critical care in acute liver failure || general supportive management

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Alexander WilmerAlexander Wilmer is Associate Clinical Professor at the Faculty of Medicine of the Catholic University of Leuven (Belgium) and Head of Clinic of the Medical Intensive Care Units of the University Hospitals Leuven (Belgium). His clinical research is focused mainly on clinical studies of the management of liver failure in the intensive care unit and nutritional support strategies in the critically ill. He is author or coauthor of numerous articles in medical journals, reviews and book chapters.

Frederik NevensFrederik Nevens is Professor of Medicine and Director of the Research Laboratory of Hepatology at the KU Leuven, Belgium. He is Head of the Department of Hepatology at the University Hospitals Leuven. His translational and clinical research encompasses a variety of liver disease-related topics including the complications of liver disease and liver transplantation. He is or has been a board member of several national and international scientific societies. He is author or coauthor of more than 300 articles in medical journals and books.

About the Authors

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© 2013 Future Medicine

doi:10.2217/EBO.12.307

75

General supportive management

Alexander Wilmer & Frederik NevensThe medical therapy of acute liver failure consists of disease-specific treatment (Chapter 5), general supportive management and the prevention/management of specific complications of the syndrome (Chapters 7–9). As acute liver failure is an orphan disorder, large clinical trials are not available and the management of acute liver failure to a large extent is based on observational studies along with clinical experience.

General supportive treatment 76

Specific treatment 83

Chapter 6

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Critical care of patients with acute liver failure (ALF) is the key to their survival, and improvements in supportive intensive care unit (ICU) management together with liver transplantation (LT) has substantially

improved their survival (Chapter 1). The incidence of death due to hemorrhage has decreased from 25 to <5%, and the incidence of death due to brainstem herniation, the most common cause of death in the past, has also decreased to only 20–25% [1]. At present, the most frequent causes of death in patients with ALF are multiorgan failure (MOF) and infections [2]. Rare complications of ALF are lung edema and pancreatitis. Therefore, the general supportive management of patients with ALF should focus on the prevention and/or treatment of MOF and infections, with appropriate management instituted as early as possible, in order to allow hepatic regeneration or stabilization of the patient until a liver graft becomes available.

In a patient with acute liver impairment and mental alteration, several important decisions need to be made at the moment of presentation (Box 6.1), namely early diagnosis of ALF (Chapter 1), decision to administer N-acetylcysteine (NAC), transfer to a specialized unit and finally the question as to whether this patient is a candidate for emergency LT (Chapter 10).

General supportive treatmentEarly referral & decisions around LTAs the evolution of ALF is highly unpredictable, all patients without a pre-existing chronic liver disease with a significant prolongation of prothrombin time (internation normalized ratio [INR] ≥1.5), and at the first signs of hepatic encephalopathy, should be transferred to a LT unit unless the decision is made that this patient is not a candidate for intensive care (on account of comorbidity or age). ALF is an unusual clinical syndrome and the experience gained in specialized liver units is required for improving the outcome of these patients. Efforts have been made to develop more sensitive measures to define early encephalopathy grades, but they are still not widely used in the clinical setting. Mental alterations may be subtle; therefore, it is advised to transfer the patient at the onset of any mental changes if the INR is increased to >1.5. Even mild encephalopathy can indicate a life-threatening situation in the following hours. Cerebral edema can appear suddenly and

will compromise the safety of the transfer. Therefore, in case of an evolving hepatic encephalopathy there is an indication for intubation and sedation prior to the transfer, as the transfer itself can be a risk factor for

Acute liver failure: an acute liver impairment characterized by coagulopathy (prolongation

of protrombin time) and hepatic encephalopathy in a patient without pre-existing liver disease.

The hemodynamic alterations in ALF mimic the systemic hemodynamic changes seen in

patients with cirrhosis and portal hypertension: low systemic vascular resistance and renal artery vasoconstriction.


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increased intracranial pressure. Owing to the increased risk of hypoglycemia during and after the transfer, intravenous (iv.) glucose in a continuous drip should be given. Glycemic levels need to be controlled regularly, aiming at levels of ±140 mg/dl.

Invasive monitoringThe first step when the patient arrives at the ICU is, in addition to routine laboratory testing, to start continuous monitoring of several parameters such as urinary output every 2 h, ECG monitoring , oxygen saturation, and frequent measurement of arterial blood gas and lactate (Figure 6.1). Ammonia levels should also be followed closely, with arterial samples to be preferential over venous samples. If not already available, chest radiography, baseline ECG, an electroencephalogram and liver echography should be obtained. An arterial catheter is required, but the administration of clotting factors such as fresh frozen plasma (FFP; 1–2 units) or blood platelets if the platelet count is <50 × 109/ml needs to be considered with utmost reserve as it will influence the INR, one of the most important factors of prognosis (Chapter 1). In case of hepatic encephalopathy stage ≥2, several additional catheters are necessary; a urinary catheter and certainly in case of oliguria, a central venous catheter. More invasive hemodynamic monitoring with a pulmonary artery catheter or pulse contour analysis (PiCCO®) is seldom necessary except in cases of severe hemodynamic instability. Finally, all patients with a hepatic encephalopathy stage >2 require intubation and mechanical ventilation. Appropriate monitoring should be instituted depending on the type of ventilatory support chosen. A nasogastric tube should be placed after intubation and the gastric residual monitored according to local practice. Nonconvulsive seizure activity may occur in ALF and more frequently in patients with advanced stages of HE. In cases of documented convulsive or nonconvulsive seizure activity, continuous electroencephalogram monitoring is recommended. In the rare patient developing important abdominal distention due to ascites or accumulation of intestinal gas, intra-abdominal pressure monitoring via the bladder method every 6 h is desirable.

Prevention of infectionsALF induces a state of immune deficiency. Infections are extremely frequent and one of the complications that directly affects

Box 6.1. Decisions to be made at presentation of acute liver failure.

�� Early diagnosis of acute liver failure, as evolution is highly unpredictable�� Decision to administer N-acetylcysteine�� Transfer to a specialized unit in due time�� If this patient is a candidate for emergency

liver transplantation

The patient with ALF can evolve from mild to grade 3 or 4 encephalopathy with severe

intracranial hypertension in a matter of only a few hours. Close and frequent neurologic evaluation is strictly necessary.

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outcome of a patient with ALF is sepsis with subsequent MOF [3]. Up to 90% of patients develop some evidence of infection, among which respiratory, urinary tract and catheter-related infections predominate [4]. Patients with ALF can be infected without obvious clinical and biochemical abnormalities [5]. Therefore, cultures from blood and urine should be taken daily and at least every 3 days from other sites. In case of sudden changes in hemodynamics and in the degree of hepatic encephalopathy, antibiotics need to be started on clinical suspicion. Both Gram-negative and -positive

Figure 6.1. Diagnostic procedures, monitoring and standard care for acute liver failure at admission to the intensive care unit.

Initial laboratory tests

Routine biochemistriesBlood gas + lactateArterial ammoniaCultures (respiratory, blood, urine)Factor VBlood group

Toxico-screening on urine and ifindicated dosage of acetaminophen

If candidate for LT

HLA typingCMV, HIV, hepatitis B and C statusLength and weight

Other tests if not already available

Chest x-rayECGEEGLiver echography

Routine monitoring

ECGOxygen saturationArterial pressureRespiratory rateUrine output every 1–2 hClinical neurological status every 1–2 h

If mechanically ventilated

Ventilation parametersGastric residuals

If abdominal distension

Intra-abdominal pressure every 4–6 h

Standard care

Quiet surroundingsHead of bed >30°Head in neutral positionIf candidate for LT: strict isolationGlucose infusions: glycemic target ± 140 mg/dlStress ulcer prophylaxisLactuloseN-acetylcysteine if encephalopathy grade <3If mechanically ventilated: provide standardenteral nutrition via nasogastric tubeLow threshold for empirical start of antibioticsif hemodynamic deterioration and increasingencephalopathyRestrict clotting factors to active bleeding orinvasive procedures

CMV: Cytomegalovirus; ECG: Electrocardiogram; EEG: Electroencephalogram; LT: Liver transplant.



bacteria should be empirically covered. In case of persistent fever or clinical deterioration after 48 h, additional antifungal coverage seems desirable. A low threshold to start antibiotics has significantly improved the outcome of patients with ALF [6]. During the first 5 days, the patient is at high risk of bacterial infections, later also for fungal infections. Antibiotic prophylaxis seems to decrease the incidence of infection but the results for outcome such as survival are inconclusive [7,8]. There also seem to be no beneficial effects of selective enteral decontamination [7]. At most centers, prophylactic antibacterial and, in some centers, antifungal agents are started the moment the patient is listed for LT. If on admission the patient is considered as a candidate for LT and because of the state of immunodeficiency before transplant and the subsequent pharmacological immunosuppression after transplant, these patients in many centers are cared for under conditions of strict isolation.

Prevention of cerebral edemaWithin the spectrum of liver diseases, cerebral edema is almost unique to ALF (Chapter 7). The pathogenesis involves osmotic (glutamine concentrations) and hemodynamic abnormalities. Cerebral edema occurs particularly in the hyperacute form of ALF and in young people where adaptation to rapid changes in brain glutamine level is impaired. Patients with grade 3 or 4 hepatic encephalopathy are at greatest risk. The risk of intracranial hypertension and cerebral herniation significantly increases at a level of arterial ammonia >200 mM/l [9,10].

Several procedures decrease the risk for intracranial hypertension and should be part of the general management of ALF, for instance manipulation of the patient should be restricted to a minimum, the patient should be cared for in a quiet surrounding, and the head position of the bed must be elevated to >30° and kept in a neutral position (Figure 6.2). Spontaneous hyperventilation and spontaneous hypothermia up to 35°C can be allowed. Lactulose should be administered cautiously to avoid aspiration, diarrhea and gaseous distention of a degree that may interfere with LT. Standard doses are 30–60 ml orally or via nasogastric tube every 6 h aiming at 2–4 soft stools per day. Monitoring for neurological signs of cerebral edema should be instituted at two-hourly intervals and more frequently if the patient is deteriorating. Appropriate treatment needs to be started as soon as possible (Chapter 7). The value of intracranial pressure monitoring remains controversial [11].

Most patients with ALF will develop infection. There is no evidence to support the use of

prophylactic antibiotics, and selective enteral decontamination remains controversial. However, a low threshold for antibiotics in cases of clinical suspicion of infection seems to improve the outcome.

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NutritionALF is a catabolic state. Nutritional support by enteral route is recommended without restriction of proteins (80–100 g/day) [12]. Caloric targets in this population are unclear, but more than 600–800 kcal per day during the first week of ICU stay seems unnecessary. In patients in ICU there seems to be no benefit of supplemental parenteral nutrition during this time period [13]. Vitamin deficiency frequently appears to be present in patients with ALF and therefore vitamin supplementation is necessary [14].

Respiratory managementEncephalopathy provokes a loss of the gag reflex and effective cough. In case

of encephalopathy grade 3 or signs of cerebral edema, intubation and ventilation are necessary. Intubation should be done very carefully to prevent aspiration and, in cases of encephalopathy with agitation, a

If the need for renal replacement therapy arises, continuous veno–venous hemofiltration

is the preferred modality, owing to lower swings in intercranial pressure and more stable hemodynamics compared with intermittent hemodialysis .

Figure 6.2. General support of established organ dysfunction associated with acute liver failure.

Encephalopathy

If encephalopathy grade >2: intubateIf encephalopathy grade >3: try to maintainsodium levels between 145–155 mmol/lIf EEG shows nonconvulsive epilepsy: startcontinuous EEG monitoring, if available,and treat according to local practice

Respiratory failure

Utmost care at the time of intubation toprevent aspirationShort-acting medications, such as remifentaniland propofol, work well in ALFVentilator settings aiming at ‘best PEEP’PEEP preferably <10 mmHgPaCO2 preferably ∼35 mmHg

Renal dysfunction

Maintain MAP >70 mmHgTry to avoid positive fluid balancesIn cases of fluid overload, a trial withfurosemide frip can be consideredIf indication for CRRT is present: choose CVVHRestrict CVVH with citrate to experienced centers

Hypotension

Keep MAP >65 mmHgCristalloids are acceptableAlbumin is preferredAvoid starchesIf needed: norepinephrine is the preferredvasoactive agentTerlipressine may be added safelyConsider more invasive hemodynamicmonitoring in case of severe hemodynamicinstabilityIn case of persistent hypotension: a trialwith hydrocortisone can be considered

CRRT: Continuous renal replacement therapy; CVVH: Continuous veno–venous hemofiltration; EEG: Electroencephalogram; MAP: Mean arterial pressure; PEEP: Positive end-expiratory pressure.



short-acting muscle relaxant is best used after induction of loss of consciousness (Figure 6.2). For adequate sedation, medications with a short half-life such as propofol and remifentanil, or fentanyl are preferred. Remifentanil, in this setting, is particularly convenient owing to its metabolism by tissue and plasma esterases independent of liver or kidney function. Very high levels of positive end-expiratory pressure (PEEP; >15 mmHg) will increase intracranial pressure. The lowest PEEP that achieves adequate oxygenation should be used, to avoid a possible increase of intercranial pressure (ICP) [15]. Arterial PaCO2 increases ICP in patients with ALF [16]. The initial PaCO2 goal should be approximately 35 mmHg by adjusting minute ventilation and this can later be adapted in relation to the degree of ICP elevation. Hyperventilation to levels below 30 mmHg are effective in reducing ICP but not for more than approximately 48 h. Higher PEEP levels (>10 cm H2O) have been reported to reduce liver blood flow and hepatic oxygen delivery.

Strategies in case of renal impairmentBesides acute tubular necrosis (urinary sodium level >20 mM/l with an active sediment), which occurs early and is due to the intrinsically nephrotoxic effects of some etiologies of ALF (acetaminophen or toxins from Amanita mushroom), mild functional renal failure is frequently found late in the course of ALF, mimicking the systemic hemodynamics of hepatorenal syndrome of patients with end-stage cirrhosis with a low systemic vascular resistance and renal artery vasoconstriction [17]. In this condition, the urinary sodium level is <10 mM/l, there is normal sediment and a 1.5-l volume challenge rules out prerenal azotemia [18]. More pronounced renal impairment occurs in 50–75% of acetaminophen-induced ALF patients and in 30% of cases of other etiologies (Chapter 8) [19,20] . Positive fluid balances should be avoided (Figure 6.2). However, in patients with fluid overload, a furosemide drip with 0.5–1 mg/min over 2 h may be tried. If the desired diuresis is not obtained, continuous veno–venous hemofiltration (CVVH) needs to be started. This technique is preferred instead of intermittent hemodialysis owing to its beneficial effect on cardiovascular stability and on ICP [21,22]. CVVH will also prevent sudden changes in serum osmolality, which will aggravate cerebral edema. During CVVH, citrate anticoagulation is preferred over heparin owing to the reduced risk of bleeding. However, citrate CVVH should be restricted to experienced ICUs with careful monitoring of ionized serum calcium [23,24]. At the first signs of renal dysfunction, mean arterial pressure

As the INR is a very important prognostic factor, use clotting factors only for active

bleeding or invasive procedures.

Try to maintain mean arterial pressure >65 mmHg at all times. Renal function is often

impaired in ALF and mean arterial pressures >65 mmHg may help preserve kidney blood flow autoregulation.

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(MAP) needs to be increased to levels >70–75 mmHg in an attempt to preserve the autoregulation capacity of renal blood flow. Hyponatremia is a common finding in patients with ALF and requires extra attention because a rapid increase in serum sodium concentration can cause brain damage through osmotic myelinolysis. In patients with encephalopathy stage >2, maintenance of hypernatremia between 145 and 155 mM/l has been reported to reduce the risk and severity of intracranial hypertension [25].

Cardiovascular tone & its managementPatients with ALF are relatively hypotensive with a normal to high cardiac output and vasodilatation with a low systemic vascular resistance, resembling the hemodynamics of end-stage cirrhosis or septic shock [26]. Due to mental alterations, patients have poor oral intake and therefore require iv. fluid with glucose and saline, aiming at a total daily fluid intake of 25–35 ml/kg under stable conditions. A low MAP will provoke cerebral hypoperfusion and worsen encephalopathy.

In cases of hypotension, the patients need volume expansion (Figure 6.2). Cristalloids are acceptable, albumin is preferred and starches are not recommended. The aim is to keep the MAP >65 mmHg at all times. In case of persistent hypotension, with a fall to <60 mmHg in spite of adequate volume substitution, the preferred vasopressor agent is norepinephrine. It provides a consistent and predictable increase in cerebral perfusion and has fever b-adrenergic side effects such as tachycardia in comparison with dopamine [27,28]. Recent data suggest that, in contrast to previous data, terlipressin increases cerebral perfusion without increasing ICP and that it can be safely added to norepinephrine [29]. In cases of persistent need for vasopressors, a trial dose of hydrocortisone should be considered (hydrocortisone 50 mg iv. every 6 h or 100 mg iv. every 8 h) as adrenal insufficiency occurs frequently in this setting [30,31]. The indication for placement of pulmonary artery catheter, or preferable a PiCCO catheter, is an area of uncertainty. Similar to patients with severe hemodynamic instability of other etiologies, common reasons for more invasive hemodynamic monitoring include uncertainty about the volume status of the patient and the need for more differentiated cardiac function monitoring in the presence of progressive MOF.

BleedingAccording to thromboelastography, the risk of bleeding based upon INR is overestimated in patients with ALF [32]. Indeed, clinically significant bleeding is now uncommon (5%), spontaneous intracranial bleeding is rare and, despite the development of portal hypertension, bleeding from varices almost never



occurs [33,34]. If available, daily monitoring via thromboelastography has been reported to avoid unnecessary blood product transfusions and overload of intravascular volume [32]. In ALF there is a relative preservation of hemostasis unless the platelet count is very low [32]. Thrombocytopenia occurs in 50–70% of patients with ALF. The pathogenesis remains unclear [35]. Fresh-frozen plasma, cryoprecipitate or platelets are only recommended in cases of active bleeding or if an invasive procedure such as intracranial bolts (see Chapter 9) is planned. However, in case of profound coagulopathy (INR >7) FFP transfusion to maintain INR between 5 and 7 is advised. In cases of severe, persistent bleeding, rescue therapy with recombinant activated Factor VII may be considered [36]. Temporary correction of coagulopathy may be expected for a period of 2–6 h, although thrombotic complications are possible [37]. The incidence of upper gastrointestinal bleeding in patients with ALF is decreased by gastric acid suppression [38,39] and stress ulcer prophylaxis is recommended.

Specific treatmentN-acetylcysteineNAC is the antidote for patients with acetaminophen-related liver injury and ALF (Chapter 5). Treatment with NAC is also beneficial in patients with other etiologies of ALF, either by improving systemic hemodynamics and tissue oxygen delivery [40–45] or via other mechanisms [46,47]. In patients with early-stage non-acetaminophen-related ALF, NAC improves transplant-free survival. Among those with encephalopathy grades 1–2 at admission, 52% of the patients who received NAC survived without LT versus 30% who received placebo [48]. Patients with advanced coma grades did not benefit in this study. The dosage and duration of the NAC treatment in this first randomized study was the same as for acetaminophen overdose: an initial loading dose of 150 mg/kg/h over 1 h followed by 12.5 mg/kg/h for 4 h and finally a continuous infusion of 6.25 mg/kg NAC for the remaining 67 h. Nausea and vomiting were the only symptoms seen more frequently with NAC therapy. These favorable results, however, were not observed in pediatric patients with non-acetaminophen-related ALF. Indeed, the 1-year LT-free survival was significantly lower with NAC [49].

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organi-zation or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, con-sultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Wilmer & Nevens


Summary.

�� General supportive management at intensive care units is the key to the survival of patients with acute liver failure (ALF).�� Even mild encephalopathy can indicate a life-threatening situation developing in the next few

hours. Therefore, even at the first symptoms of mental alternations, the patient with ALF needs close monitoring and a referral to a specialized liver unit should be considered.�� The administration of clotting factors must be considered with utmost reserve, as it will

influence the international normalized ratio, one of the most important factors of prognosis.�� Patients with ALF can be infected without obvious clinical or biochemical abnormalities, and in

cases of sudden change in hemodynamics and the degree of encephalopathy, antibiotics need to be started on clinical suspicion.�� The risk of intracranial pressure significantly increases at a level of arterial ammonia >200 mM/l.

In case of encephalopathy grade 3 or signs of cerebral edema, ventilation is necessary.�� Mild functional renal failure is frequently found late in the course of ALF and in this condition

mean arterial pressure needs to be increased to >70–75 mmHg. Serum sodium increases intracranial pressure and should be maintained between 145 and 155 mM/l.�� To keep mean arterial pressure >65 mmHg, the following steps are necessary: daily fluid intake

of 25–35 ml/kg, if hypotensive in spite of adequate volume substitution; norepinephrine (and, in case of failure, terlipressin can be added); and finally, with persistent need of vasopressors, a trial dose of hydrocortisone.�� In ALF, hemostasis is mostly preserved unless the platelet count is very low. Stress ulcer

prophylaxis is recommended.�� N-acetylcysteine has been shown to be beneficial for non-acetaminophen-related ALF in adults

if the grade of encephalopathy is <3.

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critical care in acute liver failure || general supportive management

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