Early effect of hepatic artery TNF-alpha infusion on systemic hemodynamics and inflammation: a dose-response study in pigs.
OBJECTIVE
Therapy of unresectable hepatic metastases may include tumor necrosis factor (TNF)-alpha treatment. Because of its serious systemic side effects, TNF-alpha is only used in isolated hepatic perfusion. This, however, is a technically demanding procedure with a substantial mortality rate. The infusion of TNF-alpha via the hepatic artery without hepatic isolation would be less invasive. Systemic side effects, however, have not been studied yet. Therefore, we evaluated in pigs the effects of TNF-alpha hepatic artery infusion (HAI) on systemic hemodynamics, inflammation, and organ injury.


METHODS
Animals were randomized in three groups. In group 1, HAI was performed with 0.9% NaCl (n = 6). In group 2, 20 microg/kg TNF-alpha (n = 6), and in group 3, 40 microg/kg TNF-alpha (n = 6) were added. HAI was performed over 15 min, followed by 120 min of observation. Finally, 250 ml hydroxyethylstarch (HAES; 6%) was administered for resuscitation and hemodynamics were analyzed for another 30 min.


RESULTS
Hepatic artery TNF-alpha infusion did not cause complications such as bleeding, cardiac depression, pulmonary dysfunction, or SIRS. TNF-alpha induced a 30% decrease of MAP and systemic vascular resistance, as well as a rise in heart rate and endexspiratory pCO(2). TNF-alpha also moderately (10-20%) lowered the cardiac preload and induced a metabolic acidosis, which, however, could easily be controlled. TNF-alpha HAI did not induce liver toxicity, and all hemodynamic changes normalized either spontaneously within the 120-min observation period, or, at least, after HAES resuscitation.


CONCLUSIONS
TNF-alpha-based HAI, which may represent a minimally invasive alternative to isolated hepatic perfusion, can be performed without early systemic hemodynamic complications.
Schäfer
Thilo
T
Department of General, Visceral, Vascular and Pediatric Surgery, University of Saarland, 66421 Homburg/Saar, Germany.
Sperling
Jens
J
Kollmar
Otto
O
Richter
Sven
S
Schilling
Martin K
MK
Menger
Michael D
MD
Lindemann
Werner
W
D000818:Animals; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D006499:Hepatic Artery; D006895:Hydroxyethyl Starch Derivatives / Q000008:administration & dosage / Q000494:pharmacology; D007249:Inflammation / Q000188:drug therapy*; D007261:Infusions, Intra-Arterial / Q000009:adverse effects*; D013552:Swine; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000494:pharmacology*; D014655:Vascular Resistance / Q000187:drug effects
D006895:Hydroxyethyl Starch Derivatives; D014409:Tumor Necrosis Factor-alpha