Systemic leakage and side effects of tumor necrosis factor alpha administered via isolated limb perfusion can be manipulated by flow rate adjustment
P. Sorkin, S. Abu-Abid, D. Lev, M. Gutman, D. Aderka, P. Halpern, A. Setton, N. Kudlik, J. Bar-On, V. Rudich and al. et
Department of Intensive Care and Anesthesiology, Ichilov Hospital, Tel Aviv, Israel.
BACKGROUND: The tolerated systemic dose of recombinant tumor necrosis
factor alpha (rTNF-alpha) is very limited, since its administration leads
to a severe septic shock-like condition. Its implementation in isolated
limb perfusion (ILP) for metastatic melanoma or advanced soft-tissue
sarcoma confined to the limb facilitates doses of rTNF-alpha 10 times
higher than the systemic tolerated dose. However, with the traditional high
flow rate used in ILP, systemic leakage and side effects are not
eliminated. OBJECTIVE: To determine if a lower perfusion flow rate would
reduce leakage and consequently toxic effects. METHODS: Isolated limb
perfusion was performed for melanoma and soft-tissue sarcoma confined to
the limb using a flow rate of 869 +/- 122 mL/min in nine patients (group 1)
and a lower rate of 286 +/- 62 mL/min in six patients (group 2). RESULTS:
The systemic leakage rate was 12.5% +/- 2.9% in group 1, compared with 2.3%
+/- 1.0% in group 2 (P = .003). Peak TNF-alpha levels were 29,000 +/- 2700
pg/mL in group 1, higher than 1580 +/- 1355 pg/mL in group 2 (P = .02). The
tachycardia, hypotension, increased cardiac output, decreased systemic
vascular resistance, bilirubinemia, elevation of liver enzyme levels,
hypocholestrolemia, thrombocytopenia, and prolongation of prothrombin and
partial thromboplastin times all observed in group 1 were significantly
attenuated or eliminated in group 2. The limb PO2, PCO2, pH, and viability
remained similar in both groups. Also, the tumor response rate remained
high and was unaffected by the decrease in flow rate. CONCLUSIONS:
Decreasing perfusion flow rate during ILP results in diminished leakage of
TNF-alpha. Consequently, the systemic hemodynamic, metabolic, and
hematologic toxic effects are virtually abolished.
