Derangement of the systemic circulation

The hemodynamic disturbances seen in AHF are similar to those of sepsis, i.e. elevated cardiac output and lowered systemic vascular resistance. Relative hypovolemia secondary to vasodilatation is frequent, and a pulmonary artery flotation catheter is often required to optimize fluid replacement. Colloid loading is almost inevitably required, usually to a greater degree than initially considered. Crystalloid is also necessary both to cover maintenance requirements and maintain euglycemia. The basis for microcirculatory dysfunction seen in liver failure is poorly understood, but evidence is accumulating to suggest the importance of interactions between the endothelium, exogenous factors such as bacterial toxins, and cytokines, particularly tumor necrosis factor and interleukins 1 and 6. Endotoxin and other bacterial toxins lead to cytokine production by activated macrophages and may be maintained in the circulation because of impaired Kupffer cell function and the presence of portosystemic shunts. Platelet activation and consumption, with formation of microthrombi within various organs, may lead to endothelial damage and release of further vasoactive compounds. Patients with AHF have elevated levels of citrulline, cyclic GMP, nitrite, and nitrate, suggesting activation of the nitric oxide pathway.

Hypotension is common in AHF and is characterized by both systolic and diastolic hypotension. Although initially responsive to fluid loading, vasopressors are frequently required, particularly in patients with concomitant cerebral edema. Agents such as dobutamine are not normally effective in increasing mean arterial pressure. The most efficacious agents are either epinephrine (adrenaline) or norepinephrine (noradrenaline), commencing at a dose of 0.1 pg/kg/min. Administration of these agents results in significant improvements in blood pressure, but the cardiac index and oxygen delivery are not always improved and there may be a fall in oxygen consumption. The role of agents to block the synthesis or effects of nitric oxide require further evaluation in clinical trials.

^-Acetylcysteine is given to many patients with AHF, regardless of etiology, at a loading dose of 150 mg/kg over 30 min followed by a maintenance dose of 150 mg/kg/day. The rationale for this has developed from the observation that patients receiving ^-acetylcysteine following acetaminophen overdose after the period where it would act as an antidote have a better prognosis than those who do not receive it. There was a lower incidence of renal failure and less progression to deeper levels of coma despite similar levels of prolongation of prothrombin times. These findings were confirmed in a prospective study ( Keays ef a/ 1991) in which treated patients displayed less hypotension and cerebral edema. More recent work has demonstrated that ^-acetylcysteine results in increased cardiac output, oxygen delivery, oxygen extraction ratio, and hence oxygen consumption in patients with AHF regardless of etiology. The beneficial mechanism of the action of ^-acetylcysteine is unclear, although it is a potent antioxidant and therefore may stabilize the effects of endothelium-derived relaxant factor and prevent endothelial damage by free radicals. It also repletes tissue sulfydryl groups either directly or by its action of increasing cysteine levels, and thus may restore full endothelium-derived relaxant factor activity by a similar mechanism to its eversal of tolerance to nitrates.

The role of agents that improve splanchnic flow requires further investigation. Another potentially beneficial therapy is high-volume plasmapheresis. Marked improvements in hemodynamic and neurological status have been reported (Larseneia/ 1994). The mode of action is presumably related to the removal of putative vasorelaxant compounds which accumulate or are produced in patients with AHF.

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