Chapter 20. Acute Liver Failure: How to Orchestrating Emergency Critical Care Interventions

A patient who presents emergently with acute liver failure (ALF) has an overall greater likelihood of either dying or requiring emergent transplantation than recovering without transplant.1 Regardless of etiology, the unifying feature of ALF is a compact clinical timeline and a rapid, often precipitous natural history of disease. Whereas spontaneous recovery of liver function is possible with supportive measures, particularly with acetaminophen overdose, there remains a significant risk of spiraling decline after presentation with multiorgan failure, bleeding, and infectious complications often heralded by high-grade encephalopathy with cerebral edema.2

The key message for the emergency critical care practitioner is that first contact with a patient with ALF requires an orchestrated team effort to be triggered to rapidly and efficiently triage and mobilize management resources. Because of the rarity and complexity of ALF, it has been argued that ALF is best managed within the framework of a previously defined protocol, similar to the standards that have gained broad acceptance in stroke and acute coronary syndrome.3 Such team efforts are crucial to give the patient with ALF the best opportunity for transplant-free survival. In the setting of deteriorating status, teams are required to rapidly mobilize those resources, interventions, and caregivers that are crucial to provide stabilization and life support as well as to triage rapidly and for transplantation in a crisis setting when time course may not forgive hesitation.

Recommendations and best evidence for developing this approach are substantially informed by the Acute Liver Failure Study Group (ALFSG) registry from a consortium of transplant centers that continues to prospectively collect data, report their findings, and grade level of evidence.4 This chapter is designed as a practical guide for the emergency critical care practitioner to provide an organizational framework for key clinical interventions.

Often used interchangeably, both the terms ALF and fulminant hepatic failure are defined by the new onset of hepatocellular dysfunction as reflected by coagulopathy (INR >1.5) and encephalopathy in the absence of preexisting liver disease.5 By convention, the further stratification of fulminant hepatic failure is based on the rapidity of encephalopathy onset in the course of illness: less than 2 weeks for acute fulminant and 8 weeks for subfulminant.6 The ALFSG study consortium has extended that time course up to 26 weeks for entry in their multicenter data analysis, and have adopted the preferred eponymous term arguing that this captures the variable pace of illness in ALF, and better encompasses an extended range of patients who share epidemiologic, etiologic, physiologic, and management characteristics.7 In the absence of encephalopathy or coagulopathy, population-based studies of patients at risk of ALF have defined hepatotoxicity by ALT >1,000.8

How to Suspect and Make the Diagnosis

As suggested by the variable terminology, the patient with ALF in the absence of prior liver disease may present with a strikingly distinct duration of symptoms, variable chief complaints, and without a clear-cut history, particularly if transaminase and INR determination are not part of initial screen. A common symptom complex of subacute fatigue, malaise, nausea, and mental status changes may be subtle and may not point overtly to ALF. Therefore, a high level of suspicion and awareness of vague or nonspecific complaints is required for an astute and rapid recognition of this disease.

Epidemiology, Etiology, and Outcomes

The emergency critical care examiner should be aware of the common etiologic categories so as to focus attention during this key initial encounter.

A handful of categories account for the bulk of etiologies, although the complete list of possible causes is extensive. In North America, acetaminophen accounts for nearly half of the ALF caused by drug toxicity, followed distantly in etiologic prevalence by antituberculous (particularly INH and PZA), antiseizure (particularly valproic acid), and antibiotic medications.9 Other identifiable causes of ALF include acute hepatitis B virus (HBV) infection (7%), other viral infections (3%), autoimmune hepatitis (5%), ischemic hepatitis (4%), and various other causes (5%) such as Wilson's disease, pregnancy-associated ALF, and other metabolic pathway abnormalities. Of importance, up to 15% of ALF cases remain of indeterminate etiology.9

As such, the first and perhaps most essential challenge is to make every attempt to obtain a complete and detailed ingestion history. To be sure, this should include all prescribed medication along with an accurate timeline. But of equal, if not more pressing, importance in the setting of ALF is that every attempt must be made to identify all nonprescription therapy, illicit drug use, and alternative/nontraditional and herbal remedy use, and to inquire about nonmedicinal ingestions (e.g., Amanita mushroom, nutritional or fitness supplements) that are new or noteworthy.10 Alcohol consumption should be scrutinized, although underreporting should be objectively ascertained by blood levels.11 Likewise, acetaminophen overdose may be underappreciated or the result of unintentional therapeutic misadventure, and the toxicity profile may be affected by sustained or coadministration.12 As such, it must be impressed upon the patient and family members to recall and report all recent therapies, including familiar household remedies that might be considered innocuous.

Etiology has a measurable effect on outcome. ALF from acetaminophen overdose, pregnancy, and hepatitis A has a more favorable outcome with transplant-free survival approaching 50%.13 Spontaneous recovery is least likely with Wilson's disease, nonacetaminophen idiosyncratic drug reactions, and indeterminant causes.14 Patients who suffer ALF due to antiepileptic medications have a significantly higher death rate after liver transplant than patients who have ALF due to other drugs.15

Early identification of a causal agent may be of therapeutic importance. Although treatment pathways are largely supportive and apply generically, some therapeutics may be tailored to specific etiology and may be time sensitive (see below).

Initial Lab Tests: Diagnosis, Prognosis, and Transplant Screens

In the context of history taking challenges, initial laboratory studies are crucial to sift through the diagnostic questions, and to lay the groundwork for assessment of transplant candidacy. In addition to liver function testing and INR, initial screening etiologic diagnostic studies should be sent as soon as feasible. Acetaminophen levels provide best guidance in the setting of single ingestion history, where prediction by nomogram has the greatest utility if the timing of ingestion is verifiably ascertained.16 Liver failure is typically associated with single ingestion in excess of 10 g, and unlikely with less than 4 g.17 However, in the setting of polypharmacy coingestion or chronic ingestion, a far lower intermittent dosage may result in hepatocellular loss. Accordingly, the receiver operating characteristic of a single acetaminophen level may have reduced negative predictive power in these settings, and thus cannot exclude acetaminophen toxicity as causal.18 Assay for acetaminophen–protein adducts may be available in some centers, and this sensitive assay may provide clues of unappreciated acetaminophen toxicity when ALF etiology remains indeterminate.19

Initial evaluation should also help to discriminate among mimics that may confusingly present with a similar triad of transaminitis or hyperbilirubinemia, coagulopathy, and altered mental status. When an initial exam suggests another etiology, ultrasound examination may provide clues to biliary tract obstruction, infiltrative hepatopathy, tumor, hepatic vein obstruction, or acute exacerbation of chronic liver disease. Nonprimary hepatic disease such as sepsis, hemolytic crisis, and acute pericardial constriction may confound the first responder if coagulation abnormalities or hyperbilirubinemia are prominent. Warfarin ingestion and consumptive coagulopathy must be considered with isolated coagulopathy. Also, adverse drug reactions may occur in the context of superimposed or concomitant illness that may further cloud the distinction between hepatocellular injury and another systemic illness.

Once the diagnosis of ALF is firmly suspected or confirmed, it is essential to obtain a battery of additional laboratory studies without delay. These studies are designed to discriminate among principal ALF etiologies, further characterize the extent of hepatocellular injury, screen for metabolic derangement, and elicit nonhepatic issues that may need attention or may impact on transplant candidacy. Table 20-1 provides a comprehensive list of lab tests that are indicated. Given the magnitude and complexity of this large list, a preestablished order set that is triggered by protocol is highly recommended.

Prognosticating from First Contact

Establishing a clear baseline for serial comparison and ALF trajectory is critical for subsequent decision making. Composite history, physical findings, and initial laboratory findings from first contact will form the basis of risk stratification and most importantly for comparative serial examinations that are crucial to the decision to list a patient for transplantation. The most commonly used prognostic classification scheme, the King's College Hospital criteria (see Table 20-2), uses simple measures that negatively predict transplant-free survival, originally derived from a cohort of acetaminophen-induced ALF.20 An unambiguous baseline and a standardized plan to serially obtain and clearly document these specific components should be part of the emergency critical care team plan.

Data that support the additive value of additional serum markers of poor outcome have been debated among the transplant community.21–23 Likewise, disease-specific prognostic indices have been evaluated in relatively small cohorts that require further validation.24 Overall, the predictive value of any modality, including the King's College Hospital criteria, may be influenced by the interruption of the natural history of disease by transplant itself. Of course, the decision, timing, availability, and effectiveness of transplantation in any given case and in different settings compound the difficulty of comparative predictive models.

How to Manage Hemodynamic Support

With progressive decline in liver function, a hyperdynamic state with low systemic vascular resistance may predominate the clinical picture, and be reminiscent of, and clinically indistinguishable from, severe sepsis. This feature correlates with the Sequential Organ Failure Assessment (SOFA) score, arterial lactate, and mortality.25 It is imperative that the mean arterial pressure (MAP) is maintained above 50–60 mm Hg to preserve organ perfusion and maintain a cerebral perfusion pressure (CPP) of >50 mm Hg. Volume resuscitation with 20–25 mL/kg isotonic crystalloid is an appropriate first maneuver, although if the patient is not responsive to an initial fluid challenge, norepinephrine is recommended.4 There are no strict prohibitions with regard to the adverse effect of vasopressors on ALF, although experimentally, the use of vasopressin appears to have a greater predilection for cerebral vasodilation.26

Adrenal hyporesponsiveness has been shown to have a high incidence in ALF, and corticosteroid replacement, though controversial, may be prudent and is recommended by ALFSG in refractory hypotension.4 Capillary permeability disturbance precipitates an increase in extravascular lung water with minimal hydrostatic pressure elevation, particularly in patients with cerebral edema, that leads to a picture of ARDS.27 Echocardiography is indicated to exclude superimposed cardiac contractile dysfunction, pericardial disease, or undisclosed regional wall motion abnormality that may point to cardiac comorbidity and impact on surgical and anesthesia tolerance. Troponin leak is prevalent in ALF with shock, as in other forms of critical illness, and this represents a poor prognostic sign.4

When to Initiate Empirical Antibiotics

With an increased duration and severity of liver dysfunction, the incidence of systemic infection rises, with bacterial and fungal sepsis reported, stemming from a blunted innate immune response coupled with catheter- and ventilator-associated barrier disruption.4 Recommendations for empirical administration of antibiotics in the presence of systemic inflammatory response syndrome and refractory hypotension, and with progression to advanced-stage hepatic encephalopathy in the patients listed for liver transplant are based in part on the difficulty in parsing signs and symptoms that point to systemic infection in this setting.4

Management of Bleeding and Bleeding Risk

The basic guideline for the emergency critical care practitioner is to recall the central tenet of avoiding injudicious use of plasma components that might obscure the triage assessment. These products increase the risk for gas exchange disturbance due to alveolar flooding, and should be avoided unless confronted with significant bleeding or concern for hemostatic integrity in conjunction with contemplated invasive procedure.4

Patients in fulminant liver failure can present with abnormalities at multiple levels of the coagulation cascade. Aside from coagulation factor and fibrinogen deficiency due to synthesis disorders, patients may also present with thrombocytopenia due to splenic sequestration, disseminated intravascular coagulopathy, or platelet abnormalities because of uremia and acute renal insufficiency. It has been recommended that the use of recombinant factor VIIa (rFVIIa) be restricted to coagulopathy reversal only in the setting of severe volume overload with predicted FFP intolerance, or prior to high-risk procedures such as liver biopsy or intracranial pressure (ICP) monitor placement. Use of rFVIIa does not replete other depleted coagulation factors and carries a higher risk of DIC than other agents.28 Additionally, the rate of arterial thrombotic events with rFVIIa is as high as 8.5%.29

Unactivated prothrombin complex concentrates (PCC) are marketed as Bebulin and Profilnine in the United States and Octaplex in Europe, and are sometimes referred to as factor IX concentrates. These include varying amounts of factors II, VII, IX, and X and proteins C and S. Using PCC, coagulopathy reversal of multiple factors can be achieved quickly with minimal volume and at a lower expense than rFVIIa. Since PCC does not contain factor V, some hematologists recommend additional FFP to replace this factor. All patients should receive vitamin K 10 mg intravenous (IV) once. Additionally, if the fibrinogen level is below 100 mg/dL, patients should be repleted with cryoprecipitate. Patients who have renal insufficiency should receive DDAVP 0.3 mcg/kg once for uremia-induced platelet dysfunction.

Adequate laboratory values for the placement of an ICP monitor include INR <1.5, platelets >50,000/mm3, fibrinogen >100 mg/dL, and a normal PTT. It should be noted that multiple doses of rFVIIa or combining rFVIIa with PCC is not recommended as this can dramatically increase the risk of DIC and DIC-related complications. In patients with persistent coagulopathy, plasma exchange has been shown to be effective.4 This may be an especially attractive option in patients who already have a dialysis catheter in place and who can tolerate an interruption from renal replacement therapy to undergo plasma exchange.

Central Line Timing and Safety Issues with Placement

In patients with severe encephalopathy, it is most prudent to combine the acts of sedation, intubation, central line access, and blood product support, followed by an assessment for transport to computed tomography (CT) that should include a head and abdominal CT. Concern for enhanced risk of catheter-associated bloodstream infection limits the utility and may increase the hazard of femoral site placement. An internal jugular (IJ) approach is preferred over the subclavian because of improved ultrasound visualization and compressibility. Additionally, there are no contraindications to IJ line placement in patients with an elevated ICP, although maintaining the head in neutral position and avoiding bilateral IJ cannulation is preferred.

Electrolyte and Fluid Management

Hypoglycemia is common and needs to be expectantly screened for and managed with glucose-containing solutions as hepatic function deteriorates. Metabolic acidosis often complicates ALF, with decreased lactate flux, increased lactate production, and strong ion gap values that maintain a persistent base deficit despite the alkalinizing effects of hypoalbuminemia and hypochloremia.30 Likewise, citrate-, acetate-, and gluconate-containing solutions may be poorly handled by the failing liver, and may represent an additional burden of unmeasured anions that can contribute to a strong ion difference and unmitigated acidosis.31

To avoid excess free water administration, glucose should be administered as 10% solution. Multiple aspects of ALF tend to produce hyponatremia. A deleterious effect of poorly managed water balance on patient outcomes has been observed, with both worsening encephalopathy and a significant decline in posttransplant neurologic recovery, in those recipients who had Na <130 at the time of surgery.32 Hypophosphatemia is a notable exception to the deleterious effect of electrolyte disturbance, in that this abnormality has been attributed to recovering hepatocyte mass, and is considered to be a marker of renewed metabolic activity.4

When to Initiate Renal Replacement Therapy

Oliguria and renal failure are common features that accompany ALF. The predilection for renal failure is highest in acetaminophen toxicity but may be precipitated in all forms of ALF.16 The pathophysiology is likely multifactorial and may include hypovolemia, acute medullary cortical microcirculatory disturbance with sodium avid renal failure similar to hepatorenal syndrome, or tubular damage directly from toxins including acetaminophen adducts or associated reactive oxygen species.33 The recovery of renal function tends to mirror that of hepatic function, so that spontaneous improvement with recovery, or after transplantation, is often seen. Nonetheless, early introduction of renal replacement therapy is recommended for patients with progressive oliguria, particularly in the setting of electrolyte disturbance and volume overload, and to assist the management of plasma administration or osmotic therapies.4 Continuous venovenous hemofiltration (CVVH) is the preferred modality by ALFSG recommendations, based on its smoother hemodynamic profile, less precipitous fluid shifts, the ability to rapidly and continuously address electrolyte disturbance, and manage osmotic therapy.4

Specific Therapeutic Initiatives

Specific therapies for unique causes of ALF are few and are detailed below.

The toxic acetaminophen metabolite N-acetyl-p-benzoquinone imine (NAPQI) is normally detoxified by glutathione conjugation. N-Acetylcysteine (NAC) for acetaminophen overdose by either oral or IV route is indicated to replenish glutathione stores, and may further act by antioxidant and vasoactive mechanisms. The IV route has the advantage of improved GI tolerance and eliminates problems related to absorption.4 Moreover, based on accumulating evidence for transplant-free survival benefit and its generally favorable safety profile, IV NAC should be strongly considered for patients with early stage nonacetaminophen ALF.34 Treatment should be initiated immediately when ALF or hepatotoxicity is established, with a loading dose of 150 mg/kg in 500 mL dextrose 5% over 30 minutes, followed by maintenance dose 50 mg/kg over 4 hours, and then 125 mg/kg in 1,000 mL dextrose 5% over 19 hours. Most experts recommend a continuous IV infusion of NAC until the INR is less than 1.5. Because of risk of hypersensitivity reaction, IV NAC should always be administered in a monitored setting, and patients with mild allergic symptoms should have the infusion rate decreased by 50% and receive corticosteroids and antihistamine.

Other therapies in use, but of unproven benefit, include activated charcoal and high-dose IV penicillin for mushroom poisoning and corticosteroids for autoimmune hepatitis. However, corticosteroids had no demonstrated benefit in a trial of drug-induced ALF. Other emergent interventions that apply to specific etiologies include prompt delivery for pregnancy-related ALF. Consultation with the transplantation team should be conducted before initiation of etiology-specific therapy with unproven initiatives such as copper chelation, plasmapheresis, and antioxidant therapy for Wilson's disease; lamivudine or entecavir for acute hepatitis B; acyclovir for herpes simplex virus infection; and decompressive surgery or transjugular intrahepatic portosystemic shunts (TIPS) for acute Budd–Chiari syndrome.9

Emerging Therapeutic Options in ALF

Hemofiltration and hemodialysis have limited capacity to remove protein-bound toxins, but newer, experimental techniques have been developed to deal with these substances. Several configurations of so-called liver support modalities have been reported in nonrandomized studies, and the results of multicenter trials are awaited. Both cell-free and bioartificial systems have been developed with the aim to remove known and unknown toxins that are released and not cleared in ALF. At present, the use of these devices has not been reported to change mortality, although endpoints such as reduced encephalopathy have raised interest in pursuing this line of research; however, their use should be considered experimental.35

Bridging therapies, such as auxiliary orthotopic transplant and two-stage transplantation where hepatectomy precedes transplantation by a variable interval up to days, are controversial, and have only been reported anecdotally. These extraordinary procedures are attempted only in specialized centers under dire circumstances, as in the setting of unavailable allograft in a patient with unmitigated intracranial hypertension.36

How to Evaluate Mental Status

Hepatic encephalopathy is a reversible form of neurologic dysfunction. Although its pathogenesis is not entirely understood, it is thought to be primarily due to ammonia-induced neurotoxicity. Ammonia, produced either by catabolism of nitrogenous sources or by glutamine metabolism at a mitochondrial level, has been shown to lead to astrocyte swelling and dysfunction.37 Metabolism of glutamine into glutamate and ammonia may additionally cause stimulation of N-methyl-d-aspartic acid (NMDA) receptors triggering nitric oxide release and subsequent vasodilation. This vasodilation may lead to hyperemia and cerebral edema.38 Additionally, cerebral autoregulation has been found to be impaired in patients with fulminant hepatic failure.39 A variety of other mechanisms may be involved in the pathogenesis of hepatic encephalopathy including inflammation, activation of the aquaporin-4 water channel protein on astrocytes, oxindole (a tryptophan metabolite), as well as catecholamine and other neurotransmitter abnormalities.40

The result of this abnormal neurochemical milieu is cerebral edema, which occurs in 80% of comatose patients with acute hepatic failure and is the leading cause of death among patients suffering from fulminant ALF.41 Hepatic encephalopathy is graded as depicted in Table 20-3.

The neurologic exam should be conducted in patients who have been free of sedation for as long as possible, balancing the risks of agitation that may elevate ICP. Since neuromuscular blockade can alter brainstem reflexes and the motor exam, recently intubated patients should be tested with a train of four stimulations to ensure that neuromuscular blockade is not confounding the neurologic assessment. Table 20-4 shows an outline of neurologic domains that should be assessed in all ALF patients.

When to Obtain Head CT Scan

Any patient with an acute deterioration in mental status or focal findings on exam should undergo a noncontrast head CT to assess for intracranial hemorrhage. Apart from this, a head CT is recommended in any patient with stage III or IV encephalopathy to evaluate for cerebral edema.4 A normal head CT does not rule out elevated ICP and should not be used as a surrogate for ICP monitoring. In addition to a baseline CT, a head CT should be performed after insertion or removal of an ICP monitor to check positioning and for hemorrhage. Although MRI may detect cerebral edema with more sensitivity and specificity than CT, the risks of transport and the time involved in obtaining an MRI outweigh the benefits in diagnostic accuracy.

When and How to Intubate

Encephalopathy can lead to aspiration and elevated Paco2, which can exacerbate cerebral edema and elevated ICP. Noncommand following (typically grade III or IV) patients should be considered for intubation. In order to avoid spikes in ICP that can occur with laryngeal stimulation, intubation should occur in a controlled setting. Either propofol or etomidate is an appropriate induction agent. Ketamine should be avoided because it can elevate ICP. Lidocaine spray or 1 mL/kg IV bolus can be given prior to laryngoscopy to blunt increases in ICP. Succinylcholine should be avoided in patients who have been sedentary for >24 hours. Use of a video-assisted laryngoscope can facilitate intubation with fewer complications than direct laryngoscopy.

Safe Mechanical Ventilation and Principles of ICP Interaction

Assist control volume control modes are reasonable in patients with hepatic encephalopathy. Since increasing positive end-expiratory pressure (PEEP) will increase mean intrathoracic pressure as well, elevated PEEP that exceeds central venous pressure can theoretically lead to elevations in ICP. However, studies with PEEP up to 15 cm H2O have not shown a significant effect on ICP or CPP.42 Permissive hypercapnia should be avoided as this will elevate ICP. Similarly, inverse ratio modes with elevated pressures for a significant duration of the respiratory cycle may inhibit jugular venous outflow and lead to increased ICP. Many fulminant liver failure patients will spontaneously hyperventilate as part of an autoregulatory response. This should not be treated. Conversely, induced hyperventilation is not recommended except in acute cases of herniation since this can lead to ischemia due to vasoconstriction.43 Maintenance of a Paco2 between 30 and 40 mm Hg is reasonable.

Sedation Practices in the Face of Encephalopathy

Minimizing oversedation and utilizing sedation interruption are essential for continuous assessment of the neurologic exam. Adequate treatment of pain and anxiety should be addressed to minimize elevation of ICP. When selecting a sedative, renal and hepatic clearance should similarly be considered. Propofol is a typical agent with a short half-life that allows for frequent exam assessment. It does not provide any analgesia, however. Other reasonable options include fentanyl, which can minimally lower the seizure threshold, and dexmedetomidine, a centrally acting α2-agonist that provides anxiolysis and analgesia with minimal respiratory or neurologic suppression. Midazolam is a reasonable choice in anxious patients and, like propofol, has anticonvulsant effects. It does, however, have active metabolites that can accumulate with prolonged use. All of the aforementioned agents can lower blood pressure. Paralysis is seldom necessary for adequate ventilation, but if used, it should be used judiciously and for as brief a period of time as necessary. It can substantially increase the risk for critical illness neuropathy and myopathy, mask seizure activity, and completely obscure the neurologic exam.

ICP Monitor

Elevated ICP occurs in 86–95% of patients with grade III or IV encephalopathy.3 Given the insensitivity of head CT to assess for cerebral edema, ICP monitoring should be considering in all noncommand following patients, typically grade III or IV encephalopathy patients. Monitoring ICP is the only way to diagnose elevated ICP and assess the efficacy of cerebral edema treatment in patients with marginal neurologic exams. Although there are no randomized trials to support the use of ICP monitoring, data suggest that monitoring can identify ICP spikes that are subclinical, lead to therapeutic changes, and provide important prognostic information. ICP monitoring is recommended by the ALFSG in grade III and IV patients who are candidates for transplantation and in some patients with advanced encephalopathy who are not liver transplant candidates, but may have survival benefit with protocolized, aggressive neurologic management.3

Since it is not clear that the risk of hemorrhage after adequate correction of coagulopathy is higher with intraparenchymal monitors compared with epidural ICP monitors, and since parenchymal monitors are more accurate, our practice is to place intraparenchymal monitors. Intraventricular monitor placement is not recommended due to the increased risk of bleeding.44

In patients who are unable to undergo ICP monitor placement, transcranial Doppler assessment of pulsatility index (peak end-diastolic flow velocity/mean flow velocity) can provide a rough assessment of whether ICP is elevated or not, but cannot quantify the ICP. Pulsatility indices >1.5 are considered abnormal. It is important to note that transcranial Doppler does not provide quantifiable or continuous ICP monitoring and in some studies has shown suboptimal sensitivity and specificity.45

Adequate reversal of coagulopathy is essential prior to ICP monitor placement, as described above. It is unclear if coagulation factors need to be corrected for the entire duration of time an ICP monitor is in place or if correction is only necessary during placement and removal of devices.3 Continued aggressive coagulopathy correction can lead to volume overload, thrombosis, or DIC and may mask spontaneous liver recovery. Additionally, the expense of continued correction should be considered.

Active Management—Principles of Osmotic Therapy, Hypothermia

The first steps in managing elevated ICP (defined as sustained ICP >25 cm H2O or 20 mm Hg) involve simple measures to maximize venous outflow and avoid increases in intrathoracic or intra-abdominal pressure that can come with agitation, coughing, or ventilator dyssynchrony. All patients should have the head of the bed elevated at least 30° (unless contraindicated by hypotension), the head should be maintained midline to promote venous drainage, bilateral jugular venous catheterization should be avoided, and patients should be maintained in a comfortable pain-free state with the minimal amount of analgesics or anxiolytics required to avoid agitation or pain. Lidocaine spray can be used prior to suctioning to avoid a cough response, and an adequate bowel regimen should be prescribed to avoid straining during defecation. Generally, patients should be maintained in a euthermic, euvolemic state.

Patients should be monitored for seizures and treated appropriately since this can elevate ICP. The true incidence of seizure in fulminant liver failure patients is not clear. In small series of patients with ALF, seizure activity, including nonconvulsive status epilepticus, was identified in up to 32% of patients.46 Additionally, paralysis should be avoided, if possible, to allow for detection of subtle clinical spells. Patients who have seized should receive antiepileptic treatment. Prophylaxis can be considered for those who have intracranial hemorrhage or very severe cerebral edema, in whom a seizure might cause herniation due to elevated ICP.47

Since cerebral autoregulation has been found to be impaired in patients with ALF, it is important to recognize the relationship between ICP and MAP. In patients with a global loss of autoregulation, cerebral blood flow (CBF) and cerebral blood volume (CBV) will vary passively with MAP. Since CBV is one component of intracranial volume, increases in CBV may increase ICP. Thus, MAP should not be excessively high. However, if autoregulation is partially or regionally intact, small cerebral arterioles will dilate in an attempt to maintain CBF under circumstances of low MAP. When these arterioles dilate in the vasodilatory cascade zone, CBV increases and, as a consequence, so can ICP. Thus, at very high and very low MAPs, ICP may be elevated. For this reason, a CPP (MAP–ICP) of at least 50 mm Hg is recommended.3

In patients with persistently elevated ICP, osmotic therapy can be considered. Mannitol (20%, 1.0 g/kg or 100 g IV bolus) is a traditional agent that can be used for induction of a hyperosmotic state. It will cause diuresis and may cause hypotension or renal insufficiency. Alternately, hypertonic saline (3%, 30 mL over 10–20 minutes via a central line) may be used. Hypertonic saline will improve CPP to a greater extent than mannitol, but can cause flash pulmonary edema or hypotension if administered too quickly. Although hypertonic saline can also cause renal insufficiency, it is not as offensive as mannitol. Both mannitol and hypertonic saline have rheologic effects that can improve ICP. Maintenance of a hyperosmotic state can be achieved with either mannitol boluses or hypertonic saline as a bolus or continuous infusion. Mannitol is typically redosed every 6 hours for elevated ICP or serum osmolality less than 320 mOsm/L or osmolal gap greater than 50 mOsm/kg.3 Renal insufficiency due to mannitol is typically seen with doses above 200 g per 24 hours or with a serum osmolal gap above 60–75 mOsm/kg. Hypertonic saline is typically dosed using 3% saline at 1 mg/kg/h titrated to a serum sodium of 150–155 mEq/L. Serum sodium values should be evaluated every 6 hours, and drips should be titrated accordingly. Care should be taken to avoid abrupt withdrawal of hyperosmolar treatment as this can lead to rebound cerebral edema.

Patients who are refractory to maximal osmolar therapy should be considered for induced hypothermia targeted to a core body temperature of 32–34°C, although it has not been studied in large randomized trials, and may be associated with serious complications.48 Other options for ICP control include hyperventilation and barbiturate coma. Hyperventilation should only be used acutely during herniation. The effect of hyperventilation is short lived (1–24 hours) since the cerebral spinal fluid (CSF) will rapidly buffer the alkalotic effect. Barbiturate coma is considered the last course of action for ICP control in liver failure patients. Pentobarbital (5–20 mg/kg IV bolus followed by 1–4 mg/kg/h) is typically used and titrated to burst suppression on continuous EEG. Barbiturates cause loss of the entire neurologic exam including brainstem reflexes and, additionally, carry the complications of cardiosuppression, immunosuppression, and profound hypotension. However, barbiturates can be powerfully effective in lowering ICP by the mechanism of metabolic suppression, when patients are refractory to all other agents.

Clearly, an organized protocol with emergency department participation is required for the efficient care of ALF patients. The emergency critical care practitioner is most often the first responder and is best situated in the clinical arena to orchestrate the triage, diagnosis, and teamwork for this complex, though thankfully, rare condition. Most, if not all, transplant centers have developed and implemented protocolized care with predetermined order sets and identified personnel who respond to triage triggers. Components of an organized protocol should include laboratory studies, specific consultants, and supplementary studies that are always indicated. Also, triggers for specific therapeutic interventions such as encephalopathy management should be developed with consultants. For the best practice in a given location, the emergency critical care responder must coordinate with the local transplant center to predetermine what information will be required by the transplant team. Finally, if the diagnosis of ALF appears likely or is confirmed, the emergency critical care practitioner should be mindful of the specific demographic information that would be required of a transplant coordinator should the need arise to prepare for potential United Network of Organ Sharing (UNOS) waiting list. Ensuring the completeness of these historical components at onset may be critical to preventing transplant delay and is best accomplished by a pre-scripted protocol. As an example, a reproduction of the current protocol from our institution is offered as a template in Figures 20-1 and 20-2.