SYSTEMIC AND HEMODYNAMIC-EFFECTS OF RECOMBINANT TUMOR-NECROSIS-FACTOR-ALPHA IN ISOLATION PERFUSION OF THE LIMBS

Objective: To describe the systemic effects of high-dose recombinant t umor necrosis factor alpha (rTNF-alpha), recombinant interferon gamma (rIFN-gamma), and melphalan administered through hyperthermic isolatio n perfusion of the limbs (IPL) in patients with melanoma and malignant soft-tissue tumors, Design: The clinical, hemodynamic, and biologic p arameters were recorded after IPL during the postoperative period, Set ting: Surgical intensive care service of a 1,000-bed tertiary universi ty medical center. Patients: Nineteen patients referred to a pluridisc iplinary Center for Oncology after relapse of regionally advanced mela noma or soft-tissues tumors, included in a phase 2 therapeutic study. Results: Major systemic and hemodynamic changes were observed after IP L in all patients, Ninety-four percent (17/18) of the evaluable patien ts presented a shock unresponsive to fluid challenge, requiring the co ntinuous perfusion of vasopressors, inotropic agents, or both, Analysi s of hemodynamic data showed two distinctive patterns: a pure distribu tive shock in nine patients requiring norepinephrine, acid a mixed dis tributive and cardiogenic shock in eight patients requiring vasopresso r and inotropic agents. The oxygen parameters were characterized by an increase in both the delivery and the uptake of oxygen, with a prolon ged reduced oxygen extraction ratio for most patients, The other obser ved effects were as follows: transient bilateral or mixed pulmonary in filtrates in all patients; some hematologic disturbances in 83% of pat ients; infection requiring a modification of the antibiotic prophylaxi s in 61%, of patients; and some liver toxic reactions in 50% of patien ts. Very high systemic TNF-alpha serum bioactivity was found in 12 pat ients for whom serum samples were available, indicating an early and i mportant rTNF-alpha leakage from the IPL. No correlations could be fou nd between the levels of TNF-alpha and the observed systemic effects. Despite the severity of the hemodynamic disturbance, no patient died. Conclusion: Major systemic effects, consisting mainly in cardiovascula r, respiratory, and hematologic disturbances, were observed in patient s after IPL with high-dose of rTNF-alpha. The likely explanation for t hese observations is an early rTNF-alpha leakage related to inadequate IPL technique. These data show that the iatrogenic administration of high circulating TNF levels lead to a ''septic shock-like'' syndrome w ithout resulting in lethal organ dysfunction.