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Assessment and management of cerebral edema and intracranial hypertension in acute liver failure
Journal of Critical Care (2013) 28, 783–791
Assessment and management of cerebral edema and intracranial hypertension in acute liver failure☆ Vahid Mohsenin MD ⁎ Section of Pulmonary, Critical Care and Sleep Medicine, Yale School of Medicine, New Haven, CT, USA
Keywords: Acute liver failure; Hepatic encephalopathy; Brain edema
Abstract Acute liver failure is uncommon but not a rare complication of liver injury. It can happen after ingestion of acetaminophen and exposure to toxins and hepatitis viruses. The defining clinical symptoms are coagulopathy and encephalopathy occurring within days or weeks of the primary insult in patients without preexisting liver injury. Acute liver failure is often complicated by multiorgan failure and sepsis. The most life-threatening complications are sepsis, multiorgan failure, and brain edema. The clinical signs of increased intracranial pressure (ICP) are nonspecific except for neurologic deficits in impending brain stem herniation. Computed tomography of the brain is not sensitive enough in gauging intracranial hypertension or ruling out brain edema. Intracranial pressure monitoring, transcranial Doppler, and jugular venous oximetry provide valuable information for monitoring ICP and guiding therapeutic measures in patients with encephalopathy grade III or IV. Osmotic therapy using hypertonic saline and mannitol, therapeutic hypothermia, and propofol sedation are shown to improve ICPs and stabilize the patient for liver transplantation. In this article, diagnosis and management of hepatic encephalopathy and cerebral edema in patients with acute liver failure are reviewed. © 2013 Elsevier Inc. All rights reserved.
1. Definition and epidemiology of acute liver failure Acute liver failure (ALF) is a life-threatening multisystem illness resulting from massive liver injury. The defining clinical symptoms are coagulopathy and encephalopathy occurring within days or weeks of the primary
☆ Conflict of interest: None to disclose. ⁎ Department of Medicine, Section of Pulmonary, Critical Care and Sleep Medicine, Yale University, PO 208057, New Haven, Connecticut 06520-8057, USA. E-mail address: [email protected].
0883-9441/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jcrc.2013.04.002
insult in patients without preexisting liver injury [1]. Acute liver failure is a relatively uncommon disorder affecting approximately 2500 patients in the United States each year [2]. Acetaminophen and nonacetaminophen drug-induced hepatotoxicity account for more than 50% of cases of ALF in the United States [3]. Other identifiable causes of ALF include acute hepatitis B virus infection (7%); other viral infections (3%); autoimmune hepatitis (5%); ischemic hepatitis (4%); and various other causes (5%) such as Wilson disease, pregnancy-associated ALF, and other metabolic pathway abnormalities. Of importance, up to 15% of ALF cases remain of unclear etiology. In the developing countries, infectious hepatitis is the most common cause of ALF. However, less than 4% of cases
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of acute hepatitis B viral infection will lead to development of the ALF, but mortality is higher than that with hepatitis A or E infections [4].
2. Hepatic encephalopathy and brain edema in ALF Hepatic encephalopathy is graded according to the degree of cognitive deficit. The West Haven criteria were originally developed for chronic liver disease but are used clinically for ALF as a bedside assessment tool (Table 1). Grades I and II have mild to moderate confusion and irritability with or without asterixis. Grade III has marked confusion with asterixis but still can follow commands. Grade IV patient is comatose [5]. In the earlier reports, the frequency of cerebral edema occurring in fulminant hepatic failure ranged from 50% to 85% [6-9]. Although the frequency of clinically overt brain edema in ALF patients has decreased over the past 2 decades, intracranial hypertension accounts for 20% to 35%
Table 1 West Haven hepatic encephalopathy grades with Amodio modifications Psychiatric Grade Level of symptoms consciousness/ cognitive function
Neuromuscular function
1
Tremor
Sleep disturbance Euphoria/ depression Mild confusion
2
Impaired computations Inattentive
3
Moderate confusion Disorientation to time Marked confusion
4
Completely disoriented Lethargic, but arousable Command following Non-command following
Irritability
Incoordination, ± asterixis
Asterixis, slurred speech Impaired handwriting
Decreased inhibitions Personality changes Anxiety or Slurred speech, apathy ataxia Inappropriate Asterixis, nystagmus Bizarre Hypoactive or behavior hyperactive reflexes Paranoia, anger or rage Coma, dilated pupils Loss of cranial nerve reflexes Signs of herniation Flexor or extensor posturing Loss of reflexes
of deaths and requires considerable resources in the intensive care unit setting [10,11]. The degree of hepatic encephalopathy on admission tends to predict outcome. In one of the largest prospective multicenter studies on 308 patients, 161 patients presented with grade I and II hepatic encephalopathy on admission; 52% survived without transplantation for 3 weeks. In contrast, of 147 patients who presented with grade III or IV hepatic encephalopathy, 33% survived 3 weeks without transplantation. The overall transplantation rate was 29% for all grades, but grade I and II had a survival rate of 77% compared with 56% in grade III and IV [12].
3. Mechanism of brain edema The pathogenesis of hepatic encephalopathy and cerebral edema is multifactorial, but it is well established that ammonia plays a central role and inflammatory cytokines accentuate the process [13]. According to the ammoniaglutamine hypothesis, the source of circulating ammonia is from glutamine metabolism in the intestinal epithelium and urease activity in the intestinal flora. In normal circumstances, the liver metabolizes all the ammonia coming from the small and large intestine via portal circulation. Ammonia is also produced in healthy individuals by muscle and the kidney. These 2 tissues have the ability to shift to ammonia detoxifying organs in the case of liver failure. However, because of loss of muscle mass in chronic liver failure, the physiologic efficiency and clinical benefits of this detoxifying process are not clear. Hyperammonemia induces accumulation of glutamine inside the astrocytes. Astrocytes are the only cells in the brain that can metabolize ammonia. The enzyme glutamine synthetase (present in the endoplasmic reticulum of astrocytes) is responsible for the conversion of equimolar concentrations of glutamate and ammonia to glutamine. Intracellular levels of glutamine, therefore, increase enormously as the ambient ammonia concentrations rise secondary to liver failure. The osmotic and metabolic effects of glutamine contribute to astrocyte swelling and cerebral edema in hepatic encephalopathy. Increased cerebral glutamine levels correlate with severity of psychoneurological signs and intracranial pressure (ICP) measurements. The “toxic liver hypothesis” implicates inflammatory cytokines and toxic products from the necrotic liver that correlate with central nervous system complication. There is evidence for neuroinflammation in ALF in experimental models and in patients with ALF showing efflux of tumor necrosis factor α, interleukin 1β, and interleukin 6 from the brain when measured in blood sampled from an artery and reverse jugular catheter [14]. Ultrastructural studies in brain sections from ALF patients have so far failed to provide evidence for blood-brain barrier breakdown, attributing brain edema and its complications to primarily cytotoxic rather than vasogenic mechanisms [15].
Cerebral edema and intracranial hypertension in ALF
4. Diagnostic modalities 4.1. Bedside assessment Hepatic encephalopathy is conventionally graded by clinical scales such as the West Haven criteria (Table 1) [5]. This scale semiquantitatively grades a patient's mental state by means of subjective assessments of behavior, intellectual function, alteration of consciousness, and neuromuscular function. The grading has high interobserver variability for grades I and II. Modification of the criteria by addition of some objective measures has improved its discriminatory function [16]. Bispectral index, a measure of spectral and time domains of electroencephalography, has been shown to have high predictive power to discriminate West Haven grades I to IV in a multicenter study [17]. Cerebral edema is seldom observed in patients with grade I and II encephalopathy. The risk of edema increases to 25% to 35% with progression to grade III and 65% to 75% or more in patients reaching grade IV encephalopathy [18].
4.2. Neuroimaging 4.2.1. Computed tomography Intracranial hypertension should be clinically suspected in ALF patients with new onset systemic hypertension, progression of hepatic encephalopathy, alterations in pupillary reactivity, abnormalities in oculovestibular reflexes, or signs of decerebration. However, most of these clinical signs are not specific or sensitive and may be developed by patients in hepatic grade IV encephalopathy without intracranial hypertension. Noncontrasted head computed tomography (CT) may show cerebral edema, compression of basal cisterns, hydrocephalus, mass effect, or midline shift (Fig. 1). However, the absence of these findings does not exclude cerebral edema or intracranial hypertension [19,20]. Therefore, its routine use is inadvisable. Its principal value is
785 to rule out other uncommon intracranial pathology, most importantly bleeding. 4.2.2. Brain magnetic resonance imaging Magnetic resonance imaging scanning provides a more accurate assessment of brain water content or underlying lesions. However, it is generally not necessary nor has been shown to be useful in patients with suspected intracranial hypertension. It may be even hazardous due to the prolonged time required for scanning and the need for the patient to lay supine, which may aggravate the ICP.
4.3. Transcranial Doppler The ability of the cerebral vascular system to constrict and dilate in response to changes in perfusion pressure is termed autoregulation. Impaired cerebral autoregulation is a recognized complication of ALF [21,22]. Cerebral blood flow has been shown to correlate with ICP in a study of patients with ALF [14]. In a series of patients from Pittsburgh, sequential measurements of blood flow and ICP have shown that an increase in cerebral blood flow (CBF) precedes the rise in ICP [23]. Patients with signs of cerebral edema and intracranial hypertension have been shown to have higher CBF compared with patients without edema. Although there is a wide interindividual variation in CBF in patients with fulminant hepatic failure, a higher CBF has been associated with a poorer prognosis. Transcranial Doppler (TCD) is a noninvasive technique that measures blood flow velocity of intracranial vessels and provide some indirect evidence regarding ICP and CBF [24]. Transcranial Doppler has been used extensively in the study of autoregulation in the critical care setting. Cerebral autoregulation can be explained at least partially by a tight coupling between O2 supply and demand of the brain. Under normal conditions, CBF is maintained at a constant flow rate of 50 to 60 mL per 100 g/min, with 50
Fig. 1 Rapid development of brain edema in a patient with fulminant hepatic failure. On the left, the CT scan done in encephalopathy grade IV showing cortical sulci and the ventricles. On the right when the patient developed unilateral fixed midriasis, the scan shows evident signs of brain edema in the form of virtual absence of cortical sulci and compression of fourth ventricle and of the brain stem (reproduced with permission from World J Gastroenterol. 2006;12:7405-7412).
786 mL oxygen being extracted every minute from 700- to 800mL blood. This occurs despite changes in mean arterial pressure within the range of 60 to 160 mm Hg. Outside this range flow becomes proportional to pressure, potentially leading to episodes of cerebral hypoperfusion and hyperperfusion. In a study of 16 patients with ALF, information obtained from TCD signal of middle cerebral artery wave forms correctly classified 61% of the patients with ICP less than 20 mm Hg, 53% of patients with ICP between 20 and 30 mm Hg, and 67% of patients with ICP more than 30 mm Hg [25]. An early indicator of this pathologic process is either a decrease in the transcranial oxygen content difference (arterial oxygen content minus jugular bulb oxygen content) to less than 4 mL per 100-mL blood or an increase in middle cerebral artery systolic blood flow velocity. As the cerebral hemodynamics continue to deteriorate with increasing ICP, CBF starts to decrease, and TCD waveform shows sharpening of peak systolic wave and loss of elasticity of the intracranial vessels (loss of the Windkessel effect, loss of vessel recoil when the blood pressure falls during diastole) due to increased extramural pressure from brain swelling (Fig. 2). The TCD parameters most sensitive to cerebral perfusion pressure seem to be the systolic velocity and the velocity peak-to-peak amplitude. Independent of the type of intracranial pathology, a strong correlation (correlation coefficient of 0.938, P b .0001) between pulsatility index (difference in the systolic and diastolic flow velocity divided by the mean flow velocity of middle cerebral artery) and ICP has been demonstrated [24].Therefore, pulsatility index may be of guiding value in the invasive ICP placement decision in the neurointensive care patient. In patients with severe coagulopathy and high risk for bleeding complications, TCD can be used serially to follow the response to treatment of intracranial hypertension. Transcranial Doppler has a better diagnostic sensitivity of 67% compared with 27% by brain CT to detect intracranial hypertension [25].
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4.4. Jugular venous oximetry In patient with hepatic encephalopathy grade III or IV, a jugular bulb catheter may be used to assess cerebrovascular autoregulation. However, this method has limited utility because of varying cerebral metabolic rate due to the patient's underlying level of inflammation or sedation [26].
4.5. Intracranial pressure monitoring The most accurate method of diagnosing intracranial hypertension is ICP monitoring. Although the advantages of this monitoring in ALF patients have not yet been demonstrated by a randomized study, ICP monitoring may be very helpful in establishing the presence of intracranial hypertension and in guiding specific therapy. Therapeutic actions resulting from the analysis of the ICP values may change the disease progression, extending the available time to liver transplantation. Intracranial pressure monitoring in ALF patients may suddenly rise from normal to lifethreatening levels within minutes. In this situation, continuous ICP monitoring may allow rapid and specific management. Several groups have included ICP monitoring in the management protocol of patients with fulminant liver failure [27]. The main argument against ICP monitoring is the enhanced risk of complications in ALF patients, mainly infection and hemorrhage. In a national survey of 262 ALF patients, the complication rate of ICP monitoring was 10%, of which 5% were significant and may have contributed to death. In this series, intracranial hemorrhages were the cause of death in 7 patients, with the epidural transducers had the lowest complication rate (3.7%) [28]. It was noteworthy that the monitored group underwent more treatment interventions; however, outcomes were not improved for those who
Fig. 2 Transcranial Doppler recordings of middle cerebral artery from a single patient with progressing ALF. In addition to sharpening of the systolic peak in the waveform, the waveform changes from one that includes a Windkessel effect (asterisks in the left panel indicating vessel recoil during diastole) to one that does not as liver failure progresses with increasing intracranial pressure. Abbreviations: CPP indicates cerebral perfusion pressure; MAP, mean arterial pressure (adapted from Liver Transpl. 2008;14:1048-1057).
Cerebral edema and intracranial hypertension in ALF were subjected to invasive monitoring. Given that this was an uncontrolled study, the number of patients observed may not have been large enough to demonstrate relative benefit. In a retrospective review of 22 pediatric patients with ALF awaiting liver transplantation who had ICP monitoring using intraparenchymal monitors for grade III and IV hepatic encephalopathy, survival after liver transplant was 88%. Hemorrhagic complications were evaluable in 17 patients. Three patients had intracranial hemorrhages anatomically associated with the monitor site. One fully recovered and the other 2 died of sepsis. In 5 patients, clinical complications of ICP monitor placement were not evaluable because they died before a CT scan was performed, and autopsy was not obtained. Although there has been improvement in safety of ICP monitoring, the decision should be on a case-by-case basis assessing the risks and benefits of the procedure [27]. With more sophisticated laboratory tests, it has been shown that patients with liver disease may be in hemostatic balance as a result of concomitant changes in both prohemostatic and antihemostatic pathways. Clinically, this rebalanced hemostatic system is reflected by the large proportion of patients with liver disease who can undergo major surgery without any requirement for blood product transfusion [29]. There is limited experience with the use of recombinant factor VIIa before insertion of ICP monitoring catheter, but it appears to minimize the risk of bleeding as the secondary hemostasis is restored [30,31].
5. Management of intracranial hypertension and brain edema The normal ICP is 5 to 10 mm Hg. Intracranial hypertension becomes clinically relevant when ICP exceeds 20 mm Hg increasing the likelihood of compromising the cerebral perfusion pressure. Severe intracranial hypertension may result in compression of brain stem, resulting in brain stem ischemia, hemorrhage, and death. The management goal of intracranial hypertension is to maintain ICP less than 20 mmHg and cerebral perfusion pressure of greater than 70 mm Hg. An evidence-based algorithm for management of hepatic encephalopathy and brain edema has recently been proposed [32,33].
6. General measures Arterial hypertension can increase intracranial blood volume and pressure compromising cerebral perfusion pressure. Likewise, arterial hypotension in the presence of impaired cerebral autoregulation will lead to decreased cerebral perfusion pressure. Optimization of blood pressure can be achieved by adequate intravascular volume and/or vasopressors such as norepinephrine in the setting of
787 hypotension and sedation in the settings of hypertension. The patient's head should be maintained in neutral position with the head of the bed at 30° to favor venous drainage and thus decrease ICP (Fig. 3). However, some patients with markedly compromised cerebral perfusion or hypotension (vasodilatory shock) may not tolerate elevation of the head of the bed, so it is important to assess ICP and cerebral perfusion pressure on an individual basis and serially over time to define the optimal position for each patient and to guide the arterial blood pressure management strategy.
7. Pharmacologic therapy Correction of the underlying factors that precipitate hepatic encephalopathy might in itself help to resolve the disease and reduces the risk of cerebral edema. Nacetylcysteine is indicated in acetaminophen-induced liver injury and has been shown to be also effective in nonacetaminophen ALF and mild hepatic encephalopathy. In addition to its liver protective effect, its ability to scavenge reactive nitrogen and oxygen species is of particular interest, as the accumulation of these compounds may be involved in the pathogenesis of brain edema. Lactulose is considered in patient with underlying cirrhosis and hepatic encephalopathy and is not generally used in ALF. In addition to having a laxative effect, lactulose reduces the colonic pH and interferes with mucosal uptake of glutamine in the gut, thereby reducing the synthesis and absorption of ammonia. Overtreatment with lactulose, however, results in the serious adverse effects of severe dehydration, hyponatremia, and worsening of hepatic encephalopathy, especially in patients treated in the intensive care unit. Nonabsorbable antibiotic, rifaximin with few adverse effects and no reported drug-drug interactions, is commonly used in conjunction with lactulose.
8. Measures to decrease intracranial volume 8.1. Hyperventilation Hyperventilation lowers PaCO2 causing cerebral vasoconstriction decreasing ICP [34]. Hyperventilation has been shown to restore cerebral autoregulation [35]. However, in a controlled study, hyperventilation did not prevent the development of brain edema in patients with fulminant liver failure [36]. In most centers, hyperventilation is only implemented for acute rise of ICP and for short period [37].
8.2. Indomethacin Indomethacin, a cyclooxygenase-2 inhibitor, induces cerebral vasoconstriction through multiple mechanisms including inhibition of the endothelial cyclooxygenase
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V. Mohsenin Hepatic Encephalopathy grade III/IV
Transcranial Doppler Jugular venous oximetry Invasive ICP monitoring
Brain Edema Intracranial Hypertension
Intubation Head elevation 30º Propofol sedation Correction of intravascular volume & hyponatremia Norepinephrine-MAP>65 mmHg
Fig. 3
Osmotic therapy
Hyperventilation for acute ICH
Mannitol: (1 g/kg iv q6h) Target:300-320 mOs/L Hypertonic saline (10%) Target Na:145-155 mEq/L
? Indomethacin for acute ICH Therapeutic hypothermia-32º C ? Extracorporeal albumin dialysis
Management algorithm for brain edema and intracranial hypertension in ALF. Abbreviation: ICH indicates intracranial hypertension.
pathway, alterations in extracellular pH, and reduction in cerebral temperature. In a case series, indomethacin reduced ICP from 30 (7-53) to 12 (4-33) mm Hg (P b .05) with an increase in cerebral perfusion pressure from 48 (0-119) to 65 (42-129) mm Hg (P b .05) [38]. However, in view of its potential adverse effects, nephrotoxicity, platelet dysfunction, and possible gut ischemia and gastrointestinal bleeding in already coagulopathic patients, its routine use should await randomized trial with special focus on its safety in this population.
8.3.2. Hypertonic saline A randomized clinical trial in 45 patients with ALF compared 30% hypertonic saline with target serum sodium between 145 and 150 mmol/L with those who received standard care. The results showed that ICP decreased significantly relative to baseline over the first 24 hours in the treatment group (P = .003) with the incidence of intracranial hypertension, defined as a sustained increase in ICP to a level of 25 mm Hg or greater, which was significantly lower in the treatment group (P = .04) [41].
8.3. Osmotic therapy
8.4. Therapeutic hypothermia
Blood-brain barrier for the most part is intact in patients with ALF, albeit there may be selective defects. Osmotic agents such as mannitol and hypertonic saline by increasing blood osmolality induce fluid movement from brain intracellular and interstitial space to intravascular space decreasing brain volume.
Therapeutic hypothermia, using external cooling system, could be an adjunct therapy for patients with grade III or IV hepatic encephalopathy or uncontrolled intracranial hypertension. Hypothermia affects the processes responsible for the development of brain edema at multiple levels, including a normalization of CBF, decreased entry of ammonia into brain, reduction in extracellular brain glutamate, and a decrease in anaerobic glycolysis [42,43]. Promising initial results have shown that hypothermia may be an effective bridge therapy in patients with refractory intracranial hypertension who are good candidates for liver transplantation [44]. The first clinical study by Jalan et al [45] showed that 7 patients with intracranial hypertension resistant to standard therapy who were chilled to 32°C had a significant fall in ICP from 45 to 16 mm Hg and improvements in cerebral perfusion pressure from 45 to 70 mmHg and a significant fall in arterial ammonia from 343 to 259 mg/dL as did cerebral uptake of ammonia. Therapeutic hypothermia may also be applied successfully in selected patients with severe brain edema from ALF who have good potential for liver recovery, such as cases of acetaminophen toxicity [46]. However, incorporation of therapeutic hypothermia into
8.3.1. Mannitol In a randomized controlled study of 34 patients with ALF and grade IV encephalopathy, episodes of cerebral edema resolved with significantly greater frequency in the 17 patients who received mannitol (1 g/kg body weight given as a rapid intravenous infusion of a 20% solution whenever the ICP rose above 30 mm Hg for N 5 minutes) than in the 17 patients who did not (44 of 53 episodes and 16 of 17 episodes, respectively, P b .001) [39]. In those who received mannitol, the survival rate was significantly higher than it was in those who did not receive it (47.1% and 5.9%, respectively, P b .008). Mannitol should only be used with normal renal function or in conjunction with hemofiltration. Continuous veno-venous hemofiltration has been shown to reduced brain edema by itself [40].
Cerebral edema and intracranial hypertension in ALF standard clinical practice needs to be confirmed in adequately designed multicenter clinical trials.
8.5. Pharmacologic coma and sedation Rescue therapy by pentobarbital coma as a way of decreasing brain metabolism and causing cerebral vasoconstriction has been replaced by therapeutic hypothermia in many liver transplantation centers because of long intrinsic recovery but also prolonged clearance of pentobarbital due to liver failure. Propofol has essentially replaced pentobarbital due to its several advantages in patients with ALF. Propofol in doses of 30 to 50 μg/kg per minute causes a prolonged reduction of ICP [47]. This is presumably through metabolic suppression and decreased cerebral perfusion pressure [40]. Liver failure does not influence propofol pharmacokinetics and, thus, permits a faster return to wakefulness and may also be a useful sedative of choice in fulminant liver failure patients. Seizures might complicate advanced hepatic encephalopathy and worsen prognosis; however, results from 1 study did not show any benefit from phenytoin prophylaxis [48].
789 de la Biomédecine) [54]. There has been concern with MARS-related increased risk of bleeding. Whether bleeding was only attributable to MARS remains unclear because the patients with bleeding had significantly more profound coagulation disorders at baseline than those without bleeding [55]. A recent report from a Japanese group using plasma exchange and high-flow dialysate continuous hemodiafiltration that provides 50 times the dialysate flow rate during ordinary continuous hemodiafiltration in 47 cases with fulminant liver failure resulted in restoration of consciousness in 70% of the patients and a higher survival compared with those on the ordinary continuous hemodiafiltration group [56]. At this juncture, blood purification or extracorporeal albumin dialysis cannot be recommended across the board for patient with ALF. However, extracorporeal albumin dialysis or high-flow dialysate continuous hemodiafiltration can be used as a bridge to liver transplantation in those for hepatic encephalopathy grade III and IV and high risk for cerebral edema.
10. Summary 9. Extracorporeal albumin dialysis Extracorporeal albumin dialysis uses a combination of albumin dialysis to remove albumin-bound substances and conventional hemodialysis to remove water-soluble substances [49,50]. Extracorporeal albumin dialysis decreases serum ammonia concentrations, improves cerebral hemodynamics [51,52], and ameliorates the proinflammatory cytokine response. Two studies in ALF in pigs demonstrated decreased of ICP by extracorporeal liver support using commercial systems (Molecular Adsorbents Recirculation System [MARS]; Gambro AB, Stockholm, Sweden) [51]. Similar to MARS, a significant reduction in ICP using Prometheus device was observed in experimental study on pigs with ALF [52]. A meta-analysis of 9 randomized controlled trials and 1 nonrandomized controlled study using the most common system, MARS, in patients with acute, acute-on-chronic, and hyperacute liver failure resulted in a significant decrease in total bilirubin levels (net change, − 7.0 mg/dL; 95% confidence interval [CI], − 10.4 to –3.7; P b .001) and in an improvement in the West Haven grade of hepatic encephalopathy (P b .001) [53]. However, there was no beneficial effect on all-cause mortality. In a French study, MARS improved liver function in 9 of 18 patients (50%; 95% CI, 29%-71%) with fulminant hepatic failure due to various etiologies (acetaminophen, hepatitis, and amatoxincontaining mushrooms) to such an extent that they were taken off the transplantation list and went on to full recovery [54]. This improvement rate was higher than the rate of improvement in the French cohort of fulminant hepatic failure patients with similar etiologies (19.3%; 95% CI, 14.9%-24.6%; P = .002) (French National database, Agence
Acute liver failure is a life-threatening multiorgan disorder with high morbidity and mortality. Cerebral edema leading to intracranial hypertension complicates approximately 50% to 80% of patients with grade III or IV hepatic encephalopathy, in whom it is the leading cause of death. Timely recognition and treatment of hepatic encephalopathy and cerebral edema in the intensive care setting using multimodality therapy are of paramount importance in the management of these patients to increase the likelihood of survival until liver transplantation. Therapeutic hypothermia and extracorporeal albumin dialysis can be considered as adjunct interventions in these patients.
Acknowledgments None.
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V. Mohsenin [30] Krisl JC, Meadows HE, Greenberg CS, et al. Clinical usefulness of recombinant activated factor VII in patients with liver failure undergoing invasive procedures. Ann Pharmacother 2011;45: 1433-8. [31] Le TV, Rumbak MJ, Liu SS, et al. Insertion of intracranial pressure monitors in fulminant hepatic failure patients: early experience using recombinant factor VII.Neurosurgery 2010;66: 455-8 [discussion 458]. [32] Gasco J, Rangel-Castilla L, Franklin B, et al. State-of-the-art management and monitoring of brain edema and intracranial hypertension in fulminant hepatic failure. A proposed algorithm. Acta Neurochir Suppl 2010;106:311-4. [33] Rabinstein AA. Treatment of brain edema in acute liver failure. Curr Treat Options Neurol 2010;12:129-41. [34] Bingaman WE, Frank JI. Malignant cerebral edema and intracranial hypertension. Neurol Clin 1995;13:479-509. [35] Strauss G, Hansen BA, Knudsen GM, et al. Hyperventilation restores cerebral blood flow autoregulation in patients with acute liver failure. J Hepatology 1998;28:199-203. [36] Ede RJ, Gimson AE, Bihari D, et al. Controlled hyperventilation in the prevention of cerebral oedema in fulminant hepatic failure. J Hepatology 1986;2:43-51. [37] Ede R, Gimson AE, Cannalese J, et al. Cerebral oedema and monitoring of intracranial pressure in fulminant hepatic failure. Gastroenterol Jpn 1982;17:163-76. [38] Tofteng F, Larsen FS. The effect of indomethacin on intracranial pressure, cerebral perfusion and extracellular lactate and glutamate concentrations in patients with fulminant hepatic failure. J Cereb Blood Flow Metab 2004;24:798-804. [39] Canalese J, Gimson AE, Davis C, et al. Controlled trial of dexamethasone and mannitol for the cerebral oedema of fulminant hepatic failure. Gut 1982;23:625-9. [40] Jalan R. Pathophysiological basis of therapy of raised intracranial pressure in acute liver failure. Neurochemistry Internat 2005;47: 78-83. [41] Murphy N, Auzinger G, Bernel W, et al. The effect of hypertonic sodium chloride on intracranial pressure in patients with acute liver failure. Hepatology 2004;39:464-70. [42] Jalan R, Rose C. Hypothermia in acute liver failure. Metab Brain Dis 2004;19:215-21. [43] Vaquero J, Blei AT. Mild hypothermia for acute liver failure: a review of mechanisms of action. J Clin Gastroenterol 2005;39:S147-57. [44] Stravitz RT, Larsen FS. Therapeutic hypothermia for acute liver failure. Crit Care Med 2009;37:S258-64. [45] Jalan R, Damink O, Steven SW, Deutz NE, et al. Moderate hypothermia for uncontrolled intracranial hypertension in acute liver failure. Lancet 1999;354:1164-8. [46] Jacob S, Khan A, Jacobs ER, et al. Prolonged hypothermia as a bridge to recovery for cerebral edema and intracranial hypertension associated with fulminant hepatic failure. Neurocrit Care 2009;11:242-6. [47] Wijdicks EF, Nyberg SL. Propofol to control intracranial pressure in fulminant hepatic failure. Transplantation Proc 2002;34:1220-2. [48] Bhatia V, Batra Y, Acharya SK. Prophylactic phenytoin does not improve cerebral edema or survival in acute liver failure–a controlled clinical trial. J Hepatology 2004;41:89-96. [49] Montejo Gonzalez JC, Catalan Gonzalez M, Meneu Diaz JC, et al. Artificial liver support system in acute liver failure patients waiting liver transplantation. Hepatogastroenterology 2009;56:456-61. [50] Huang YK, Tan DM, Xie YT, et al. Randomized controlled study of plasma exchange combined with molecular adsorbent re-circulating system for the treatment of liver failure complicated with hepatic encephalopathy. Hepatogastroenterology 2012;59:1323-6. [51] Sen S, Rose C, Ytrebo LM, et al. Effect of albumin dialysis on intracranial pressure increase in pigs with acute liver failure: a randomized study. Crit Care Med 2006;34:158-64. [52] Ryska M, Laszikova E, Pantoflicek T, et al. Fractionated plasma separation and adsorption significantly decreases intracranial
Cerebral edema and intracranial hypertension in ALF pressure in acute liver failure: experimental study. Eur Surg Res 2009;42:230-5. [53] Vaid A, Chweich H, Balk EM, et al. Molecular adsorbent recirculating system as artificial support therapy for liver failure: a meta-analysis. ASAIO J 2012;58:51-9. [54] Camus C, Lavoue S, Gacouin A, et al. Liver transplantation avoided in patients with fulminant hepatic failure who received albumin dialysis
791 with the molecular adsorbent recirculating system while on the waiting list: impact of the duration of therapy. Ther Apher Dial 2009;13:549-55. [55] Bachli EB, Schuepbach RA, Maggiorini M, et al. Artificial liver support with the molecular adsorbent recirculating system: activation of coagulation and bleeding complications. Liver Int 2007;27:475-84. [56] Shinozaki K, Oda S, Abe R, et al. Blood purification in fulminant hepatic failure. Contrib Nephrol 2010;166:64-72.
Assessment and management of cerebral edema and intracranial hypertension in acute liver failure☆ Vahid Mohsenin MD ⁎ Section of Pulmonary, Critical Care and Sleep Medicine, Yale School of Medicine, New Haven, CT, USA
Keywords: Acute liver failure; Hepatic encephalopathy; Brain edema
Abstract Acute liver failure is uncommon but not a rare complication of liver injury. It can happen after ingestion of acetaminophen and exposure to toxins and hepatitis viruses. The defining clinical symptoms are coagulopathy and encephalopathy occurring within days or weeks of the primary insult in patients without preexisting liver injury. Acute liver failure is often complicated by multiorgan failure and sepsis. The most life-threatening complications are sepsis, multiorgan failure, and brain edema. The clinical signs of increased intracranial pressure (ICP) are nonspecific except for neurologic deficits in impending brain stem herniation. Computed tomography of the brain is not sensitive enough in gauging intracranial hypertension or ruling out brain edema. Intracranial pressure monitoring, transcranial Doppler, and jugular venous oximetry provide valuable information for monitoring ICP and guiding therapeutic measures in patients with encephalopathy grade III or IV. Osmotic therapy using hypertonic saline and mannitol, therapeutic hypothermia, and propofol sedation are shown to improve ICPs and stabilize the patient for liver transplantation. In this article, diagnosis and management of hepatic encephalopathy and cerebral edema in patients with acute liver failure are reviewed. © 2013 Elsevier Inc. All rights reserved.
1. Definition and epidemiology of acute liver failure Acute liver failure (ALF) is a life-threatening multisystem illness resulting from massive liver injury. The defining clinical symptoms are coagulopathy and encephalopathy occurring within days or weeks of the primary
☆ Conflict of interest: None to disclose. ⁎ Department of Medicine, Section of Pulmonary, Critical Care and Sleep Medicine, Yale University, PO 208057, New Haven, Connecticut 06520-8057, USA. E-mail address: [email protected].
0883-9441/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jcrc.2013.04.002
insult in patients without preexisting liver injury [1]. Acute liver failure is a relatively uncommon disorder affecting approximately 2500 patients in the United States each year [2]. Acetaminophen and nonacetaminophen drug-induced hepatotoxicity account for more than 50% of cases of ALF in the United States [3]. Other identifiable causes of ALF include acute hepatitis B virus infection (7%); other viral infections (3%); autoimmune hepatitis (5%); ischemic hepatitis (4%); and various other causes (5%) such as Wilson disease, pregnancy-associated ALF, and other metabolic pathway abnormalities. Of importance, up to 15% of ALF cases remain of unclear etiology. In the developing countries, infectious hepatitis is the most common cause of ALF. However, less than 4% of cases
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of acute hepatitis B viral infection will lead to development of the ALF, but mortality is higher than that with hepatitis A or E infections [4].
2. Hepatic encephalopathy and brain edema in ALF Hepatic encephalopathy is graded according to the degree of cognitive deficit. The West Haven criteria were originally developed for chronic liver disease but are used clinically for ALF as a bedside assessment tool (Table 1). Grades I and II have mild to moderate confusion and irritability with or without asterixis. Grade III has marked confusion with asterixis but still can follow commands. Grade IV patient is comatose [5]. In the earlier reports, the frequency of cerebral edema occurring in fulminant hepatic failure ranged from 50% to 85% [6-9]. Although the frequency of clinically overt brain edema in ALF patients has decreased over the past 2 decades, intracranial hypertension accounts for 20% to 35%
Table 1 West Haven hepatic encephalopathy grades with Amodio modifications Psychiatric Grade Level of symptoms consciousness/ cognitive function
Neuromuscular function
1
Tremor
Sleep disturbance Euphoria/ depression Mild confusion
2
Impaired computations Inattentive
3
Moderate confusion Disorientation to time Marked confusion
4
Completely disoriented Lethargic, but arousable Command following Non-command following
Irritability
Incoordination, ± asterixis
Asterixis, slurred speech Impaired handwriting
Decreased inhibitions Personality changes Anxiety or Slurred speech, apathy ataxia Inappropriate Asterixis, nystagmus Bizarre Hypoactive or behavior hyperactive reflexes Paranoia, anger or rage Coma, dilated pupils Loss of cranial nerve reflexes Signs of herniation Flexor or extensor posturing Loss of reflexes
of deaths and requires considerable resources in the intensive care unit setting [10,11]. The degree of hepatic encephalopathy on admission tends to predict outcome. In one of the largest prospective multicenter studies on 308 patients, 161 patients presented with grade I and II hepatic encephalopathy on admission; 52% survived without transplantation for 3 weeks. In contrast, of 147 patients who presented with grade III or IV hepatic encephalopathy, 33% survived 3 weeks without transplantation. The overall transplantation rate was 29% for all grades, but grade I and II had a survival rate of 77% compared with 56% in grade III and IV [12].
3. Mechanism of brain edema The pathogenesis of hepatic encephalopathy and cerebral edema is multifactorial, but it is well established that ammonia plays a central role and inflammatory cytokines accentuate the process [13]. According to the ammoniaglutamine hypothesis, the source of circulating ammonia is from glutamine metabolism in the intestinal epithelium and urease activity in the intestinal flora. In normal circumstances, the liver metabolizes all the ammonia coming from the small and large intestine via portal circulation. Ammonia is also produced in healthy individuals by muscle and the kidney. These 2 tissues have the ability to shift to ammonia detoxifying organs in the case of liver failure. However, because of loss of muscle mass in chronic liver failure, the physiologic efficiency and clinical benefits of this detoxifying process are not clear. Hyperammonemia induces accumulation of glutamine inside the astrocytes. Astrocytes are the only cells in the brain that can metabolize ammonia. The enzyme glutamine synthetase (present in the endoplasmic reticulum of astrocytes) is responsible for the conversion of equimolar concentrations of glutamate and ammonia to glutamine. Intracellular levels of glutamine, therefore, increase enormously as the ambient ammonia concentrations rise secondary to liver failure. The osmotic and metabolic effects of glutamine contribute to astrocyte swelling and cerebral edema in hepatic encephalopathy. Increased cerebral glutamine levels correlate with severity of psychoneurological signs and intracranial pressure (ICP) measurements. The “toxic liver hypothesis” implicates inflammatory cytokines and toxic products from the necrotic liver that correlate with central nervous system complication. There is evidence for neuroinflammation in ALF in experimental models and in patients with ALF showing efflux of tumor necrosis factor α, interleukin 1β, and interleukin 6 from the brain when measured in blood sampled from an artery and reverse jugular catheter [14]. Ultrastructural studies in brain sections from ALF patients have so far failed to provide evidence for blood-brain barrier breakdown, attributing brain edema and its complications to primarily cytotoxic rather than vasogenic mechanisms [15].
Cerebral edema and intracranial hypertension in ALF
4. Diagnostic modalities 4.1. Bedside assessment Hepatic encephalopathy is conventionally graded by clinical scales such as the West Haven criteria (Table 1) [5]. This scale semiquantitatively grades a patient's mental state by means of subjective assessments of behavior, intellectual function, alteration of consciousness, and neuromuscular function. The grading has high interobserver variability for grades I and II. Modification of the criteria by addition of some objective measures has improved its discriminatory function [16]. Bispectral index, a measure of spectral and time domains of electroencephalography, has been shown to have high predictive power to discriminate West Haven grades I to IV in a multicenter study [17]. Cerebral edema is seldom observed in patients with grade I and II encephalopathy. The risk of edema increases to 25% to 35% with progression to grade III and 65% to 75% or more in patients reaching grade IV encephalopathy [18].
4.2. Neuroimaging 4.2.1. Computed tomography Intracranial hypertension should be clinically suspected in ALF patients with new onset systemic hypertension, progression of hepatic encephalopathy, alterations in pupillary reactivity, abnormalities in oculovestibular reflexes, or signs of decerebration. However, most of these clinical signs are not specific or sensitive and may be developed by patients in hepatic grade IV encephalopathy without intracranial hypertension. Noncontrasted head computed tomography (CT) may show cerebral edema, compression of basal cisterns, hydrocephalus, mass effect, or midline shift (Fig. 1). However, the absence of these findings does not exclude cerebral edema or intracranial hypertension [19,20]. Therefore, its routine use is inadvisable. Its principal value is
785 to rule out other uncommon intracranial pathology, most importantly bleeding. 4.2.2. Brain magnetic resonance imaging Magnetic resonance imaging scanning provides a more accurate assessment of brain water content or underlying lesions. However, it is generally not necessary nor has been shown to be useful in patients with suspected intracranial hypertension. It may be even hazardous due to the prolonged time required for scanning and the need for the patient to lay supine, which may aggravate the ICP.
4.3. Transcranial Doppler The ability of the cerebral vascular system to constrict and dilate in response to changes in perfusion pressure is termed autoregulation. Impaired cerebral autoregulation is a recognized complication of ALF [21,22]. Cerebral blood flow has been shown to correlate with ICP in a study of patients with ALF [14]. In a series of patients from Pittsburgh, sequential measurements of blood flow and ICP have shown that an increase in cerebral blood flow (CBF) precedes the rise in ICP [23]. Patients with signs of cerebral edema and intracranial hypertension have been shown to have higher CBF compared with patients without edema. Although there is a wide interindividual variation in CBF in patients with fulminant hepatic failure, a higher CBF has been associated with a poorer prognosis. Transcranial Doppler (TCD) is a noninvasive technique that measures blood flow velocity of intracranial vessels and provide some indirect evidence regarding ICP and CBF [24]. Transcranial Doppler has been used extensively in the study of autoregulation in the critical care setting. Cerebral autoregulation can be explained at least partially by a tight coupling between O2 supply and demand of the brain. Under normal conditions, CBF is maintained at a constant flow rate of 50 to 60 mL per 100 g/min, with 50
Fig. 1 Rapid development of brain edema in a patient with fulminant hepatic failure. On the left, the CT scan done in encephalopathy grade IV showing cortical sulci and the ventricles. On the right when the patient developed unilateral fixed midriasis, the scan shows evident signs of brain edema in the form of virtual absence of cortical sulci and compression of fourth ventricle and of the brain stem (reproduced with permission from World J Gastroenterol. 2006;12:7405-7412).
786 mL oxygen being extracted every minute from 700- to 800mL blood. This occurs despite changes in mean arterial pressure within the range of 60 to 160 mm Hg. Outside this range flow becomes proportional to pressure, potentially leading to episodes of cerebral hypoperfusion and hyperperfusion. In a study of 16 patients with ALF, information obtained from TCD signal of middle cerebral artery wave forms correctly classified 61% of the patients with ICP less than 20 mm Hg, 53% of patients with ICP between 20 and 30 mm Hg, and 67% of patients with ICP more than 30 mm Hg [25]. An early indicator of this pathologic process is either a decrease in the transcranial oxygen content difference (arterial oxygen content minus jugular bulb oxygen content) to less than 4 mL per 100-mL blood or an increase in middle cerebral artery systolic blood flow velocity. As the cerebral hemodynamics continue to deteriorate with increasing ICP, CBF starts to decrease, and TCD waveform shows sharpening of peak systolic wave and loss of elasticity of the intracranial vessels (loss of the Windkessel effect, loss of vessel recoil when the blood pressure falls during diastole) due to increased extramural pressure from brain swelling (Fig. 2). The TCD parameters most sensitive to cerebral perfusion pressure seem to be the systolic velocity and the velocity peak-to-peak amplitude. Independent of the type of intracranial pathology, a strong correlation (correlation coefficient of 0.938, P b .0001) between pulsatility index (difference in the systolic and diastolic flow velocity divided by the mean flow velocity of middle cerebral artery) and ICP has been demonstrated [24].Therefore, pulsatility index may be of guiding value in the invasive ICP placement decision in the neurointensive care patient. In patients with severe coagulopathy and high risk for bleeding complications, TCD can be used serially to follow the response to treatment of intracranial hypertension. Transcranial Doppler has a better diagnostic sensitivity of 67% compared with 27% by brain CT to detect intracranial hypertension [25].
V. Mohsenin
4.4. Jugular venous oximetry In patient with hepatic encephalopathy grade III or IV, a jugular bulb catheter may be used to assess cerebrovascular autoregulation. However, this method has limited utility because of varying cerebral metabolic rate due to the patient's underlying level of inflammation or sedation [26].
4.5. Intracranial pressure monitoring The most accurate method of diagnosing intracranial hypertension is ICP monitoring. Although the advantages of this monitoring in ALF patients have not yet been demonstrated by a randomized study, ICP monitoring may be very helpful in establishing the presence of intracranial hypertension and in guiding specific therapy. Therapeutic actions resulting from the analysis of the ICP values may change the disease progression, extending the available time to liver transplantation. Intracranial pressure monitoring in ALF patients may suddenly rise from normal to lifethreatening levels within minutes. In this situation, continuous ICP monitoring may allow rapid and specific management. Several groups have included ICP monitoring in the management protocol of patients with fulminant liver failure [27]. The main argument against ICP monitoring is the enhanced risk of complications in ALF patients, mainly infection and hemorrhage. In a national survey of 262 ALF patients, the complication rate of ICP monitoring was 10%, of which 5% were significant and may have contributed to death. In this series, intracranial hemorrhages were the cause of death in 7 patients, with the epidural transducers had the lowest complication rate (3.7%) [28]. It was noteworthy that the monitored group underwent more treatment interventions; however, outcomes were not improved for those who
Fig. 2 Transcranial Doppler recordings of middle cerebral artery from a single patient with progressing ALF. In addition to sharpening of the systolic peak in the waveform, the waveform changes from one that includes a Windkessel effect (asterisks in the left panel indicating vessel recoil during diastole) to one that does not as liver failure progresses with increasing intracranial pressure. Abbreviations: CPP indicates cerebral perfusion pressure; MAP, mean arterial pressure (adapted from Liver Transpl. 2008;14:1048-1057).
Cerebral edema and intracranial hypertension in ALF were subjected to invasive monitoring. Given that this was an uncontrolled study, the number of patients observed may not have been large enough to demonstrate relative benefit. In a retrospective review of 22 pediatric patients with ALF awaiting liver transplantation who had ICP monitoring using intraparenchymal monitors for grade III and IV hepatic encephalopathy, survival after liver transplant was 88%. Hemorrhagic complications were evaluable in 17 patients. Three patients had intracranial hemorrhages anatomically associated with the monitor site. One fully recovered and the other 2 died of sepsis. In 5 patients, clinical complications of ICP monitor placement were not evaluable because they died before a CT scan was performed, and autopsy was not obtained. Although there has been improvement in safety of ICP monitoring, the decision should be on a case-by-case basis assessing the risks and benefits of the procedure [27]. With more sophisticated laboratory tests, it has been shown that patients with liver disease may be in hemostatic balance as a result of concomitant changes in both prohemostatic and antihemostatic pathways. Clinically, this rebalanced hemostatic system is reflected by the large proportion of patients with liver disease who can undergo major surgery without any requirement for blood product transfusion [29]. There is limited experience with the use of recombinant factor VIIa before insertion of ICP monitoring catheter, but it appears to minimize the risk of bleeding as the secondary hemostasis is restored [30,31].
5. Management of intracranial hypertension and brain edema The normal ICP is 5 to 10 mm Hg. Intracranial hypertension becomes clinically relevant when ICP exceeds 20 mm Hg increasing the likelihood of compromising the cerebral perfusion pressure. Severe intracranial hypertension may result in compression of brain stem, resulting in brain stem ischemia, hemorrhage, and death. The management goal of intracranial hypertension is to maintain ICP less than 20 mmHg and cerebral perfusion pressure of greater than 70 mm Hg. An evidence-based algorithm for management of hepatic encephalopathy and brain edema has recently been proposed [32,33].
6. General measures Arterial hypertension can increase intracranial blood volume and pressure compromising cerebral perfusion pressure. Likewise, arterial hypotension in the presence of impaired cerebral autoregulation will lead to decreased cerebral perfusion pressure. Optimization of blood pressure can be achieved by adequate intravascular volume and/or vasopressors such as norepinephrine in the setting of
787 hypotension and sedation in the settings of hypertension. The patient's head should be maintained in neutral position with the head of the bed at 30° to favor venous drainage and thus decrease ICP (Fig. 3). However, some patients with markedly compromised cerebral perfusion or hypotension (vasodilatory shock) may not tolerate elevation of the head of the bed, so it is important to assess ICP and cerebral perfusion pressure on an individual basis and serially over time to define the optimal position for each patient and to guide the arterial blood pressure management strategy.
7. Pharmacologic therapy Correction of the underlying factors that precipitate hepatic encephalopathy might in itself help to resolve the disease and reduces the risk of cerebral edema. Nacetylcysteine is indicated in acetaminophen-induced liver injury and has been shown to be also effective in nonacetaminophen ALF and mild hepatic encephalopathy. In addition to its liver protective effect, its ability to scavenge reactive nitrogen and oxygen species is of particular interest, as the accumulation of these compounds may be involved in the pathogenesis of brain edema. Lactulose is considered in patient with underlying cirrhosis and hepatic encephalopathy and is not generally used in ALF. In addition to having a laxative effect, lactulose reduces the colonic pH and interferes with mucosal uptake of glutamine in the gut, thereby reducing the synthesis and absorption of ammonia. Overtreatment with lactulose, however, results in the serious adverse effects of severe dehydration, hyponatremia, and worsening of hepatic encephalopathy, especially in patients treated in the intensive care unit. Nonabsorbable antibiotic, rifaximin with few adverse effects and no reported drug-drug interactions, is commonly used in conjunction with lactulose.
8. Measures to decrease intracranial volume 8.1. Hyperventilation Hyperventilation lowers PaCO2 causing cerebral vasoconstriction decreasing ICP [34]. Hyperventilation has been shown to restore cerebral autoregulation [35]. However, in a controlled study, hyperventilation did not prevent the development of brain edema in patients with fulminant liver failure [36]. In most centers, hyperventilation is only implemented for acute rise of ICP and for short period [37].
8.2. Indomethacin Indomethacin, a cyclooxygenase-2 inhibitor, induces cerebral vasoconstriction through multiple mechanisms including inhibition of the endothelial cyclooxygenase
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V. Mohsenin Hepatic Encephalopathy grade III/IV
Transcranial Doppler Jugular venous oximetry Invasive ICP monitoring
Brain Edema Intracranial Hypertension
Intubation Head elevation 30º Propofol sedation Correction of intravascular volume & hyponatremia Norepinephrine-MAP>65 mmHg
Fig. 3
Osmotic therapy
Hyperventilation for acute ICH
Mannitol: (1 g/kg iv q6h) Target:300-320 mOs/L Hypertonic saline (10%) Target Na:145-155 mEq/L
? Indomethacin for acute ICH Therapeutic hypothermia-32º C ? Extracorporeal albumin dialysis
Management algorithm for brain edema and intracranial hypertension in ALF. Abbreviation: ICH indicates intracranial hypertension.
pathway, alterations in extracellular pH, and reduction in cerebral temperature. In a case series, indomethacin reduced ICP from 30 (7-53) to 12 (4-33) mm Hg (P b .05) with an increase in cerebral perfusion pressure from 48 (0-119) to 65 (42-129) mm Hg (P b .05) [38]. However, in view of its potential adverse effects, nephrotoxicity, platelet dysfunction, and possible gut ischemia and gastrointestinal bleeding in already coagulopathic patients, its routine use should await randomized trial with special focus on its safety in this population.
8.3.2. Hypertonic saline A randomized clinical trial in 45 patients with ALF compared 30% hypertonic saline with target serum sodium between 145 and 150 mmol/L with those who received standard care. The results showed that ICP decreased significantly relative to baseline over the first 24 hours in the treatment group (P = .003) with the incidence of intracranial hypertension, defined as a sustained increase in ICP to a level of 25 mm Hg or greater, which was significantly lower in the treatment group (P = .04) [41].
8.3. Osmotic therapy
8.4. Therapeutic hypothermia
Blood-brain barrier for the most part is intact in patients with ALF, albeit there may be selective defects. Osmotic agents such as mannitol and hypertonic saline by increasing blood osmolality induce fluid movement from brain intracellular and interstitial space to intravascular space decreasing brain volume.
Therapeutic hypothermia, using external cooling system, could be an adjunct therapy for patients with grade III or IV hepatic encephalopathy or uncontrolled intracranial hypertension. Hypothermia affects the processes responsible for the development of brain edema at multiple levels, including a normalization of CBF, decreased entry of ammonia into brain, reduction in extracellular brain glutamate, and a decrease in anaerobic glycolysis [42,43]. Promising initial results have shown that hypothermia may be an effective bridge therapy in patients with refractory intracranial hypertension who are good candidates for liver transplantation [44]. The first clinical study by Jalan et al [45] showed that 7 patients with intracranial hypertension resistant to standard therapy who were chilled to 32°C had a significant fall in ICP from 45 to 16 mm Hg and improvements in cerebral perfusion pressure from 45 to 70 mmHg and a significant fall in arterial ammonia from 343 to 259 mg/dL as did cerebral uptake of ammonia. Therapeutic hypothermia may also be applied successfully in selected patients with severe brain edema from ALF who have good potential for liver recovery, such as cases of acetaminophen toxicity [46]. However, incorporation of therapeutic hypothermia into
8.3.1. Mannitol In a randomized controlled study of 34 patients with ALF and grade IV encephalopathy, episodes of cerebral edema resolved with significantly greater frequency in the 17 patients who received mannitol (1 g/kg body weight given as a rapid intravenous infusion of a 20% solution whenever the ICP rose above 30 mm Hg for N 5 minutes) than in the 17 patients who did not (44 of 53 episodes and 16 of 17 episodes, respectively, P b .001) [39]. In those who received mannitol, the survival rate was significantly higher than it was in those who did not receive it (47.1% and 5.9%, respectively, P b .008). Mannitol should only be used with normal renal function or in conjunction with hemofiltration. Continuous veno-venous hemofiltration has been shown to reduced brain edema by itself [40].
Cerebral edema and intracranial hypertension in ALF standard clinical practice needs to be confirmed in adequately designed multicenter clinical trials.
8.5. Pharmacologic coma and sedation Rescue therapy by pentobarbital coma as a way of decreasing brain metabolism and causing cerebral vasoconstriction has been replaced by therapeutic hypothermia in many liver transplantation centers because of long intrinsic recovery but also prolonged clearance of pentobarbital due to liver failure. Propofol has essentially replaced pentobarbital due to its several advantages in patients with ALF. Propofol in doses of 30 to 50 μg/kg per minute causes a prolonged reduction of ICP [47]. This is presumably through metabolic suppression and decreased cerebral perfusion pressure [40]. Liver failure does not influence propofol pharmacokinetics and, thus, permits a faster return to wakefulness and may also be a useful sedative of choice in fulminant liver failure patients. Seizures might complicate advanced hepatic encephalopathy and worsen prognosis; however, results from 1 study did not show any benefit from phenytoin prophylaxis [48].
789 de la Biomédecine) [54]. There has been concern with MARS-related increased risk of bleeding. Whether bleeding was only attributable to MARS remains unclear because the patients with bleeding had significantly more profound coagulation disorders at baseline than those without bleeding [55]. A recent report from a Japanese group using plasma exchange and high-flow dialysate continuous hemodiafiltration that provides 50 times the dialysate flow rate during ordinary continuous hemodiafiltration in 47 cases with fulminant liver failure resulted in restoration of consciousness in 70% of the patients and a higher survival compared with those on the ordinary continuous hemodiafiltration group [56]. At this juncture, blood purification or extracorporeal albumin dialysis cannot be recommended across the board for patient with ALF. However, extracorporeal albumin dialysis or high-flow dialysate continuous hemodiafiltration can be used as a bridge to liver transplantation in those for hepatic encephalopathy grade III and IV and high risk for cerebral edema.
10. Summary 9. Extracorporeal albumin dialysis Extracorporeal albumin dialysis uses a combination of albumin dialysis to remove albumin-bound substances and conventional hemodialysis to remove water-soluble substances [49,50]. Extracorporeal albumin dialysis decreases serum ammonia concentrations, improves cerebral hemodynamics [51,52], and ameliorates the proinflammatory cytokine response. Two studies in ALF in pigs demonstrated decreased of ICP by extracorporeal liver support using commercial systems (Molecular Adsorbents Recirculation System [MARS]; Gambro AB, Stockholm, Sweden) [51]. Similar to MARS, a significant reduction in ICP using Prometheus device was observed in experimental study on pigs with ALF [52]. A meta-analysis of 9 randomized controlled trials and 1 nonrandomized controlled study using the most common system, MARS, in patients with acute, acute-on-chronic, and hyperacute liver failure resulted in a significant decrease in total bilirubin levels (net change, − 7.0 mg/dL; 95% confidence interval [CI], − 10.4 to –3.7; P b .001) and in an improvement in the West Haven grade of hepatic encephalopathy (P b .001) [53]. However, there was no beneficial effect on all-cause mortality. In a French study, MARS improved liver function in 9 of 18 patients (50%; 95% CI, 29%-71%) with fulminant hepatic failure due to various etiologies (acetaminophen, hepatitis, and amatoxincontaining mushrooms) to such an extent that they were taken off the transplantation list and went on to full recovery [54]. This improvement rate was higher than the rate of improvement in the French cohort of fulminant hepatic failure patients with similar etiologies (19.3%; 95% CI, 14.9%-24.6%; P = .002) (French National database, Agence
Acute liver failure is a life-threatening multiorgan disorder with high morbidity and mortality. Cerebral edema leading to intracranial hypertension complicates approximately 50% to 80% of patients with grade III or IV hepatic encephalopathy, in whom it is the leading cause of death. Timely recognition and treatment of hepatic encephalopathy and cerebral edema in the intensive care setting using multimodality therapy are of paramount importance in the management of these patients to increase the likelihood of survival until liver transplantation. Therapeutic hypothermia and extracorporeal albumin dialysis can be considered as adjunct interventions in these patients.
Acknowledgments None.
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