Repeated Doses of Adriamycin Infused In Swine through the Intraosseous Route In the Same Bone May Result In Osteomyelitis

Intraosseous (IO) vascular access has been shown to be a safe and effective alternative to central venous lines for the use of emergency drugs, but its utility for the delivery of chemotherapy has not been determined. A 2007 study detected marginal changes in bone morphology after delivery of single doses of a variety of vesicant chemotherapeutic agents. However, Adriamycin in the previous study involved only a single dose and examined only acute effects to bone marrow morphology. This study was designed to determine the safety of multiple rounds of Adriamycin delivery via the IO route repeatedly in the same bone in a swine model.

An IO needle (EZ IO, Vidacare Corporation, Shavano Park, TX) was aseptically placed into both tibias of 14 Yorkshire swine. On 3 occasions, 21 days apart, a dose of Adriamycin (60mg/m²) was delivered over 15 minutes followed by 2 minutes of saline infusion through a proximal tibia. For control purposes, the contra-lateral tibia received saline infusions. A radiologist reviewed films pre and post drug delivery. Bone samples were harvested 30 days post last drug delivery. Paired t-tests were used to compare changes between treated and saline controls. Two pathologists separately reviewed the slides of 14 animals. One pathologist scored the slides and both pathologists’ comments were recorded in a masked fashion without knowledge of treatment groups, according to animal number and left or right limb. A one-way analysis of variance was used to evaluate the treatment effect (Adriamycin vs. saline control). A two-sided alpha level of 0.05 was used to define statistical significance.

After the 2nd infusion, visual examination revealed small dime-sized lesions over the injection site in 4 animals. After the third injection almost all animals developed some form of leg swelling and limping. Radiologically, osteomyelitis was detected in 6 animals (43%), 2 of which had fractures to the proximal head of the tibia. An additional 4 animals had fractures to the proximal head of the tibia without osteomyelitis. Of the 10 affected animals, half the complications occurred after the second Adriamycin dose and half occurred after the third dose. Histologically, there was no statistical significance for the parameters of marrow cell loss (p=0.85), bone spicule loss (p=1.0), blood in the field (p=0.20), or necrosis (p=0.33) between drug infused limbs and their paired controls. Matrix formation and scar formation were significantly greater in the drug limbs when compared to the saline control limbs (p<0.001 and p<0.05, respectively). There was no statistical significance for the parameters of hypocellularity (p=0.77), marrow degeneration (p=0.33), or blood (p=0.33) comparing drug limb to control limb. Severity of necrosis (p= 0.001) and fibrosis (p=0.001) formation were significantly higher for the drug limb compared to the control limb.

Results suggest the repeated doses of Adriamycin in the same bone led to formation of osteomyelitis in 6 of 14. Two of the 6 swine had fracture confirmed at study end; 4 other pigs fracture were without signs of osteomyelitis while there was no evidence of osteomyelitis in saline-infused bones. The Adriamycin infusion in the same bone caused a significant increase in matrix and scar formation in histological samples taken from the drug limb compared to the saline control limb. In addition, there was a significant increase in necrosis and fibrosis in the drug infused limb. On the long-term evaluation, these increases suggest that Adriamycin has some direct effect on inducing bone pathology. Additionally, these complications may have been exacerbated by additional factors—including hurricane evacuation. A number of recommendations have been given to address these issues. The most important considerations could be the alternation of infusion limbs during drug delivery and increased post flush volumes.

Hoskins:Vidacare Corporation: Research Funding. Philbeck:Vidacare Corporation: Employment. Miller:Vidacare Corporation: Employment, Equity Ownership. Kramer:Vidacare Corporation: Consultancy, Patents & Royalties, Research Funding.