Large volume hepatic freezing: association with significant release of the cytokines interleukin-6 and tumor necrosis factor a in a rat model

Although cryotherapy of liver tumors is generally considered a safe procedure, a syndrome of coagulopathy and fatal multiorgan failure has been observed in some patients and is called the cryoshock phenomenon. Our aim was to establish an animal model of this phenomenon and examine the effects of the basic parameters of freezing or cryotherapy on it. A group of 75 female Sprague-Dawley rats were allocated randomly to five groups: (1) sham laparotomy (n=15); (2) small (25% liver volume) single freeze (n=15); (3) small (25% liver volume) double freeze (n=15); (4) large (50% liver volume) single freeze (n=15); (5) large (50% liver volume) double freeze (n=15). Blood samples were collected at different postoperative times, and organs were harvested for histopathology. There was a significant release of tumor necrosis factor-α (TNFα:) and interleukin 6 (IL-6) following hepatic freezing, which was greatest in group 5. Postoperative serum cytokine levels were significantly associated with hepatocellular injury, as measured by postoperative serum aspartate transaminase (AST) concentrations. Severe hemoglobinuria and renal injury, as demonstrated by the serum creatinine level and the glomerular neutrophil count, were observed and were greatest in group 5. Hepatic cryosurgery is associated with release of IL-6 and TNFα and renal injury in a rat model. It is likely that the cryoshock phenomenon is another form of the systemic inflammatory response syndrome. Based on the results of this study, it is possibly mediated by cytokines released from the frozen liver tissue. We therefore caution against cryothérapy of large tumor volumes.RésuméAlors que la cryothérapie des tumerus du foie est généralement considérée comme un procédé sur, on peut observer quelque fois un syndrome de coagulopathie et de défaillance multiviscérale fatale, appelé le phénomène du «cryochoc». Notre but a été et d’étudier les effets de la cryothérapie sur les paramètres de base chez un modèle animal. 75 rates femelles Sprague-Dawley ont été randomisées en cinq groupes: (1) laparotomie factice «sham» (n=15); (2) un seul «gel» de petit volume (25% volume du foie) (n=15): (3) deux «gels» de petit volume (25% du volume du foie) (n=15); (4) un seul «gel» de volume important (50% du volume du foie) (n=15); (5) deux «gels» de volume important (50% du volume du foie) (n=15). Les échantillons sanguins ont été collectés à des moments postopératoires différents et les organes ont été prélevés pour examen histopathologique. On a constaté un largage significatif de TNFα: et d’IL-6 après cryothérapie du foie, plus important dans le groupe 5. Les taux de cytokines du sérum ont été significativement córreles avec les lésions hépatocellulaires, mesurées par les taux postopératoires des AST. Une hémoglobinurie et des lésions rénales sévères, mises en évidence par un taux élevé de créatinine et par la numération des neutrophils, ont été observées surtout dans le groupe 5. La cryothérapie hépatique est associée à un largage d’lL-6 et de TNFα ainsi que de lésions rénales dans le modèle du rat. 11 est probable que le phénomène du cryochoc est une manifestation du syndrome de réponse systémique inflammatoire. Basé sur les résultats de cette étude, on pense que les cytokines largués par le tissu hépatique refroidi sont les médiateurs de ce phénomène. Nous ne recommandons donc pas la cryothérapie pour les tumeurs volumineuses.ResumenAunque la crioterapia de los tumores hepáticos es una técnica bastante segura, se han descrito algunos casos en los que se produjo un sÍndrome coagulopático y fracaso multiorgánico mortal. Este sÍndrome se ha considerado como un fenómeno del crioshock (shock por congelación). El objetivo del trabajo fue conseguir un modelo animal del llamado fenómeno del crioshock y evaluar en el mismo, los efectos de la congelación o de la crioterapia sobre parámetros básicos. 75 ratas hembras Sprague-Dawley se distribuyeron de forma aleatoria en 5 grupos: (1) Laparatomía simulada ( n=15); (2) Pequeña (25% del volumen hepático) congelación única (n=15); (3) Pequeña (25% volumen hepático) congelación doble (n=15); (4) Gran (50% volumen hepático) congelación única (n=15); (5) Gran (50% volumen hepático) congelación doble (n=15). Muestras de sangre se obtuvieron en diversos momentos del periodo postoperatorio y los órganos fueron recogidos para su ulterior estudio histopatológico. Tras la congelación hepática se constato una significativa liberación de TNFα y IL-6, que fue más marcada en el grupo 5. Los niveles séricos de citocinas en el postoperatorio guardan estrecha relación con el trauma hepatocelular, como se constató midiendo las concentraciones séricas postoperatorias de la AST. Se observó grave hemoglobinuria y lesión renal, demostrada por los valores séricos de creatinina y el recuento de neutrófilos en los glomerulos, siendo estas alteraciones mucho más graves en el grupo 5. En un modelo de rata la criocirugía hepática produce una liberación de IL-6 y TNFα así como lesiones renales. Posiblemente el denominado fenómeno del crioshock no es más que una forma diferente del sÍndrome de respuesta sistémica inflamatoria. Según nuestros hallazgos los mediadores de dicho fenómeno son citocinas liberadas del tejido hepático congelado. De ahí, que se aconseje prudencia en la crioterapia de grandes tumores hepáticos.

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