Therapeutic hypothermia in the management of acute liver failure

Neurochemistry International 60 (2012) 723–735

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Review

Therapeutic hypothermia in the management of acute liver failure Javier Vaquero ⇑ Laboratorio de Investigación en Hepatología y Gastroenterología, Hospital General Universitario Gregorio Marañón – CIBERehd, c/Maiquez No. 9, Madrid 28009, Spain

a r t i c l e

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Article history: Available online 22 September 2011 Keywords: Hypothermia Acute liver failure Intracranial pressure Ammonia Brain edema

a b s t r a c t A large body of experimental data and preliminary clinical studies point to the induction of mild hypothermia (32–35 °C) as a valuable approach to control the development of brain edema and intracranial hypertension in acute liver failure (ALF). The ability of hypothermia to affect multiple processes probably explains its efficacy to prevent these cerebral complications. Remarkably, mild hypothermia has been shown to prevent or attenuate most of the major alterations involved in the pathogenesis of the cerebral complications of ALF, including the accumulation of ammonia in the brain and the circulation, the alterations of brain glucose metabolism, the brain osmotic disturbances, the accumulation of glutamate and lactate in brain extracellular space, the development of inflammation and oxidative/nitrosative stress, and others. Limited information suggests that the systemic effects of hypothermia may also be beneficial for some peripheral complications of ALF. Translation of the beneficial effects of therapeutic hypothermia into standard clinical practice, however, needs to be confirmed in adequately designed clinical trials. Such trials will be important to determine the safety of therapeutic hypothermia, to identify which patients might benefit from it, and to provide the optimal guidelines for its use in patients with ALF. Ó 2011 Elsevier Ltd. All rights reserved.

1. Introduction The development of brain edema and high intracranial pressure (ICP) are unique complications of patients with acute liver failure (ALF) developing severe hepatic encephalopathy (Blei, 2007). Traditionally considered the major cause of death in ALF, the relevance of intracranial hypertension and brain herniation may have decreased in developed countries relative to other mortality causes such as sepsis or multi-organ failure, due to improvements in critical care and the use of liver transplantation (LT) (Larsen and Wendon, 2008). Episodes of high ICP, however, may be detected during the course of ALF in between 80% and 95% of patients with stage III–IV hepatic encephalopathy undergoing ICP monitoring (Jalan, 2003; Raschke et al., 2008). High ICP remains responsible for substantial mortality (25–50%) and for neurocognitive sequalae in patients surviving ALF (Bernal et al., 2007; Bhatia et al., 2006; Jalan, 2003; Tofteng et al., 2002), justifying the need for more effective therapies. Induction of mild hypothermia (32–35 °C) effectively prevents brain edema and intracranial hypertension in experimental models of ALF (Vaquero et al., 2005b). Encouraged also by promising clinical experience (Jalan, 2005), several centers are progressively incorporating therapeutic hypothermia into the management of patients with ALF, particularly to bridge patients to LT when they Abbreviations: ALF, acute liver failure; CBF, cerebral blood flow; ICP, intracranial pressure; LT, liver transplantation; RCT, randomized-controlled clinical trial. ⇑ Tel./fax: +34 91 586 6453. E-mail address: [email protected] 0197-0186/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.neuint.2011.09.006

present high ICP that cannot be controlled by conventional therapies (Jalan et al., 1999a; Raschke et al., 2008; Tofteng et al., 2002). The optimal guidelines for its use and the subgroups of patients with ALF that might benefit from therapeutic hypothermia, however, need to be refined. Clinical experiences in non-ALF conditions (traumatic brain injury, cardiac arrest) suggest that the success of this therapy critically depends on how it is implemented and on adequate patient selection (Clifton et al., 2001a; Polderman, 2009; Polderman et al., 2002; Shann, 2003). Hypothermia has profound effects at molecular, cellular, and systemic levels and, therefore, awareness of the physiology of hypothermia is essential for taking full advantage of this therapy.

2. Hypothermia research in ALF: aiming for a successful translational story Body temperature is one of the most tightly regulated physiological parameters in humans. The deleterious effects of unintentional hypothermia are well known (Danzl and Pozos, 1994), and the inability to maintain a normal body temperature in patients with critical illnesses has been associated with a poor prognosis (Brun-Buisson et al., 1995; Margolis, 1979; Wang et al., 2005). The modern concept of therapeutic hypothermia originates in 1950 from the work of Bigelow and associates (Fig. 1), who challenged the prevailing observations that induction of hypothermia resulted in increased metabolic demands and O2 consumption (Bigelow et al., 1950a,b). In contrast, they showed that metabolism

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1st report of HT prevents therapeutic HT Further brain edema and in patients experimental high ICP in with ALF NH3-infused rats (Jalan et al., (Butterworth’s group) and clinical (Córdoba et al., 1999) 1999a) (Jalan’s group) 1999 studies of HT in ALF

ALF Concept of therapeutic HT (Bigelow et al., 1950a,b)

1950

HT reduces NH3 toxicity in mice (Schenker and Warren, 1962)

1960

HT prevents brain edema in rats with ALF (Traber et al., 1989)

1970

1980

Non-ALF

1990

1st RCT of HT for TBI -Positive trial(Marion et al., 1997)

2000 2nd RCT of HT for TBI -Negative trial(Clifton et al., 2001b)

Completion of the 1st RCT of 2010 mild HT in ALF (Larsen et al., 2011)

HT included as standard of care in cardiac arrest Two RCTs (Nolan et al., of HT for 2003) cardiac arrest -Both positive(2002; Bernard et al., 2002)

Fig. 1. Schematic showing some major events in the development of research of therapeutic hypothermia in acute liver failure (ALF) and non-ALF conditions. Abbreviations: ALF, acute liver failure; HT, hypothermia; ICP, intracranial pressure; NH3, ammonia; RCT, randomized controlled clinical trial; TBI, traumatic brain injury.

and O2 consumption decreased in parallel with the reduction of body temperature as long as the normal thermoregulatory responses to hypothermia, particularly shivering and autonomic activation, were prevented by adequate anesthetic management. Differences between these modes of hypothermia are not limited to metabolism; for example, the increased production of proinflammatory cytokines reported with unintentional hypothermia contrasts with the consistent anti-inflammatory properties of therapeutic hypothermia (Aibiki et al., 1999; Vaquero and Blei, 2005). These observations indicate that therapeutic hypothermia entails more than simply lowering the body temperature of a patient, and that the mechanisms and adverse effects related to the development of unintentional or illness-related hypothermia may not be directly extrapolated to its therapeutic use. Since Bigelow’s landmark observations, the neuroprotective properties of hypothermia have been extensively demonstrated in experimental models of brain ischemia-reperfusion, traumatic brain injury, myocardial infarction and other conditions, leading to the investigation of its clinical use (reviewed in (Bernard and Buist, 2003)). Several large randomized-controlled clinical trials (RCT) of therapeutic hypothermia have been performed in patients with traumatic brain injury (Clifton et al., 2001b; Marion et al., 1997), cardiac arrest, and other conditions, but only the RCTs of hypothermia for the treatment of out-of-hospital cardiac arrest (Hypothermia After Cardiac Arrest Study Group, 2002; Bernard et al., 2002) and of neonates with perinatal asphyxia (Azzopardi et al., 2009; Shankaran et al., 2005) have been sufficiently conclusive to recommend therapeutic hypothermia as standard of care (Nolan et al., 2003; Pfister and Soll, 2010) (Fig. 1). Despite the inability to show improved clinical outcomes in other conditions, therapeutic hypothermia is often used in patients with traumatic brain injury or intracranial bleeding due to its efficacy for reducing intracranial hypertension (Pemberton and Dinsmore, 2003). Research on therapeutic hypothermia and its translation into clinical practice have evolved at a slower pace in ALF (Fig. 1). Prompted by the use of hypothermia (30 °C) during the surgical treatment of patients with cirrhosis and variceal bleeding (Clauss

et al., 1959), Schenker and Warren demonstrated in 1962 the efficacy of hypothermia (28 °C) to provide resistance against the lethal toxicity of acute ammonia loads in mice (Schenker and Warren, 1962). In 1982, Peignoux et al. noted that rats undergoing total hepatectomy or hepatic devascularization survived longer if their body temperature was maintained at 35.5 °C as compared to 37.5 °C (Peignoux et al., 1982). In a landmark study from Dr. Andrés T. Blei’s Laboratory, Traber et al. further demonstrated in 1989 the remarkable influence that body temperature had on the course and the neurological complications of experimental ALF (Traber et al., 1989). In this study, they showed that the spontaneous development of hypothermia (mean 26.9 °C, range 22.5–30 °C) in rats with ALF induced by hepatic devascularization was associated with longer time to develop coma and with a significant attenuation of brain edema, compared to rats maintained at normothermia. Ten years later, Jalan et al. reported the first series of patients with ALF treated with therapeutic hypothermia (Jalan et al., 1999a). Since then, the ability of hypothermia for preventing the cerebral complications of ALF and its potential mechanisms have been investigated in multiple experimental studies (Table 1), mainly from Dr. Butterworth’s Laboratory, as well as in small series of patients with ALF (Table 2). Fourteen years after the first RCT of therapeutic hypothermia in traumatic brain injury was reported, the preliminary results of the first RCT of hypothermia in patients with ALF, involving a prophylactic use and three major European centers (King’s College Hospital, London, UK; Queen Elizabeth Hospital, Birmingham, UK; and University Hospital of Copenhagen, Copenhagen, Denmark), have been presented at the 2011 European Association for the Study of the Liver (EASL) meeting recently held in Berlin (Larsen et al., 2011) (Fig. 1).

3. Does therapeutic hypothermia effectively control brain edema and intracranial hypertension in ALF? There are currently no fully-published RCTs evaluating its efficacy in patients with ALF, but most available evidence suggest that

Table 1 Summary of experimental studies exploring the effects of hypothermia in acute liver failure and hyperammonemia. Effects of hypothermia on:

Ref.

Experimental models

Body temperature Species (°C)

Encephalopathy Brain edema

Liver injury

Survival time

(Schenker and Warren, 1962)

Acute NH3 bolus

Mouse

26.9°C

x

x

x

LD50 of NH3 almost doubled Increased

(Peignoux et al., 1982)

Rat

35.5°C

Delayed

x

(Traber et al., 1989)

Total hepatectomy Hepatic devascularization Hepatic devascularization

Rat

Delayed

Reduced

(Jiang et al., 2009b)

Hepatic devascularization

Rat

26.9°C [22.5°30°C] 33°C

Delayed

Reduced

Lower ALT Lower AST x

(Jiang et al., 2009c)

Hepatic devascularization

Rat

33°C

Delayed

Reduced

x

x

(Rose et al., 2000)

Hepatic devascularization

Rat

35°C

Delayed

Reduced

x

x

(Chatauret et al., 2001) (Chatauret et al., 2003)

Hepatic devascularization Hepatic devascularization

Rat Rat

35°C 35°C

Delayed Delayed

Reduced Reduced

x x

x x

(Zwingmann et al., 2004) (Belanger et al., 2005)

Hepatic devascularization Hepatic devascularization

Rat Rat

35°C 35°C

Delayed Delayed

Reduced Reduced

x x

x x

(Barba et al., 2008)

Hepatic devascularization

Rat

35°C

Delayed

x

x

x

(Sawara et al., 2009) (Oria et al., 2010) (Eguchi et al., 1996)

Rat Rat Rat

35°C 35°C 29.1°C

Delayed x x

Reduced Reduced x

x x x

x x Increased

(Cordoba et al., 1999)

Hepatic devascularization Hepatic devascularization Hepatectomy of anterior lobes + devascularization of right lobes PCA + NH3 infusion

Rat

33°C and 35°C x

Reduced at 33°C x and 35°C

(Vaquero et al., 2007)

APAP-induced liver injury

Mouse

Between 32° and 35°C

x

x

Reduced Increased

(Belanger et al., 2006)

Azoxymethane-induced liver injury

Mouse

35°C

Delayed

Reduced

Reduced x

(Bemeur et al., 2010)

Azoxymethane-induced liver injury

Mouse

35°C

Delayed

Reduced

Reduced x

Other effects of hypothermia Attenuated the " of brain NH3 concentration

x x

Both 33°C and 35°C attenuated the: " of ICP " of CBF and cerebral O2 consumption. ; hepatic hemorrhagic congestion " hepatic glycogen recovery ; hepatocyte apoptotic markers did not affect the hepatocyte necrosis/ proliferation ratio Attenuated the: " of NH3 in brain and plasma. changes in plasma and brain concentration of specific amino acids. Attenuated the: " of NH3 in plasma. " of hepatic neutrophil infiltration. ; of hepatic GSH and of brain GSH/GSSG ratios. " of pro-inflammatory cytokines.

725

Abbreviations: ALT, alanine transaminase; AST, aspartate transaminase; APAP, acetaminophen; CBF, cerebral blood flow; CSF, cerebrospinal fluid; eNOS, endothelial nitric oxide synthase; GSH/GSSG, reduced/oxidized glutathione ratio; HO-1, hemeoxygenase-1; ICP, intracranial pressure; IL-1b, interleukin-1b; IL-6, interleukin-6; IL-10, interleukin-10; iNOS, inducible nitric oxide synthase; MEP, motor-evoked potential; NAA, N-acetylaspartate; NH3, ammonia; PCA, portacaval anastomosis; PTBR, peripheral-type benzodiazepine receptor; TNF-a, tumor necrosis factor-a. ‘‘x’’ means ‘‘not available or not applicable’’.

J. Vaquero / Neurochemistry International 60 (2012) 723–735

x

Attenuated the " of: NH3 in plasma and CSF. IL-1b, TNF-a and IL-6, but not of IL-10, in plasma and CSF. IL-1b, TNF-a and IL-6 mRNA expression in brain. Attenuated the " of: NH3 and nitrite/nitrate levels in plasma and brain. HO-1, iNOS and eNOS mRNA expression in brain. Attenuated the: " of NH3 levels in CSF " of extracellular brain glutamate Attenuated the " of NH3 and lactate in CSF Attenuated in brain the " of: alanine and lactate de-novo synthesis of lactate Prevented the ; of brain myo-inositol and taurine Attenuated the " of PTBR expression and pregnenolone concentration in brain. Attenuated in the brain the: " of alanine and lactate. ; of NAA and myo-inositol. Attenuated the " of eNOS mRNA in brain. Prevented the ; in amplitude of MEP.

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J. Vaquero / Neurochemistry International 60 (2012) 723–735

Table 2 Summary of clinical studies exploring the use of therapeutic hypothermia in patients with acute liver failure. Refs.

(Jalan et al., 1999a)

(Jalan et al., 2001) (Jalan et al., 2003) (Jalan et al., 2004)

n

7

9b 5 14

LT listed (n)

APAP etiology (n)

Induced hypothermia

ICP

Body temperature (°C)

Duration (h)

Before hypothermia

Initial control (n, %)

Rebound during maintenance

4

6

32–33.5

8–14 h

>25 mmHg, refractory a

7 (100%)

LT listed: 1/4 (25%) Non-LT: 3/3 (100%) x 1/5 (during LT) 1 uncontrolled ICP

x 5 14

7 5 13

x x 10–118 h

(Jacob et al., 2009)

1

x

1

5 days

(Castillo et al., 2009)

1

1

No (HAV)

122 h

(Jalan, 2003)

5

x

x

35

23–119 h

Survival

9 (100%) 5 (100%) 14 (100%) 16 ± 0.7

60 mmHg despite treatment 25 mmHg despite treatment <20 mmHg ‘‘prophylactic use’’

LT listed: 3/4 (75%) Non-LT: 0/3 (0%)

1/1 (100%)

5 transient ICP increase No

x 4/5 (80%) – 10/14 (71%) alive 3 months from LT – 3 died after LT – 1 died without LT Survived without LT

x

x

Survived after LT

4 (100%)

0/4 (0%) in first 24 h

– 3 bridged to LT – 1 spontaneous recovery – 1 died without LT at 120 h from sepsis and MOF

Abbreviations: APAP, acetaminophen; HAV, hepatitis A virus; ICP, intracranial pressure; LT, emergency liver transplantation; MOF, multi-organ failure. ‘‘x’’ means ‘‘not available or not applicable’’. a Refractory ICP was defined as persistently elevated ICP of >25 mmHg for 1 h or longer despite 2 separate treatments with mannitol (1 g/kg body wt over 20 min) and removal of 500 mL of fluid by continuous veno-venous hemofiltration. b Two of the patients were also reported in Jalan et al. (1999a).

the induction of mild hypothermia is a highly effective measure for controlling the cerebral complications of ALF. First, therapeutic hypothermia effectively reduces intracranial hypertension in a variety of conditions other than ALF (Andrews et al., 2011; Schwab et al., 2001). The mechanisms by which therapeutic hypothermia reduces ICP in those patients, such as the reduction of cerebral metabolism and cerebral blood flow (CBF), are also pertinent to the control of intracranial hypertension of patients with ALF (Larsen and Wendon, 2002). Secondly, a reduction of body temperature consistently delays the progression of encephalopathy and attenuates the development of brain edema and intracranial hypertension in experimental models of ALF (Barba et al., 2008; Belanger et al., 2006, 2005; Bemeur et al., 2010; Chatauret et al., 2001, 2004; Jiang et al., 2009b,c; Oria et al., 2010; Rose et al., 2000; Sawara et al., 2009; Traber et al., 1989; Zwingmann et al., 2004) (Table 1). This remarkable efficacy of hypothermia may be due to the multiple pathogenetic mechanisms affected by hypothermia as opposed to the single pathways targeted by other measures. Indeed, no other interventions have equaled the ability of hypothermia for preventing the cerebral complications of experimental ALF in such a systematic and reproducible way. Third, the experience with the use of therapeutic hypothermia in patients with ALF is encouraging, although limited to a small number of patients (Table 2). In these uncontrolled case series, therapeutic hypothermia was induced in patients with ALF presenting two circumstances leading to difficult management and high mortality, namely the episodes of high ICP unresponsive to conventional therapy and the surges of ICP that occur during the surgery of emergency LT. In three studies (Jalan et al., 1999a, 2001, 2004), the use of therapeutic hypothermia was reported in a total of 28 patients with ALF meeting King’s College criteria for poor prognosis who had high ICP refractory to conventional measures. Remarkably, the induction of therapeutic hypothermia (32–33 °C) was associated with a rapid reduction of ICP toward normal values in all patients. During the maintenance of hypother-

mia, between 25% (Jalan et al., 1999a) and 40% (Jalan et al., 2004) of the patients presented transient increases of ICP that were generally controlled by the administration of mannitol. One of the patients, however, presented a persistently high ICP and died (Jalan et al., 2004). In those patients undergoing emergency LT, maintenance of mild hypothermia during the surgical procedure was noted to facilitate anesthetic and hemodynamic management. Focusing on this situation, Jalan et al. reported in a fourth study that the majority of patients with ALF transplanted under normothermic conditions (n = 11), including those with normal ICP values before the operation, present surges of high ICP during the dissection and reperfusion phases of the operation (Jalan et al., 2003). In contrast, no significant increase of ICP was observed in 5 patients who had high ICP treated with therapeutic hypothermia before the operation and in whom mild hypothermia was maintained during the surgical procedure. Despite these promising observations, conclusive demonstration of the efficacy of therapeutic hypothermia to control brain edema and intracranial hypertension in patients with ALF requires the performance of RCTs.

4. Mechanisms of therapeutic hypothermia in ALF Therapeutic hypothermia in adults is achieved by cooling the whole body, as selective cooling of the brain using ‘‘cooling helmets’’ or intracarotideal devices/cold infusions is more complex and generally results in concomitant decrease of core body temperature. Temperature is one of the factors (together with the concentration of substrates and pH) that determines the rate of all biochemical reactions in nature; consequently, a reduction of body temperature may essentially affect all biological processes in the human body. While probably accounting for its remarkable efficacy, the plethora of processes affected by therapeutic hypothermia hinders the identification of the specific mechanisms by which it operates. Research has focused, therefore, on investigating how hypothermia affects each of the main pathogenic factors of

J. Vaquero / Neurochemistry International 60 (2012) 723–735

brain edema and intracranial hypertension in ALF (Fig. 2). The reductions of cerebral blood flow and ammonia concentrations in blood and brain are probably two major mechanisms explaining the neuroprotective effects of therapeutic hypothermia in ALF, as they can affect many downstream processes. 4.1. Effects on the brain Mild hypothermia attenuates many of the alterations induced by ALF and hyperammonemia in the brain (Fig. 2). Some of these effects are due to a direct effect of hypothermia locally in the brain, as they were observed in ammonia-infused portacaval-shunted rats and in rats with hepatic devascularization, experimental models in which the circulating levels of ammonia were unchanged by mild hypothermia or in which an effect of hypothermia on the degree of liver injury was not an issue (Table 1). 4.1.1. Brain ammonia In ALF, there is an up to 8-fold increase of the normal blood-tobrain ammonia ratio (Cooper and Plum, 1987; Swain et al., 1992). The accumulation of ammonia within the brain is considered a key event for the development of brain edema in ALF, as it causes abnormal brain glucose metabolism, increased glutamine synthesis in astrocytes, oxidative/nitrosative stress, and other alterations (Albrecht and Norenberg, 2006; Butterworth, 2003). A reduction of body temperature was shown to decrease the concentration of ammonia in brain and cerebro-spinal fluid, respectively, in mice receiving a bolus of ammonium chloride (Schenker and Warren, 1962) and in rats with hepatic devascularization (Rose et al., 2000), in the absence of changes in the circulating levels of ammo-

POTENTIAL ADVERSE EFFECTS

Rebound ICP surges

HIGH RISK DURING REWARMING

Increase of CBF

Increased risk and severity of infections (mainly pneumonia) and sepsis Cardiac arrhythmias

727

nia (Table 1). A decrease of CBF by hypothermia may largely contribute to this finding, but a direct effect of hypothermia on the cerebral metabolism of ammonia may also contribute (Schenker and Warren, 1962). 4.1.2. Brain glucose metabolism The alterations of brain glucose metabolism characteristic of ALF and hyperammonemia may be instrumental in the development of brain edema and high ICP (Butterworth, 2003). An increased glycolytic flux of glucose leading to increased de novo synthesis of lactate has been demonstrated in the brain of rats with hepatic devascularization (Zwingmann et al., 2003). Increased concentrations of lactate in the brain extracellular space have also been described in patients with ALF, with lactate peaks usually preceding ICP surges (Tofteng et al., 2002). Importantly, a decrease of brain energy metabolism, evidenced by a reduction of the cerebral metabolic rates of glucose and oxygen, is a major effect of hypothermia (Cordoba et al., 1999; Jalan et al., 1999b). In patients with ALF treated with therapeutic hypothermia, the reduction of the cerebral metabolic rate of glucose was larger than the reduction of the cerebral metabolic rate of oxygen, suggesting a relative improvement of brain oxidative metabolism (Jalan et al., 1999b). In rats with hepatic devascularization, a 2 °C reduction of body temperature completely prevented the increased de novo synthesis of lactate and alanine (Chatauret et al., 2003) and attenuated the elevation of lactate in cerebro-spinal fluid (Chatauret et al., 2001), effects that preceded the attenuation of brain edema by hypothermia (Table 1). These observations highlight the ability of hypothermia for attenuating the important alterations of brain glucose metabolism observed in ALF.

PROTECTIVE MECHANISMS • of brain NH3 uptake and concentration. • Improvement of glucose metabolism, with of CMRO2, CMRGlc, and glycolytic flux. • Attenuation of: - Disturbance in organic osmolytes. - The in extracellular glutamate and lactate. - Oxidative/ nitrosative stress. - Inflammation and microglial activation. - Changes in gene expression (PTBRs, GFAP, etc...). - Seizure activity? • Decrease of CBF and prevention of cerebral hyperemia: delivery of NH3 to the brain. hydrostatic pressure in brain capillaries. cerebral blood volume. • Restoration of cerebro-vascular autoregulation. Decrease in the circulation of: - NH3 concentration. - Levels of pro-inflammatory mediators.

Increase of bleeding complications: platelet number - Prolongation of coagulation times

Electrolyte and fluid shifts

Improvement of systemic hemodynamic alterations. • Attenuation of liver injury (ischemia-reperfusion, drugs): - hemorrhagic congestion. - Improved recovery of glycogen and glutathione. - neutrophil infiltration. - hepatocyte apoptosis. • Decrease of renal ammonia production. • “Cold-induced” diuresis.

Decrease of intestinal ammonia production.

Fig. 2. Schematic showing the main protective mechanisms of hypothermia in acute liver failure (right side) and its major potential adverse effects (left side). Abbreviations: CBF, cerebral blood flow; CMRO2, cerebral metabolic rate of oxygen; CMRGlc, CMR of glucose; GFAP, glial fibrillary acidic protein; ICP, intracranial pressure; NH3, ammonia; PTBR, peripheral-type benzodiazepine receptor.

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4.1.3. Brain osmotic disturbance In the brain, the rapid metabolism of ammonia by the enzyme glutamine synthetase in astrocytes results in the intracellular accumulation of glutamine, which is thought to cause osmotic swelling (the glutamine hypothesis) and a compensatory decrease of other organic osmolytes (Cordoba et al., 1996). The topic of glutamine accumulation in ALF is complex, however, and recent findings suggest that glutamine may also get trapped inside astrocytes due to a down-regulation of the high affinity glutamine transporter SNAT5. Other compounds that increase significantly in the brain in ALF, such as alanine and lactate, could also contribute to the brain osmotic disturbance (Zwingmann et al., 2003). Interestingly, the prevention of brain edema by mild hypothermia was not accompanied by a reduction of brain glutamine accumulation neither in portacaval-shunted rats receiving an ammonia infusion (Cordoba et al., 1999) nor in rats with ALF induced by hepatic devascularization (Chatauret et al., 2003; Rose et al., 2000). In these experimental models, however, mild hypothermia significantly attenuated the alterations of other organic osmolytes in the brain, such as the depletion of myo-inositol, taurine, and glutamate and the increase of alanine and lactate, suggesting a global improvement of the brain osmotic disturbance (Fig. 2 and Table 1). 4.1.4. Extracellular concentration of brain amino acids ALF induces important alterations in the brain glutamate system, including a consistent decrease of its total concentration (Vaquero and Butterworth, 2006). The concentration of glutamate in the brain extracellular space, in contrast, is known to increase both in patients (Tofteng et al., 2002) and in experimental models of ALF (Michalak et al., 1996), probably due to a combination of increased release and decreased astrocytic uptake (Rose, 2002). The induction of hypothermia prevents the progressive increase of brain extracellular glutamate that is observed in rats with hepatic devascularization maintained normothermic (Rose et al., 2000) (Table 1), and it also attenuates glutamate-induced astrocyte swelling in vitro (Bender and Norenberg, 1994). In rats with hepatic devascularization, mild hypothermia also attenuates other alterations in the composition of the brain extracellular fluid, such as the increases of glycine and aromatic amino acids (Vaquero et al., 2005b), suggesting that the preservation of a normal composition of brain extracellular fluid may be another mechanism by which hypothermia attenuates the cerebral complications of ALF (Fig. 2). 4.1.5. Brain inflammation and microglial activation By measuring cerebral blood flow and arterio-venous differences across the brain, a positive efflux of pro-inflammatory cytokines from the brain has been noted in patients with ALF developing high ICP (Jalan et al., 2003, 2004). Increased mRNA and protein expression of IL-1b, TNF-a, IL-6 and markers of microglial activation have also been reported in the brain of rats with hepatic devascularization at the time of brain edema (Jiang et al., 2009a). The induction of mild hypothermia was associated with the reduction of the brain efflux of pro-inflammatory cytokines in patients with ALF (Jalan et al., 2003, 2004) and with the attenuation of microglial activation, brain cytokine production and brain edema in rats with hepatic devascularization (Jiang et al., 2009b) (Table 1), suggesting that the anti-inflammatory properties of mild hypothermia may also contribute to its beneficial effects in ALF (Fig. 2). 4.1.6. Other factors in the brain Other cerebral alterations in ALF that may be sensitive to hypothermia include the development of oxidative/nitrosative stress, seizure activity, and anomalies in gene expression (Fig. 2). The development of oxidative/nitrosative stress in astrocytes may be a key step in the toxicity of ammonia, and it could be further en-

hanced by the action of inflammatory mediators (Norenberg et al., 2007). As in experimental models of stroke and inflammation (Han et al., 2002), a reduction of body temperature led to the attenuation of indirect markers of oxidative/nitrosative stress in the brain of rats with hepatic devascularization, including the concentration of nitrite/nitrate and the mRNA induction of hemeoxygenase-1, inducible nitric oxide synthase (NOS) and endothelial NOS (Jiang et al., 2009c) (Table 1). In patients with ALF, therapeutic hypothermia reduced the arterial concentration of nitrite/nitrate and malondialdehyde, but the cerebral efflux of these compounds remained close to zero and, therefore, a reduction of oxidative/ nitrosative stress in the brain could not be demonstrated (Jalan et al., 2004). Subclinical seizure activity has also been proposed to increase the risk of developing brain edema in ALF (Ellis et al., 2000). No specific studies have been performed in ALF, but the induction of hypothermia has been reported to abrogate seizure activity in patients with refractory status epilepticus (Corry et al., 2008) and to reduce neuronal synchronization in stimulated rat hippocampal slices (Javedan et al., 2002), suggesting another mechanism of hypothermia that may be relevant in ALF. Finally, the induction of mild hypothermia in rats with hepatic devascularization normalized the brain expression of a number of genes that were altered in rats maintained normothermic, including the glial fibrillary acidic protein, the peripheral-type benzodiazepine receptor, hemeoxygenase-1, and others (Belanger et al., 2005; Jiang et al., 2009c; Sawara et al., 2009). It remains to be elucidated, however, which of those changes in gene expression are mechanistically relevant. 4.2. Effects on cerebrovascular hemodynamics An increase of cerebral blood flow (in absolute values as well as relative to cerebral energy demands) and a loss of the normal cerebrovascular autoregulation are two common alterations in patients with ALF and severe encephalopathy (Aggarwal et al., 2005; Wendon et al., 1994). Both alterations are thought to be the consequence of a state of ‘‘cerebral vasoparalysis’’ (Larsen et al., 1996), and both are highly relevant for the development of brain edema and high ICP in ALF (Larsen and Wendon, 2002). Mild hypothermia has been shown to correct both cerebral hyperemia and the loss of cerebrovascular autoregulation in patients with ALF presenting high ICP unresponsive to conventional measures (Jalan et al., 1999a, 2001, 2003, 2004). The rapidity by which therapeutic hypothermia reduced ICP in these patients (1 h), even before the target temperature of 32 °C was reached, points to the effect on cerebral blood flow as a major mechanism by which ICP was lowered. This is not surprising, given that a reduction of cerebral blood flow decreases ICP by diverse independent mechanisms, such as by decreasing the cerebral blood volume compartment, the hydrostatic pressure in brain capillaries, and the delivery to the brain of ammonia, cytokines and other circulating mediators (Fig. 2). Therapeutic hypothermia also reversed the state of ‘‘cerebral vasoparalysis’’, as assessed by the restoration of cerebrovascular autoregulation to changes in mean arterial pressure and of the vasodilatory response of the cerebral vasculature to carbon dioxide (Jalan et al., 2001). Maintenance of mild hypothermia during surgery for emergency LT in patients with ALF also prevented the development of cerebral hyperemia and high ICP that often occur during the dissection and reperfusion phases of the operation (Jalan et al., 2003). 4.3. Systemic effects The systemic effects of therapeutic hypothermia probably contribute to the attenuation of the cerebral complications of ALF, and

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could also be beneficial for some of its peripheral complications (Fig. 2). 4.3.1. Circulating ammonia concentration A sustained reduction in the concentration of ammonia in arterial blood after the induction of therapeutic hypothermia (32– 34 °C) has been noted in patients with ALF (Jalan et al., 1999a, 2004) and with urea-cycle defects (Whitelaw et al., 2001). In mice with azoxymethane-induced liver injury, mild hypothermia also reduced the plasma concentration of ammonia, which occurred in association with attenuated hepatocyte damage (Belanger et al., 2006; Bemeur et al., 2010). In an experimental model where there is no role of hepatic detoxification, the rat with hepatic devascularization, the plasma ammonia concentration was unchanged in rats with body temperature maintained at 35 °C compared to normothermic controls (37 °C) (Chatauret et al., 2003; Rose et al., 2000), but it was significantly reduced in those studies where their body temperature was maintained at 33 °C (Jiang et al., 2009b,c). Together, these observations suggest that the processes leading to the formation of ammonia are temperature-dependent and more sensitive to hypothermia than those leading to its detoxification. Indeed, the capacity of the liver to detoxify ammonia appears to be preserved in hypothermic conditions (Keirle et al., 1961), and hypothermia has been reported to decrease both the bacterial formation of ammonia in the intestine (Welch et al., 1961), the release of ammonia to the circulation by the kidney (Keirle et al., 1964), and the catabolism of proteins (Johnson et al., 1986). The reduction of ammonia in the circulation, thus, may be a major mechanism explaining the sustained effects of hypothermia in the prevention of the cerebral complications of ALF (Fig. 2). 4.3.2. Systemic hemodynamics Patients with ALF generally develop a hyperdynamic circulation characterized by increased cardiac output, tachycardia and low systemic vascular resistance, which may progress to hemodynamic instability and shock (Ellis and Wendon, 1996). The hemodynamic alterations play an important role in the development of renal failure and other complications of ALF. Importantly, Jalan et al. noted that the induction of therapeutic hypothermia in patients with ALF and high ICP was associated with a reduction of cardiac output and heart rate toward normal values and with an increase of systemic vascular resistance (Jalan et al., 1999a, 2004). Even though mean arterial pressure did not change, the amount of noradrenaline required to maintain safe values of mean arterial pressure was significantly lower during mild hypothermia. Maintenance of therapeutic hypothermia during emergency LT was also noted to facilitate the hemodynamic management during the surgical procedure (Jalan et al., 2003). These hemodynamic effects of therapeutic hypothermia could be beneficial in ALF by facilitating the hemodynamic management of the patients and by attenuating other peripheral complications (Fig. 2). 4.3.3. Systemic inflammation Systemic inflammation is inherently present in patients with ALF of any etiology, and its severity is independently correlated with the morbidity and mortality of the syndrome (Rolando et al., 2000). Systemic inflammation also contributes to the progression of liver injury, of hemodynamic instability and of most systemic complications of ALF. Remarkable anti-inflammatory properties of hypothermia have been demonstrated in a variety of conditions other than ALF (reviewed in (Vaquero and Blei, 2005)). In patients with ALF and high ICP, therapeutic hypothermia induced consistent decreases in the circulating concentration of the pro-inflammatory cytokines IL-1b, TNF-a, and IL-6 (Jalan et al., 2003, 2004). These observations have been reproduced in

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experimental models of ALF, such as in the rat with hepatic devascularization (Jiang et al., 2009b) and the mouse with azoxymethane-induced liver injury (Bemeur et al., 2010) (Table 1). Interestingly, the induction of some cytokines, such as the antiinflammatory cytokine IL-10, was not affected by the induction of hypothermia (Bemeur et al., 2010; Jiang et al., 2009b). Together, these studies point to the modulation of systemic inflammation as another effect of hypothermia that could be valuable in ALF (Fig. 2). 4.3.4. Liver injury and liver regeneration Investigation of the effects of mild hypothermia on the liver is important, particularly if hypothermia is to be used in patients that have contraindications for LT and depend on the functional recovery of their own liver for survival. Several observations suggest that the induction of mild hypothermia may attenuate the progression of liver injury without necessarily impeding liver regeneration. Most studies of hypothermia and the liver have focused on the hepatoprotective effects of hypothermia against ischemiareperfusion liver injury, which have been consistently shown in both large and small animals. The beneficial effects of hypothermia in these models have included significant increases of survival, attenuation of liver damage, improved sinusoidal perfusion and sinusoidal endothelial cell function, and improved recovery of bile production (Bernhard et al., 1957; Biberthaler et al., 2001; Choi et al., 2005; Heijnen et al., 2003; Kato et al., 2002; Kuboki et al., 2007; Niemann et al., 2006). A decrease in metabolic demand and oxidative metabolism during ischemia, and attenuation of the inflammatory cascade and free radical production that occur during reperfusion, are thought to mediate the hepatoprotective effects of hypothermia in these experimental models (Kuboki et al., 2007; Vaquero and Blei, 2005, and references therein). Information regarding the effects of hypothermia on liver injury induced by causes other than ischemia-reperfusion is limited. Even though a reduction of body temperature is a feature in most mouse models of liver injury, this variable has rarely been controlled (Vaquero et al., 2006). In studies from Dr. Butterworth’s Laboratory, a mild reduction of body temperature attenuated the progression of liver injury and increased survival in mice with liver injury induced by acetaminophen (Vaquero et al., 2007) and by azoxymethane (Belanger et al., 2006; Bemeur et al., 2010), two potent hepatotoxic drugs. Several mechanisms could account for the hepatoprotective effects of hypothermia in these hepatotoxic models (Table 1 and Fig. 2). Derangement of hepatic microcirculation leading to hepatocyte ischemia is common in the setting of massive liver injury from any etiology and, therefore, the protective mechanisms of hypothermia against ischemia-reperfusion are likely to be relevant. Indeed, an attenuation of the hemorrhagic congestion of the liver was a striking macroscopic and histological feature in the hepatotoxic models (Belanger et al., 2006; Vaquero et al., 2007). An improved recovery of hepatic glutathione and hepatic glycogen stores, a selective decrease in the expression of circulating pro-inflammatory cytokines, and a reduction of apoptosis were other potentially protective effects of hypothermia. An increased cell survival was also observed in primary cultures of mouse hepatocytes exposed to diverse apoptotic stimuli when they were incubated at 32 °C as compared with those incubated at 37 °C (Fu et al., 2004). Interestingly, hypothermia specifically suppressed cytochrome C release and the subsequent caspase 9 activation, pointing to the mitochondria as a major site of action of hypothermia. A potential impairment of liver regeneration was a major concern raised when considering the clinical use of hypothermia in patients with ALF (Munoz, 2005). In a model of 30% partial LT in the rat, cold preservation (4 °C) of the liver graft for 30 min enhanced the regenerative ability of hepatocytes as compared to that observed in the remnant liver of rats subjected to 70% hepatec-

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tomy, whereas cold preservation for long periods (10 h) was associated with impaired regeneration (Selzner et al., 2002). Limited information is available regarding the effects of a mild degree of hypothermia (32–35 °C) on liver regeneration. In mice undergoing a partial (70%) hepatectomy, a 3-h period of mild hypothermia (32 °C) immediately after the surgery did not impair liver regeneration (Arab et al., 2009). In a mouse model of acetaminophen hepatotoxicity, a mild reduction of body temperature (32–35 °C) resulted in both decreased liver injury and decreased hepatocyte proliferation, but the extent of hepatocyte proliferation strongly correlated with the extent of the injury regardless of the body temperature of the mice (Vaquero et al., 2007). Finally, instances of spontaneous survival (without LT) in patients with ALF treated with prolonged mild hypothermia have been occasionally reported (Jacob et al., 2009; Jalan, 2003). Even though more studies are clearly required, the previous observations suggest that the induction of mild hypothermia is not necessarily associated with an abrogation of liver regeneration. 5. A note of caution on translational hypothermia research Both clinical and experimental studies provide an ample rationale for the use of therapeutic hypothermia in ALF (Fig. 2 and Tables 1 and 2). Several limitations should be considered, however, when assessing the evidence from experimental models of ALF, as they may impact on direct extrapolation of findings to the human condition (Table 3). First, inter-species differences in basic physiology and pathophysiology may be important, including a wider tolerance of rodents to changes in body temperature (Gordon, 1990). Second, experimental animal models do not reproduce all aspects of human ALF, such as its diverse etiologies or the development of systemic complications such as sepsis, renal failure, and others. An important difference also exists in the manner of inducing hypothermia. Animals are awake and hypothermia develops spontaneously in many experimental models, with animals even requiring external warming to avoid excessive reductions of body temperature. In contrast, therapeutic hypothermia must be actively induced in patients with ALF, generally by external cooling of the body, and requires the patients to be anesthetized and mechanically ventilated. The time of induction of hypothermia relative to the course of the disease is another differentiating factor that should be recognized, particularly in studies exploring the effect of hypothermia on liver injury. Whereas hypothermia develops in parallel or precedes the progression of liver failure and hyperammonemia in experimental studies, hypothermia is induced in human disease once liver failure is fully established. Finally, the effects of rewarming, a crucial phase in which the benefits from hypothermia may be completely lost, have not been

Table 3 Relevant translational limitations of experimental research of hypothermia in acute liver failure. 1. Inter-species differences in basic physiology and pathophysiology between animals and humans 2. Experimental animal models do not reproduce all the complexity of ALF in humans 3. Manner of developing hypothermia: – Experimental models: Spontaneous reduction of body temperature; animals generally awake – Humans: Active induction of hypothermia; patients anesthetized and mechanically ventilated 4. Timing of hypothermia: – Experimental models: Hypothermia preceding or in parallel with disease – Humans: Hypothermia induced after liver disease is fully established 5. Terminal nature of many experimental models of ALF 6. Effects of rewarming have not been explored in experimental models of ALF

explored in any of the experimental models of ALF. Importantly, many of the experimental models are terminal in nature, preventing the assessment of rewarming, liver regeneration, and recovery or final survival. 6. Can therapeutic hypothermia improve survival in ALF? No RCTs have been performed in ALF evaluating the safety of therapeutic hypothermia, its efficacy for preventing brain edema and intracranial hypertension, or its impact on survival. The difficulties for performing a RCT in ALF are well known, and include the multiple etiologies of ALF, the rarity of the disease, the need for participation of multiple centers, the lack of a uniform ‘‘standard of care’’ across centers, the ‘‘disrupting’’ effect of LT on the natural course of the disease when assessing outcomes, and others (Stravitz et al., 2008; Vaquero and Blei, 2005). Investigation of therapeutic hypothermia in ALF faces further specific obstacles such as the identification of appropriate endpoints and study populations, the lack of interest from funding institutions in non-patentable measures, or the reluctance among practicing clinicians to apply therapeutic hypothermia in humans (Abella et al., 2005; Wolfrum et al., 2007). Given that the correct management of specific aspects of hypothermia is critical for a successful therapy, a ‘‘training’’ phase has also been recommended in order to gain familiarity with the therapy and to standardize management protocols across participating centers (Clifton et al., 2001a). Regardless of all these difficulties, three distinct subgroups of patients may be distinguished when considering a theoretical use of therapeutic hypothermia in ALF. 6.1. Candidates for LT who have intracranial hypertension refractory to conventional measures These patients rapidly deteriorate and in many centers they will be removed from the waiting list for a donor organ due to the high risk of mortality or permanent neurological damage (Lidofsky et al., 1992). Despite the small sample-sized and uncontrolled nature of the studies, Jalan et al. have repeatedly reported in this type of patients the ability of therapeutic hypothermia to normalize ICP, to facilitate the hemodynamic management, and to successfully bridge the patients to LT (Jalan et al., 1999a, 2004). In these patients, mild hypothermia was maintained until a donor organ was available and during the surgery for LT. Remarkably, the 70– 80% survival rate associated with the use of therapeutic hypothermia (Table 2) compares very favorably with the 90% mortality historically expected in this group of patients, and is strikingly similar to the global survival rate of patients with ALF who undergo LT (Jalan, 2003; Lee et al., 2008). Therefore, the use of therapeutic hypothermia may successfully bridge these patients to LT and have a positive impact in their survival. 6.2. Patients who are candidates for LT who develop or are at high risk of developing intracranial hypertension The relevance of therapeutic hypothermia as a prophylactic or a first-line therapy for intracranial hypertension is uncertain because the experience with this indication is very limited in patients with ALF (Jalan, 2003). The value of therapeutic hypothermia versus or in combination with other interventions such as osmotherapy, plasmapheresis (Clemmesen et al., 2001) or N-acetylcysteine (Lee et al., 2009) is unknown. Despite a high rate of recurrence of high ICP, conventional measures such as the infusion of hypertonic saline (Murphy et al., 2004) or the administration of mannitol, prevent or control a first episode of intracranial hypertension in up to 80% of the patients (Hoofnagle et al., 1995), and may have better safety

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profiles than hypothermia. A potential advantage of mild hypothermia over conventional therapies may derive from its potential to beneficially affect other complications and to prolong survival time, as noted in experimental models of ALF and in patients with unresponsive intracranial hypertension (Belanger et al., 2006; Jalan et al., 1999a; Vaquero et al., 2007) (Tables 1 and 2). In a recent report from the US Acute Liver Failure Study group, it was noted that approximately 23% of the patients with ALF listed for emergency LT eventually died without ever receiving a donor organ (Lee et al., 2008). It is therefore conceivable that therapeutic hypothermia could improve survival by increasing the percentage of these patients that are successfully bridged to LT. The preliminary analysis from a first RCT of therapeutic hypothermia in ALF (clinicaltrials.gov # NCT00670124) presented at the 2011 EASL meeting, however, did not support this possibility (Larsen et al., 2011). In this trial, Larsen et al. included 54 patients with ALF in whom a decision had been made to undertake ICP monitoring, randomizing them to receive either standard medical therapy (n = 33 patients) or standard medical therapy plus mild hypothermia (33–34 °C, n = 21 patients) for a fixed duration of time (3 consecutive days). Even though the incidence of adverse effects was similar between the two groups, therapeutic hypothermia was not found to decrease the incidence of high ICP (>25 mmHg) or the mortality. The final analysis from this multi-center trial will undoubtedly provide important information for optimizing the use of therapeutic hypothermia in patients with ALF. 6.3. Patients who fulfill criteria for poor prognosis but have no option to undergo LT This category includes patients who present contra-indications for LT as well as patients who live in countries where LT is not an option due to logistical or religious reasons. Although the poor prognosis of these patients (>90% mortality) together with the beneficial effects of hypothermia on liver injury and survival noted in experimental models of ALF make the induction of therapeutic hypothermia an attractive possibility, the limitations of animal models and the high risk of potential adverse effects during rewarming are a source of concern. In a total of 6 patients with ALF and high ICP, early initiation of rewarming after 8 h of therapeutic hypothermia was uniformly associated with rebound of high ICP, rapid clinical deterioration and death (Jalan et al., 1999a, 2003). These observations suggest that the initiation of therapeutic hypothermia may commit patients to hypothermia until the recovery of liver function occurs, therefore increasing the duration of the therapy and the risk of adverse effects. Further information on the use and safety of therapeutic hypothermia in patients with ALF and on how hypothermia and rewarming affect liver injury and regeneration, is required before therapeutic hypothermia can be recommended in this category of patients. 7. Practical aspects and areas of uncertainty in the use of therapeutic hypothermia in patients with ALF Several practical aspects should be born in mind regarding the clinical use of therapeutic hypothermia. For detailed insights, we refer the reader to recent reviews dealing with thermoregulatory defense mechanisms (Sessler, 2009), methods of cooling (Seder and Van der Kloot, 2009), implementation of therapeutic hypothermia protocols (Kupchik, 2009), physiological effects and complications of hypothermia (Polderman, 2009; Schubert, 1995), and specific management issues of hypothermia in ALF (Stravitz and Larsen, 2009; Stravitz et al., 2008). Some practical issues and areas of uncertainty relevant for patients with ALF will be briefly discussed in this section.

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Therapeutic hypothermia comprises 3 distinct phases, each of them presenting specific questions and concerns (Fig. 3). 7.1. Induction phase For hypothermia to be therapeutic, the reduction of body temperature needs to be accomplished without triggering the physiological thermoregulatory responses against hypothermia. Such responses include the sympathetic and adrenomedullary activation, the hypothalamic-pituitary-adrenal stress response with increased release of cortisol, and the development of shivering, resulting in cutaneous vasoconstriction, glycogenolysis, and marked increases of whole body metabolism, and glucose and O2 consumption (Sessler, 2009). Even though a reduction of body temperature is easily achieved in patients with ALF due to their characteristic peripheral vasodilatation and comatose state, all patients with ALF should be adequately anesthetized, intubated and mechanically ventilated before the induction of hypothermia, and they may also require the administration of neuromuscular blocking agents to prevent shivering. Development of bradychardia is a normal feature of therapeutic hypothermia (Polderman, 2009), and its absence or an increase of heart rate may be indicative of inadequate sedation. Some medications that are recommended for the induction of hypothermia in patients with cardiac arrest and other conditions, such as acetaminophen or benzodiazepines (Kupchik, 2009; Seder and Van der Kloot, 2009), should be avoided in patients with ALF. Propofol and atracurium besylate are the agents used to prevent thermoregulatory responses in the studies performed so far in patients with ALF (Jalan et al., 1999a, 2004). The doses of these agents should be individually adjusted to the lowest dose necessary to suppress shivering, taking into account that a 2–3 °C reduction of body temperature nearly doubles the duration of action of atracurium. The reduction of body temperature is quickly achieved (1–2 h) in patients with ALF by means of external cooling devices such as airor water-circulating cooling blankets (Jalan et al., 1999a, 2004). Cooling with endovascular devices, which may be more precise, has only been anecdotally reported (Castillo et al., 2009). Even though surface cooling may be preferable in ALF due to the lower risk of infection, important attention should be paid to avoid unintentional overcooling (Merchant et al., 2006). Rigorous monitoring of body temperature during all phases of the therapy is essential. This is preferably attained by measuring core body temperature (esophagus or pulmonary artery), although the measurement of temperature in the urinary bladder is also frequently used. The induction phase of therapeutic hypothermia entails a high risk of developing hypovolemia and electrolyte alterations and, therefore, important attention should be paid to monitor and treat these complications (Polderman, 2009). Coagulation abnormalities should also be aggressively corrected before performing any invasive interventions in these patients. In addition to which group of patients with ALF should be treated (discussed previously), there is insufficient information to determine which is the ideal target temperature to be attained, or whether ICP monitoring should be mandatory for establishing the indication of therapeutic hypothermia and guiding its management (Fig. 3). In patients with ALF treated with therapeutic hypothermia, a fast reduction of ICP was observed even before reaching the target temperature of 32 °C (Jalan et al., 1999a, 2004). In a rat model of ammonia-induced brain edema, both 33 °C and 35 °C of body temperature afforded the same protection against brain edema and intracranial hypertension (Cordoba et al., 1999). Given that the risk of adverse effects from therapeutic hypothermia is higher as temperature decreases, it is possible that targeting smaller reductions of body temperature, e.g. to 34° or 35 °C, in patients with ALF could be safer and equally effective. ICP monitoring in patients with ALF is controversial, due to its invasive nature and the

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Induction

37 ºC

ATTENTION TO: - Avoid shivering. - Correct coagulation before invasive interventions. - Avoid over-cooling. - Avoid hypovolemia and electrolyte alterations.

Maintenance

Rewarming

ATTENTION TO: - Avoid shivering.

ATTENTION TO: - Avoid shivering.

- Hygienic measures/Prophylaxis of infection.

- Hygienic measures/Prophylaxis of infection.

- Adjust doses of drugs.

- Re-adjust doses of drugs.

- Correct electrolyte and fluid shifts.

- Avoid electrolyte and fluid shifts.

- Prevent and detect complications: • Bleeding • Infections • Pancreatitis • Cardiac arrhythmias

- High risk of: • Rebound of ICP surges • Hemodynamic instability • Cardiac arrhythmias • Hypoglycemia

- Avoid over-correction of normal parameters for hypothermic individuals.

35 ºC 33 ºC

?

• WHICH PATIENTS? • HOW COOL? • HOW LONG?

• WHEN TO REWARM?

• HOW COOL?

• HOW FAST?

• ICP MONITORING?

• HOW TO ASSESS IMPROVEMENT?

• WHAT GUIDING PARAMETERS?

• WHICH ANESTHETICS AND ANTI-SHIVERING MEDICATIONS?

• INTERFERENCE WITH OTHER THERAPIES?

• HOW TO RE-WARM?

• WHICH COOLING DEVICES?

• INTERFERENCE WITH PROGNOSTIC PARAMETERS? (pH, lactate, coagulation...)

~ 2 to 4 h

Time

?

Fig. 3. Schematic showing the three different phases of therapeutic hypothermia, with the main adverse effects and areas of uncertainty concerning each phase. Abbreviations: ICP, intracranial pressure.

risk of intracranial bleeding (Bernuau and Durand, 2006; Wendon and Larsen, 2006). At this time, however, the use of ICP monitoring seems an essential tool to confirm the neuroprotective effects of hypothermia in patients with ALF and to provide the guiding principles for its utilization. Fortunately, complications from ICP monitoring in patients with ALF appear to have progressively decreased due to an increased experience and better management of coagulation abnormalities (Blei et al., 1993; Vaquero et al., 2005a). 7.2. Maintenance phase The aim in this phase is to maintain the target temperature with the minimum variation possible, and to prevent potential adverse effects. The presence of coronary artery disease, a low body-surface area, the need for major fluid resuscitation, an advanced age (older than 60 year-old), a state of immune suppression, a baseline coagulopathy, prolonged hypothermia and the lack of adequate technical resources or of personnel trained in the prevention and treatment of hypothermic complications, are general conditions associated with increased risk of hypothermia-related complications (Schubert, 1995). Shivering is less common once body temperature falls below 34 °C, but it may still occur. In conditions other than ALF, shivering was frequently detected in patients undergoing therapeutic hypothermia and, therefore, the use of a simple Bedside Shivering Assessment Scale may be a valuable monitoring tool (Badjatia et al., 2008). In a temperature-dependent manner, hypothermia may increase the severity and susceptibility to infections, decrease the number of platelets, increase coagulation times, and cause electrolyte alterations and cardiac arrhythmias (Polderman, 2009). Hyperamylasemia, generally without evidence of pancreatitis, may also develop (Shiozaki et al., 2001). Importantly, all of these complications are already common in the natural history of ALF and, therefore, their careful prophylaxis and early detection are of paramount importance. In the studies performed so far in patients with ALF undergoing therapeutic hypothermia, no abnor-

mal increase of infection, bleeding complications or transfusion requirements of blood, platelets or plasma have been noted (Jalan et al., 1999a, 2003, 2004). On the other hand, the normal ‘‘physiological’’ range for some parameters at normothermia may be different at hypothermia, and care should be taken to avoid overcorrection of those that may be adequate for an hypothermic individual (lower heart rate and mean arterial pressure, etc.). Adjustment of insulin dose and mechanical ventilation parameters may be needed, as hypothermia may cause hyperglycemia and hypocapnia due to the reductions of glucose consumption and carbon dioxide production. Hypothermia also alters the metabolism and disposition of many drugs (Tortorici et al., 2006, 2007), which may be already altered due to the presence of liver failure. Monitoring of circulating drug levels and adjustments of the dosage of certain medications may be needed. Apart from ICP monitoring, there are currently no clear guidelines regarding how to assess improvement in patients with ALF undergoing therapeutic hypothermia or information on how hypothermia may affect the efficacy of other therapeutic interventions. Remarkably, hypothermia is known to interfere with parameters that are commonly used to assess prognosis in ALF. Coagulation times, pH and blood gases, for example, are commonly assayed at 37 °C in the laboratory, not reflecting the actual situation in the patient with hypothermia. Therapeutic hypothermia could also interfere with the interpretation of blood lactate and pulsioxymetry values, as hypothermia causes peripheral vasoconstriction and a left-shift of the dissociation curve of oxyhemoglobin, and may increase lactate as a consequence of reduced hepatic clearance as well as of increased production due to impaired oxygenation of peripheral tissues (Polderman, 2009). 7.3. Rewarming phase Rewarming is the most critical phase of therapeutic hypothermia, and it is characterized by an increase of the metabolic rate resulting in increased glucose and O2 consumption. Rewarming

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bears a high risk of complications and it is fraught with a number of specific management issues. Serious events that are frequently associated with rewarming, especially if rewarming speed is high, include the development of hypoglycemia, increase of circulating pro-inflammatory cytokines, hyperkalemia and other electrolyte alterations, peripheral vasodilatation, hemodynamic instability, cardiac arrhythmias, cerebral hyperemia and, importantly, rebound of intracranial hypertension (Marion et al., 1997; Polderman, 2009). In addition to the prevention, early detection and treatment of these complications, attention should also be paid to the appearance of shivering and to the adjustment of mechanical ventilation parameters and drug doses. In the studies performed so far in patients with ALF undergoing therapeutic hypothermia, rewarming appeared to be safe when initiated slowly after successful LT had been completed (Jalan et al., 1999a, 2004). In marked contrast, early rewarming in patients with contraindications for LT was uniformly fatal (Jalan et al., 1999a, 2003). Spontaneous survival (without LT) in patients with ALF treated with prolonged therapeutic hypothermia is, however, possible (Jacob et al., 2009; Jalan, 2003). In the absence of specific studies focused on how to prevent the complications of rewarming in patients with ALF, therefore, it would seem prudent to maintain therapeutic hypothermia as long as possible until liver function is recovered (spontaneously or via a donor organ) and to rewarm the patients slowly, maybe 1° or 2 °C every 24 h. Further studies are required to evaluate which is the best way to rewarm these patients (passive vs. active warming, external vs. core warming) and which are the best guiding parameters. 8. Conclusions A growing body of experimental studies and preliminary clinical observations indicate that the induction of therapeutic hypothermia may be a valuable therapy for controlling the cerebral complications of ALF and improving survival. Further information only attainable from appropriately designed clinical studies is clearly needed regarding specific management issues of the use of therapeutic hypothermia in ALF, including which subgroups of patients should be treated, how they should be monitored, how hypothermia affects the efficacy of other therapeutic measures, how deeply patients should be cooled, and how rewarming should be performed. These and other factors may critically determine the impact of therapeutic hypothermia on clinical outcomes. At this time, the use of therapeutic hypothermia outside of clinical trials can only be recommended as a last resort in those patients with ALF who are candidates for LT presenting intracranial hypertension that cannot be controlled by conventional measures. Acknowledgements Dr. Vaquero is funded by a 5-year Ramón y Cajal grant from the Ministerio de Ciencia e Innovación (Spain). The author would like to dedicate this review to the memory of his beloved mentor Dr. Andrés T. Blei, whose work was fundamental for initiating and advancing clinical and experimental research of hypothermia in ALF. The author would also like to acknowledge the important contributions of Drs. Roger F. Butterworth, Rajiv Jalan and their associates, as their work constitutes most of the information currently available in this area of research. References Abella, B.S., Rhee, J.W., Huang, K.N., Vanden Hoek, T.L., Becker, L.B., 2005. Induced hypothermia is underused after resuscitation from cardiac arrest: a current practice survey. Resuscitation 64, 181–186.

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