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The Prolonged Gastrointestinal Syndrome in Rhesus Macaques

The Relationship Between Gastrointestinal, Hematopoietic, and Delayed Multi-organ Sequelae Following Acute, Potentially Lethal, Partial-body Irradiation

MacVittie, Thomas J.*; Bennett, Alexander*; Booth, Catherine; Garofalo, Michael*; Tudor, Gregory; Ward, Amanda*; Shea-Donohue, Terez; Gelfond, Daniel§; McFarland, Emylee**; Jackson, William I I I††; Lu, Wei‡‡; Farese, Ann M.*

doi: 10.1097/HP.0b013e318266eb4c
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The dose response relationship for the acute gastrointestinal syndrome following total-body irradiation prevents analysis of the full recovery and damage to the gastrointestinal system, since all animals succumb to the subsequent 100% lethal hematopoietic syndrome. A partial-body irradiation model with 5% bone marrow sparing was established to investigate the prolonged effects of high-dose radiation on the gastrointestinal system, as well as the concomitant hematopoietic syndrome and other multi-organ injury including the lung. Herein, cellular and clinical parameters link acute and delayed coincident sequelae to radiation dose and time course post-exposure. Male rhesus Macaca mulatta were exposed to partial-body irradiation with 5% bone marrow (tibiae, ankles, feet) sparing using 6 MV linear accelerator photons at a dose rate of 0.80 Gy min−1 to midline tissue (thorax) doses in the exposure range of 9.0 to 12.5 Gy. Following irradiation, all animals were monitored for multiple organ-specific parameters for 180 d. Animals were administered medical management including administration of intravenous fluids, antiemetics, prophylactic antibiotics, blood transfusions, antidiarrheals, supplemental nutrition, and analgesics. The primary endpoint was survival at 15, 60, or 180 d post-exposure. Secondary endpoints included evaluation of dehydration, diarrhea, hematologic parameters, respiratory distress, histology of small and large intestine, lung radiographs, and mean survival time of decedents. Dose- and time-dependent mortality defined several organ-specific sequelae, with LD50/15 of 11.95 Gy, LD50/60 of 11.01 Gy, and LD50/180 of 9.73 Gy for respective acute gastrointestinal, combined hematopoietic and gastrointestinal, and multi-organ delayed injury to include the lung. This model allows analysis of concomitant multi-organ sequelae, thus providing a link between acute and delayed radiation effects. Specific and multi-organ medical countermeasures can be assessed for efficacy and interaction during the concomitant evolution of acute and delayed key organ-specific subsyndromes.

*University of Maryland, School of Medicine, Department of Radiation Oncology; †Epistem Ltd, Manchester, UK; ‡University of Maryland, School of Medicine, Mucosal Biology Research Center; §Digestive Diseases and Nutrition Center, Women and Children’s Hospital of Buffalo; **U.S. Army Medical Research Institute of Chemical Defense, Oak Ridge Institute for Science and Education; ††Statistician, Rockville, MD; ‡‡University of Maryland Medical Center, Department of Radiation Oncology.

The authors declare no conflict of interest.

For correspondence contact: Thomas J. MacVittie, University of Maryland, School of Medicine, Department of Radiation Oncology, 10 S. Pine St., Room 6-34E, Baltimore, MD 21201, or email at tmacvittie@som.umaryland.edu.

(Manuscript accepted 27 June 2012)

© 2012 by the Health Physics Society