title: Venovenous perfusion-induced systemic hyperthermia: five-day sheep survival studies.
abstract: OBJECTIVE
  Since hyperthermia selectively kills lung cancer cells, we developed a venovenous perfusion-induced systemic hyperthermia system for advanced lung cancer therapy. Our objective was to test the safety and accuracy of our venovenous perfusion-induced systemic hyperthermia system in 5-day sheep survival studies, following Good Laboratory Practice standards.
  
  
  METHODS
  Our venovenous perfusion-induced systemic hyperthermia system, which included a double-lumen cannula (Avalon Elite, Rancho Dominguez, Calif), a centrifugal pump (Bio-Pump 560; Medtronic Inc, Minneapolis, Minn), a heat exchanger (BIOtherm; Medtronic Perfusion Systems, Brooklyn Park, Minn), and a heater/cooler (modified Blanketrol IIIl Cincinnati Subzero, Cincinnati, Ohio), was tested in healthy adult sheep (n=5). The perfusion circuit was primed with prewarmed Plasma-Lyte A (Baxter Healthcare Corp, Deerfield, Ill) and de-aired. Calibrated temperature probes were placed in the right and left sides of the nasopharynx, bladder, and blood in/out tubing in the animal. The double-lumen cannula was inserted through the jugular vein into the superior vena cava, with the tip in the inferior vena cava.
  
  
  RESULTS
  Therapeutic core temperature (42°C-42.5°C), calculated from the right and left sides of the nasopharynx and bladder temperatures, was achieved in all sheep. Heating time was 21±5 minutes. Therapeutic core temperature was maintained for 120 minutes followed by a cooling phase (35±6 minutes) to reach baseline temperature. All sheep recovered from anesthesia with spontaneous breathing within 4 hours. Arterial, pulmonary, and central venous pressures were stable. Transient increases in heart rate, cardiac output, and blood glucose occurred during hyperthermia but returned to normal range after venovenous perfusion-induced systemic hyperthermia termination. Electrolytes, complete blood counts, and metabolism enzymes were within normal to near normal range throughout the study. No significant venovenous perfusion-induced systemic hyperthermia-related hemolysis was observed. Neurologic assessment showed normal brain function all 5 days.
  
  
  CONCLUSIONS
  Our venovenous perfusion-induced systemic hyperthermia system safely delivered the hyperthermia dose with no significant hyperthermia-related complications.
authors.affiliation: Department of Surgery, University of Kentucky College of Medicine, Lexington, Ky.
authors.forename: Cherry
authors.initials: C
authors.lastname: Ballard-Croft
authors.affiliation: Department of Surgery, University of Kentucky College of Medicine, Lexington, Ky. Electronic address: dnwang2@uky.edu.
authors.forename: Dongfang
authors.initials: D
authors.lastname: Wang
authors.affiliation: Department of Surgery, University of Kentucky College of Medicine, Lexington, Ky.
authors.forename: Kyle
authors.initials: K
authors.lastname: Rosenstein
authors.affiliation: Department of Surgery, University of Kentucky College of Medicine, Lexington, Ky.
authors.forename: Jingkun
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Surgery, University of Kentucky College of Medicine, Lexington, Ky.
authors.forename: Robert
authors.initials: R
authors.lastname: Pollock
authors.affiliation: Department of Surgery, University of Kentucky College of Medicine, Lexington, Ky.
authors.forename: J Ann
authors.initials: JA
authors.lastname: Morris
authors.affiliation: Department of Surgery, University of Kentucky College of Medicine, Lexington, Ky.
authors.forename: Joseph B
authors.initials: JB
authors.lastname: Zwischenberger
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood; D001833:Body Temperature Regulation; D004867:Equipment Design; D005112:Extracorporeal Circulation / Q000009:adverse effects / Q000295:instrumentation / Q000379:methods*; D005260:Female; D006439:Hemodynamics; D006461:Hemolysis; D006979:Hyperthermia, Induced / Q000009:adverse effects / Q000295:instrumentation / Q000379:methods*; D008175:Lung Neoplasms / Q000628:therapy*; D008422:Materials Testing; D023421:Models, Animal; D010477:Perfusion / Q000009:adverse effects / Q000295:instrumentation / Q000379:methods*; D034561:Sheep, Domestic; D013997:Time Factors
chemical_list: D015415:Biomarkers