To elucidate the hepatic microvascular response to cryothermia, we studied the liver microcirculation of SpragueDawley rats after one and two 4-minute freeze-thaw cycles using intravital fluorescence microscopy. Irrespective of the number of freeze-thaw cycles applied, the nature of hepatic microvascular injury was characterized by complete stasis of sinusoidal blood flow within the central part of the cryolesions and heterogeneous sinusoidal perfusion in a critically perfused border zone located at the periphery of the lesions. Analysis over time (2 hours) revealed a successive shutdown of sinusoidal perfusion within this critically perfused border zone, which was caused by intravascularly lodging cell aggregates, blocking the lumen of individual sinusoids. The aggregates consisted of parenchymal cells and cell fragments, but did not include leukocytes or platelets. Strikingly, microvascular perfusion failure was associated with Ito cell disintegration and marked dilation of sinusoids (15.6 ؎ 0.8 m vs. 8.8 ؎ 0.8 m; P F .05). This excludes sinusoidal constriction as the cause of nutritive perfusion failure, and may indicate dysfunction of Ito cell-regulated vasomotor control by cryothermia. However, because circulating cell aggregates were frequently observed plugging individual microvessels, dilation of sinusoids may just be the result of passive distension caused by outflow blockade. Analysis of hepatic tissue at 8 weeks after cryothermia did not reveal regeneration and microvascular remodeling, but loss of hepatic tissue, which corresponded well with the tissue area presenting with sinusoidal perfusion failure during the initial observation period after cryothermia. The fact that there was no recovery of sinusoidal perfusion over the initial 2-hour observation period, but loss of tissue after 8 weeks, supports the view that cryothermia induces injury not only by direct low-temperaturemediated action, but also through ischemia caused by irreversible deterioration of the microcirculation. (HEPATOL-OGY 1999;29:801-808.)In recent years, cryotherapy of hepatic metastatic cancer has gained new attraction, 1 probably as a result of the technical developments that today allow for a sophisticated instrumentation and monitoring of the freezing process. 2,3 The recent advances have made focal tumor destruction using cryotherapy a more practical proposition, 4-6 in particular in patients with multiple spreading and/or disadvantageous anatomical location of metastases, unsuitable for surgical resection. 5,[7][8][9][10] Cryothermia causes cell necrosis predominantly by intracellular ice-crystal formation, 11 which seems to be determined by the rate of both freezing and thawing. 12 Bayjoo, 13 however, demonstrated that tumors implanted in rat livers are completely destroyed by cryotherapy without evidence of regrowth over weeks, while if the tumors are excised immediately after cryotherapy, a proportion of cells is found still viable and can be grown successfully in vitro. Thus, additional host-associated factors must be in...