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.

Figure 1

Hyperthermia Temperature Profile. 1A: Bladder, right/left nasopharynx temperatures measured during heating, therapeutic, and cooling phases. Homogeneous heat distribution was observed with no temperatures above 42.5°C. 1B: Relationship between core temperature and circuit infusion (blood in)/drainage (blood out) temperatures. Maximal circuit blood infusion temperature was 42.3°C.

Figure 1

Hyperthermia Temperature Profile. 1A: Bladder, right/left nasopharynx temperatures measured during heating, therapeutic, and cooling phases. Homogeneous heat distribution was observed with no temperatures above 42.5°C. 1B: Relationship between core temperature and circuit infusion (blood in)/drainage (blood out) temperatures. Maximal circuit blood infusion temperature was 42.3°C.