**Hypothermia in Acute Liver Failure**

Rahul Nanchal and Gagan Kumar

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/55629

#### **1. Introduction**

Acute liver failure (ALF), the manifestation of severe hepatocellular injury in the absence of pre-existing liver disease is a catastrophic and frequently fatal disorder. Though the injury is potentially reversible, the clinical course often culminates in multiple organ failure which is associated with a poor prognosis. The incidence is between 1 and 6 per million population per year [1]. However this data is predominantly from developed countries, data from developing countries where the etiology of ALF is very different is virtually absent. The most common etiologies in the developing world are hepatotrophic viruses (Hepatitis A, B and E) in comparison to drug induced liver failure which predominates in developed countries [2]. Amongst drugs, acetaminophen is the leading cause of acute liver failure and accounts for approximately 50% of the cases in the US [3]. Other etiologies include other viral infections and drugs, ischemic hepatitis, Wilson's disease, autoimmune hepatitis, pregnancy related liver disorders and a large sero-negative cohort where no inciting cause can be identified.

 Originally the definition of acute liver failure encompassed the development of coagulopathy and encephalopathy within 8 weeks of the original hepatic insult [4]. Newer definitions differentiate between, hyper-acute, acute and sub-acute liver failure contingent on the time period between the onset of jaundice and the onset of encephalopathy [5]. Regardless of definition used, the onset of hepatic encephalopathy especially Grade III/IV encephalopathy defines a turning point in the clinical course of this disease [6]. Occurrence of hepatic encephalopathy or coma in ALF is a poor prognostic sign and is associated with the development of cerebral edema, intracranial hypertension and subsequent mortality from brain herniation [7]. Though advances in the care of the patient with ALF have led to both a decrease in the incidence and associated mortality of persons developing cerebral edema and intracranial hypertension [7], careful vigilance should be exercised because development and progression of encephalopathy can be rapid and fatal. Further data on the declining incidence and mortality are from a single tertiary care academic center with

© 2013 Nanchal and Kumar, licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 Nanchal and Kumar, licensee InTech. This is a paper distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

immediate access to transplantation services. Such expertise may not be readily available at other facilities and therefore the outcomes at such centers could be considerably different. Moreover, cerebral edema and raised intracranial pressure in persons with ALF accounts for substantial mortality (between 25 and 50%) as well as neurocognitive sequalae in survivors.

Hypothermia in Acute Liver Failure 101

alterations in brain glucose metabolism. Together these mechanisms lead to accumulation of brain water and astrocyte swelling [18]. Though the aforementioned cytotoxic mechanisms predominate, an increasing role of vasogenic edema contributing to increased brain water and consequent raised intracranial pressure has been recently recognized. Although structurally normal the blood brain barrier becomes selectively leaky to certain polar molecules through

Cerebral blood flow is often dysregulated in ALF. Loss of auto-regulation [20] and cerebral hyperemia [21] are two common manifestations of ALF and encephalopathy. Systemic inflammatory response syndrome, particularly tumor necrosis factor has been shown to correlate with development of encephalopathy and raised intracranial pressure [22].

The combination of cerebral edema and increased cerebral blood volume from dysregulated

Arterial ammonia concentrations greater than 100 umol/L predict the onset of hepatic encephalopathy [23] and concentrations greater than 200 umol/L are associated with the development of intracranial hypertension and subsequent brain herniation [24]. Younger age, development of renal failure, hyponatremia, inflammatory response and the need for hemodynamic support for cardiovascular collapse are additional risk factors associated with the development of intracranial hypertension [24]. Similarly higher cerebral blood flow rates are seen in patients with cerebral edema and intracranial hypertension and are associated

A growing body of experimental data and clinical data promotes the concept that induction of mild hypothermia (between 32 and 35 degrees centigrade) is an important therapy in the armamentarium against the development of cerebral edema and intracranial hypertension in fulminant hepatic failure. Hypothermia has been shown to either attenuate or reverse most pathophysiological pathways involved in the development of cerebral edema in ALF.

In the context of liver injury, hypothermia was first shown to be efficacious in 1962 against the toxicity of acute ammonia loading in mice [25]. Thereafter, Traber et al demonstrated that spontaneous development of hypothermia in a rat model of ALF was associated with

Cerebral hyperemia may also contribute to the development of cerebral edema.

cerebral blood flow lead to increased intracranial pressure in ALF.

subtle perturbations of the tight junctions [19].

**2.2. Cerebral blood flow** 

**2.3. Raised intracranial pressure** 

**2.4. Clinical correlates** 

with higher mortality [21].

**3. The role of hypothermia** 

**3.1. Mechanism of hypothermia** 

Given the devastating consequences of development of raised ICP in patients with ALF, it is imperative that early recognition and effective therapies be promptly instituted. Unfortunately prognosis in the absence of liver transplantation is dismal. Medical therapies are frequently utilized to control ICP as bridge to transplant. Often however medical therapies fail to adequately control ICP. Application of induced therapeutic hypothermia has shown promise in controlling ICP when medical therapies have failed. An increasing number of centers have incorporated hypothermia into their armamentarium of therapies to treat raised ICP associated with ALF as a bridge to liver transplant [8]. Emerging data also suggests that this modality of treatment can successfully be used as a strategy to allow for hepatocellular regeneration and bridge patients with ALF and cerebral edema to recovery [9, 10]. Timing of institution, identification of sub groups that benefit and guidelines for use in this condition remain unclear. This aim of this review is to highlight the pathogenesis of cerebral edema and attempt to elucidate the role of hypothermia is patients with ALF.
