Mild hypothermia delays the onset of coma and prevents brain edema and extracellular brain glutamate accumulation in rats with acute liver failure

Abstract

Mild hypothermia is effective in the prevention of brain edema associated with cerebral ischemia and traumatic brain injury. Brain edema is also a serious complication of acute liver failure (ALF). To assess the effectiveness of hypothermia in ALF, groups of rats were subjected to hepatic devascularization (portacaval anastomosis, followed 48 hours later by hepatic artery ligation), and body temperatures were maintained at either 35ЊC (hypothermic) or 37ЊC (normothermic). A major cause of death in patients with acute liver failure (ALF) is brain herniation resulting from raised intracranial pressure caused by a progressive increase in brain water content. 1 It has been estimated that up to 40% of patients with ALF die while on the waiting list for liver transplantation, 2 in whom, in almost all cases, death results from brain herniation. Despite several decades of investigation, the pathophysiological mechanisms responsible for the central nervous system consequences of ALF have not been fully elucidated. However, ammonia remains a prime candidate. Hyperammonemia is a consistent finding in experimental animal models of ALF resulting from hepatectomy, 3 hepatic devascularization, 4,5 or toxic liver injury 6 , and, in these cases, brain edema is invariably observed. In ALF, brain ammonia may reach millimolar concentrations, 7 and exposure of various in vitro brain preparations to millimolar concentrations of ammonia results in significant cell swelling. 8,9 Hyperammonemia is a feature of Reye' s Syndrome 10 and congenital urea cycle enzymopathies, 11 conditions in which cerebral edema is also consistently observed.Previous studies showed that hypothermia extended the survival time and prevented the development of brain edema in rats with ALF. 12 Furthermore, mild hypothermia (33°C-35°C) has been shown to be neuroprotective in experimental models of traumatic 13 and ischemic brain injury. 14 In the case of the latter, it was suggested that the beneficial effects of hypothermia were the result of inhibition of the release of neurotransmitters, rather than of an effect on cerebral energy metabolism. 15 The goals of the present investigation, therefore, were to study the effect of hypothermia on the development of hepatic encephalopathy and brain edema in relation to blood and cerebrospinal fluid (CSF) ammonia levels, and to extracellular glutamate and glutamine concentrations in rats with ALF caused by hepatic devascularization. MATERIALS AND METHODSO-phthaldialaldehyde reagent solution, 2-mercaptoethanol, Trisacetate, Ringer' s solution constituents, and amino acid standards were purchased from Sigma Chemical Co. (St. Louis, MO). Sodium phosphate (monobasic), methanol (high-performance liquid chromatography [HPLC]-grade), and tetrahydrofuran (HPLC-grade) were obtained from Anachemia (Montreal, Quebec, Canada). Doubledistilled deionized water was used for preparation of standard amino acid solutions and buffers. The mobile phase used for HPLC was filtered through 0.45-mm-pore-size membrane filters (Millipore Corp., B...

Hypothermia in Acute Liver Failure

“…Recently, a more defined mild hypothermia (33-35 • C) showed a beneficial effect in prolonging the time of onset of hepatic encephalopathy (HE) and preventing brain edema in rats with liver devascularization (Rose et al, 2000). These data support earlier stud-ies where hypothermia prevented CNS consequences of pure hyperammonemia (Schenker and Warren, 1962), hepatectomy (Peignoux et al, 1982), and more recently, the delay in ammonia-induced brain edema in rats following portacaval shunting (Cordoba et al, 1999).…”

“…This is supported by studies demonstrating the administration of the glutamine synthetase inhibition, methionine sulfoximine, reduces ammonia-induced brain edema both in vitro (Norenberg and Bender, 1994) and in vivo (Chodobski et al, 1986;Takahashi et al, 1991). However, recently hypothermia-induced reductions in brain water content in ALF rats were not accompanied by significant reductions of microdialysate (extracellular) brain glutamine (Rose et al, 2000) or brain glutamine (Chatauret et al, 2003) at time points associated with brain edema. This suggests that mild hypothermia's major protective effect on brain edema is not mediated via an effect on brain glutamine synthesis.…”

“…We have demonstrated the beneficial effects of hypothermia are not mediated by an effect on blood ammonia, but on cerebral spinal fluid (CSF) ammonia where in hypothermic rats with ALF at times when blood ammonia levels were unchanged, CSF ammonia concentrations were significantly less (Rose et al, 2000). These findings suggest that one of the beneficial mechanisms of action of mild hypothermia in ALF may be to limit blood-brain barrier transfer of ammonia.…”

Keeping cool in acute liver failure: Rationale for the use of mild hypothermia

“…Mild hypothermia, however, is effective for preventing the neurological complications of ALF in experimental studies [75], [76], [77] and [78]. The effects of hypothermia on the major factors considered to determine brain edema and intracranial hypertension in ALF have been the focus of both clinical and experimental studies (summarized in Table 1).…”

“…The effects of hypothermia on the major factors considered to determine brain edema and intracranial hypertension in ALF have been the focus of both clinical and experimental studies (summarized in Table 1). ↓ Arterial concentration of ammonia [80] and [81] ↓ Production of ammonia by intestinal bacteria [83] ↓ Renal release of ammonia to the blood [85] ↓ Proteolysis [86] Brain osmolarity Prevention of brain lactate and alanine accumulation [96] Prevention of changes of brain organic solutes [97] Brain extracellular space ↓ Accumulation of glutamate [76] ↓ Of glutamate-induced astrocyte swelling [107] ↓ Accumulation of lactate [77] Cerebro-vascular haemodynamics…”