Role of nitric oxide in recombinant tumor necrosis factor-alpha-induced circulatory shock: a study in patients treated for cancer with isolated limb perfusion.
OBJECTIVE
To analyze the mechanism of vasodilation and circulatory shock occurring in patients who are treated with isolated limb perfusion with melphalan and recombinant tumor necrosis factor (TNF)-alpha for locally advanced malignant tumors. To determine the role of nitric oxide, if any, by measuring plasma nitrite and nitrate concentrations.


METHODS
Observational survey.


METHODS
A 12-bed surgical intensive care unit in a university referral hospital.


METHODS
Eight patients treated with hyperthermic isolated limb perfusion.


METHODS
Ninety minutes of hyperthermic isolated limb perfusion with recombinant TNF-alpha (3 or 4 mg) and melphalan (10 to 13 mg/L limb volume).


RESULTS
All patients developed sepsis syndrome due to leakage of recombinant TNF-alpha from the perfusion circuit to the systemic circulation. Despite the presence of very high systemic TNF-alpha concentrations during and immediately after perfusion, and despite definite signs of hyperdynamic circulatory shock (increased heart rate, increased cardiac index, decreased systemic vascular resistance), nitrite and nitrate concentrations, as measured in plasma at several time points, were not increased.


CONCLUSIONS
The hypothesis that in humans, TNF-alpha induces vasodilation and shock through activation of inducible nitric-oxide synthase and subsequent formation of excessive quantities of nitric oxide is not substantiated by our results. Normal nitric oxide metabolite concentrations were found in the presence of high TNF-alpha concentrations and shock. Other mechanisms that do not involve the nitric oxide pathway are likely to play a role in the generation of hypotension and septic shock in this setting.
Department of Surgery, University Hospital Groningen, The Netherlands.
J H
JH
Zwaveling
J K
JK
Maring
H
H
Moshage
R J
RJ
van Ginkel
H J
HJ
Hoekstra
H
H
Schraffordt Koops
I F
IF
Donse
A R
AR
Girbes
D000368:Aged; D000369:Aged, 80 and over; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage* / Q000009:adverse effects*; D010478:Chemotherapy, Cancer, Regional Perfusion / Q000379:methods*; D005121:Extremities; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D008297:Male; D008558:Melphalan / Q000008:administration & dosage* / Q000009:adverse effects*; D008875:Middle Aged; D009369:Neoplasms / Q000628:therapy*; D009566:Nitrates / Q000097:blood; D009569:Nitric Oxide / Q000378:metabolism*; D009573:Nitrites / Q000097:blood; D018805:Sepsis / Q000209:etiology; D012769:Shock / Q000139:chemically induced*; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage* / Q000009:adverse effects* / Q000378:metabolism
D018906:Antineoplastic Agents, Alkylating; D009566:Nitrates; D009573:Nitrites; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D008558:Melphalan