The impact of supportive care on survival in large animal models of total body irradiation

Abstract

Purpose

Well-characterized animal models that mimic the human response to potentially lethal doses of radiation are necessary in order to assess the efficacy of candidate medical countermeasures under the criteria of the U.S. Food and Drug Administration ‘Animal Rule’. Development of a model requires the determination of the radiation dose response relationship and time course of mortality and morbidity under scenarios likely to be present in the human population during mass casualty situations. These scenarios include understanding the impact of medical management on survival of the hematopoietic acute radiation syndrome (H-ARS). Little information is available to compare the impact of medical management under identical study conditions. The work presented here provides a comparison of the impact of different levels of medical management (supportive care) on the survival outcome in two large animal models: the male Gottingen minipig and the male rhesus macaque (NHP).

Materials and Methods

In the context of this comparison, limited supportive care consisted of administration of analgesics only, standard supportive care consisted of prophylactic administration of analgesics, antibiotics and fluids (minipigs) or analgesics, antibiotics, antidiarrheals, nutritional and fluid support (NHP) on a set schedule regardless of indication, and full supportive care (NHP only) consisted of analgesics, antibiotics, antidiarrheals, nutritional and fluid support, antiemetics and blood transfusions on an individual animal, trigger-to-treat regimen. Regardless of level of supportive care, minipigs were exposed to total body irradiation using a Co⁶⁰ source and NHPs were exposed to total body irradiation using 6 MV photon energy.

Results

Based on estimated LD50 values, the inclusion of antimicrobial or broad-spectrum antibiotics provided a dose modifying factor (DMF) of 1.09 in the minipig, and by 1.15 in the NHP (standard supportive care to limited supportive care ratio. For the NHP, the administration of supportive care based on symptomology rather than a set schedule, and inclusion of blood transfusions yielded a DMF of 1.05 (full supportive care to standard supportive care ratio). Conversely, comparison of the estimated LD50 values between full supportive care and limited supportive care in the NHP provided a DMF of 1.21.

Conclusion

The study reported here provides a comparison of the impact of antibiotic administration on radiation-induced lethality.

Keywords:

• Minipig
• non-human primate
• total body irradiation

Acknowledgements

The authors wish to acknowledge and thank the dedicated animal care staff for their skilled handling of the animals.

Declaration of interest

The authors declare no conflicts of interest.

Additional information

Funding

This work has been funded in part with Federal funds from the Department of Health and Human Services, Office of the Assistant Secretary for Preparedness and Response; Biomedical Advanced Research and Development Authority, under Contract No. HHS000201000010C and partial funding from Shin Nippon Biomedical Laboratories.

Notes on contributors

Karla D. Thrall

Karla D. Thrall, PhD, DABT, is the Senor Director of Radiation Biology at Altasciences Preclinical Seattle, Everett WA.

Saikanth Mahendra

Saikanth Mahendra, MS, DABR, is a board-certified Medical Physicist at Northwest Medical Physics Center, Lynnwood, WA.

Jamie Lovaglio

Jamie Lovaglio, DVM, DACLAM, is a board-certified Clinical Veterinarian at Rocky Mountain Laboratories, Hamilton, MT.

M. Keven Jackson

M. Keven Jackson, DVM, DACVP, is a board-certified research pathologist at Altasciences Preclinical Seattle, Everett WA.