosis in the neonate is always pathological Use of sodium bicarbonate therapy is indicated in severe refractory acidosis, bicarbonate loss and a number of inborn errors
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