Abstract
Pediatric acute liver failure (ALF) is a rare complex clinical syndrome with a fatal outcome, if not diagnosed and treated at the right time. ALF in children can be difficult to recognize and is very different from ALF in adults; in terms of definition, etiology, symptomatology and management. The causes of ALF in children represent a large heterogeneous list, which vary by age and geographical location. The management of ALF mandates multidisciplinary approach with comprehensive intensive and supportive care; which at times is complex and can be challenging to a pediatric intensivist. The key steps in management are to monitor and support affected organ systems; anticipate, identify and treat complications; and maintain optimal clinical condition till spontaneous recovery or liver transplantation. This review describes definitions, etiopathogenesis, clinical features and the most recent management strategies, including emergency liver transplantation considerations in pediatric ALF.
Key Words: Acute liver failure, pediatric, liver transplantation, Hepatic encephalopathy
Introduction
Acute liver failure (ALF) in pediatrics represents a syndrome with numerous etiologies, diverse and unclear pathophysiology, complex clinical features and lack of specific therapies. Over the last three decades ALF has transformed from a condition with a near fatal outcome, to one in which complex critical care protocols are applied and emergency liver transplantation (LT) is an established treatment option, thus overall improving prognosis.1 The pediatric intensivist has to focus on meticulous supportive measures, fluid therapy, metabolic correction, aggressive control of sepsis, neuro- monitoring and neuro-critical interventions; with major intention of providing supportive care till spontaneous regeneration of the diseased liver or recovery by liver transplantation. There is no other critical illness or multi-organ failure in pediatric intensive care like acute liver failure which poses so many controversies at each and every step of its management. Acute liver failure in children is not very common and although definitions and management have been adapted from adult literature, yet there are many unique aspects specific to pediatrics.
Definition and Classification: Pandora's Box
ALF is a better overall term and to avoid confusion it has replaced previous descriptions like fulminant hepatic failure and fulminant hepatitis or necrosis.2 The definitions used in adults have few essential requirements like presence of encephalopathy, coagulopathy, time limit (within 8 to 26 weeks) in a patient with no preexisting liver disease.3 These adult descriptions are not apt for defining ALF in children due to following reasons:
1. ALF in children may present without clinical evidence of hepatic encephalopathy (HE). Also HE is difficult to recognize in infants and small children.
2. ALF can present in neonates, hence time limit of within 8 weeks is not appropriate in children.
3. Uncorrectable coagulopathy is the essential, consistent, reliable finding in children with ALF, with or without encephalopathy. In adults, deranged coagulation, without encephalopathy with evidence of hepatitis is termed acute liver injury, not ALF.
<br/>4. ALF may be the first manifestation of an underlying unrecognized metabolic problem, which is usually associated with variable degree of chronic liver injury, such as Wilsons disease, inborn error of metabolism etc. Therefore ALF in children may reveal an underlying chronic liver disease.
Pediatric ALF is thus best described as a clinical syndrome associated with massive necrosis of liver cells or sudden, severe impairment of liver function, with or without hepatic encephalopathy (HE) developing in an individual with no recognized chronic liver disease. The Pediatric Acute Liver Failure (PALF) Study Group used the following criteria 4,5.
(1) No evidence of a known chronic liver disease
(2) Biochemical evidence of acute liver injury
(2) Hepatic-based coagulopathy that is not corrected by parenteral administration of vitamin K:
HE must be present if the uncorrected prothrombin time (PT) or international normalized ratio (INR) is between 15 and 19.9 seconds or 1.5 to 1.9, respectively.
HE is not required if the PT or INR is greater than or equal to 20 seconds or 2.0, respectively.
Some authors have sub-classified ALF into distinct groups: hyperacute liver failure, acute liver failure, and subacute liver failure since the tempo of its clinical evolution provides clinicians
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valuable clues about probable etiology and may predict outcome (Table 1). In brief, a short interval between symptoms or jaundice and encephalopathy (like acetaminophen-induced ALF and some of hepatitis A etiology) is associated with the high risk of brain edema and greater probability of spontaneous recovery, whereas a long interval is associated with less frequency of brain edema, but lower survival, and more commonly, non–A-to-E/ cryptogenic as etiology.6,7,8 Although this type of multiple categorization creates confusion, yet it is important for an intensivist to recognize the clinical utility of same.
The term ‘acute on chronic liver failure’ (ACLF) is used in adults; however there is no clear consensus on its definition9. It is generally used to indicate rapid deterioration of a pre-existent chronic liver disease (CLD) which has high short term mortality10,11.
Etiology and epidemiology :
ALF affects children worldwide and the etiology remains age and region dependent. Causes of ALF can be classified into seven categories: metabolic, infective, toxic, autoimmune, malignancy-induced, vascular-induced, and indeterminant. In infants, metabolic disease is the most frequent cause of ALF, whereas in children, viral hepatitis (in developing countries) or drug induced ALF (in North America and United Kingdom) is the commonest cause12,13,14. ALF of indeterminate cause is frequently observed in children. It is seen in 40% of ALF among children younger than 3 years and in 60% of ALF in the age-group of 3 years and older5 (Table 2). With extensive latest investigations, the rate of indeterminate causes of ALF has decreased, however it still remains a challenge in resource limited countries.
Pathogenesis of acute liver failure
The specific pathogenesis of liver injury is dependent mostly on the etiology. But irrespective of etiology, it is now clear that ALF is not one disease of the liver but rather a consequence of multiple organ dysfunctions at various levels. Characteristically, hepatocellular injury is central to pathogenesis of ALF. The initial direct insult and subsequent interplay of cytokines leads ultimately to hepatocyte necrosis or apoptosis15,16.The innate immunity mediated response through monocytes, macrophages, leucocytes etc, express receptors on their cells, which are able to recognize pathogen-associated molecular patterns (PAMPs) in viral hepatitis and damage-associated molecular pattern (DAMPs) in toxin mediated liver injury; which result in release of proinflammatory cytokines initially locally in liver, eventually spilling over to systemic circulation. In addition to this, general loss of Kupffer cell function and severe hepatocellular injury results in compromised glucose hemostasis, increased lactate production with reduced clearance of endotoxin and other substrates leading to an intense systemic inflammatory response syndrome(SIRS)17. This disturbed endothelial, coagulation and immunological system subsequently results in organ cross talk, leading to distant organ damage. The existence of compensatory anti inflammatory response syndrome (CARS) - mediated by anti inflammatory cytokines is not only insufficient to counter the response, but predisposes to bacterial and fungal sepsis during evolution of ALF18.
Hepatic encephalopathy (HE) that occurs in ALF is complex and multifactorial. Exact pathogenesis is not completely understood and various hypothesis have been suggested 19,20. Hyperammonemia, increased levels of false neurotransmitters and neuroinhibitory GABA along with various other cytokines and chemicals are believed to contribute to cerebral edema and dysregulation of metabolism in the brain leading to HE.
Ammonia, infection/inflammation, and hyponatremia are the main contributors to the development of cerebral edema in ALF. Ammonia that reaches the brain is converted to glutamine by astrocytes, which then accumulates and in high concentrations exert an osmotic effect leading to cerebral edema. Systemic Inflammatory response syndrome (SIRS) and sepsis further cause oxidative injury and endothelial damage leading to increased permeability of cerebral circulation, adding further to brain swelling and raised intracranial pressure(ICP). Also this holds true for hyperammonemia seen in ALF which develops rapidly and hence the osmotic compensatory mechanisms are ineffective, unlike in subacute or decompensation of chronic liver failure where compensatory mechanisms are functioning, and so intracranial hypertension is uncommon21.This has been substantiated by studies where higher arterial ammonia levels have been found to be predictive of higher mortality and are associated with more complications including cerebral edema ( ammonia serum levels > 124umol/L), seizures, and cerebral herniation (ammonia serum levels > 150 - 200umol/L) in ALF, but this correlation does not exist in subacute or ACLF22,23,24.
Clinical features
The chaos surrounding the patient with ALF at admission makes the initial assessment challenging, but a detailed history with physical examination cannot be abbreviated. Clinical examination should be carried with two major intents; first to establish the etiology and second to determine the status of major organ systems (renal, cerebral, hepatic, cardio-vascular and
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respiratory). In viral-induced ALF, jaundice is preceded by symptoms such as fever, myalgia, arthralgia, and nausea. Thereafter, jaundice worsens, liver enzymes become increasingly elevated, and prothombin time becomes prolonged before HE appears. In an infant, symptoms can be nonspecific, sometimes only related to vomiting, altered general condition and jaundice may develop subsequently. On examination a rapidly shrinking liver with falling liver enzymes and rising bilirubin, suggests massive hepatocellular necrosis and can be used as an indicator for poor prognosis. Ascites is mostly seen in ACLF, rather than ALF, with the exception of Budd-Chiari syndrome.
Hepatic encephalopathy (HE) may be absent in spite of severe liver dysfunction or develop within a few hours to days to weeks from onset of liver failure in children. HE is classified into four grades using a modification of the West Haven criteria 25,26 (Table 3 and 4). From an intensivists point of view, the patient should be clinically assessed initially and then multiple times during the day for each component of the HE score, as clinical progression can be devastatingly rapid.
Diagnostic workup
Initial laboratory tests should be focused into three main areas: (a) general laboratory investigations: for assessment of major organ systems, (b) etiological investigations and (c) serial liver investigations.
(a) General laboratory investigations: to assess sepsis, hematological, renal status etc (Table 5).
(b) Etiological tests: need to be prioritized according to age and history (Table 6). Wilson's disease presenting as ALF needs special consideration, as it may be difficult to diagnose. This is because low ceruloplasmin level can be present in most patients with ALF, regardless of etiology and is not specific for Wilson’s disease. Also, KF rings are not uniformly present and serum copper levels may take several days to obtain and may not be reliable. In these cases, the following tests aid in making a diagnosis of Wilson’s disease in ALF:
Presence of Coomb’s negative hemolytic anemia
Very low serum alkaline phosphatase or uric acid levels
Combining ratios: Ratio of serum alkaline phosphatase to total bilirubin < 4 and aspartate to ALT >2.2 can be used as a reliable markers27,28
(c) Liver Tests - Liver status can be assessed by serial measurement of serum aminotransferase levels, total and direct bilirubin, ammonia, prothrombin time, partial thromboplastin time, lactate and ammonia. It is recommended that if an arterial line is present, ammonia should be sampled preferably from that access as it is thought that significant ammonia extraction occurs across the skeletal muscles. To determine if there is evidence of significant liver synthetic dysfunction, factors V, VII, VIII, and fibrinogen should be measured. Factor VIII level will be normal even in the face of ALF and can help in differentiation from DIC, where it is low. Ultrasound abdomen is essential to look at liver parenchyma (nodularity, texture etc), varices, splenomegaly, portal hypertension and doppler to look for patency of hepatic veins, portal veins and hepatic artery.
HAV- Hepatitis A, HbsAg- Hepatitis B surface antigen, CMV- cytomegalovirus, EBV- Ebstein Barr virus, ANA- Antinuclear Antibody, ASMA- Anti Smooth Muscle antibody, anti- LKM- anti Liver, Kidney Microsome, NK- Natural Killer, OTC- ornithine transcarbamylase
Management (Figure 2)
Advances in critical care medicine and management strategies have reduced mortality in ALF. Mortality is mainly attributed to three complications in particular: cerebral edema, multiorgan dysfunction syndrome (MODS) and sepsis. The following section will review ICU based management strategies and interventions that have evolved to address the various organ dysfunctions associated with ALF.
Principles of management
1. Monitor and support the patient and organ systems.
2. Identify and treat complications
3. Treat the patient to maximize chances of spontaneous recovery and maintain optimal clinical condition for best post-transplant survival
Although these principles appear straightforward, their practical applications are more complex. Due to the rapidity of the illness and potentially devastating course, the patient requires close observation in a suitable facility, where mechanical ventilation, rapid availability of blood products, intra cranial pressure monitoring (if deemed beneficial) and renal replacement therapy are present. Typically, this level of support warrants referral to transplant center, where emergency liver transplantation if needed, may be life saving.
Electrolytes and sugar:
- Hypoglycemia - Hypoglycaemia may be present in most of patients with ALF. So regular blood sugar monitoring is important (every 1-2 hours). Hypoglycemia can worsen hepatic encephalopathy and cause rapid neurological deterioration. Intravenous glucose infusion (6-8mg/kg/min) is recommended in patients who develop hypoglycemia.
- For Dextrose concentration greater than 12.5% - central venous catheters should be used, femoral or jugular access is preferred.
- Frequent monitoring and correction of other metabolic derangements like hypokalemia, hypophosphatemia, and hypomagnesemia are critical.
Fluid therapy and hemodynamic considerations
- Fluid: The aim is to maintain hydration and renal function, while not causing cerebral edema and fluid overload. Restriction of fluids to 2/3rd maintenance is generally advisable, provided the child is haemodynamically stable. Children are frequently hypovolemic due to inadequate fluid intake and due to vomiting / diarrhea which could be a part of preceding illness. This requires adequate fluid replacement and fluid titration.
- Shock: Patients with ALF usually have a sepsis-like hyperdynamic circulation with low systemic vascular resistance. This is due to vasoplegia with intense arterial vasodilatation which follows release of endogenous vasodilators
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especially nitric oxide which escape from the splanchnic to systemic circulation. This hyperdynamic circulation with low systemic vascular resistance (SVR) necessitates fluids followed by inotropic agent (Nor-epinephrine is preferred via central line, preferably jugular/femoral) 29, 30.Bedside echocardiography can guide fluid therapy, by assessing pre-load, contractility and ejection fraction. Arterial line must be inserted in patients with cardio pulmonary instability or in whom ICP monitoring is planned. In refractory hypotension, hydrocortisone may be beneficial (adrenal insufficiency can occur in ALF).
Respiratory system & ventilation
- Oral intubation is preferred by modified RSI (rapid sequence intubation), with a cuffed endo tracheal tube, due to risk of bleeding and aspiration. Indications of intubation are:
> Grade 2 encephalopathy
Raised intracranial pressure
Rapidly deteriorating course
Respiratory failure
Cardiovascular collapse
- Aim to oxygenate (SpO2 >90 %) and maintain normocarbia (PaCO2 35-45 mmHg)
- Excessive hyperventilation should be avoided and must not be used as a prophylactic measure, but only as a transient maneuver to control surges of ICP31 , as it may paradoxically compromise the cerebral perfusion pressure(CPP). Partial pressure of CO2 (PaCO2) < 30 mmHg must be avoided.
- Mechanical ventilation exposes patient to a spectrum of ventilator-associated complications such as pneumonia and acute respiratory distress syndrome (ARDS). Protective lung strategy is the gold standard to manage acute lung injuries, but with a careful balancing act as high PEEP with low tidal volume can adversely affect cerebral edema.
- Effective sedation before tracheal suction is essential to prevent ICP surges
Cerebral edema and intracranial hypertension
The first line of treatment is to minimize aggravating conditions that can increase ICP. Therefore, any precipitating events that can result in hyperammonemia or raised ICP should be avoided. The treatment is divided into 2 parts for better understanding, depending of the stage of encephalopathy.
Treatment for Grade I and II encephalopathy:
The usual line of treatment includes the following:
(a) Lowering endogenous nitrogen intake (by limiting bleeding and controlling infection ) or exogenous nitrogen intake (avoiding unjustified fresh frozen plasma administration)
(b) Lactulose was recommended by some groups in early stages of encephalopathy but there is presently insufficient evidence to support the use of non-absorbable disaccharides
(Lactulose and Lactitol) for HE in ALF32. It may be useful for chronic encephalopathy of CLD but not in HE of ALF. On the contrary, lactulose in critically ill patients with ALF may be harmful. Lactulose may aggravate ileus and can cause abdominal distention & osmotic diarrhea; which can lead to electrolyte disturbance and hypovolemia.
(c) Neomycin is not recommended and should not be used, as it may precipitate renal failure and has not shown a benefit when combined with lactulose.
(d) Ornithine aspartate and sodium benzoate have been proposed to decrease serum ammonia, in Reye syndrome and in urea cycle defects, but hemofiltration remains the main treatment of acute hyperammonemia. Recent randomized controlled trial has shown no benefit of ornithine aspartate infusion in adult ALF33.
(e) Efforts should be made to minimize neurosensory and painful stimulation (quiet room, limited nasopharyngeal aspiration).
(f) A patient with aggressive behaviors or delirium is a challenge for intensivist. Elective ventilation should be considered if encephalopathy progresses or airway becomes an issue. If short sedation is required for procedure or restraint, propofol or opiates can be used 34. Benzodiazepenes should be avoided.
(g) Osmotic therapy: They act by raising blood osmolarity, thereby reducing astrocyte swelling in brain. Mannitol can be used as first-line therapy (2ml/kg/dose of 20% mannitol) and given as repeated boluses, provided serial serum osmolality is below 320 mOsm/L, as the equilibrium in osmolality will render the drug ineffective 35.The rapidity with which mannitol acts, suggests it also acts by increasing cerebral blood flow. Its use however is limited once patients develop significant kidney injury or patient is in shock. In contrast to mannitol, hypertonic saline can be used as a prophylactic measure with few adverse effects, with a goal of achieving sodium of 145 to 155 mEq/L, provided serum osmolality remains below 360 mOsm/L36.
(h) Raising the head end of bed to 20-30 degree, provided there is no shock. Avoidance of neck rotation additionally helps to reduce cerebral edema.
Treatment for grade III and IV encephalopathy:
(a) Intubation and ventilation: At this point adequate analgesia and sedation are required. Propofol and fentanyl are suggested combination 37. However, one needs to be careful in using propofol in hemodynamically unstable patients as it can drop the BP, and further compromise CPP. However, propofol has 2 advantages: it can decrease cerebral blood flow and thereby lower ICP and secondly it can decrease the risk of seizure activity, which can be sub clinical 38. But due to the risk of propofol infusion syndrome, its use beyond 24 hours is controversial in children.
(b) If osmotic therapies fail to adequately control ICP, other adjunctive measures to reduce ICP include:
Transient hyperventilation-only if there are signs of impending herniation
Moderate hypothermia (32oC-33oC)- so far it appears to be a formidable tool for managing refractory ICP elevations39. Starting paralysis at this time helps to avoid surges in raised ICP secondary to shivering/rigors due to cooling
Barbiturate coma- It is used to reduce brain metabolism, although incremental benefit is unclear if the patient is already in stage 4
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encephalopathy with coma. Continuous EEG is recommended till burst-suppression is achieved. Thiopental levels to be done frequently.
Hepatectomy- is rarely considered especially when the intensivist has exhausted all measures to neuroprotect the patient; it is in most instances an act of desperation in refractory cases, provided a potential donor has been identified. In these patients, CRRT also has to be continued intra-operatively till the patient is anhepatic. It acts as an artificial liver in these instances.
(c) ICP monitoring: No consensus exists on the use of invasive ICP monitoring. The risk of intracranial hemorrhage and absence of evidence of improved survival are the major reasons against its routine use40. However some centers do practice insertion of ICP monitors, indications being hyper acute liver failure with grade 4 encephalopathy, patient listed for LT, patient on vasopressors41. Although the goals for CPP are less well defined, most authorities treat hypotension with vasopressors (usually norepinephrine) to maintain a CPP of >50 to 60 mm Hg. Non invasive methods of neuro-monitoring – transcranial doppler examination, near-infra red spectroscopy, tympanic membrane displacement, optic nerve sheath diameter are emerging as useful tools to identify ICH. However, evidence is still insufficient for routine use 42.
(d) Seizures: If seizure occurs in ALF, it has to be treated with phenytoin or levetiracetam as seizures cause spikes in ICP. But prophylactic anti-epileptics in ALF are not recommended43. Continuous EEG monitoring is advisable especially in high risk patients. EEG changes occur very early in HE, even before physiological or biochemical disturbances.
Infectious disease consideration
Infection is a common complication of acute liver failure. In a recent study by the USALFG, the progression of hepatic encephalopathy was associated with sepsis, especially in those with acetaminophen-induced ALF.
Patients with ALF are prone to infections because they have impaired polymorphonuclear leukocyte function, impaired cell-mediated and humoral immunity, and diminished opsonic and complement activity. Some of the factors that predispose to infection are presence of indwelling catheters, H2-receptor blockers, steroid therapy and broad spectrum antibiotics.
Empirical administration of broad spectrum antibiotics is recommended in the following circumstances where infection or the likelihood of impending sepsis is high44:
a) Surveillance cultures reveal significant isolates
b) Advanced stage (III/IV) hepatic encephalopathy
c) Persistent hypotension
d) Presence of systemic inflammatory response syndrome
e) Patients listed for liver transplant (LT).
Prophylactic systemic antifungal therapy may be warranted in patients who are listed for LT, have renal failure or those septic patients who show poor response to antibacterial therapy. The choice of an antimicrobial agent must take into account the need to cover a broad spectrum of
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gram-positive and gram-negative organisms, with special consideration to antibiogram of the institute. In general, third-generation cephalosporin are recommended. Aminoglycosides are to be avoided if possible, owing to their potential for nephrotoxicity. Eventually antimicrobial therapy may be narrowed accordingly, as per organism identified and sensitivity reports. The administration of oral non-absorbable antibacterials for selective decontamination of the gut does not appear to improve survival in patients already receiving prophylactic systemic antibacterials45.
Hematologic failure: Dealing with coagulopathy
Overt bleeding is not so common in patients with ALF and this reflects a rebalanced haemostatic defect. In most cases, the loss of hepatic synthesis of procoagulant factors is compensated by the loss of hepatically derived anticoagulants (protein C/S or antithrombin III) also, thus leading to a relatively balanced state of hemostasis46. Despite profound elevation in INR in most patients with ALF, there appears to be minimal global effects on haemostasis. In situ, a hypofibrinolytic state is present in ALF, due to decreased plasminogen and elevated plasminogen activator type 1. These findings substantiate the recommendation that prophylactic correction of coagulopathy in ALF patients should not be done without overt bleeding. Also, unnecessary FFP will interfere with the evaluation of liver function (prothrombin time) which is essential for monitoring disease progression and for assessment of prognosis in ALF. Other disadvantages associated with unnecessary FFP include fluid and protein overload and hyperviscosity syndrome. An exception to this would be if an invasive procedure is planned, such as placement of a central venous catheter or ICP monitor or if a patient is listed for LT. In these cases, procedures can be performed under cover of FFP, platelet or cryoprecipitate. Although strict guidelines do not exist, a rough target would be to correct the INR to approximately 1.5 and platelet count to approximately 50,000/mm3 before procedures. Newer studies suggest using thromboelastography for finer management in bleeding patient47. Concomitant administration of cryoprecipitate is recommended for patients who have significant hypofibrinogenemia (less than 100 mg/dL) in a bleeding patient. When FFP fails to adequately normalize PT/INR, the use of recombinant factor 7a (rF7) can be considered. Cryoprecipitate should be administered before rF7 (40 mg/kg) if fibrinogen levels are less than 100 mg/dL to replete factors involved in the clotting cascade.48
Gastrointestinal haemorrhage
In presence of gastrointestinal bleeding, coagulopathy and thrombocytopenia should be corrected. One must ensure prompt availability of packed cells and other blood products in such cases. Administration of Vitamin K 5-10 mg intravenously is recommended49 but it can be avoided in G6PD deficient patients due to added risk of hemolysis. Octreotide infusion (0.5-1mcg/kg/min) may be considered in cases of active profuse gastrointestinal bleeding, to decrease portal pressures. Patients with ALF in the ICU should receive prophylaxis with H2 blocking agents (ranitidine 1-3mg/kg dosed every 8 hours or PPIs (pantoprazole 0.5 to 1.0mg/kg/day upto 20 mg for children <40 kg) or sucralfate as a second-line agent for acid-related gastrointestinal bleeding associated with stress50.
Acute Kidney Injury
The incidence of acute kidney injury in acute liver failure varies from 30 to 85% depending on
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the etiology. As discussed above acute liver failure is a state of hyperdynamic circulation with low SVR and resultant decreased blood pressure which shifts the renal autoregulation curve to the right making it pressure dependant and hence predisposing to the development of acute tubular necrosis.
The aim is to maintain optimal circulating blood volume and ensure good urine output ( greater than 1 ml/kg/hr). An early fluid challenge is indicated in patients who develop oliguria, followed by a trial of diuretic (if child is hemodynamically stable). The prophylactic use of low dose dopamine is no longer advisable. Where available and when needed, early CRRT, preempting standard indications is worth considering. Starting RRT in acute liver failure serves dual purpose: for the acute kidney injury which sets in the setting of acute liver failure plus a detoxification mechanism for the high ammonia, lactate for the metabolic disturbances which set in acute liver failure along with manipulation of fluid balance. This is one condition where CRRT should be considered for non-renal conditions before AKI kicks in – for hyperammonemia > 200 micromoles/L, grade III/IV encephalopathy with high ammonia, metabolic disarray and fluid overload. Continuous CRRT rather than intermittent dialysis is advisable in ALF, because of the reduced shifts in blood pressure associated with its use and subsequently less shifts in ICP 51,52.
Nutrition
There is a need for nutritional supplementation in ALF, because these patients are catabolic and enteral nutrition should be administered whenever possible. Higher caloric density feeds are preferred to avoid excessive free water and hypo-osmolality, which may exacerbate cerebral edema. Parenteral nutrition (35–40 kcal/kg per day) delivered by a dedicated central venous catheter, should be reserved for patients with specific contraindications to enteral nutrition. Normal protein intake recommended till stage I & II encephalopathy and thereafter restriction (0.5 - 1 g/kg/day) is recommended 53,54. Metabolic liver disease presenting as ALF needs special nutrition plan, as diet modification in early stages can be life saving.
Etiology specific treatment (Table 7)
Liver support systems
An extracorporeal support for short period to replace the acutely failing liver seems a reasonable approach, while the native liver recovers or a liver transplant becomes available. The ideal replacement for the failing liver would detoxify, metabolize and synthesize; in short, perform all the liver’s many functions. A variety of systems have been tested to date, with no certain evidence of efficacy. Currently available liver support systems are not recommended outside of research trials. 55
N-acetylcysteine( NAC) : Use in acetaminophen ALF as antidote and non-acetaminophen ALF as adjuvant therapy
When used early as an antidote after a single, intentional acetaminophen overdose, NAC is extremely effective at replenishing hepatic glutathione stores and preventing severe N-acetyl-p-benzoquinone imineinduced hepatotoxicity and liver failure. N-acetylcysteine is now increasingly been used for ALF of any cause, because of its complex anti-oxidant, immunological effects which results in improved tissue oxygenation. Added advantages also are that it improves systemic circulation parameters with improved hepatic blood flow due to its vasodilator property. It is believed to be efficacious if given early in liver failure, though a recent pediatric trial did not support its broad use in non-acetaminophen pediatric ALF 56, 57. The optimal duration of NAC therapy in these patients is unclear, some say till reversal of encephalopathy or till resolving liver enzymes or standard 3 to 7 days protocol. The route IV is preferred for NAC in ALF and dose for non acetaminophen ALF is 100 – 150 mg/kg/day; diluted in 5-10% dextrose57.
Emergency Liver transplantation (ELT)
ELT)
Emergency liver transplantation remains the only treatment for poor prognosis group in ALF. There may be no weightier a management decision than whether a patient with ALF should be listed for ELT, or more time to be given for spontaneous recovery. Unnecessary transplant introduces the need for lifelong immunosuppression therapy and the inevitability of long-term metabolic complications while if you delay transplant, the chance to recovery might be null. This decision to transplant or to wait remains fraught with uncertainty; although a number prognostic scores have been described. The most commonly used transplantation criteria are those developed at King's College in London and Beaujon's Hospital in Paris (Table 8)58,59 . However, these criteria fail to be adequate in children, mainly due to a very weak negative predictive value. In a recent study in non-acetaminophen-induced ALF in children; INR > 4, bilirubin >13.74 mg/dL micromol/L, age< 2 years and WBC > 9 X 109/L were associated with poor outcome without liver transplantation and the group recommended using an INR >4 or factor V concentration of <25% as the best available criteria for listing for LT in the present era60. These prognostic
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scores do assist in decision making but are not absolute. There always remains a need for clinical judgment in any decision to proceed with liver transplantation, keeping in mind the dynamicity of disease progression.
In children, etiology is also a critical determinant of outcome. Fulminant Wilson’s disease and undetermined ALF carry the worst prognosis and require emergency liver transplantation, whereas hepatitis A-induced and acetaminophen-induced ALF have significant spontaneous recovery without transplantation. A number of scoring systems have been developed in pediatric Wilson’s disease to predict mortality like Nazer’s score61 or Wilson’s disease index62, which can be helpful in identifying children with Wilsonian ALF, where LT is indicated. Table 9 shows Wilson’s Index, which has 5 parameters and a score of 11 or more indicates need for LT.
LT may be contraindicated in 11-20% of cases, such as metastatic malignant disease, lymphohistiocytosis, systemic metabolic or systemic mitochondrial respiratory chain disorders. Other contraindications are uncontrolled sepsis, fixed dilated pupils and severe respiratory failure.
Family Support:
The parents are devastated by the rapid development of a potentially fatal, acute organ failure in their child. The possibility and the urgency of emergency liver transplantation adds further stress to the family in terms of donor availability, finances and the need for long term immunosuppression. Herein lays another important responsibility of the intensivist to provide psychological support and counselling to help the parents/relatives assimilate the seriousness of their child's condition and if needed, in preparing them for emergency LT.
Conclusion:
ALF in the present era is a treatable syndrome, due to advanced intensive care management and available option of emergency liver transplant. Also, the relative decrease in the number of indeterminate causes with early recognition of ALF and early referral to tertiary centers has additionally contributed to decreased mortality. The relative frequencies of complications of ALF leading to death are also evolving, with a decrease in the number of cerebral deaths, and an increase in the number of patients with sepsis and multiorgan dysfunction syndrome. This highlights the changing scenario of ALF in children and newer challenges for an intensivist.
Key Points
In pediatrics presence of encephalopathy is not an essential criterion for diagnosing ALF.
FFP should be avoided as long as no active bleeding is present.
Coagulopathy (INR) is not only the key criteria in diagnosing pediatric ALF, but also act as a dynamic indicator of disease progression, which determines the need for emergency liver transplant.
Given the potential rapidity of deterioration in pediatric ALF, early referral must be made as soon as possible to a liver transplant center.
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There is an important role of vigilant intensive care measures to support the failing liver and other organs - early aggressive treatment of sepsis; extensive neuro-monitoring and neuro-protection; and early use of hemofiltration.
The emergence of successful pediatric liver transplantation over the last decade has drastically changed prognosis of pediatric ALF.
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