Brain edema

Brain edema can be induced via cytotoxic or vasogenic mechanisms. An accumulation of brain water resulting from alterations in cellular metabolism, with an intact blood-brain barrier (BBB), is defined as cytotoxic edema. The BBB is a highly selective and regulated physiological multicellular vascular structure that protects the brain from endogenous and exogenous neurotoxins. Composed of endothelial cells with tight intercellular junctions surrounded by a basal lamina, astrocytes and pericytes, molecules (amino acids, metabolites, ions, etc.) are enabled to cross through specific channels and transporters. Vasogenic edema occurs following physical breakdown and/or metabolic dysregulation of the BBB, which causes an increase in molecules and solutes into the brain, followed by brain water uptake. Advanced MRI techniques, such as diffusion-weighted imaging, allow for a noninvasive method to differentiate between vasogenic and cytotoxic brain edema. By calculating the apparent diffusion coefficient (ADC), the diffusivity of water molecules can be quantified. Given that primarily low ADC values were found in patients with ALF, these MRI studies support a cytotoxic origin of brain edema, corresponding to an increase in intracellular water and astrocytic swelling. ^{Reference Rai, Nath, Saraswat, Purwar, Rathore and Gupta14–Reference Saksena, Rai and Saraswat16}

Ammonia

Ammonia exists in equilibrium between unionized form (NH3) and ionized form (NH4+), with the equilibrium between the two being defined by the Henderson–Hasselbach equation. At a physiological pH (7.4), 98% of ammonia is present as NH4+ and only 2% as NH3. The gaseous NH3 can cross all plasma membranes through passive diffusion and NH4+ and, due to similar ionic properties to those of K+, can also cross biological membranes through K + channels as well as K + cotransporters. ^{Reference Moser17,Reference Aickin, Deisz and Lux18} Therefore, these properties imply that blood-derived ammonia, both as NH3 and NH4+, can easily cross the BBB. Therefore, conditions of hyperammonemia lead to elevated and toxic levels of ammonia in the brain causing deleterious effects. ^{Reference Bosoi and Rose19} Increased brain ammonia has long been considered to be the main pathogenic factor in hepatic encephalopathy (HE) since ammonia homeostasis is maintained primarily by the liver via the hepatocyte-specific urea cycle. ^{Reference Cooper and Plum20} Within the brain, the astrocyte bears the brunt in attempting to detoxify toxic levels of ammonia since it houses glutamine synthetase, an enzyme that catalyzes the condensation of glutamate and ammonia to form glutamine. Consequently, an accumulation of intracellular astrocytic glutamine leads to osmotic imbalance and cellular edema. ^{Reference Rama Rao, Jayakumar and Norenberg21} For this, elevated brain levels due to ALF-induced hyperammonemia are the primary pathogenic factor involved in the development of brain edema and have been reported to be associated with high ICP. ^{Reference Bernal, Hall, Karvellas, Auzinger, Sizer and Wendon8,Reference Clemmesen, Larsen, Kondrup, Hansen and Ott22,Reference Tofteng, Hauerberg, Hansen, Pedersen, Jørgensen and Larsen23}

Lactate

In patients with ALF, it has been shown that increases in extracellular lactate correlate with rises in intracranial pressure. ^{Reference Tofteng and Larsen24} Lactate:pyruvate ratio has been elevated in the extracellular space of patients with ALF, which reflects compromised oxidative metabolism. ^{Reference Bjerring, Hauerberg and Frederiksen25} It has been shown that elevated ammonia can redirect the citric acid cycle, leading to less ATP production and energy impairment and swelling of astrocytes. ^{Reference Drews, Zimmermann and Westhoff26} Interestingly, lactate is not only a product of anaerobic glycolysis but also a metabolite used by neurons as an energetic substrate. ^{Reference Descalzi, Gao, Steinman, Suzuki and Alberini27} An increase in cerebral lactate, due to increased glycolytic activity and/or energy failure, can osmotically induce an increase in water influx in the brain and thus lead to brain edema. ^{Reference Bosoi, Zwingmann and Marin28}

Inflammation

Severe systemic inflammation (infection) could also have an impact on the development of high ICP since a systemic inflammatory state accentuates brain inflammation by activating immune cells like microglia and astrocytes, releasing inflammatory mediators (cytokines, reactive oxygen species) that can breach the BBB, increasing BBB permeability, causing impairment in cerebral autoregulation. ^{Reference Rama Rao, Jayakumar and Norenberg21}

Hemodynamic management

Patients with ALF develop systemic hypotension due to vasodilation. This results in decreased CPP and subsequent secondary injury due to ischemia, but systemic hypertension may result in cerebral edema. ^{Reference Ede, Gimson, Bihari and Williams93} Blood pressure targets are disputed in the literature, with guidelines generally recommending a target mean arterial pressure (MAP) of > 60 mmHg. ^{Reference Shingina, Mukhtar and Wakim-Fleming33,Reference Wendon, Cordoba and Dhawan58} Patients with known elevated ICP have a target MAP of 70–80 mmHg with a central venous pressure < 20 mmHg to permit venous return. ^{Reference Wendon, Cordoba and Dhawan58,Reference Lee, Stravitz and Larson92,Reference Cardoso, Marcelino, Bagulho and Karvellas94–Reference Jörres96} Volume repletion is recommended early. EASL 2017 guidelines indicate little literature to suggest the use of specific fluid but generally recommend the use of crystalloid over colloid fluids. ^{Reference Wendon, Cordoba and Dhawan58} Norepinephrine is the recommended first-line vasopressor after appropriate fluid resuscitation with a starting dose of 0.05 μg/kg/min, with low-dose vasopressin (1–2 units/hour) as a second-line agent, if norepinephrine requirements are greater than 0.2–0.3 μg/kg/min. ^{Reference Shingina, Mukhtar and Wakim-Fleming33,Reference Nanchal, Subramanian and Karvellas57,Reference Wendon, Cordoba and Dhawan58,Reference Dellinger, Rhodes and Evans97,Reference Shi, Hamzaoui, De Vita, Monnet and Teboul98} Venous drainage is facilitated through the elevation of the patient’s head to ≥30°, though elevation beyond 30° may compromise CPP. ^{Reference Davenport, Will and Davison99}

Respiratory management

Airway protection is beneficial in cases of decreased level of consciousness. Guidelines recommend intubation in patients with high-grade HE (West Haven grade 3–4). ^{Reference Shingina, Mukhtar and Wakim-Fleming33,Reference Wendon, Cordoba and Dhawan58} EASL guidelines specifically recommend against noninvasive ventilation in patients at risk of HE or significant metabolic disturbance, given the high risk for progression in neurological impairment. ^{Reference Wendon, Cordoba and Dhawan58} Positive end-expiratory pressure (PEEP) can be beneficial in ALF patients with lung injury but consequentially may increase ICP and impair venous return. ^{Reference Nanchal, Subramanian and Karvellas57,Reference Laffey, Bellani and Pham100} PEEP levels should be titrated cautiously, though there is minimal effect on ICP with PEEP < 15. ^{Reference Kandiah and Kumar85} As recommended by EASL, CO₂ levels should be targeted between 34 and 41 mmHg to avoid hypercarbia and hypocarbia. ^{Reference Wendon, Cordoba and Dhawan58}

Sedation

Noxious and environmental stimuli may also increase intracranial pressure and should be minimized as much as possible. ^{Reference Bernal, Auzinger, Sizer and Wendon50,Reference Lee, Stravitz and Larson92} Procedures such as endotracheal suctioning, which results in elevated intrathoracic pressures, may result in venous outflow obstruction and indirectly increase intracranial pressure; therefore, minimizing these procedures is of additional importance. ^{Reference Lee, Stravitz and Larson92,Reference Citerio, Vascotto, Villa, Celotti and Pesenti101} Short-term neuromuscular blockade or lidocaine during procedures may be useful in minimizing elevated pressures. Sedation may interfere with serial assessment; therefore, continuous sedation is not recommended and, if required, should be achieved with short-acting medications such as propofol or dexmedetomidine. ^{Reference Wendon, Cordoba and Dhawan58} Seizures should be treated, though prophylactic anti-seizure medications do not reduce the seizure incidence or mortality in ALF. ^{Reference Bhatia, Batra and Acharya102}

Metabolic management

Nutritional support is recommended in patients with ALF, with preference for enteral nutrition when possible. ^{Reference Shingina, Mukhtar and Wakim-Fleming33,Reference Wendon, Cordoba and Dhawan58} Guidelines recommend the delay of protein support until ammonia levels stabilize, which often occurs after 24 hours. ^{Reference Bischoff, Bernal and Dasarathy103} Hypoglycemia is frequently observed in ALF and may contribute to clinically observed encephalopathy. Guidelines recommend frequent blood glucose monitoring, and supplementation is recommended to a target of 8.3–10 mmol/L. ^{Reference Shingina, Mukhtar and Wakim-Fleming33,Reference Wendon, Cordoba and Dhawan58} Rapid bolus correction should be avoided when possible due to the risk of osmotic shifts resulting in fluid movement into the intravascular and cerebral space, posing risk for edema.

Hyponatremia is a frequent complication of ALF and should be avoided. Treatment with large volume hypotonic fluids used in volume resuscitation may result in hyponatremia and subsequent worsening edema. ^{Reference Bernal and Wendon7,Reference Fernández, Bassegoda, Toapanta and Bernal104} Hypertonic saline (HTS) is often infused to prevent increased ICP. Rapid correction also poses risk of osmotic demyelination; therefore, guidelines suggest maximum correction of 8–10 mmol/L over 24 h. ^{Reference Shingina, Mukhtar and Wakim-Fleming33,Reference Wendon, Cordoba and Dhawan58} Mild hypernatremia is often targeted, with sodium maintained between 145 and 155 mmol/L. ^{Reference Murphy, Auzinger, Bernal and Wendon54,Reference Wendon, Cordoba and Dhawan58}

Practice recommendations by the American College of Gastroenterology recommend the use of CRRT in patients with HE meeting West Haven grade 2 or higher. ^{Reference Shingina, Mukhtar and Wakim-Fleming33} This is discussed in further detail below. There is no data to support the use of ammonia-lowering drugs such as lactulose or rifaximin. ^{Reference Stravitz and Lee6} Lactulose should be avoided in patients with high-grade HE due to poor effect and risk of ileus. ^{Reference Fernández, Bassegoda, Toapanta and Bernal104,Reference Maiwall, Kulkarni, Arab and Piano105}

Mannitol

Reduction of brain volume is facilitated as a first-line measure with either mannitol or HTS. The subsequent osmotic dehydration shifts fluids into the intravascular space and reduces cerebral edema. ^{Reference Wendon, Cordoba and Dhawan58,Reference Winkler and Munoz-Ruiz107,Reference Suarez108} Mannitol is the most widely accepted first-line therapy in elevated ICP. ^{Reference Rabinowich, Wendon, Bernal and Shibolet59,Reference Lee, Stravitz and Larson92} A controlled trial demonstrated a significant reduction of ICP with the use of mannitol (1 g/kg) in ALF; however, no significant effect was observed in patients with renal failure ^{Reference Canalese, Gimson, Davis, Mellon, Davis and Williams109} or with severe elevation of ICP (> 60 mmHg). ^{Reference Hanid, Davies and Mellon110} EASL 2017 guidelines recommend a bolus of 150 mL of 20% mannitol to be administered over 20 minutes. ^{Reference Wendon, Cordoba and Dhawan58} Serum osmolality should be measured regularly. ^{Reference Garcia-Morales, Cariappa, Parvin, Scott and Diringer111} The administration of mannitol may be repeated 1–2 times if serum osmolality remains below 320 mOsm/L. ^{Reference Lee, Stravitz and Larson92} Repeated use of mannitol may result in rebound ICP elevation, intravascular volume depletion and renal failure. ^{Reference Diringer and Zazulia112,Reference Wakai, Roberts and Schierhout113} Concurrent ultrafiltration may be required to maintain volume status and prevent increased central venous pressure due to expansion of circulating blood volume. ^{Reference Lee, Stravitz and Larson92} The prophylactic administration of mannitol has not been studied and is not recommended. ^{Reference Lee, Stravitz and Larson92}

Hypertonic saline

HTS has demonstrated similar efficacy to mannitol. ^{Reference Harutjunyan, Holz, Rieger, Menzel, Grond and Soukup114,Reference Battison, Andrews, Graham and Petty115} In a prospective randomized controlled trial, HTS resulted in a reduction of the incidence of intracranial hypertension and reduced measured ICP. ^{Reference Murphy, Auzinger, Bernal and Wendon54} Certain guidelines recommend prophylactic use of HTS in patients at higher risk of HE. ^{Reference Lee, Stravitz and Larson92} The use of HTS carries risk due to osmotic shifts causing dehydration, hypernatremia and pontine/extrapontine myelinolysis. ^{Reference Suarez108,Reference Qureshi and Suarez116,Reference Martin117} To avert this, serum osmolality should be serially monitored and maintained at< 320 mOsm/L. ^{Reference Suarez108,118} The 2017 EASL guidelines recommend maintenance of serum sodium at 140–145 mmol/L with additional bolus (200 mL of 2.7% HTS or 20 mL of 30% HTS) only when intracranial hypertension has developed. ^{Reference Wendon, Cordoba and Dhawan58} Hyponatremia itself is not a contraindication to the use of HTS in ALF, though clinicians should remain cautious. To reduce the risk of osmotic demyelination, US Acute Liver Failure Study Group guidelines recommend a slow rate of correction, which is inversely proportional to the known preceding duration of hyponatremia. ^{Reference Lee, Stravitz and Larson92} HTS may also be useful in preventing rapid shifts of osmolality in CRRT, preventing subsequent cerebral edema and neurological deterioration. A study by Liotta et al. noted that ALF patients who received concurrent HTS with CRRT were less likely to demonstrate radiographic evidence of cerebral edema or a decrease in osmolality. ^{Reference Liotta, Romanova and Lizza119} Concurrent infusion of HTS may be cautiously applied to patients undergoing CRRT, though infusions should remain gradual to prevent dramatic shifts.

Renal replacement therapy

Early use of CRRT has shown benefit in the management of hyperammonemia, even in the absence of acute kidney injury. ^{Reference Germani, Theocharidou and Adam5,Reference MacDonald, Speiser and Ganger10,Reference Karvellas, Leventhal and Rakela120–Reference Cardoso, Gottfried, Tujios, Olson and Karvellas122} Early use of CRRT in patients with arterial ammonia >150 μmol/L is associated with improved neurological status, reduced mortality and TFS. ^{Reference Cardoso, Gottfried, Tujios, Olson and Karvellas122,Reference Warrillow, Fisher and Bellomo123} There is no clear superior method between continuous venovenous hemodialysis, continuous venovenous hemofiltration or continuous venovenous hemodiafiltration, as long as therapy remains continuous rather than intermittent. ^{Reference Fisher, Baldwin, Fealy, Naorungroj and Bellomo124} Multiple clinical guidelines have suggested the early use of CRRT in hyperammonemia in ALF, even in the absence of standard RRT indications. ^{Reference Shingina, Mukhtar and Wakim-Fleming33,Reference Nanchal, Subramanian and Karvellas57,Reference Wendon, Cordoba and Dhawan58} Intermittent hemodialysis should not be used in ALF as, although ammonia clearance is greater, it may exacerbate high ICP and neural injury due to resulting systemic hypotension and dialysis disequilibrium. ^{Reference Wendon, Cordoba and Dhawan58}

Plasma exchange

There is evidence to support the use of plasmapheresis in ALF. A study by Larsen et al. compared high-volume plasmapheresis to standard medical therapy, which demonstrated increased TFS, though there was no difference in ICP or the observed change in ICP across groups. ^{Reference Larsen, Schmidt and Bernsmeier125} A study examining standard volume plasma exchange again not only noted higher TFS but also noted improvement in arterial ammonia and ICP measured noninvasively through ONSD. ^{Reference Maiwall, Bajpai and Singh126} Plasma exchange may be considered in ALF patients with vasoplegia refractory to CRRT, at a standard volume replacement.

Therapeutic hypothermia

The clinical rationale in the use of hypothermia in ALF relies on the suspected physiological benefit due to decreased cerebral metabolic rate, decreased accumulation of brain lactate and intracellular glutamine, normalization of CBF and shift to an anti-inflammatory cytokine environment. ^{Reference Stravitz and Larsen127} There is no evidence of the benefit of therapeutic hypothermia in the prevention of high ICP in ALF. ^{Reference Karvellas, Todd Stravitz, Battenhouse, Lee, Schilsky and Group128,Reference Bernal, Murphy and Brown129} However, there is utility in the use of therapeutic hypothermia in patients with refractory intracranial hypertension. ^{Reference Karvellas, Todd Stravitz, Battenhouse, Lee, Schilsky and Group128,Reference Bernal, Murphy and Brown129} ALF patients with refractory elevation in ICP treated with hypothermia to 32–33 °C core temperature demonstrated reduction in CBF and improved cerebral perfusion. ^{Reference Jalan, O.D., Deutz, Lee and Hayes130} Therapeutic hypothermia remains a recommendation for patients with refractory elevation in ICP, but otherwise, the target core body temperature should remain 35–36 °C. ^{Reference Bernal and Wendon7,Reference Wendon, Cordoba and Dhawan58}

Sedation

Propofol is the first-line sedative agent in ALF that has demonstrated benefit in the prevention and control of high ICP in ALF. ^{Reference Wijdicks and Nyberg131} It is commonly used in ALF due to its neuroprotective and short duration of action. Propofol reduces ICP by decreasing neuronal activity, which decreases subsequent metabolic demand. This causes proportionate physiologic decrease in CBF, subsequently reducing cerebral blood volume and reducing ICP. ^{Reference Shawcross and Wendon39,Reference Wijdicks, Plevak, Rakela and Wiesner47,Reference Ravussin, Guinard, Ralley and Thorin132,Reference Hartung133} Propofol is additionally neuroprotective by increasing the seizure threshold. ^{Reference Shawcross and Wendon39} Unlike barbiturates, the pharmacokinetics of propofol are unchanged in ALF, making it a more reliably used sedative agent.

Barbiturates including thiopental and pentobarbital may similarly be used to decrease ICP, as they also decrease cerebral metabolic rate. ^{Reference Forbes, Alexander and O’Grady134,Reference Raghavan and Marik135} The reduction in ICP from the use of barbiturates does not persist, and therefore, this class of medication is used only as a rescue therapy. It is additionally associated with cardiac depression and systemic hypotension, which may decrease cerebral perfusion. ^{Reference Forbes, Alexander and O’Grady134}

Hyperventilation

Hyperventilation can cause brief vasoconstriction, briefly improving CBF that has been impaired due to cerebral vasodilation seen in ALF. ^{Reference Strauss, Hansen, Knudsen and Larsen136} However, the consequential vasoconstriction also presents the risk of cerebral ischemia and therefore is recommended as a temporary rescue therapy. ^{Reference Wendon and Lee137,Reference Ellis and Wendon138} Spontaneous hyperventilation generally does not require treatment. ^{Reference Lee, Stravitz and Larson92} Forced hyperventilation is still used as a short-term rescue therapy in patients with evidence of life-threatening elevation of ICP and herniation and, in such a situation, would only be recommended for a limited period. ^{Reference Bernal and Wendon7,Reference Jalan139} EASL 2017 guidelines recommend the use of hyperventilation to a target arterial PaCO₂ of 25–30 mmHg only in the case of resistant elevation in ICP. ^{Reference Wendon, Cordoba and Dhawan58} Ventilation targets in ALF should generally remain pCO2 35–40 or to the patient’s prior non-intubated pCO2. ^{Reference Fernández, Bassegoda, Toapanta and Bernal104,Reference Baquerizo, Anselmo and Shackleton140}

Transplant

Medical management of intracranial hypertension may act as a bridge to transplant. ^{Reference Stravitz and Lee6,Reference Nanchal, Subramanian and Karvellas57,Reference Kok and Karvellas141} Patients deemed ineligible for transplant should still receive appropriate medical management and may demonstrate spontaneous recovery in the absence of transplant. ^{Reference Bernal, Hyyrylainen and Gera11,Reference Rajajee, Fontana, Courey and Patil61} In practice, the presence of cerebral edema does not preclude patients from undergoing a liver transplant. Patients with cerebral edema identified on CT imaging have demonstrated similar transplant selection rates to those without evidence of cerebral edema. ^{Reference Cardoso, Lee and Karvellas48} Intensive care and early transplant are important variables in patient outcome. Complications of cerebral edema remain one of the leading causes of mortality in patients on the waitlist for liver transplant. ^{Reference Karvellas, Leventhal and Rakela120} Guidelines suggest that a transplant may be futile in patients with irreversible brain injury, including absent cerebrovascular blood flow, cerebral herniation or fixed nonreactive pupils. ^{Reference Fernández, Bassegoda, Toapanta and Bernal104}