Therapeutic hypothermia in acute liver failure: Not that hot?

Abstract

Acute liver failure (ALF) is a rare and devastating clinical syndrome comprising the sudden loss of hepatic function and the development of complications such as coagulopathy, vasoparesis, renal failure, and hepatic encephalopathy. 1 As the syndrome progresses, cerebral edema may occur and lead to intracranial hypertension (ICH), which can progress to brain death from cerebral herniation. During the last 30 years, significant progress has been made in the management of patients with ALF, and survival rates greater than 70% are now reported; this represents a dramatic improvement from early series in which survival rates as low as 16.7% were observed. 2 Undoubtedly, the most significant factor in this improvement is the use of liver transplantation (LT), which results in excellent survival rates for patients who fulfill poor prognostic criteria. 3 Factors that may also be associated with improved outcomes are earlier referral to transplant centers, more frequent use of renal replacement therapy, prophylactic antimicrobials/antifungals, and specific therapies for addressing ICH such as osmotherapy with mannitol and/or hypertonic saline. Despite the advent of LT as the definitive therapy for patients predicted to have the worst outcome, this is not a therapy that can be applied to all. Patients may have contraindications to LT, and approximately 20% of patients who are listed will ultimately not receive a transplant because of the lack of an available graft. In these patients, mortality is almost universal and is usually due to sepsis-induced multiorgan failure, but a significant proportion will die because of cerebral herniation secondary to ICH. 4 The treatment and prevention of ICH, therefore, represent an important target for therapy in patients with ALF.The prevention and management of ICH in patients with ALF are based on therapies that reflect our current understanding of its pathophysiology. Management is, therefore, focused on the control of arterial ammonia levels by the use of continuous renal replacement therapy, the reduction of brain edema by the use of osmotherapy (mannitol and hypertonic saline), the control of cerebral blood flow (monitoring of CO 2 and sedation), and the prevention of systemic inflammation (broad-spectrum antibiotics and antifungals). Despite these measures, 20% of patients still develop ICH in the course of their illness, which may prove refractory to treatment and be associated with significant mortality and morbidity. 2 Therapeutic hypothermia (TH) has been proposed as a rational treatment for ICH in patients with ALF. Early work in animal models characterized by hyperammonemia has shown convincingly that hypothermia protects rodents from a lethal dose of ammonia and attenuates the development of brain edema. 5 TH potentially affects multiple pathways in ALF-related ICH by reducing brain energy demands, stabilizing the blood-brain barrier, decreasing the release of excitatory neurotransmitters, and reducing cerebral blood flow. 6 Jalan et al. 7 reported the first clinical appli...

Targeted temperature management in acute liver failure: A systematic review

“…If a few isolated early cases reported a direct relationship between its use and survival or neurological recovery, methodologically stronger studies mitigate those findings and fail to demonstrate clearly any difference between treatment and control groups in terms of survival. Overall, human controlled studies contradict uncontrolled data and animal studies and their appealing pathophysiological concept of TTM as an effective treatment of ICH associated with ALF 33 …”

“…A future trial could isolate specific categories of population, for example, the young population after paracetamol overdose and those not listed for transplantation (with chances of spontaneous recovery). Such a trial could then measure if TTM improves their outcomes, such as survival or hepatic regeneration, without the variable set by transplantation 33 …”

“…Overall, human controlled studies contradict uncontrolled data and animal studies and their appealing pathophysiological concept of TTM as an effective treatment of ICH associated with ALF. 33 …”

“…Such a trial could then measure if TTM improves their outcomes, such as survival or hepatic regeneration, without the variable set by transplantation. 33 Other trials could also aim to answer questions about the intervention parameters, such as what the optimal target temperature is and for which indication (ALF, TBI, post-resuscitation), or what is the ideal method of cooling that conveys the most benefits (machine and consumables cost, easiness of use) with fewer risks of complications (invasiveness, pressure ulcers).…”

Therapeutic hypothermia in acute liver failure: A multicenter retrospective cohort analysis

“…5 However, hepatic regeneration was not measured in this study. Survival in ALF is a function covariant with myriad variables, including the stage at diagnosis, etiology, and quality of care.…”