Perioperative management of pediatric patients with inborn errors of metabolism during liver transplantation

Abstract

Inborn errors of metabolism (IEM) are rare disorders, most are liver-based with liver transplantation (LT) emerging as an effective cure in the pediatric population. LT has been shown to offer a cure or deter disease progression and provide symptomatic improvement in patients with IEM. Each metabolic disorder is unique, with the missing enzyme or transporter protein causing substrate deficiency or toxic byproduct production. Knowledge about the distribution of deficient enzymes, the percentage of enzymes replaced by LT, and the extent of extrahepatic involvement helps anticipate and manage complications in the perioperative period. Most patients have multisystem involvement and can be on complex dietary regimens. Metabolic decompensation can be triggered due to the stress response to surgery, fasting and other unanticipated complications perioperatively. Thus, a multidisciplinary team’s input including those from metabolic specialists is essential to develop disease and patient-specific strategies for the perioperative management of these patients during LT. In this review, we outline the classification of IEM, indications for LT along with potential benefits, basic metabolic defects and their implications, details of extrahepatic involvement and perioperative management strategies for LT in children with some of the commonly presenting IEM, to assist anesthesiologists handling this cohort of patients.

Key Words: Inborn errors of metabolism; Anaesthesia for paediatric liver transplantation; Metabolic crisis; Hyperammonemia in paediatric liver transplantation; Perioperative care in metabolic liver diseases

Core Tip: Most metabolic disorders are liver-based, and liver transplantation (LT) has emerged as an effective cure for a variety of inherited metabolic disorders in the pediatric population. LT has been shown to offer a cure, deter disease progression and provide symptomatic improvement in patients with inherited metabolic disorders. Perioperative management of these children presenting for LT with inborn errors of metabolism requires disease specific and patient specific strategies in all aspects right from preoperative assessment, intraoperative and postoperative management compared to those presenting with other indications. Knowledge about the distribution of deficient enzymes, the percentage of enzymes replaced by LT, and the extent of extrahepatic involvement helps anticipate and manage complications in the perioperative period.

INTRODUCTION

Inborn errors of metabolism (IEM) are a group of disorders with impairment of a critical pathway in the cellular metabolism resulting in multisystem disabilities or even death[1]. These rare disorders have a collective incidence ranging from 1 in 800 to 1 in 2500 live births, which varies based on the geographical distribution[2-4]. Each metabolic disorder is unique, with the missing enzyme or transporter protein causing substrate deficiency (e.g., glucose in glycogen storage disorder) or toxic byproduct production (e.g., succinyl-acetone in tyrosinemia). Most metabolic disorders are liver-based, and liver transplantation (LT) has emerged as an effective cure for a variety of inherited metabolic disorders in the paediatric population. The utility of LT varies widely within the spectrum of metabolic disorders. At one end of the spectrum, it is offered as a life-saving curative procedure, in disorders such as urea cycle defects. On the other end, it is offered to improve the quality of life, in disorders such as bile acid transporter defects by relieving pruritus. LT has been shown to offer a cure, deter disease progression and provide symptomatic improvement in patients with inherited metabolic disorders[1]. Innovations and advancements in surgical techniques, such as the use of mono-segment grafts, have made it possible to transplant even small infants with minimal complications. Here, in this review, we aim to provide an overview of specific strategies in this cohort of patients that will benefit paediatric anaesthesiologists caring for this group of patients.

Perioperative management of these children presenting for LT with IEM requires specific strategies in all aspects right from preoperative assessment, intraoperative and postoperative management compared to those presenting with other indications.

PREOPERATIVE ASSESSMENT AND CONCERNS

Most patients have multisystem involvement and can be on complex dietary regimens. Thus, a multidisciplinary team’s input is essential while performing LT for these patients to develop disease and patient specific strategies. From LT perspective, Menon et al[5] in their review article, divided metabolic disorders into three broad categories (Table 1).

Table 1 Classification of metabolic disorders from a perspective of liver transplantation.

Category	Description	Examples
A	Disorders with enzyme defect only in the liver and LT is done predominantly for ESLD and its related complications	Tyrosinemia (HT-1); A1AT deficiency; galactosemia (type 1); WD; hereditary fructosemia; GSD 3 and 4; CDG
B	Disorders with enzyme defects limited to the liver. These patients rarely have ESLD; LT is performed for extrahepatic organ involvement	UCD; porphyrias; GSD type 1 PH, FH; Crigler-Najjar syndrome
C	Disorders having enzyme defect in the liver and extrahepatic tissue and LT only partially corrects underlying metabolic disease and alleviates symptoms of extrahepatic organ involvement	MMA; PA; MSUD; MH

ESLD: End-stage liver disease; HT-1: Hereditary tyrosinemia type 1; A1AT: Alpha-1 antitrypsin; WD: Wilson disease; GSD: Glycogen storage disorder; CDG: Congenital disorder of glycosylation; LSD: Lysosomal storage disorders; UCD: Urea cycle disorders; PH: Primary hyperoxaluria; FH: Familial hypercholesterolemia; LT: Liver transplantation; MMA: Methyl malonic acidemia; PA: Propionic acidemia; MSUD: Maple syrup urine Disease; MH: Mitochondrial hepatopathies.

Category A

The enzyme is deficient in the liver, causing liver cirrhosis that progresses to end-stage liver disease.

Category B

The enzyme is solely expressed in the liver with extrahepatic organ involvement and an LT offers a complete cure.

Category C

The enzyme is expressed throughout the body, and LT provides a partial cure.

Table 2 summarizes the various metabolic disorders and their common clinical features. Knowledge about the distribution of deficient enzymes, the percentage of enzymes replaced by LT, and the extent of extrahepatic involvement helps anticipate and manage complications in the perioperative period. Typically, LT is performed for end-stage liver disease and its complications in Category A patients. In Category B, LT is offered to cure the underlying problem, which predominantly affects extrahepatic organs. In Category C patients, where there is predominant extrahepatic involvement, LT offers metabolic control but may not completely correct the underlying problem due to ongoing toxin accumulation from extrahepatic tissues. Understanding these nuances aids in anticipating and managing complications during the perioperative period both in the living donor as well as the deceased donor LT setting.

Table 2 Summary of various metabolic disorders and their common clinical features.

Metabolic defect involving	Disorders	Extrahepatic organs involved	Major clinical features
Carbohydrate	Glycogen storage disease Ia	Kidneys, pancreas	Hypoglycemia, lactic acidosis, HCC and adenoma
	Glycogen storage disease Ib	WBC, colon, small bowel	Features of type 1a along with recurrent infections and inflammatory bowel disease, liver cancers and adenoma
	Glycogen storage disease III and IV	Skeletal muscle	Chronic liver disease (IV > III), hypoglycemia (rare), myopathy (proximal)
	Transaldolase deficiency	Hematological, cardiac, renal	Cirrhosis, cardiac malformations, seizures, renal tubular acidosis
	Fructosemia	Renal	Cirrhosis, HCC, sweet aversion, poor growth, renal tubular defects,
	Galactosemia	Brain, Eyes, Renal	Cirrhosis, neonatal liver failure, hypoglycemia, oil drop cataract, autism
Amino acids	Tyrosinemia type I	Renal, peripheral nerves, pancreas	Neonatal liver failure, cirrhosis, HCC, adenomas in liver, neurological crises, RTA, islet cell hyperplasia, cabbage odor in urine
	Maple syrup urine disease	Brain	Recurrent seizures, cycling movements in infancy, ataxia, dystonia, maple syrup odor in body secretions
	Urea cycle disorders	Brain	Hyperammonemia coma, developmental delay, seizures, liver dysfunction (rare) (Reye syndrome)
	Methyl malonic Acidemia	Brain, renal, hematological cardiac and skeletal muscle	Developmental delay, metabolic crises and strokes, chronic renal failure (mainly after 2nd decade), bone marrow suppression, cardiomyopathy
	Propionic acid acidemia	Brain, skeletal muscle, hematological cardiac	Metabolic crises, bone marrow suppression, cardiomyopathy, muscle weakness, strokes (rare)
Fatty acids	Fatty acid oxidation defects	Muscle, cardiac	Acute liver failure and Reye like illness, muscle weakness, cardiomyopathy and conduction defects (sudden deaths)
Peroxisomal	Primary hyperoxalosis type 1	Kidneys, musculo-osseous, eyes, cardiac	Chronic kidney failure, hyperostosis and fractures, myopathy, cardiac infiltration with oxalate and dysfunction, oxalate retinopathy
	Zellweger syndrome	Brain, cardiac, kidneys, musculoskeletal	Developmental delay, hypotonia, seizures in infantile variant, liver cirrhosis and HCC in late variant, chondrodysplasia punctata, renal cysts
Bile transporter defects	PFIC-1, VI	Intestines, pancreas, sensory hearing	Cholestasis, liver cirrhosis, protein loosing enteropathy, pancreatic insufficiency, hearing loss, sweat chloride elevation: Type 1 tufting enteropathy: Type VI
	Non 1 PFIC	Nil	Cholestasis, liver cirrhosis, HCC, gall stones (Type III), acute liver failure like presentation (Type V)
Mitochondrial disorders and energy cycle defects	DNA depletion defect	Kidneys, intestines, brain, muscle	Liver: ALF and Reye syndrome (common drug triggered), Cirrhosis (rare), cholestasis. Brain: Recurrent seizures, developmental delay, extra pyramidal issues. Muscles: Skeletal and cardiac myopathy; Small bowel: Enteropathy, pseudo-obstruction. Pancreas: Insufficiency. Eye: Retinitis pigmentosa. Ear: Sensory hearing loss
Bilirubin Conjugation	Crigler Najjar syndrome	Brain	Acute bilirubin encephalopathy, Kern icterus causing developmental delay, extra pyramidal movements
Heme metabolism	Porphyrias	Liver, skin, dental, peripheral nerves	Recurrent pain abdomen; porphyric crises (can cause respiratory failure), seizures, peripheral neuropathy, chronic liver disease (rare), photosensitivity, erythrodontia (73)
Cholesterol excretion	Familial hypercholesterolemia	Skin, joints, cardiovascular	Generalised atherosclerosis, disfiguring skin and tendon xanthomas, aortic root dilatation

RTA: Renal tubular acidosis; HCC: Hepatocellular carcinoma; WBC: White blood cell count; ALF: Acute liver failure; PFIC: Progressive familial intrahepatic cholestasis.

CARDIOVASCULAR ASSESSMENT

12-lead electrocardiogram (ECG) and 2-D transthoracic echocardiography are performed routinely for all patients as part of the pre-operative assessment. Cardiomyopathy is seen in IEMs such as Glycogen Storage Disease (GSD), organic acidemia (OA), primary hyperoxaluria (PH1), and mitochondrial disorders[6]. Patients with PH1 can often present with reduced ejection fraction (EF) attributable to oxalate deposits induced cardiomyopathy. Such patients demonstrate improvement in EF following aggressive hemodialysis[7,8]. An EF of less than 40% is considered a contraindication for LT by most centers and requires appropriate optimization. ECG findings such as conduction defects and ventricular tachycardias have been recorded in PH1 patients[6]. In conditions like GSD and OA, there are reports showing improvement in cardiomyopathy following LT. This is considered likely due to the repopulation of cardiac muscle fibers by donor stem cells from the transplanted liver[9-12]. However, in mitochondrial disorders, cardiac involvement is considered a surrogate marker of a generalized disease process and remains a contraindication for LT[13].

Patients with homozygous familial hypercholesterolemia (FH) stand at the risk of developing atherosclerotic complications such as coronary artery disease, aortic valve stenosis, supra valvular aortic stenosis, and thoracic/abdominal aortic aneurysms[14,15]. In addition to 2D echo, carotid and abdominal ultrasonography will be required in these patients. In the presence of atherosclerotic plaques in carotid ultrasonography or when the Achilles tendon is thick, extensive atherosclerotic disease should be suspected, and further evaluation with coronary CT or cardiac MRI is warranted to rule out coronary artery disease[14,15].

NEUROLOGICAL ASSESSMENT

Neurological involvement is a frequent finding in many IEMs[16]. Extent of neurological involvement and chances of post-transplant neurological recovery/improvement needs to be addressed with the family before transplantation in IEM such as OA and tyrosinemia[12]. Preoperative magnetic resonance imaging (MRI) should be performed to assess and evaluate the extent and pattern of brain involvement before transplant. MRI findings such as cerebral volume loss, gliosis, hypomyelination, and diffusion restriction in midbrain structures are frequently recorded in OA disorders[17]. Incidences of intracranial hemorrhages have also been reported here. Cerebral edema is another feature noted in patients with poor metabolic control here while cerebral atrophy can be seen in mitochondriopathies[18]. Neurocognitive functions remain static post LT in amino acid (AA) disorders while intelligence quotient may improve in maple syrup urine disease (MSUD) after LT[19,20]. Neuropathy, myopathy, movement disorders and neurobehavioral problems are other concerns encountered in many metabolic disorders.16 (Table 2). A record of the antiepileptic medications, if any, has to be noted and any potential hepatotoxic medications should be avoided. Ideally, analysis of the POLG1 gene is recommended for all patients with suspected mitochondrial disease before initiating valproate therapy because of high incidences of valproate-induced acute liver failure in such patients[21]. If this analysis is not feasible, treatment with valproic acid should be avoided in these patients[21]. Children with AA disorders benefit from early transplantation to prevent the worsening of neurocognitive impairment. LT as a quality-of-life improving strategy in contrast to a life-saving strategy is increasingly applied for IEM due to overall improvement in LT outcomes. Evaluation of risk- benefit ratio is important to address the complex ethical challenges in this cohort[20,22].

LIVER AND RENAL CONSIDERATIONS

Features of hepatocellular dysfunction such as jaundice, ascites, and coagulopathy are frequently seen in patients in the Class A IEM (Table 1).

Patients with PH1 are offered combined liver and kidney transplantation (CLKT). This subset of patients presents with dialysis-dependent renal failure, cardiomyopathy and/or brittle bones due to oxalate deposition. Patients with high oxalate load should be planned for aggressive hemodialysis (HD) before the transplant, especially to optimize the cardiac EF and a plan must also be made for intraoperative continuous renal replacement therapy (CRRT)[23]. Hypertension is a frequent concern in patients with PH requiring multiple antihypertensives. The loss of contractile function of the arteries due to oxalate deposits also contributes to the development of hypertension in addition to renal failure[24]. Prolonged duration of surgery should be anticipated in cases of CLKT[8]. CLKT should be considered in other disorders when accompanied by chronic kidney disease such as methylmalonic acidemia, alpha-1 antitrypsin deficiency, and GSD type 1A[25-27].

OTHER SPECIFIC CONSIDERATIONS

Hyperammonemic encephalopathy

Hyperammonemia is generally defined as a plasma level above 80 μmol/L in infants from birth to 1 month of age and above 55 μmol/L in older children and adults[28].

This a major concern in urea cycle disorders (UCD), OA and MSUD which can progress to seizures and coma[29,30]. Prolonged fasting, fever, infections, Gastrointestinal bleeding, and increased protein intake have all been shown to trigger protein catabolism, thereby leading to hyperammonemia[31]. Hence, special attention to triggers of hyperammonemic episodes in the past, along with the continuation of antiepileptics and supplemental cofactors that optimize the abnormal metabolic pathway or aid in the elimination of toxic metabolites (e.g., ammonia scavengers like Sodium Benzoate) is important[23,24]. Symptoms of acute hyperammonemia can vary from gastrointestinal symptoms to cerebral oedema[31]. Patients with symptomatic hyperammonemia require stabilization in the intensive care unit and can be managed with ammonia scavengers along with antiedema measures.

Resource availability and institutional preferences usually determine the choice of dialysis modality. Intermittent HD and CRRT have demonstrated superior efficacy in hyperammonemia crisis than peritoneal dialysis[29,30]. In our experience, we prefer using CRRT intraoperatively and in the immediate postoperative period. In the consensus developed by the Pediatric CRRT group[32]; CRRT was recommended for hyperammonemia when the following indications are met: (1) Rapidly deteriorating neurological status, coma, or cerebral oedema with blood ammonia level > 150 μmol/L; (2) Presence of either moderate or severe encephalopathy; (3) Persistently high blood ammonia levels > 400 μmol/L refractory to medical measures; and (4) Rapid rise in blood ammonia levels to > 300 μmol/L within a few hours that cannot be controlled with medical therapies. For neonates, given open fontanelles, HD can be considered beyond 350 micromol/L[33]. Precipitants must be identified and tackled. Nutritional supplementation must be continued with protein suppression for not more than 48 hours along with 1-1.5 times the maintenance glucose infusion rates (GIR). The timing of transplantation following an acute hyperammonemic event can be decided based on the clinical status and at the discretion of the treating team. A special mention about ammonia level assessments is that careful blood extraction without a tourniquet, preferably an arterial sample, must be used to prevent false hyperammonemia. The samples must be kept cold and processed within the next hour. Metabolic decompensation can be triggered due to the stress response to surgery and fasting perioperatively. Hence prolonged fasting periods must be avoided and glucose-containing intravenous fluids must be started once fasting commences. Standard GIR can be initiated based on age. However, in the event of hyperglycemia during the standard recommended GIR, glycemic control with insulin infusion is advised rather than reducing or stopping the GIR as the latter could precipitate a metabolic crisis[34].

Contraindications for LT

The major contraindication for LT in metabolic liver disease is presence of severe extrahepatic disease. This includes advanced neurological and cardiopulmonary dysfunction. A typical example of the above is mitochondrial disorders and hence their outcomes following an LT depend on the aforementioned factors, as these could manifest at a later age. The same scenario is noted in patients with lysosomal storage disorders (Eg Nieman Pick disease type-C) as a liver transplant offered for cirrhosis does not have an impact on the nervous system manifestations. Another scenario is in Wolman disease, which is a lysosomal storage disorder. Apart from the progression of neurological illness in the post-transplant period, these patients can have a recurrence of storage disease in the graft leading to graft dysfunction in the future[35].

Donor selection in living donor LT

In the majority of metabolic liver disorders, heterozygous donors could be safely utilized[36]. In patients with Wilson disease, heterozygous donors with normal urine copper excretion can be safely considered as donors[37]. In patients with primary hyperoxalosis, heterozygous donors with a normal 24-hour urine oxalate are accepted[38]. In patients with OA like propionic acidemia[36], heterozygous donors are safely used but there are a few reports of metabolic decompensation while utilizing livers from heterozygous donors of MSUD[39]. However, at our center, we have routinely used livers from heterozygous donors with MSUD and no metabolic dysfunction has been noted in recipients in the post-LT period. Since the majority of reported liver-related mitochondrial disorders are autosomal recessive, heterozygous donors can be utilized in case of acute liver failure scenarios in case of organ scarcity. In tyrosinemia type-1, the continued excretion of succinyl acetone is independent of the donor status and occurs as a part of the persisting defect in the kidneys. In autosomal dominant disorders like FH, the use of a heterozygous donor can only be justified in the absence of a cadaveric organ and this has been proven safe in LDLT centres[15]. In cases of X linked disorders like Ornithine transcarbamylase deficiency, females can be used as donors if their hepatic enzyme activity is established as normal[40].

INTRAOPERATIVE MANAGEMENT

These patients must be scheduled first on the operating list to avoid prolonged fasting period[41,42]. Preoperative arterial blood gas analysis should be obtained in AA and OA disorders to record baseline biochemical parameters. Continuation of ammonia scavengers is important even while the patient is fasting (Table 3).

Table 3 Anesthetic implications in inherited metabolic disorders during liver transplantation.

Metabolic defect involving	Disorders	Specific anesthetic considerations
Carbohydrate	Glycogen storage disease I	Dextrose infusion. In case of hyperglycemia-insulin to be started along with dextrose infusion. Avoid Ringer’s Lactate. Difficult IV access and airway
	Glycogen storage disease III and IV	Dextrose infusion. In case of hyperglycemia - insulin to be started along with dextrose infusion. Avoid Succinylcholine. Difficult IV access and airway
Amino acids	Tyrosinemia type I	Dextrose infusion. Fracture prone hence caution while positioning
	Maple syrup urine disease	Ensure BCAA free supplements, isoleucine and valine supplements are give preoperatively. Dextrose infusion. Avoid Ringer’s lactate and resuscitation with Albumin. Hemodialysis standby
	Urea cycle disorders	Intraoperatively use Ammonia scavenging agents such as sodium benzoate and/or phenylbutarate and arginine infusion along with serial ammonia monitoring. Dextrose infusion along with intralipid infusion and low protein parenteral nutrition. Avoid Ringer’s lactate and resuscitation with Albumin. Hemodialysis standby
	Methyl malonic Acidemia	Avoid propofol, atracurium, cisatrcurium, Nitrous oxide, Naproxen, Ketoprofen. Intraoperatively use ammonia scavenging agents such as sodium benzoate and Carnitine along with serial ammonia monitoring. Dextrose infusion. Avoid Ringer’s lactate and resuscitation with Albumin. Metronidazole prophylaxis. Hemodialysis standby. Continue carnitine postoperatively. Renal sparing immunosuppression
	Propionic acid acidemia
Fatty acids	Fatty acid oxidation defects	Dextrose infusion. Perioperative seizure prophylaxis. Avoid Ringer’s lactate and resuscitation with Albumin. Hemodialysis standby
Peroxisomal	Primary hyperoxalosis type 1	Perioperative CRRT. Platelet dysfunction. Hypertensive crises. Renal sparing Immunosuppression. Fracture prone hence caution while positioning
Bile transporter defects	PFIC-1, VI	Malnutrition/growth retardation. Fracture prone hence caution while positioning
Mitochondrial disorders and energy cycle defects	DNA depletion defect	Perioperative seizure prophylaxis. Avoid succinylcholine, isoflurane and propofol
Bilirubin conjugation	Crigler Najjar syndrome	Malnourished/growth retardation. Fracture prone hence caution while positioning
Cholesterol excretion	Familial hypercholesterolemia	May need planning for lipid apheresis 2-4 weeks prior to surgery. If on Preoperative blood thinners, appropriate bridging and safe discontinuation to be planned. Anticipate Difficult airway due to facial asymmetry and xanthomas. Anticipate difficult vascular access Perioperative thromboembolic events

Induction

Propofol, as the induction agent of choice, is specifically avoided in cases of propionic acidemia, since the emulsion contains polyunsaturated fatty acid which gets metabolized to propionyl CoA which in turn can increase the patient’s levels of propionic acid leading to acidemia. The accumulation of propionyl CoA and other metabolites have been shown to result in cardiotoxicity by free radical induced damage and may also predispose them to development of fatal arrhythmias[33,42]. Propofol should also be avoided in mitochondrial disorders due to the risk of precipitation of metabolic decompensations[43,44]. Special consideration should be given, in the presence of cardiomyopathy, since a sudden drop in the afterload on induction of anesthesia can result in cardiac ischemia. For maintenance of adequate tissue perfusion, age specific perfusion pressure targets should be maintained. Thiopentone, Etomidate and ketamine or any inhalational agent can be used safely for induction.

Muscle relaxants

Atracurium and cisatracurium are best avoided in patients with OA since these agents undergo ester hydrolysis and produce metabolites such as odd chain organic molecules[45]. Use of succinylcholine is best avoided because of concerns of hyperkalemia and rhabdomyolysis in patients with IEMs associated with myopathies[46]. Other muscle relaxants can be safely used.

Maintenance

Surgical stress response and the associated catabolic states and could precipitate a metabolic decompensation[47]. Volatile anesthetics, isoflurane, sevoflurane, and desflurane suppress oxidative phosphorylation, particularly at complex I and complex V and coenzyme Q and patients with mitochondrial disorders exhibit markedly increased sensitivities[48]. It has been shown that if used at appropriate concentrations to maintain adequate depth of anesthesia, they are well tolerated. The rapid elimination of newer volatile anaesthetic agents allows rapid return of mitochondrial function at the end of surgery[49].

Parenteral anesthetic agents undergo extensive hepatic metabolism and excretion. Of the parenteral agents, Propofol is unique and affects mitochondrial metabolism by uncoupling oxidative phosphorylation, inhibiting complexes I, II, and IV and inhibiting the transport of long-chain acylcarnitine esters[50] which is implicated as the mechanism behind propofol infusion syndrome. Therefore, it is advisable to avoid propofol-based anesthetic techniques to patients with mitochondrial disorders but intermittent boluses during induction seem to be well tolerated[49,51].

Airway positioning

Positioning of patients warrants special attention, especially in cases with contractures, cervical spine instability and brittle bones in diseases such as PH1 and PFIC. In PH1 patients, deposition of calcium oxalate crystals in bone can predispose these patients to pain, recurrent low-intensity fractures and deformations. Severe malnutrition and fat-soluble Vitamin deficiency are frequently noted in patients with PFIC. They present with brittle bones and poor muscle mass[52]. Hence appropriate airway assessment & preparation must be planned before induction of anesthesia.

Vascular access

In addition to securing 2 wide-bore peripheral lines, a central line in the internal jugular must be secured. Preemptive placement of a HD catheter should be considered in patients with recurrent severe decompensations or when expertise for emergency intraoperative placement is limited[53]. Arterial cannula, usually placed in the radial artery, will aid in frequent ammonia sampling in addition to continuous monitoring of blood pressure and blood gases.

FLUIDS, ACID-BASE BALANCE AND INTRAOPERATIVE TESTING

Lactate-containing fluids such as Ringer’s lactate are generally not recommended during LT. Few studies have shown the safe usage of Ringer lactates in patients with OA for short surgeries and may be considered cautiously in well-compensated patients undergoing minor procedures[54]. Resuscitation with Albumin has to be performed cautiously as it could increase protein load, in patients with USD and OA[55]. Blood gas analysis, electrolytes, blood glucose, ammonia, urinary ketones and temperature need to be monitored meticulously along with optimization of volume status. Risk factors for metabolic acidosis such as hypovolemia, hypothermia, hypoglycemia, hyperlactatemia and hemodynamic instability should be carefully sought and corrected.

Dextrose

There is a significant risk of intraoperative hypoglycemia and hence dextrose at 6-10 mg/kg/minute must be started and titrated as per hourly blood glucose monitoring. In cases of hyperglycemia, it is recommended to start insulin infusion and continue dextrose infusion alongside[34] (Table 4).

Table 4 Standard Glucose infusion rates as per age cut offs in the pre transplant period.

Age	Glucose infusion rates	10% glucose infusion rate
< 2 years	10 mg/kg/minute	150 mL/kg/day
2-6 years	8 mg/kg/minute	120 mL/kg/day
> 6 years weight < 30	6 mg/kg/minute	90 mL/kg/day
> 6 years weight 30-50	4.5 mg/kg/minute	67 mL/kg/day

In patients with MSUD, special attention must be paid to prevent cerebral oedema and an increase in intracranial pressure. It should be noted that ammonia may not be a good marker of metabolic decompensation in MSUD (ideally leucine levels need to be monitored), and this could mislead the clinical management. There have been reports of increased cerebral oedema with overhydration and hypertonic infusions of glucose in these patients. Hence intravenous lipid formulations like 20% Intralipid can be used intraoperatively to avoid this complication at an infusion rate of up to 2.5 g of fat/kg/24 hours[56].

Ammonia scavengers

These agents play a vital role in the management of hyperammonemia. Sodium benzoate binds with glycine while Sodium phenylacetate or sodium phenylbutyrate binds with glutamine to produce byproducts which get excreted in urine[31]. L- Carnitine is another agent of benefit in hyperammonemia. Carnitine increases acetyl CoA which enhances the production of N-acetyl glutamate, thereby activating urea synthesis and ammonia utilization[31].

In the perioperative period, sodium benzoate, carnitine and phenylbutyrate can be converted to equivalent doses of intravenous preparation and given as a 24-hour infusion or as boluses every 6th hourly intraoperatively to avoid acute increases in ammonia levels due to the catabolic stress from the surgery. Carnitine at 25 mg/kg made in 50 mL should be infused over 60 minutes every 6 hours[57]. Sodium benzoate at a dose of 80 mg/kg diluted in 50 mL of 10% dextrose should be infused over 60 minutes every 6 hours. Sodium phenylbutyrate at a dose of 60 mg/kg diluted in 50 mL of 10% dextrose should be infused over 60 minutes every 6 hours. In case of non-availability of intravenous preparations, these can be given as bolus doses via the nasogastric tube. Intraoperative CRRT should be considered when the ammonia levels remain persistently high or increasing, > 200-350 micromol/L in children < 18 months and > 150 micromol/L in older children[31]. Intraoperative CRRT has been shown to be safe, efficacious and feasible[58,59]. In centers where resources and expertise are available, CRRT can be safely performed. Flushing the extracorporeal circuit with normal saline every 30-60 minutes can offset the concern of circuit clotting due to the risk of bleeding with anticoagulation. In resource-limited settings, intermittent HD has also been shown to be safe and efficacious in the intraoperative period[60]. CRRT may decrease the problem of rebound increase in ammonia compared to intermittent HD[61]. In patients with hyperammonemia, high-dose CRRT commencing with 50 mL/kg/hour of effluent flow rate is generally recommended[62]. Choice of CRRT modality also depends on institutional preference, but we use continuous venovenous hemodiafiltration because of the advantages of prolonged circuit lifespan[63]. Hence, frequent monitoring of acid-base status and ammonia levels should be planned during surgery. Ionic formulations containing sodium can lead to dangerous increases in sodium levels and hence require close observation.

In case of acute decompensation

Intravenous boluses of Carnitine 100 mg/kg, sodium benzoate 250 mg/kg over 90-120 minutes, sodium phenyl butyrate 250 mg/kg over 90-120 minutes can be administered. N Carbamoyl glutamate 100 mg/kg is given as oral dose and is to be followed by 25-62 mg/kg every 6 hours.

Arginine: Arginine is used as a urea cycle enhancer aiding in nitrogen excretion through the Urea cycle. For patients on preoperative Arginine, the total daily dose shall be continued as an infusion diluted in 10% dextrose and run over 24 hours when metabolically stable. The oral dose recommended is 100-200 mg/kg Q6H with a maximum dose of 6 g in 24 hours. However, in sicker patients, the dose can be increased up to 150-400 mg/kg/day. Sodium benzoate and phenylbutyrate can be prepared together as one infusion while Arginine needs to be run through a separate infusion line. Maximum drug concentration to be made at 50 mg/mL of each drug. In case of acute decompensation, 250 mg/kg as a bolus over 90-120 minutes is to be administered followed by maintenance doses of 250 mg/kg/day.

Coagulation

Platelet dysfunction is frequently encountered in primary hyperoxalosis[41], increasing the risk of perioperative bleeding in these patients. Point of care modalities such as viscoelastic testing (ROTEM and TEG) are of great assistance for coagulation correction here.

Others

Broad-spectrum antibiotics, for perioperative surgical prophylaxis, can be based on the local antibiogram. Metronidazole 10-20 mg/kg/day in 2-3 divided doses should be used perioperatively in cases of propionic acidemias. Metronidazole has been shown to reduce the production of propionyl CoA derived from anaerobic bacterial fermentation of carbohydrates in the gut which usually accounts for a large proportion of the total body propionate and hence has been recommended for prophylactic usage in this subset of patients. Antiemetic medications with antidopaminergic effects such as metoclopramide should be avoided in cases at risk of exacerbation of extrapyramidal symptoms[34].

POSTOPERATIVE CONSIDERATIONS

General aspects: Weaning from mechanical ventilation can be a challenge because of preoperative comorbid conditions such as encephalopathy and myopathy. Hence thorough assessment must be made prior to extubation in order to avoid airway catastrophes.

Close monitoring in the postoperative period for acid base balance and glycemic control must be continued to avoid metabolic decompensations. In cases such as PH1, dialysis should be continued for at least 48 hours postoperatively along with monitoring of oxalate levels[8,64].

Nutritional aspects

The majority of these children will have a new “Roux en Y” Hepaticojejunostomy loop and can be started on oral feeds postoperatively on days 3-5. These patients are either on parenteral fluids or total parenteral nutrition till initiation of enteral feeding. In most of these disorders, postoperative glucose infusions need to be maintained at 8-10 mg/kg/minute and 6-8 mg/kg/minute for neonates and older children respectively. Transient insulin resistance is commonly encountered here leading to the requirement for insulin infusions to deliver glucose intracellularly for metabolism. Protein in the form of AA infusion is started at 0.8 to 1 g/kg/day and with serial monitoring of ammonia values, the requirement per day is increased by 0.5 g/kg/day till a recommended intake of 3-3.5 g/kg/day is reached. This ensures that the graft has adapted to the increasing protein load. A moderate protein intake of 2.5 g/kg/day is recommended in patients with methyl malonic acidemia (MMA). Some authorities recommend avoiding drain replacement with albumin, but this practice is not universally followed[53]. The main aim of nutritional support is to avoid protein catabolism and provide appropriate substrates for energy and growth.

Ammonia is monitored once a day for the first 3-5 days and later once a week until the child is on a full-protein diet. Ammonia scavenging agents can be gradually stopped in the post-LT period once normal levels are attained on a normal protein diet. It should be remembered that serum ammonia levels > 150-200 mmol/dL warrant CRRT in the post-LT period also. Patients with PA have to continue carnitine intake in the post-LT period as the metabolic defect is not fully corrected and these patients can have urinary carnitine loss due to accumulating organic acids. None of the other patients needs to be started on a special or restricted formula as the metabolic defects get rapidly corrected post-LT. Routine monitoring of specific metabolites is not recommended unless there is an unexpected clinical course in the postoperative period. In patients with MSUD, ammonia may not be a good marker to look for metabolic resolution, which is elucidated with serum leucine levels.

In addition to the above specific strategies for LT in IEM, routine postoperative care should be given as for any LT patient[65]. Monitoring of graft function involves daily liver function tests including prothrombin time, blood counts, renal function tests and electrolyte profiles. Doppler Ultrasound is performed daily or twice daily in some centers for the first 5 days and then on alternate days until discharge to evaluate the patency and flow patterns of hepatic artery and portal vein and to look for intrahepatic biliary radical dilatation and or intraabdominal collections. Usually, children are started on triple immunosuppression (IS) consisting of steroid, tacrolimus and mycophenolate mofetil in most of the centers including ours. Renal sparing IS, using Basiliximab and mycophenolate mofetil can be considered in patients with MMA with renal involvement, PH-1 for pre-emptive LT, to decrease the potential incidence of renal adverse effects caused by Tacrolimus.

Role of auxiliary LT in IEM

An auxiliary (partial) orthotopic LT (APOLT) performed in patients with IEM, is intended to supply enzymes that are deficient in the recipient. It is offered to patients suffering from non-cirrhotic IEM. The major advantage of offering an APOLT for IEM is to avoid metabolic stress which can result in a metabolic crisis, during anhepatic phase. Since a part of the native liver is left behind, a scenario of complete anhepatic phase doesn’t occur in patients undergoing an APOLT. It also decreases the intraoperative cardiac stress. An APOLT is not offered for conditions like Primary hypercholesterolemia or Primary hyperoxalosis as the remnant native liver would continue to synthesize significant amount of metabolites which continues to cause organ damage[66].

LONG TERM OUTCOMES AFTER LT FOR IEM

Several studies have suggested improved or better outcomes in LT for IEMs compared to LT performed for nonmetabolic liver diseases[67,68]. It has been observed that ten years patient survival post LT was significantly better in patients with IEM when compared to non metabolic liver diseases[69,70]. Chronic rejection is more commonly encountered in this cohort of patients. In a single center study with 15% of LT performed for IEM, the rate of retransplantation has been around 6%[71]. Complete metabolic recovery has been reported in most IEMs especially with MMA with normal dietary protein intake although on the pediatric quality of life inventory scale, social functioning, performance at school, treatment anxiety, and communication appeared to lag behind in comparison to other non metabolic pediatric recipients[70].

CONCLUSION

Anaesthesiologists caring for children with IEM during LT should have a thorough knowledge of the metabolic defect, associated dysfunction in other systems, triggers for metabolic decompensation and the appropriate and timely intervention in such scenarios. Multidisciplinary inputs including that from metabolic specialists are essential for the safe conduct of LT in this cohort of patients.