Acute Management of Sick Infants with Suspected Inborn Errors of Metabolism

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1 Indian J Pediatr (July 2011) 78(7): DOI /s SYMPOSIUM ON PICU PROTOCOLS OF AIIMS Acute Management of Sick Infants with Suspected Inborn Errors of Metabolism Neerja Gupta Madhulika Kabra Received: 15 February 2011 /Accepted: 6 April 2011 /Published online: 18 June 2011 # Dr. K C Chaudhuri Foundation 2011 Abstract Diagnosis of inborn errors of metabolism (IEM) such as an organic acidemia or urea cycle defects requires high index of suspicion in a critically ill infant as these conditions mimic common pediatric illnesses. Prompt initiation of the treatment is mandatory even if a definitive diagnosis is not established immediately. Initial screening investigations may give clues and help to classify these disorders in broad categories. It is of utmost importance to preserve samples for testing. Keywords IEM. Suspicion. Acute management Introduction Inborn errors of metabolism (IEM) are a heterogeneous group of disorders with protean manifestations. Usually they present in the neonatal period or infancy but can occur at any time, even at a later age. IEMs, though individually are rare, but one should have a high index of suspicion as mortality in severe forms is very high if prompt treatment is not initiated. Clinicians generally have a tendency to pursue this possibility only after other more common conditions, such as sepsis, have been excluded. Diagnosis of IEMs does not require extensive knowledge of biochemical pathways or individual metabolic diseases. A proper understanding of the major clinical manifestations of inborn errors of metabolism provides the basis for considering the diagnosis and further management. An early diagnosis and N. Gupta (*) : M. Kabra Division of Genetics, Department of Pediatrics, All India Institute of Medical Sciences, Ansari Nagar, New Delhi , India neerjaagarwal@yahoo.co.in institution of appropriate therapy is often life saving and can prevent permanent neurologic sequelae in these patients. This review would focus on the acute management of a child with IEM. The categories of IEM that may present acutely during infancy can be broadly divided into 1. Encephalopathy without metabolic acidosis: Urea cycle defects, nonketotic hyperglycinemia, defects in branched chain aminoacids like maple syrup urine disease(msud), peroxisomal disorders, molybdenum cofactor deficiency, and pyridoxine dependent seizures. 2. Encephalopathy with metabolic acidosis: Organic acidemias, congenital lactic acidosis, dicarboxylic aciduria. 3. Hepatic involvement with or without hepatocellular dysfunction: Amino acidopathies like tyrosinemia, fatty acid oxidation defects, mitochondrial defects, disorders of carbohydrate metabolism like Glycogen storage disorder, hereditary fructose intolerance and galactosemia. 4. Cardiac manifestations: Glycogen Storage disease type II, Fatty acid oxidation defects etc. Acute Management of IEM [1 3] The three important steps in the acute management of an IEM are: Suspicion, Evaluation and Emergency Management. I. Suspicion A metabolic disorder should be suspected in the following situations: Rapid deterioration of general condition and/ or reduced consciousness, particularly when preceded by vomiting, fever, or fasting

2 Indian J Pediatr (July 2011) 78(7): II. Nonspecific, unexplained findings of sepsis, like poor feeding, drowsiness, lethargy, vomiting, hypotonia, failure to thrive, abnormal breathing, seizures and jaundice in the presence of normal sepsis screen Rapidly progressive encephalopathy of unknown etiology Family history of neonatal death ( sepsis or SIDS ) or parental consanguinity Intractable hiccups Apnea or respiratory distress Sepsis, particularly with E. coli Dysmorphic features (in very few IEMs) Organomegaly Metabolic acidosis, Hyperammonemia, Peculiar odor*[*musty phenylketonuria; cabbage like tyrosinemia; maple syrup maple syrup urine disease; sweaty feet isovaleric academia, glutaric acidemia type II; cat urine 3-methylcrotonyl CoA carboxylase and multiple carboxylase deficiencies] Evaluation and Emergency Management This involves history, physical examination, screening investigations and initiation of therapy based on results. (A) In a neonate, the early clinical features of acute metabolic decompensation are nonspecific and include not looking well, lethargy, feeding problems, vomiting, abnormal breathing, hypotonia and seizures. Disorders of glucose, protein and fat breakdown (intermediary metabolism) in the neonatal period typically have an asymptomatic interval with the manifestations usually from the second day of life, although hyperammonemia due to transient hyperammonemia of newborn (THAN) in premature and glutaric acidemia type II or with pyruvate carboxylase (PC) in full term may present on day 1 of life. A quick history including family history (previous sib death due to sepsis, SIDS, or unexplained disorders like progressive neurological disease, multiple miscarriages,history suggestive of HELLP syndrome etc. in other family members or consanguinity) can provide useful clues about a particular disorder and its inheritance pattern. After the neonatal period, slightly older infants with metabolic disorder may present with recurrent vomiting, lethargy progressing to coma without any focal neurological signs. They may also have had episodic problems associated with minor illnesses or may just have failure to thrive and developmental delay. Physical Examination is usually normal except for nonspecific findings like lethargy, coma, (B) apnea or hyperpnea, seizures, hypotonia etc. Presence of facial dysmorphism, cataract, retinopathy, structural brain anomalies, hypertrophic or dilated cardiomyopathy, hepatomegaly, multicystic dysplastic kidneys, myopathy and peculiar odor can give clue towards a specific diagnosis. Investigations and Initial Management: Goals of treatment for patients with an inborn error of metabolism (IEM) are prevention of further accumulation of harmful substances, correction of metabolic abnormalities, and elimination of toxic metabolites. Even the apparently stable patient with mild symptoms may deteriorate rapidly with progression to death within hours. With appropriate therapy, patients may completely recover without sequelae. The initial screening investigations can be done in two phases: (1) Basic Metabolic Emergency Investigations and First Line Management The initial stabilization of an infant presenting with an acute IEM is not so much dependant on the particular disorder involved but rather on the specific metabolic abnormalities found on the initial screening tests. First insert i.v line and take blood samples for urgent analysis of initial screening tests like CBC Neutropenia is frequent in some organic acidemias. Electrolytes, ABG To evaluate for metabolic acidosis and anion gap. Glucose To rule out hypoglycaemia (also is a feature of many IEM) C-reactive protein, creatinine phosphokinase, liver function test, renal function test Ammonia Hyperammonemia is present in urea cycle abnormalities and some organic acidemias. Rapidly flowing fasting blood (uncuffed venous or arterial) should be obtained and the sample placed on ice and hand carried to the lab. The test should be done within 1 h, so prior notification to the lab is desirable. NH 3 values at various ages {Healthy neonate <110 micromol/l; Sick neonate up to 180 micromol/l; Suspect metabolic disease >200 micromol/l; After neonatal period, Healthy micromol/l; Suspect metabolic disease >100 micromol/l}

3 856 Indian J Pediatr (July 2011) 78(7): Uric acid Low uric acid especially with neurologic abnormalities, is suggestive for molybdenum cofactor deficiency. Lactate, pyruvate Elevation of lactate is a frequent secondary finding in many IEM s, but there are primary lactic acidosis due to defects in energy metabolism. The lactate/ pyruvate ratio (normal <25) will help to evaluate the possibilities. These tests are notoriously subject to artifactual changes because of sample collection or handling errors. Freely flowing blood (usually arterial) should be drawn with a minimum of tourniquet time and muscular action of the infant and transported on ice to the lab immediately. Some of the blood gas analysers have facilities of measuring blood lactate. (2) Sample collection for specific tests Plasma amino acid: 1 2 ml of blood in a heparin or EDTA tube, to be transported on ice preferably. It is important to draw this while the patient is ill, and not after treatment. Many abnormalities will disappear when the child improves and may make the diagnosis difficult. Urinalysis: The presence of ketones is unusual even in sick neonates and suggests an organic acidemia. Clinitest for reducing substances should be performed, but should be interpreted carefully because of a high false positive rate. Other tests like ferric chloride for ketoacids (positive in phenylketonuria, tyrosinemia, maple syrup urine disease, histidinemia, alkaptonuria, and in the presence of other substances such as acetoacetic acid, salicylates, phenothiazines, isoniazid, and acetaminophen), and a cyanide nitroprusside test for disulfides (positive in cystinuria and homocystinuria) may be useful if clinically there is high suspicion. Urine organic acids: ml of urine is required and is kept at 20 in an air tight container. If the sample is allowed to remain at room temperature or even in the refrigerator, volatile organic acids may disappear. It is important to obtain this sample when the patient is ill. Remember, urine is a very valuable sample for diagnosis of IEMs and should be obtained during the illness. In addition, store dried blood spot for tandem mass spectrometry (TMS), EDTA sample for DNA analysis and freeze 1 2 ml of plasma. (C) (D) Store CSF (should be frozen immediately) if lumbar puncture is performed. Follow General Treatment Protocol: Immediate elimination of dietary or parenteral intake of the potentially toxic compounds like protein, fat, galactose, fructose. Provide adequate glucose to prevent catabolism after establishing airway, breathing and circulation. Prevent catabolism: A metabolically simple source of calories, such as glucose at a rate sufficient to slow the catabolism and to suppress mobilization of endogenous sources of the metabolite, like protein should be administered. An increase in catabolism due to stress from infection, surgery etc. can rapidly overwhelm the compensatory mechanisms and result in clinical decompensation and hence should be avoided. 1. Administer high calorie, high carbohydrate intravenous fluids: 10% Dextrose in 0.2% of NaCl at 1.5 times calculated maintenance, and add KCl when urinary output is established. Start at least 60 kcal/kg/day (preferably ml/kg/day). The caloric intake can be increased up to kcal/kg/day. 2. Withhold intake of protein: Protein should not be withheld indefinitely. If clinical improvement is observed and a final diagnosis has not been established, some amino acid intake should be provided after a maximum of 2 to 3 days of complete protein restriction. Essential amino acids or total protein can be provided orally or intravenously at an initial dose of 0.5 g protein/kg/24 h. This should be increased incrementally to 1.0 g/kg/24 h and held at that level until the diagnostic evaluation is complete and plans can be made for definitive long-term therapy. 3. IV intralipids may be used to increase the caloric intake if the patient does not have a defect in fatty acid oxidation. 4. Avoid Ringer lactate. Treatment and Investigations according to the Initial Findings: If the emergency investigations show a specific abnormality, then treatment is provided accordingly as follows: a. Increase excretion of toxic metabolites by using alternative pathways. For example, carnitine is useful in the elimination of

4 Indian J Pediatr (July 2011) 78(7): organic acids in the form of carnitine esters. Sodium benzoate and phenylacetate are useful in treating hyperammonemia. Treat Hyperammonemia [4]: If acute hyperammonemia is associated with encephalopathy due to urea cycle defect, administer sodium phenylacetate and sodium benzoate. These compounds are conjugated with glycine and glutamine respectively, resulting in the excretion of 1 and 2 ammonia molecules per molecule of drug, respectively. Give priming doses of the following immediately in 20 ml/kg of 10% glucose, to be infused with in 1 2 h: Sodium Benzoate, load 250 mg/kg (5.5 g/m 2 ) Sodium Phenylacetate, load 250 mg/kg (5.5 g/m 2 ) In patients suspected of having a urea cycle defect because of significant hyperammonemia without acidosis, an infusion of mg/kg of 10% arginine HCL can be given intravenously over 60 min and then 6 ml/kg/d IV in four divided doses. 0 After initial loading, continue infusions of sodium benzoate mg/kg/24 h, sodium phenyl acetate mg/kg/24 h and arginine mg/kg/24 h. All these are usually prepared as 1 2% solutions. 0 When used intravenously, sodium phenylacetate and sodium benzoate must be given by central line. Arginine HCl can be mixed with it; arginine HCl dose can be decreased to 200 mg/kg if known carbamyl phophate synthetase (CPS) or ornithine transcarbamylase (OTC) deficiency. 0 L-carnitine conjugates with and inactivates sodium benzoate; therefore, this must not be given with sodium phenylacetate and sodium benzoate. 0 Unfortunately, intravenous preparations of Sodium Benzoate, Phenylacetate and Arginine are not easily available in India and oral preparations are to be used in same doses. 0 Peritoneal dialysis or hemodialysis is required if the ammonia is 4 times normal or rising quickly. Nephrologist should be notified early so that they can be prepared. Although peritoneal dialysis, continuous arteriovenous hemoperfusion, and ex- change transfusion have been used in the past to lower plasma ammonia levels, all are substantially less effective than hemodialysis. In infants who are comatose or ventilator-dependent, or who exhibit evidence of cerebral edema, dialysis should be instituted immediately without waiting to determine whether there is a response to dietary manipulation, medication, or other less aggressive therapy. If hemodialysis is not readily available, peritoneal dialysis (<10% as effective as hemodialysis) or double volume exchange transfusion (even less effective) can be performed while arrangements are made to transport to a center where hemodialysis is possible, as long as this does not delay transfer. Two to 3 days of therapy is usually necessary. b. Correct Metabolic Acidosis Increased Anion Gap [>16 mmol/l] It should be treated cautiously. Bicarbonates is generally not indicated unless the plasma bicarbonate is <10 mmol/l; deficits are only half corrected. [Sodium bicarbonate: meq/ kg/h (up to 1 2 meq/kg/h) IV; Calculations of bicarbonate requirements appropriate for the treatment of other conditions are rarely adequate in these disorders because of ongoing production of organic acids or lactate. The acid-base status should be monitored frequently, with therapy adjusted accordingly. Hemodialysis should be considered for severely acidotic neonates with organic acidemias, regardless of whether hyperammonemia is present. (peritoneal dialysis, hemofiltration, exchange transfusion are much less effective). c. Correct Hypoglycemia (blood glucose <45 mg/dl at all ages) 0 10% glucose with electrolytes ( ml/kg/d) 8 12 mg/kg/min IV at times maintenance to maintain serum glucose level at mg/dl which should prevent catabolism. High-volume maintenance fluid will also promote urinary excretion of some toxic metabolites. 0 If the patient is hypoglycemic and dextrose is administered as a bolus, give normal saline without D10. 0 Avoid hypotonic fluid load due to the risk of cerebral edema, particularly if hyperammonemia is present. 0 If necessary, treat hyperglycemia with insulin ( U/kg/h). d. Increase the residual enzyme activity This is usually accomplished by administration of pharmacologic doses of the vitamin cofactor for the defective enzyme. If the binding constant for the vitamin has been altered and the enzyme is otherwise reasonably functional, increasing the vitamin concentration will increase enzyme activity via a mass action effect. Hence, one should consider empiric vitamin therapy until the disorder is diagnosed (Table 1).

5 858 Indian J Pediatr (July 2011) 78(7): Table 1 Vitamins used to treat various Inborn errors of metabolism Vitamin Dose Disorder treated Thiamine 5 20 mg/kg po qd (up to 500 mg) Maple syrup urine disease Biotin 5 20 mg po qd Biotinidase or holocarboxylase synthase deficiencies Vit B mg cyanocobalamin IM qd Methylmalonic aciduria Riboflavin mg tid po qd Glutaric acidemia types I and II L-carnitine at mg/kg tid given po/ng or mg/kg IV over 2 3 min or as infusion, followed by mg/kg/d (maximum 3 g/d) may be administered empirically in life-threatening situations associated with carnitine deficiency. Administration of L-carnitine to patients with secondary carnitine deficiency is controversial. Consultation with an IEM specialist is recommended. e. Treat shock, electrolyte imbalance, infection and coagulopathies f. Nonacidotic, Nonhyperammonemic Seizures 1. Pyridoxine mg IV trial. If there is a response (pyridoxine responsive seizures), give mg of pyridoxine po qd. It should be given to neonates with seizures unresponsive to conventional anticonvulsants. 2. Riboflavin mg tid po qd (glutaric acidemia type I). 3. High dose benzodiazepines, sodium benzoate (nonketotic hyperglycinemia). If results are inconclusive but metabolic disease remains a possibility: 0 Continue glucose infusion 0 Review the history and clinical signs. Consult a metabolic specialist 0 Send samples for specialized tests like for acylcarnitines etc 0 Monitor electrolytes, glucose, lactate, acid-base status (E) Specialized and Definitive Tests: Numerous other specialized tests are performed depending on the clinical context. Examples include carnitine, acylcarnitines (TMS), Urine organic acids by Gas Chromatography mass Spectroscopy (GCMS),very long chain fatty acids, lysosomal enzymes, etc. Many of these tests are done at only few places in the country and it can take weeks to get results. These tests should generally be ordered after consultation with the clinical geneticist or metabolic specialist. A definitive diagnosis may sometimes be made from screening tests but often specific enzymatic analysis (F) or DNA testing is required. It may be necessary to biopsy tissues such as liver or muscle. These tests, if done at all, are usually done in research laboratories and it may take months for results. Ongoing Management [5]: Once a specific diagnosis is established then depending upon the disorder, specific treatment (mainly diet) is initiated and genetic counseling is done. Specific Treatment Specific treatment, depending upon the type of metabolic disorder, is provided. These diets are commercially available but are quite costly. Hence, treatment should be closely supervised by a team of metabolic expert, dietician and social worker. Liver transplantation may be curative in disorders like in severe neonatal form of urea cycle defects and tyrosinemia. Genetic Counseling Family should be provided with adequate genetic counseling regarding prognosis, recurrence risk, and possibility of prenatal diagnosis. Post Mortem Specimen Collection [1] Usually patients with metabolic diseases are quite sick and often die. Hence, one should try to preserve the samples, especially biopsy samples soon after death (within 1-2 h of death). SAVE: 0 Serum and plasma (centrifuge about 10 ml) 0 Dried blood spot on filter paper card used for TMS 0 Freeze ml of urine at 20 C 0 EDTA blood (3-5 ml) for future DNA analysis 0 Skin biopsy for fibroblast culture Points to Remember Treatable inherited metabolic diseases often present in early infancy or childhood as acute life threatening illness. Appropriate and aggressive empiric treatment before the confirmation of a diagnosis may be life-saving and may avert or reduce the neurologic sequelae of some of these disorders.

6 Indian J Pediatr (July 2011) 78(7): It is of the greatest importance that the appropriate sample collection be made before starting any treatment, because abnormal biochemical data can help in initial management and allow the definitive diagnosis. References 1. Burton BK. Inborn errors of metabolism in infancy: a guide to diagnosis. Pediatrics. 1998;102:E Clarke JTR. Acute metabolic illness in the newborn. In: Clarke JTR, editor. A clinical guide to inherited metabolic diseases. 3rd ed. Cambridge: Cambridge University Press; pp Ogier de Baulny H. Management and emergency treatments of neonates with a suspicion of inborn error of metabolism. Seminars in Neonatology. 2002;7: Summar M. Current strategies for the management of neonatal urea cycle disorders. J Pediatr. 2001;138:S Clarke JTR. Treatment. In: Clarke JTR, editor. A clinical guide to inherited metabolic diseases. 3rd ed. USA: Cambridge University Press; p