Systemic Toxicity and Cytokine/Acute Phase Protein Levels in Patients After Isolated Limb Perfusion With Tumor Necrosis Factor-a Complicated by High Leakage

Abstract

Background: Since the introduction of high-dose tumor necrosis factor-α (TNFα) in the settingof isolated limb perfusion (ILP) in the clinic, prevention of leakage to the body of the patient ismonitored with great precision for fear of TNF-mediated toxicity. That we observed remarkablylittle toxicity in patients with and without leakage prompted us to determine patterns of cytokinesand acute phase proteins in patients with high leakage and in patients without any leakage. Methods: TNFa, interleukin (IL)-6, IL-8, C-reactive protein, and secretory (s)-phospholipase A2 weremeasured at several time points during and after (until 7 days) ILP in 10 patients with a leakage to thesystemic circulation varying in percentage from 12% to 65%. As a control, the same measurements, bothin peripheral blood and in perfusate, were performed in nine patients without systemic leakage. Results: In patients with systemic leakage, levels of TNFaincreased during ILP, reaching valuesto 277 ng/ml. IL-6 and IL-8 peaked 3 hours after ILP with values significantly higher compared withpatients without systemic leakage. C-reactive protein and s-phospholipase A2 peaked at day 1 inboth patient groups, s-phospholipase A2 with significant higher levels and C-reactive protein, incontrast, with lower levels in the leakage patients. Conclusions: High leakage of TNFα to the systemic circulation, caused by a complicated ILP,led to 10-fold to more than 100-fold increased levels of TNFα, IL-6, and IL-8 in comparison withpatients without leakage. The increase of the acute phase proteins was limited. Even when highleakage occurs, this procedure should not lead to fatal complications. The most prominent clinicaltoxicity was hypotension (grade III in four patients), which was easily corrected. No pulmonary orrenal toxicity was observed in any patient. It is our experience that, even in the rare event ofsignificant leakage during a TNFα-based ILP, postoperative toxicity is usually mild and can beeasily managed by the use of fluid and, in some cases, vasopressors.