critical care in acute liver failure || management of encephalopathy and cerebral edema

88 © 2013 Future Medicine8888 www.futuremedicine.com

Fin Stolze LarsenLead physician of liver intensive care and the research laboratorium in a national liver transplantation unit at Rigshospitalet, Copenhagen, Denmark.

Peter BjerringSenior clinical research fellow at Department of Hepatology, Rigshospitalet (Copenhagen, Denmark) with focus on cerebral complications associated with liver failure.

About the Authors

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© 2013 Future Medicine 89

doi:10.2217/EBO.12.398

Management of encephalopathy and cerebral edema

Fin Stolze Larsen & Peter BjerringAcute liver injury or dysfunction can result in development of hepatic encephalopathy (HE) and often also in cerebral edema, which is a potentially fatal complication. The degree of HE and cerebral edema is correlated to the level and persistence of hyperammonemia and systemic inflammation. Monitoring of intracranial pressure, brain perfusion and metabolism may be indicated in severe cases to guide management until spontaneous recovery or liver transplantation. Treatment of HE and cerebral edema is based on restoring and maintaining normal physiological variables, including blood tonicity, blood gasses, lactate, body temperature and vascular resistance by a wide variety of interventions. This chapter will focus on the pathogenesis of HE/cerebral edema and the basic principles of management.

Pathophysiology 90

Monitoring 91

Management 93

Conclusion & perspective/summary 96

Chapter 7

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Patients with a severe deterioration of liver function due to ischemic injury, viral infection or toxins may result in development of hepatic encephalopathy (HE) occurring within days or weeks of the

primary insult and is termed acute liver failure (ALF) if the patient is not known with pre-existing liver disease. Although the prognosis has improved over the last four decades owing to continuous advances in critical care management, ALF often leads to a life-threatening multisystem illness with an unfavorable prognosis. In contrast to patients with cirrhosis, the development of HE in patients with ALF is frequently associated with brain swelling and a rise in intracranial pressure (ICP). Although the frequency of clinically overt cerebral edema in ALF patients has decreased significantly during the last two decades, the development of a high ICP is still a complication that requires considerable resources in the intensive care unit setting and is associated with a high mortality [1].

The primary goal of resuscitating patients with ALF to secure brain viability is to ensure optimal oxygenation, maintenance of sufficient brain blood flow for aerobic cerebral metabolism, and maintenance of ICP at a level lower than 20–25 mmHg. To achieve these goals, fluid therapy, inotropic support, control of body temperature and ventilation are cornerstones in the management of these patients. This chapter first briefly summarizes the pathophysiology of cerebral edema and methods used to monitor the brain in ALF. Then, the focus is turned to how cerebral edema can be prevented and how it can be managed if it is already overt.

PathophysiologySwelling of the astrocyte is a prominent feature of HE. This is caused by hyperammonemia and to some extent also by systemic inflammation. Cerebral detoxification of ammonia takes place by incorporating ammonia in amino acid synthesis, predominantly glutamine. This attenuates the neurotoxic effect but causes metabolic disturbances by substrate depletion and dysequilibrium of biochemical pathways. Once ammonia has crossed the blood–brain barrier (BBB), glutamine synthetase (GS), primarily found in astrocytes [2], is amidating glutamate to glutamine by utilization of ammonia and ATP. A shortage of glutamate is partly prevented by amination of a-ketoglutarate to glutamate. The consequence of this is substrate depletion of the tricarboxylic acid (TCA) cycle where a-ketoglutarate is an essential metabolite. Furthermore, it has been suggested that ammonia inhibits two rate-limiting enzymes, pyruvate dehydrogenase and a-ketoglutarate dehydrogenase. This inhibition will

Hepatic encephalopathy: neuropsychiatric abnormalities associated with liver damage.

Cerebral edema: common in acute liver failure, not in cirrhosis.

Management of encephalopathy & cerebral edema

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slow the overall oxidative metabolism and lead to depletion of energy-rich phosphate compounds (ATP and GTP) and accumulation of lactate [3,4]. The supply of intermediates in the TCA cycle can, in part, be restored by anaplerosis – that is, an energy consuming processes that bypasses the normal flow of metabolites in the TCA cycle. The primary anaplerotic pathway is thought to be carboxylation of pyruvate to oxaloacetate yielding substrates for the first steps in the TCA cycle and thereby providing carbon skeletons for glutamate synthesis and subsequent ammonia detoxification by glutamine synthesis.

Accumulated glutamine within the brain acts as an organic osmolyte and increases astrocyte volume. In the mitochondria, ammonia both induces oxidative and nitrosative stress by formation of free radicals and this in turn leads to the preapoptotic process called mitochondrial permeability transition (MPT), that is, a state with imminent ‘power failure’. Normally, dynamic processes are rapidly initiated to counteract astrocyte volume changes by restoration of an optimal osmotic balance between the intracellular and extracellular milieu. The intracellular osmotic load is decreased by the combined activation of chloride and potassium channels and later by release of organic osmolytes such as myo-inositol and taurine [5]. However, these processes are highly energy dependent and require optimal metabolic conditions to operate. Such a favorable milieu is not present in the brain in ALF. The consequence is failure of ‘regulatory volume decrease’ of astrocytes [6]. Thus, an integrated view implies that the osmotic stress caused by accumulation of glutamine in the astrocytes is only the ‘first hit’ to the brain. The ‘second hit’ is that this osmotic challenge cannot be compensated for due to ammonia glutamine-induced MPT. In severe cases with persistent hyperammonemia gross swelling of the brain evolves and causes a high ICP.

MonitoringThe human brain, embedded in the dura mater and skull, is protected against physical damage. This protection may, however, become counterproductive in severe cases of cerebral edema, as frequently seen in patients with ALF. Because of the minimal compliance of the skull, such an increase in brain water content will increase pressure; that is, the skull functions as a resistor, compromising cerebral perfusion pressure (CPP) whenever ICP exceeds the central venous pressure.

Studies in patients with ALF have indicated that cerebral blood flow (CBF) is increased during the course of the disease because of dilation of

Mitochondrial permeability transition: hyper-ammonemia induces oxidative and nitrosative

stress by formation of free radicals, which can lead to mitochondrial dysfunction by depolarisation of the mitochondrial inner membrane.

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cerebral arterioles, that is, a decrease in the cerebral vasoreactivity [7]. Furthermore, patients with signs of high ICP have on average a higher CBF than patients without brain swelling, and clinical studies have also shown that systemic inflammation correlates with high CBF and ICP in such patients. This finding has been speculated to result from activation of cation channels in the BBB [8].

Examination for cerebral edema in ALF patients is still in many transplant facilities based on repeated evaluation of the coma grade and pupil size. Although there may be a reasonably good correlation between the severity of coma and the risk of intracranial hypertension, it is also evident that a clinical examination, including an inspection of the pupils and fundus, is not reliable for identifying high ICP, as the signs of edema occur late, usually when ICP is considerably higher than 30 mmHg [9]. Thus, ICP monitoring is of value for the early detection of intracranial hypertension. Usually it is used in patients with persistence of severe hyperammonemia with or without concomitant systemic inflammation or sepsis [10]. Indeed, ICP monitoring helps to detect surges of intracranial hypertension that otherwise often would remain undetected and could result in ischemic brain damage and herniation in the perioperative period to liver transplantation (Box 7.1).

At present, there is no accurate noninvasive method to record continuous online ICP measurements. However, transcranial Doppler ultrasonography, using measurement of the velocity of blood flow in the basal cerebral arteries, shows characteristic changes with rising ICP. As CPP falls, the diastolic velocity falls, reflecting increased overall resistance to flow. In cases with severe intracranial hypertension, the diastolic flow velocity may cease or even show a retrograde pattern. The caveats with transcranial Doppler sonography are that the changes in flow pattern are often found only with a highly elevated ICP and that the technique is not sensitive to mild-to-moderate ICP elevations. It should not be used however as the sole monitoring technique of the brain in human ALF. Although it is often

Box 7.1. Proposed indications for intracranial pressure monitoring in patients with acute liver failure.

1. Those with pupillary abnormalities or seizures2. Fulfillment of three to four criteria of systemic inflammatory response syndrome3. When arterial ammonia concentration above 150 μmol/l for more than 24 h4. Those with a low plasma sodium concentration (lower than 130 mmol/l)5. Acute liver failure patients who require vasopressor support6. Patients with surrogate markers (e.g., jugular oxygen saturations or middle cerebral artery

Doppler monitoring) that indicate a very low or high cerebral blood flow



assumed that a level of CPP over 40–50 mmHg reflects sufficient CBF, this assumption is invalidated by the fact that CBF autoregulation is absent in these patients [7]. Preferably ICP monitoring should be supplemented by transcranial Doppler monitoring or by monitoring cerebral microdialysis [4] at the bedside through the ana lysis of the lactate/pyruvate ratio in the brain cortex. The use of such multimodality monitoring of the brain, in selected cases with a high risk of development of cerebral edema secure more accurate evaluation and timely intervention; that is, a high ICP in a patient with low cerebral perfusion and an increased cerebral tissue lactate/pyruvate ratio should be treated differently than the patient with a high ICP, cerebral hyperemia and a normal lactate/pyruvate ratio (reduction of CBF by cerebral vasoconstrictors).

ManagementAn accurate clinical evaluation is essential in the assessment of the patient with ALF as it optimizes the chance of survival by either hepatic regeneration or liver transplantation. In this context, it is imperative to identify potential complications that later may compromise vital organ functions. Indeed, early resuscitation should be instituted and based on the VIP (ventilate, infuse, pump) principle, as follows:

V: ventilateThe airway must be secured, with mechanical ventilation being used if necessary. Hypoxemia can worsen outcomes, and arterial oxygen saturation should be maintained at ≥90–95% at all times. There should be a low threshold for endotracheal intubation in ALF patients and mechanical ventilation is indicated when HE stage III is clinically overt. Hyperventilation induces precapillary hypocapnic vasoconstriction and decreases CBF and ICP [7]. However, in most centers, patients with ALF are normoventilated, and hyperventilation should be reserved for cases with imminent cerebral herniation (as manifested by high ICP and/or motor posturing, and papillary dilation).

I: infuseArterial hypotension results from central hypovolemia. Volume expansion with saline and colloids (or crystalloids) of the circulating blood volume should be initiated after admittance of the patient to the hospital. A central venous line is of vital importance and should be inserted regardless of the compromised secondary hemostasis before transport of the patient to a liver failure center. Volume expansion often increases arterial pressure and systemic oxygenation and corrects lactate acidosis [11].

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P: pumpIf the patient suffers from severe lactate acidosis in spite of volume expansion vasopressor support may be needed. Noradrenalin may not be sufficient due to the low pH and at the time of referral adrenalin infusion with small bolus doses of terlipressin may be indicated [12]. If cerebral edema is severe, the diastolic arterial pressure should be kept at more than 40 mmHg higher than ICP to secure sufficient CBF [6].

The prophylactic use of intravenous antibiotics and antifungal agents has never been shown to prevent sepsis, or decrease the risk of progression to high-grade encephalopathy [13]. It is, however, widely used, as development of a severe infection may become a contraindication for liver transplantation.

Prevention of brain complications Short-acting sedatives are most often indicated for allowing mechanical ventilation. These sedatives induce hypometabolic vasoconstriction in the brain. Propofol is a widely used neurosedative agent because of its rapid onset and short duration of action. Alternatively, midazolam infusion can be used. Fentanyl is commonly added to provide for adequate analgesia. Caution should be exerted with bolus administration as this may be associated with a significant fall in CPP and a rise in ICP.

An additional approach used to prevent cerebral edema is to restore the normal osmotic gradient across the BBB by keeping the blood tonicity high. Indeed, infusion of hypertonic saline can prevent the development of high ICP in patients with ALF [14].

Continuous renal replacement therapy (cRRT) may help to decrease the level of circulating ammonia and correct electrolyte disturbances gradually. During high-dose cRRT the body temperature is often reduced to 34–35°C, which per se may decrease the arterial ammonia concentration. A reduction of ammonia from the circulation may also be achieved by plasmapheresis (which tends to stimulate ureagenesis) or by extracorporeal albumin dialysis techniques [15].

The NSAID indomethacin has been shown to prevent intracranial hypertension in the rat with a portacaval anastomosis and hyperammonemia [16]. This effect is also seen after the administration of diclofenac, indicating that NSAIDs may be effective by blocking the cyclooxygenases. However, the prophylactic use of these NSAIDs in patients with ALF cannot be recommended, as they may also induce renal failure, and they should be used mainly in patients manifesting intracranial hypertension with a documented cerebral hyperemia [7].



The role of glutamine-induced MPT in the development of cerebral edema and high ICP in ALF patients introduces the possibility of new therapeutic approaches in achieving neuroprotection by use of pharmacological MPT-inhibition by administration of, for example, the calcineurine inhibitor cyclosporin. MPT-inhibitors are under current investigation for beneficial effects in other clinical conditions such as traumatic and ischemic brain injury where disruption of the BBB facilitates the bioavailability. In ALF the BBB is considered to be largely intact and may be a critical issue in addition to the fact that cyclosporine may cause systemic infection and renal dysfunction.

Other clinical and randomized, controlled studies of reducing cerebral metabolism by lowering the body temperature of ALF patients have been carried out and the final results are pending.

Management of manifest cerebral edemaPatients with an ICP higher than 20–25 for 5 min or more should be placed in a 30° head-up position to reduce ICP without compromising arterial pressure and CPP. Basic care principles should be secured by prevention of arterial hypotension and hypoxemia. Also, normovolemia, normocapnia, normoglycemia, and mild hypo- or normo-thermia should be ensured.

In patients with signs of (or measured) high ICP and indications of low cerebral perfusion maintenance of CPP above 55 mmHg in ALF patients is recommended. Theoretically, ICP should decrease during a norepinephrine-induced rise in arterial pressure because of autoregulatory vasoconstriction. However, with CBF autoregulation absent in ALF, effects on ICP are unpredictable [7]. Terlipressin mediates systemic vasoconstriction via V1 receptors even during systemic inflammatory response syndrome and metabolic (lactate) acidosis. In fact, terlipressin has been shown to be effective in reversing catecholamine-resistant hypotension and imminent cerebral hypoperfusion in severely ill ALF patients.

A high ICP may also compromise CPP and result in low brain perfusion. In such cases, the aim is to reduce ICP and thereby improve cerebral perfusion. An obvious way to decrease ICP and increase cerebral perfusion is to drain cerebrospinal fluid, as is routinely done in patients with cerebral edema after subarachnoid hemorrhage and traumatic brain injury. However, the safety and efficacy of this method remains to be determined in ALF patients.

Hypertonic saline (30%) infusion and mannitol infusion are the primary treatments of choice to reduce a high ICP. It may be more rational to use hypertonic saline instead of mannitol as the BBB is less permeable to hypertonic saline because of its higher polarity and the presence of tight gap junctions, which result in a reflection coefficient of 1.0 for sodium chloride

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versus 0.9 for mannitol. Although the decrease in ICP during hypertonic saline/mannitol infusion may result from cerebral vasoconstriction, the effect is more likely generated by a reduction in the interstitial water content, that is, by restoration of the osmotic pressure gradient. Indeed, several studies have shown effective control of ICP in ALF [6,14]. If the patient does not respond to the administration of mannitol or hypertonic saline, that is, ICP remains unaltered, the reliability of the ICP signal should be checked.

It has been shown that the induction of mild hypothermia may be lifesaving in patients awaiting emergency liver transplantation. It remains questionable if ALF patients who are not liver transplantation candidates will benefit from this kind of intervention [17,18]. In some ALF patients with high ICP, cerebral hyperemia develops [7], and the prognosis for such patients remains poor. In this setting, an attempt to reduce ICP by reducing cerebral blood volume, that is, by inducing cerebral vasoconstriction, is recommended. Hyperventilation induces precapillary hypocapnic vasoconstriction and decreases CBF and ICP. Clinical experience also indicates that the intravenous injection of indomethacin decreases high ICP and increases CPP in patients with ALF. This does not compromise cerebral oxygenation or the lactate concentration within the brain and is currently used as a rescue treatment of uncontrolled intracranial hypertension in human ALF.

Barbiturates have a negative inotropic effect, and another unwanted side effect is the development of arterial hypotension, which makes barbiturates a poor choice for the treatment of high ICP.

Total hepatectomy and use of various liver assist devices as a bridge to transplantation have been reported but such extreme measure for the treatment of refractory intracranial hypertension in ALF patients is not recommended, and it is likely that such interventions may simply reduce the high ICP by induction of hypothermia.

Conclusion & perspective/summaryPatients with acute liver injury may develop HE, cerebral edema and multiorgan failure. Our knowledge of the pathophysiology has improved significantly in recent years showing that hyperammonemia, systemic inflammation and changes in the immune system are of key importance. ALF patients with persistence of hyperammonemia (>150 µM), sepsis, need for inotropic support, or hyponatremia often develop cerebral edema and high ICP. In such cases, ICP measurement is an essential component of the monitoring systems in the intensive care unit. It is only moderately invasive, and the complication rate has decreased with the development of new devices and knowledge of how to prevent such complications.



In daily practice many interventions are based upon experimental observations and/or uncontrolled studies of patients with ALF. At first glance, most of these therapies work by reducing brain blood volume rather than by decreasing the amount of water within the brain tissue. Although this may be appropriate in some patients, it raises the concern of a critically restricted capillary flow that fail to provide adequate oxygen, glucose and other substrates to the brain. So far, clinical experience and reports indicate that cerebral edema can be prevented, and managed by the maintenance of high plasma tonicity and removal of ammonia by cRRT. There are some indications that liver assist systems may have a role in increasing ammonia clearance, in modulating the immune system and improving even transplant-free survival.

In the future, development of treatments that specifically counteract cerebral edema formation will probably be based on the identification of the endogenous factor that dilates the cerebral arterioles and of the ion channels in the BBB that control cerebral water in- and out-flux.

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.

Summary.

�� Hyperammonemia and high brain concentrations of organic osmolytes are of central importance in the pathophysiology of encephalopathy and brain edema.�� Systemic inflammation and recurrent infections together with hyperammonemia accelerates

development of brain edema.�� Keeping a high tonicity is central to avoid high intracranial pressure. Early use of continuous

renal replacement therapy is of central importance.�� Induction of hypothermia reverses high intracranial pressure, but its efficacy as a prophylactive

intervention remains unsettled.

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critical care in acute liver failure || management of encephalopathy and cerebral edema

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