Annals of Biomedical Engineering

, Volume 45, Issue 6, pp 1581–1588 | Cite as

The Interaction of Intramuscular Ketorolac (Toradol) and Concussion in a Rat Model

  • Amanda O. Esquivel
  • Sarah S. Sherman
  • Cynthia A. Bir
  • Stephen E. Lemos


The purpose of this study was to examine the interaction of a single dose of Toradol and head impact in an in vivo rat model for sport-related concussion using a validated rat concussion model. Thirty-five Sprague–Dawley rats were placed into one of four groups: (1) Control, (2) Impact Only, (3) Toradol Only, (4) Impact and Toradol. Animals in the impact groups were subjected to a single head impact. Animals in the Toradol group received a single intramuscular injection of Toradol prior to impact. We examined magnetic resonance imaging, serum S100-B and cognitive function using a Morris Water Maze. In the control group, latency decreased significantly from day 0 (74.9 s) to 24 h (57.4 s) after anesthesia. There was no statistically significant difference between time zero and 24 h after impact in the Impact only or Impact and Toradol group. Our findings indicate that there were no differences between cognitive ability, MRI findings or S100B in rats that were administered a single dose of Toradol and subjected to a single impact and rats that were subjected to a single impact only. In both impact groups there were transient changes in cognitive ability as measured by the Morris Water Maze.


Head impact Mild traumatic brain injury Sport related concussion 



We thank Amanda Luba and Dr. Yimin Shen for their assistance with data collection. This study was funded internally. There are no financial conflicts of interest for any authors. This study was conducted at the Wayne State University Sports Injury Biomechanics Laboratory located at 818 W. Hancock, Detroit, MI.


  1. 1.
    Ali, M. S., M. Harmer, and R. Vaughan. Serum s100 protein as a marker of cerebral damage during cardiac surgery. Br. J. Anaesth. 85:287–298, 2000.CrossRefPubMedGoogle Scholar
  2. 2.
    Bolouri, H., A. Saljo, D. C. Viano, and A. Hamberger. Animal model for sport-related concussion; icp and cognitive function. Acta Neurol. Scand. 125:241–247, 2012.CrossRefPubMedGoogle Scholar
  3. 3.
    Bouvier, D., T. Duret, M. Abbot, T. Stiernon, B. Pereira, A. Coste, J. Chazal, and V. Sapin. Utility of S100B serum level for the determination of concussion in male rugby players. Sports Med. 2016. doi: 10.1007/s40279-016-0579-9.
  4. 4.
    Broglio, S. P., B. Schnebel, J. J. Sosnoff, S. Shin, X. Fend, X. He, and J. Zimmerman. Biomechanical properties of concussions in high school football. Med. Sci. Sports Exerc. 42:2064–2071, 2010.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Buckley, E. M., B. F. Miller, J. M. Golinski, H. Sadeghian, L. M. McAllister, M. Vangel, C. Ayata, W. P. Meehan, 3rd, M. A. Franceschini, and M. J. Whalen. Decreased microvascular cerebral blood flow assessed by diffuse correlation spectroscopy after repetitive concussions in mice. J. Cereb. Blood Flow Metab. 35:1995–2000, 2015.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Connolly, E. S., Jr., C. J. Winfree, A. Rampersad, R. Sharma, W. J. Mack, J. Mocco, R. A. Solomon, G. Todd, D. O. Quest, Y. Stern, and E. J. Heyer. Serum S100B protein levels are correlated with subclinical neurocognitive declines after carotid endarterectomy. Neurosurgery 49:1076–1082; discussion 1082–1083, 2001.Google Scholar
  7. 7.
    Crisco, J. J., B. J. Wilcox, J. G. Beckwith, J. J. Chu, A. C. Duhaime, S. Rowson, S. M. Duma, A. C. Maerlender, T. W. McAllister, and R. M. Greenwald. Head impact exposure in collegiate football players. J. Biomech. 44:2673–2678, 2011.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    D’Hooge, R., and P. P. De Deyn. Applications of the morris water maze in the study of learning and memory. Brain Res. 36:60–90, 2001.CrossRefGoogle Scholar
  9. 9.
    Daneshvar, D. H., C. J. Nowinski, A. C. McKee, and R. C. Cantu. The epidemiology of sport-related concussion. Clin. Sports Med. 30:1–17, vii, 2011.Google Scholar
  10. 10.
    Di Pietro, V., A. M. Amorini, G. Lazzarino, K. M. Yakoub, S. D’Urso, G. Lazzarino, and A. Belli. S100b and glial fibrillary acidic protein as indexes to monitor damage severity in an in vitro model of traumatic brain injury. Neurochem. Res. 40:991–999, 2015.CrossRefPubMedGoogle Scholar
  11. 11.
    Dietzel, D. P., and E. C. Hedlund. Injections and return to play. Curr. Sports Med. Rep. 3:310–315, 2004.PubMedGoogle Scholar
  12. 12.
    Dobre, M. C., K. Ugurbil, and M. Marjanska. Determination of blood longitudinal relaxation time (t1) at high magnetic field strengths. Magn. Reson. Imaging 25:733–735, 2007.CrossRefPubMedGoogle Scholar
  13. 13.
    Havnes, M. B., Y. Kerlefsen, and A. Mollerlokken. S100B and NSE serum concentrations after simulated diving in rats. Physiol. Rep. 3:e12546, 2015.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Houck, Z., B. Asken, R. Bauer, J. Pothast, C. Michaudet, and J. Clugston. Epidemiology of sport-related concussion in an ncaa division i football bowl subdivision sample. Am. J. Sports Med. 44:2269–2275, 2016.CrossRefPubMedGoogle Scholar
  15. 15.
    Huang, L., J. S. Coats, A. Mohd-Yusof, Y. Yin, S. Assaad, M. J. Muellner, J. E. Kamper, R. E. Hartman, M. Dulcich, V. M. Donovan, U. Oyoyo, and A. Obenaus. Tissue vulnerability is increased following repetitive mild traumatic brain injury in the rat. Brain Res. 1499:109–120, 2013.CrossRefPubMedGoogle Scholar
  16. 16.
    Kallakuri, S., S. Bandaru, N. Zakaria, Y. Shen, Z. Kou, L. Zhang, E. M. Haacke, and J. M. Cavanaugh. Traumatic brain injury by a closed head injury device induces cerebral blood flow changes and microhemorrhages. J. Clin. Imaging Sci. 5:52, 2015.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Kerr, Z. Y., A. C. Littleton, L. M. Cox, J. D. DeFreese, E. Varangis, R. C. Lynall, J. D. Schmidt, S. W. Marshall, and K. M. Guskiewicz. Estimating contact exposure in football using the head impact exposure estimate. J. Neurotrauma 32:1083–1089, 2015.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Lalonde, R., and C. Strazielle. The effects of cerebellar damage on maze learning in animals. Cerebellum 2:300–309, 2003.CrossRefPubMedGoogle Scholar
  19. 19.
    Luh, W. M., E. C. Wong, P. A. Bandettini, and J. S. Hyde. Quipss ii with thin-slice ti1 periodic saturation: a method for improving accuracy of quantitative perfusion imaging using pulsed arterial spin labeling. Magn. Reson. Med. 41:1246–1254, 1999.CrossRefPubMedGoogle Scholar
  20. 20.
    Marmarou, A., M. A. Foda, W. van den Brink, J. Campbell, H. Kita, and K. Demetriadou. A new model of diffuse brain injury in rats. Part i: pathophysiology and biomechanics. J. Neurosurg. 80:291–300, 1994.CrossRefPubMedGoogle Scholar
  21. 21.
    Matava, M., D. C. Brater, N. Gritter, R. Heyer, D. Rollins, T. Schlegel, R. Toto, and A. Yates. Recommendations of the national football league physician society task force on the use of toradol((r)) ketorolac in the national football league. Sports Health 4:377–383, 2012.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Mychasiuk, R., A. Farran, and M. J. Esser. Assessment of an experimental rodent model of pediatric mild traumatic brain injury. J. Neurotrauma 31:749–757, 2014.CrossRefPubMedGoogle Scholar
  23. 23.
    Nepple, J. J., and M. J. Matava. Soft tissue injections in the athlete. Sports Health 1:396–404, 2009.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Pellman, E. J., J. W. Powell, D. C. Viano, I. R. Casson, A. M. Tucker, H. Feuer, M. Lovell, J. F. Waeckerle, and D. W. Robertson. Concussion in professional football: epidemiological features of game injuries and review of the literature—part 3. Neurosurgery 54:81–94; discussion 94–96, 2004.Google Scholar
  25. 25.
    Powell, E. T., J. M. Tokish, and R. J. Hawkins. Toradol use in the athletic population. Curr. Sports Med. Rep. 1:191, 2002.CrossRefPubMedGoogle Scholar
  26. 26.
    Sakurai, A., C. M. Atkins, O. F. Alonso, H. M. Bramlett, and W. D. Dietrich. Mild hyperthermia worsens the neuropathological damage associated with mild traumatic brain injury in rats. J. Neurotrauma 29:313–321, 2012.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Sawyer, G. A., B. C. Anderson, N. P. Raukar, and P. D. Fadale. Intramuscular ketorolac injections in the athlete. Sports Health 4:319–327, 2012.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Schulte, S., L. W. Podlog, J. J. Hamson-Utley, F. G. Strathmann, and H. K. Struder. A systematic review of the biomarker S100B: implications for sport-related concussion management. J. Athl. Train 49:830–850, 2014.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Schulte, S., N. N. Rasmussen, J. W. McBeth, P. Q. Richards, E. Yochem, D. J. Petron, and F. G. Strathmann. Utilization of the clinical laboratory for the implementation of concussion biomarkers in collegiate football and the necessity of personalized and predictive athlete specific reference intervals. EPMA J. 7:1, 2015.CrossRefPubMedGoogle Scholar
  30. 30.
    Shaikh, H., M. Lechpammer, F. E. Jensen, S. K. Warfield, A. H. Hansen, B. Kosaras, M. Shevell, and P. Wintermark. Increased brain perfusion persists over the first month of life in term asphyxiated newborns treated with hypothermia: does it reflect activated angiogenesis? Transl. Stroke Res. 6:224–233, 2015.CrossRefPubMedGoogle Scholar
  31. 31.
    Shultz, S. R., F. Bao, V. Omana, C. Chiu, A. Brown, and D. P. Cain. Repeated mild lateral fluid percussion brain injury in the rat causes cumulative long-term behavioral impairments, neuroinflammation, and cortical loss in an animal model of repeated concussion. J. Neurotrauma 29:281–294, 2012.CrossRefPubMedGoogle Scholar
  32. 32.
    Shultz, S. R., D. F. MacFabe, K. A. Foley, R. Taylor, and D. P. Cain. Sub-concussive brain injury in the long-evans rat induces acute neuroinflammation in the absence of behavioral impairments. Behav. Brain Res. 229:145–152, 2012.CrossRefPubMedGoogle Scholar
  33. 33.
    Tokish, J. M., E. T. Powell, T. F. Schlegel, and R. J. Hawkins. Ketorolac use in the national football league: prevalence, efficacy, and adverse events. Phys. Sportsmed. 30:19–24, 2002.CrossRefPubMedGoogle Scholar
  34. 34.
    Veilleux-Lemieux, D., A. Castel, D. Carrier, F. Beaudry, and P. Vachon. Pharmacokinetics of ketamine and xylazine in young and old sprague–dawley rats. J. Am. Assoc. Lab. Anim. Sci. 52:567–570, 2013.PubMedPubMedCentralGoogle Scholar
  35. 35.
    Viano, D. C., A. Hamberger, H. Bolouri, and A. Saljo. Concussion in professional football: animal model of brain injury—part 15. Neurosurgery 64:1162–1173; discussion 1173, 2009.Google Scholar
  36. 36.
    Vonder Haar, C., D. M. Friend, D. B. Mudd, and J. S. Smith. Successive bilateral frontal controlled cortical impact injuries show behavioral savings. Behav. Brain Res. 240:153–159, 2013.CrossRefPubMedGoogle Scholar
  37. 37.
    Vorhees, C. V., and M. T. Williams. Morris water maze: procedures for assessing spatial and related forms of learning and memory. Nat. Protoc. 1:848–858, 2006.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Wang, J., D. J. Licht, G. H. Jahng, C. S. Liu, J. T. Rubin, J. Haselgrove, R. A. Zimmerman, and J. A. Detre. Pediatric perfusion imaging using pulsed arterial spin labeling. J. Magn. Reson. Imaging 18:404–413, 2003.CrossRefPubMedGoogle Scholar
  39. 39.
    Warner, D. C., G. Schnepf, M. S. Barrett, D. Dian, and N. L. Swigonski. Prevalence, attitudes, and behaviors related to the use of nonsteroidal anti-inflammatory drugs (NSAIDs) in student athletes. J. Adolesc. Health 30:150–153, 2002.CrossRefPubMedGoogle Scholar
  40. 40.
    Wong, R. H., A. K. Wong, and J. E. Bailes. Frequency, magnitude, and distribution of head impacts in pop warner football: the cumulative burden. Clin. Neurol. Neurosurg. 118:1–4, 2014.CrossRefPubMedGoogle Scholar

Copyright information

© Biomedical Engineering Society 2017

Authors and Affiliations

  • Amanda O. Esquivel
    • 1
  • Sarah S. Sherman
    • 2
  • Cynthia A. Bir
    • 3
  • Stephen E. Lemos
    • 2
    • 4
  1. 1.Department of Mechanical Engineering, College of Engineering and Computer ScienceUniversity of Michigan - DearbornDearbornUSA
  2. 2.Wayne State UniversityDetroitUSA
  3. 3.Keck School of MedicineThe University of Southern CaliforniaLos AngelesUSA
  4. 4.Department of Sports MedicineDetroit Medical CenterWarrenUSA

Personalised recommendations