Systemic toxicity and cytokine/acute phase protein levels in patients after isolated limb perfusion with tumor necrosis factor-alpha complicated by high leakage

Background: Since the introduction of high-dose tumor necrosis factor-alpha (TNF alpha) in the setting of isolated limb perfusion (ILP) in the clinic, prevention of leakage to the body of the patient is monitored with great p recision for fear of TNF-mediated toxicity. That we observed remarkably lit tle toxicity in patients with and without leakage prompted us to determine patterns of cytokines and acute phase proteins in patients with high leakag e and in patients without any leakage. Methods: TNF alpha, interleukin (IL)-6, IL-8, C-reactive protein, and secre tory (s)-phospholipase A(2) were measured at several time points during and after (until 7 days) ILP in 10 patients with a leakage to the systemic cir culation varying in percentage from 12% to 65%. As a control, the same meas urements, both in peripheral blood and in perfusate, were performed in nine patients without systemic leakage. Results: In patients with systemic leakage, levels of TNF alpha increased d uring ILP, reaching values to 277 ng/ml. IL-6 and IL-8 peaked 3 hours after ILP with values significantly higher compared with patients without system ic leakage. C-reactive protein and s-phospholipase A(2) peaked at day 1 in both patient groups, s-phospholipase A(2) with significant higher levels an d C-reactive protein, in contrast, with lower levels in the leakage patient s. Conclusions: High leakage of TNF alpha to the systemic circulation, caused by a complicated ILP, led to 10-fold to more than 100-fold increased levels of TNF alpha, IL-6, and IL-8 in comparison with patients without leakage. The increase of the acute phase proteins was limited. Even when high leakag e occurs, this procedure should not lead to fatal complications. The most p rominent clinical toxicity was hypotension (grade III in four patients), wh ich was easily corrected, No pulmonary or renal toxicity was observed in an y patient. It is our experience that, even in the rare event of significant leakage during a TNF alpha-based ILP, postoperative toxicity is usually mi ld and can be easily managed by the use of fluid and, in some cases, vasopr essors.