Mild Hypothermia for the Treatment of Acute Liver Failure
Intracranial hypertension leading to brain herniation is a major cause of mortality in patients with acute liver failure (ALF), and reflects the limitations of conventional therapy in this setting. Uncontrolled clinical studies (see Supplementary Table 1 ), and a large body of experimental evidence strongly suggest that mild hypothermia (32.0-35.0ºC) is effective for reducing intracranial pressure (ICP) in patients with ALF. The cerebro-protective mechanisms of mild hypothermia include a reduction in cerebral blood flow and arterial ammonia concentrations, which together result in reduced delivery of ammonia to the brain. Reduction of cerebral blood flow by hypothermia also decreases hydrostatic pressure in brain capillaries and prevents cerebral hyperemia; increased hydrostatic pressure and cerebral hyperemia are factors that accelerate the development of brain edema in patients with ALF. In addition, mild hypothermia attenuates pathophysiological events in the brain that occur downstream of ammonia exposure, such as lactate and glutamate accumulation, as well as the altered expression of a wide range of genes that encode key astrocytic and endothelial cell proteins. Mild hypothermia also corrects abnormalities in the concentration of organic osmolytes and pro-inflammatory cytokines in the brain of patients with ALF.
In addition to improvements in cerebral function, there is evidence to suggest that the systemic effects of mild hypothermia are beneficial in patients with ALF. Mild hypothermia facilitates the hemodynamic management of patients with ALF by counteracting the hyperdynamic circulation of these patients, reducing vasopressor requirements, and restoring cerebrovascular autoregulation. Furthermore, mild hypothermia attenuates ischemia-reperfusion and acetaminophen-induced liver injury in experimental animals, and apoptotic cell death in cultured hepatocytes.
Issues that impair the acceptance of mild hypothermia as a treatment paradigm for patients with ALF are not related to its mechanisms of action or efficacy, but rather to its potential adverse effects, which include infection, bleeding because of prolonged coagulation time, and cardiac arrhythmias. Adequate sedation is an essential component of hypothermia therapy to avoid shivering-related complications. The risk of adverse effects increases with the duration and degree of hypothermia. Specific preventive and therapeutic measures are available to reduce complications of hypothermia and no adverse effects have been attributed to the use of mild hypothermia in patients with ALF. Data regarding the safety of mild hypothermia in patients with ALF are, however, limited. This lack of data is attributable to the small number of patients with ALF who have been treated with hypothermia, the variable degree and duration of hypothermia that has been used in studies, the lack of a clear distinction between hypothermia-related and ALF-related complications, and the lack of systematic patient assessment. Finally, it is important to bear in mind that rewarming of the patient is an integral part of hypothermia treatment. Whereas rewarming patients after orthotopic liver transplantation (OLT) seems to be safe, rewarming after hypothermia therapy in three patients with ALF who did not undergo OLT resulted in a rapid rebound of ICP and death shortly afterwards.
Concerns regarding the potential inhibition of liver regeneration by hypothermia have also been raised, but no studies have specifically addressed this issue. Data from studies in mice with acetaminophen hepatotoxicity suggest that mild hypothermia does not impair liver regeneration, and spontaneous recovery has been reported in a patient with ALF during mild hypothermia; however, this issue clearly needs further study.
An accurate assessment of the viability and safety of mild hypothermia in patients with ALF is precluded by virtue of the small sample size and uncontrolled nature of the studies that have been performed, but three groups of ALF patients that might benefit from mild hypothermia therapy can be distinguished. Firstly, patients scheduled for OLT whose intracranial hypertension is unresponsive to conventional therapy. Mortality in these patients is >90%, and death frequently occurs before an organ is available for OLT. Moreover, the eligibility of this type of patient for OLT might be revoked in some centers because of the high risk of mortality and neurological sequelae. In such patients, evidence strongly indicates that mild hypothermia might be life saving as it could control ICP until OLT can be performed. Studies also suggest that, once initiated, mild hypothermia should be maintained during OLT surgery in order to prevent surges of cerebral hyperemia and ICP. Rewarming of the patient before or during the surgical procedure would probably increase the risk of these intraoperative complications. Secondly, in patients awaiting OLT who develop or are at high risk of developing intracranial hypertension, mild hypothermia could be used as a first-line therapy or prophylactic measure. The value of mild hypothermia, however, to replace or complement conventional measures for the control of intracranial hypertension is uncertain at the moment as collective clinical experience with this approach is extremely limited. Finally, mild hypothermia could be beneficial in patients who fulfill criteria for bad prognosis but have no option to undergo OLT. This category includes a large number of patients with acetaminophen-related ALF (the most common etiology of ALF in many countries) that present psychiatric or other contraindications for OLT, and is also particularly relevant for patients in countries where OLT is not an option for religious or logistical reasons. Early rewarming after mild hypothermia therapy in patients with ongoing liver injury seems, however, to carry a poor prognosis. This finding suggests that the initiation of mild hypothermia might commit such patients to therapy for several days until liver function is recovered; therefore, increasing their risk of adverse effects. Despite these concerns, hypothermia has been safely used for more than 7 days in patients with head trauma. Furthermore, patients with some ALF etiologies (hepatitis A virus-related ALF and acetaminophen-related ALF) have a relatively short course of illness and a reasonable prognosis for liver regeneration. Further clinical information on the use of mild hypothermia, as well as studies of its effects on liver injury and regeneration, are needed before it can be recommended for patients who do not have the option to undergo OLT.
In summary, some issues need to be addressed in order to fully establish the place of hypothermia in the management of patients with ALF. Many questions remain to be answered: to what extent, and how, should body temperature be reduced? Should patients with ALF who spontaneously develop mild hypothermia be rewarmed? Does hypothermia modify the efficacy or hepatic metabolism of drugs, such as antibiotics or N-acetylcysteine? Should ICP monitoring be mandatory in all patients treated with mild hypothermia? Importantly, and regrettably, controlled clinical trials are still missing from the equation. This lack of data is partly due to the inherent difficulties of conducting clinical trials in patients with ALF as multicenter studies are required, and there are geographical differences in ALF etiologies and management protocols. A decade has now passed since Jalan and colleagues pioneered the use of mild hypothermia in patients with ALF and intracranial hypertension. Had any other experimental therapeutic innovation shown the same promise it would surely have been tested by now in randomized clinical trials. Until such studies are performed, mild hypothermia will remain a last resort to control high ICP in patients with ALF when all other approaches have failed.
Supplementary information in the form of a table is available on the Nature Clinical Practice Gastroenterology & Hepatology website.
CLICK HERE for subscription information about this journal.
Intracranial hypertension leading to brain herniation is a major cause of mortality in patients with acute liver failure (ALF), and reflects the limitations of conventional therapy in this setting. Uncontrolled clinical studies (see Supplementary Table 1 ), and a large body of experimental evidence strongly suggest that mild hypothermia (32.0-35.0ºC) is effective for reducing intracranial pressure (ICP) in patients with ALF. The cerebro-protective mechanisms of mild hypothermia include a reduction in cerebral blood flow and arterial ammonia concentrations, which together result in reduced delivery of ammonia to the brain. Reduction of cerebral blood flow by hypothermia also decreases hydrostatic pressure in brain capillaries and prevents cerebral hyperemia; increased hydrostatic pressure and cerebral hyperemia are factors that accelerate the development of brain edema in patients with ALF. In addition, mild hypothermia attenuates pathophysiological events in the brain that occur downstream of ammonia exposure, such as lactate and glutamate accumulation, as well as the altered expression of a wide range of genes that encode key astrocytic and endothelial cell proteins. Mild hypothermia also corrects abnormalities in the concentration of organic osmolytes and pro-inflammatory cytokines in the brain of patients with ALF.
In addition to improvements in cerebral function, there is evidence to suggest that the systemic effects of mild hypothermia are beneficial in patients with ALF. Mild hypothermia facilitates the hemodynamic management of patients with ALF by counteracting the hyperdynamic circulation of these patients, reducing vasopressor requirements, and restoring cerebrovascular autoregulation. Furthermore, mild hypothermia attenuates ischemia-reperfusion and acetaminophen-induced liver injury in experimental animals, and apoptotic cell death in cultured hepatocytes.
Issues that impair the acceptance of mild hypothermia as a treatment paradigm for patients with ALF are not related to its mechanisms of action or efficacy, but rather to its potential adverse effects, which include infection, bleeding because of prolonged coagulation time, and cardiac arrhythmias. Adequate sedation is an essential component of hypothermia therapy to avoid shivering-related complications. The risk of adverse effects increases with the duration and degree of hypothermia. Specific preventive and therapeutic measures are available to reduce complications of hypothermia and no adverse effects have been attributed to the use of mild hypothermia in patients with ALF. Data regarding the safety of mild hypothermia in patients with ALF are, however, limited. This lack of data is attributable to the small number of patients with ALF who have been treated with hypothermia, the variable degree and duration of hypothermia that has been used in studies, the lack of a clear distinction between hypothermia-related and ALF-related complications, and the lack of systematic patient assessment. Finally, it is important to bear in mind that rewarming of the patient is an integral part of hypothermia treatment. Whereas rewarming patients after orthotopic liver transplantation (OLT) seems to be safe, rewarming after hypothermia therapy in three patients with ALF who did not undergo OLT resulted in a rapid rebound of ICP and death shortly afterwards.
Concerns regarding the potential inhibition of liver regeneration by hypothermia have also been raised, but no studies have specifically addressed this issue. Data from studies in mice with acetaminophen hepatotoxicity suggest that mild hypothermia does not impair liver regeneration, and spontaneous recovery has been reported in a patient with ALF during mild hypothermia; however, this issue clearly needs further study.
An accurate assessment of the viability and safety of mild hypothermia in patients with ALF is precluded by virtue of the small sample size and uncontrolled nature of the studies that have been performed, but three groups of ALF patients that might benefit from mild hypothermia therapy can be distinguished. Firstly, patients scheduled for OLT whose intracranial hypertension is unresponsive to conventional therapy. Mortality in these patients is >90%, and death frequently occurs before an organ is available for OLT. Moreover, the eligibility of this type of patient for OLT might be revoked in some centers because of the high risk of mortality and neurological sequelae. In such patients, evidence strongly indicates that mild hypothermia might be life saving as it could control ICP until OLT can be performed. Studies also suggest that, once initiated, mild hypothermia should be maintained during OLT surgery in order to prevent surges of cerebral hyperemia and ICP. Rewarming of the patient before or during the surgical procedure would probably increase the risk of these intraoperative complications. Secondly, in patients awaiting OLT who develop or are at high risk of developing intracranial hypertension, mild hypothermia could be used as a first-line therapy or prophylactic measure. The value of mild hypothermia, however, to replace or complement conventional measures for the control of intracranial hypertension is uncertain at the moment as collective clinical experience with this approach is extremely limited. Finally, mild hypothermia could be beneficial in patients who fulfill criteria for bad prognosis but have no option to undergo OLT. This category includes a large number of patients with acetaminophen-related ALF (the most common etiology of ALF in many countries) that present psychiatric or other contraindications for OLT, and is also particularly relevant for patients in countries where OLT is not an option for religious or logistical reasons. Early rewarming after mild hypothermia therapy in patients with ongoing liver injury seems, however, to carry a poor prognosis. This finding suggests that the initiation of mild hypothermia might commit such patients to therapy for several days until liver function is recovered; therefore, increasing their risk of adverse effects. Despite these concerns, hypothermia has been safely used for more than 7 days in patients with head trauma. Furthermore, patients with some ALF etiologies (hepatitis A virus-related ALF and acetaminophen-related ALF) have a relatively short course of illness and a reasonable prognosis for liver regeneration. Further clinical information on the use of mild hypothermia, as well as studies of its effects on liver injury and regeneration, are needed before it can be recommended for patients who do not have the option to undergo OLT.
In summary, some issues need to be addressed in order to fully establish the place of hypothermia in the management of patients with ALF. Many questions remain to be answered: to what extent, and how, should body temperature be reduced? Should patients with ALF who spontaneously develop mild hypothermia be rewarmed? Does hypothermia modify the efficacy or hepatic metabolism of drugs, such as antibiotics or N-acetylcysteine? Should ICP monitoring be mandatory in all patients treated with mild hypothermia? Importantly, and regrettably, controlled clinical trials are still missing from the equation. This lack of data is partly due to the inherent difficulties of conducting clinical trials in patients with ALF as multicenter studies are required, and there are geographical differences in ALF etiologies and management protocols. A decade has now passed since Jalan and colleagues pioneered the use of mild hypothermia in patients with ALF and intracranial hypertension. Had any other experimental therapeutic innovation shown the same promise it would surely have been tested by now in randomized clinical trials. Until such studies are performed, mild hypothermia will remain a last resort to control high ICP in patients with ALF when all other approaches have failed.
Supplementary information in the form of a table is available on the Nature Clinical Practice Gastroenterology & Hepatology website.
CLICK HERE for subscription information about this journal.
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