Repeated Doses of Adriamycin May Be Safely Delivered through the Intraosseous Route In Different Bones In Swine

Vascular access is critical to the management of patients undergoing chemotherapeutic treatments. Chemotherapy regimens are delivered via long-term vascular access, which are associated with increased rate of infection and vessel damage. The safety of intraosseous (IO) drug delivery of common cardiovascular drugs has been well established and is accepted as the primary alternative to IV access. The safety of multiple rounds of tissue disruptive chemotherapeutic agents via the IO route, however, is unknown. A 2007 study conducted by this group examined single dose administration of Mitomycin, Adriamycin, and CHOP (cyclophosphamide, doxorubicine hydrochloride, Oncovin, and prednisolone) through the IO route. Results suggested that the IO route of infusing chemotherapy agents could be a safe alternative to IV infusion, based on the short-term evaluation of 7 days. But in a 2008 follow-up study of Adriamycin administered through the IO route in the same bone 3 times over a 72-day period, 10 of 14 animals suffered osteomyelitis and/or fractures in the bones used for the infusions. The current study was designed to explore different drug administration regimens designed to prevent these complications.

This study consisted of two groups of swine, each receiving three rounds of Adriamycin infusions, in three different limbs spaced 21 days apart. Group 1: (High Dose-High Concentration, n = 6): 60mg/m² of Adriamycin was delivered into the bone over 15 minutes (concentration 2mg/ml). Group 2: (Low Dose-Low Concentration, n=6): 25mg/m² of Adriamycin was delivered into the bone over 15 minutes (concentration 0.4 mg/ml). Sedation was induced with Ketamine, Xylazine, and Telazol and maintained with Propofol. An IO needle (EZ IO, Vidacare Corporation, Shavano Park, TX) was aseptically placed into the left humerus (first infusion), or left tibia (second infusion), or right tibia (third infusion). Saline was delivered before (manual syringe flush of 10 ml) and after the IO drug infusion (10ml/min over 5 minutes via syringe pump) in both groups. Radiographic images were obtained before and after every drug infusion and prior to euthanasia. Animals were monitored daily for signs of pain, swelling, or tissue necrosis and treated as needed for the duration of the study. Thirty days after the last drug infusion, animals were anesthetized and euthanized. Bone samples were harvested and sent for histological evaluation. A scoring system, in which changes in morphology were scored on a 0 to 4 scale with 4 representing the most severe changes, was used for the histological evaluation.

The clinical complications observed were related to the usual adverse events of the drug, such as diarrhea and vomiting observed during the first week post injection in both groups. There was no clinical, radiological, or histological evidence of osteomyelitis or fracture. Radiological evaluation showed a delay of the healing process and an increase of the osteoblastic activity in the bones previously injected with Adriamycin in both groups. Histological evaluation showed higher scores for blood (p<0.001), scar (p=0.002), and edema (p=0.04) in the left tibia of the animals of Group 1 versus Group 2. There was a higher incidence of normal marrow tissue present in the left tibia of the animals of Group 2 (p=0.04) and a higher incidence of normal bone spicules was found in the right tibia of the animals of Group 2 versus Group 1 (p=0.04).

The IO delivery of lower dose and diluted concentrations of Adriamycin was safer and resulted in less tissue abnormality when compared with higher dose/higher concentration. The IO route with rotation of sites for placement of IO needles may be a feasible option for Adriamycin or other vesicant delivery.

Lima:Vidacare Corporation: Research Funding. Navarro:Vidacare Corporation: Research Funding. Philbeck:Vidacare Corporation: Employment. Miller:Vidacare Corporation: Employment, Equity Ownership.