title: High plasma tumor necrosis factor (TNF)-alpha concentrations and a sepsis-like syndrome in patients undergoing hyperthermic isolated limb perfusion with recombinant TNF-alpha, interferon-gamma, and melphalan.
abstract: OBJECTIVE
  To describe the postoperative course of patients who underwent hyperthermic isolated limb perfusion with recombinant tumor necrosis factor (TNF)-alpha and melphalan after pretreatment with recombinant interferon-gamma as treatment for recurrent melanoma, primary nonresectable soft-tissue tumors, planocellular carcinoma, or metastatic carcinoma. To measure systemic TNF-alpha concentrations and relate these values with indices of disease severity.
  
  
  METHODS
  A 12-bed surgical intensive care unit (ICU) in a university referral hospital.
  
  
  METHODS
  Prospective, descriptive study.
  
  
  METHODS
  Consecutive patients (n=25) treated with hyperthermic isolated limb perfusion.
  
  
  METHODS
  Blood samples were taken at regular intervals to determine TNF-alpha concentrations during and after hyperthermic isolated limb perfusion with recombinant TNF-alpha. Hemodynamic variables were obtained with a Swan-Ganz pulmonary artery catheter.
  
  
  RESULTS
  All patients developed features of sepsis syndrome and required intensive care treatment. Most patients recovered quickly, with a median ICU stay of 2 days (range 1 to 25). Maximum systemic TNF-alpha concentrations ranged from 2284 to 83,000 ng/L (median 25,409) and returned to baseline values within 8 hrs. Despite these high concentrations of TNF-alpha, no patient died in the ICU, although the patient with the highest TNF-alpha concentration developed multiple organ failure and required continuous venovenous hemofiltration for 16 days. Linear regression analysis showed positive correlations between maximum TNF-alpha concentrations and systemic vascular resistance (p < .01), cardiac index (p < .02), Lung Injury Score (p < .02), prothrombin time (p < .02), and activated partial thromboplastin time (p < .05).
  
  
  CONCLUSIONS
  Hyperthermic isolated limb perfusion with recombinant TNF-alpha leads to high systemic concentrations of TNF-alpha, probably due to leakage of recombinant TNF-alpha from the perfusion circuit, mainly through collateral blood flow. A sepsis-like syndrome is seen in all patients. Despite high concentrations of systemic TNF-alpha, this sepsis syndrome is short-lived and recovery is rapid and complete in most patients.
authors.affiliation: Department of Anesthesia, Royal Victoria Infirmary, Newcastle on Tyne, UK.
authors.forename: J H
authors.initials: JH
authors.lastname: Zwaveling
authors.forename: J K
authors.initials: JK
authors.lastname: Maring
authors.forename: F L
authors.initials: FL
authors.lastname: Clarke
authors.forename: R J
authors.initials: RJ
authors.lastname: van Ginkel
authors.forename: P C
authors.initials: PC
authors.lastname: Limburg
authors.forename: H J
authors.initials: HJ
authors.lastname: Hoekstra
authors.forename: H S
authors.initials: HS
authors.lastname: Koops
authors.forename: A R
authors.initials: AR
authors.lastname: Girbes
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D018906:Antineoplastic Agents, Alkylating / Q000009:adverse effects*; D010478:Chemotherapy, Cancer, Regional Perfusion / Q000009:adverse effects*; D003131:Combined Modality Therapy; D005121:Extremities; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D006979:Hyperthermia, Induced / Q000009:adverse effects*; D007371:Interferon-gamma / Q000009:adverse effects*; D016014:Linear Models; D008297:Male; D008558:Melphalan / Q000009:adverse effects*; D008875:Middle Aged; D009369:Neoplasms / Q000628:therapy*; D011446:Prospective Studies; D011994:Recombinant Proteins; D012720:Severity of Illness Index; D018746:Systemic Inflammatory Response Syndrome / Q000097:blood / Q000139:chemically induced*; D014409:Tumor Necrosis Factor-alpha / Q000009:adverse effects* / Q000378:metabolism*
chemical_list: D018906:Antineoplastic Agents, Alkylating; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D008558:Melphalan