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AAP&MR November 2014

Lower Extremity Motor Function in Chronic Spinal Cord Injury After Exposure to Ibuprofen & Intermittent Hypoxia A Randomized Trial. AAP&MR November 2014.

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AAP&MR November 2014

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  1. Lower Extremity Motor Function in Chronic Spinal Cord Injury After Exposure to Ibuprofen & Intermittent HypoxiaA Randomized Trial AAP&MR November 2014 Meaghan Lynch, MD; SudarshanSrivatsan, BS; Kelly Deatsch, DPT; LynseyDuffell, PhD; Allison Kessler, MD; ArunJayaraman, PhD, PT; William Zev Rymer, MD, PhD

  2. Background • Majority of new traumatic SCI are incomplete, and the extent of spontaneous neurological recovery is limited1,2 • Acute intermittent hypoxia (AIH) strengthens spared neural pathways3-5 and potentiates functional motor output in chronic incomplete SCI6,7 • Serotonin mediated8,9 • Inhibited by inflammation10 • Elevated circulating cytokines persist in chronic SCI in the absence of infection or wounds11-13

  3. BACKGROUND continued • AIH… • Periodic hypoxia alternating with normoxia • Promotes lower extremity strength in chronic SCI compared to sham6 • Improves walking speed and endurance when combined with PT7 • Safein humans, first utilized in altitude training14,15

  4. Objective & Hypothesis • Reduce systemic inflammation to enhance effects of AIH on motor strength in chronic SCI • Pilot study hypothesis: • Pre-treatment with ibuprofen 800mg will enhance effect of AIH on ankle strength compared to placebo in individuals with chronic incomplete SCI

  5. Methods: participants • 10 adults with chronic motor-incomplete SCI • Exclusion criteria: • CV disease, pulmonary disease, infection, ulcers, HO, DVT, rheumatologic disease, cancer, chronic NSAID or steroid use

  6. Methods: design Double blinded Randomized Placebo controlled Cross-over

  7. Methods: outcome measures • Primary: lower extremity strength • Maximum torque during isometric ankle plantar flexion • Secondary: surface EMG • Medial gastroc, soleus, tibialis anterior

  8. Results: absolute torque * p<0.05 compared to baseline **p<0.01 compared to baseline Torque increased with time after AIH in both groups. No statistical difference between ibuprofen and placebo groups.

  9. Results: % change from baseline

  10. Results: EMG activity Significant association between torque and EMG activity in gastroc(p<0.005) and soleus(p<0.005). No association with tibialisanterior No significant effect of drug administration on EMG activity

  11. Discussion • AIH systematically increased lower extremity torque • Replicates ability of AIH to enhance motor output in chronic incomplete SCI • No differential effect with pre-treatment of single dose of ibuprofen 800mg • Length of study limited, perhaps difference seen if outcome measures repeated later

  12. Discussion continued • Change in inflammatory cytokine level unknown • Future directions: • Alternative ibuprofen dosing or corticosteroids to better reduce inflammatory inhibitory pathway • SSRIs to target neuroexcitatory pathway • Long term consequences/safety of AIH

  13. Conclusion AIH holds promise in promoting plasticity and motor output in spared neural pathways. AIH enhances lower extremity strength in individuals with chronic SCI, but is not affected by single dose of ibuprofen 800mg.

  14. References 1 DevivoMJ. Epidemiology of traumatic spinal cord injury: trends and implications. Spine Cord 2012;50:365-372. 2 Shin JC, et al. Epidemiology change of patients with spinal cord injury. Ann Rehabil Med 2013;37:50-56. 3 Golder FJ, Mitchell GS. Spinal synaptic enhancement with acute intermittent hypoxia improves respiratory function after chronic cervical spinal cord injury. J Neurosci 2005;25:2925-2932. 4 Fuller DD et al. Synaptic pathways to phrenic motoneurons are enhanced by chronic intermittent hypoxia after cervical spinal cord injury. J Neurosci 2003;23:2993-3000. 5 LovetteBarr MR, et al. Repetitive intermittent hypoxia induces respiratory and somatic motor recovery after chronic cervical spinal cord injury. J Neurosci 2012;32:3591-3600. 6 Trumbower RD, et al. Exposure to acute intermittent hpyoxia augments somatic motor function in humans with incomplete spinal cord injury. Neurorehabil Neural Repair 2012;26:163-172. 7 Hayes HB, et al. Daily intermittent hpyoxia enhances walking after chronic spinal cord injury: a randomized trial. Neurology 2014;82:1-10. 8 Baker-Herman TL, Mitchell GS. Phrenic long-term facilitation requires spinal serotonin receptor activation and protein synthesis. J Neurosci 2002;22:6239-6246.. 9 Kinkead R, et al. Plasticity in respiratory motor control: intermittent hypoxia and hypercapnia activate opposing serotonergiv and noradreniergic modulatory systems. Comp BiochemPhysiol A MolIntegrPhysiol 2001;130:207-218. 10 Huxtable AG, et al. Systemic LPS induces spinal inflammatory gene expression and impairs phrenic long-term facilitation following acute intermittent hypoxia. J ApplPhysiol 2013;114:879-887. 11 Wang TD, et al. Circulating levels of markers of inflammation and endothelial activation are increased in men with chronic spinal cord injury. J Formos Med Assoc 2007;106:919-928. 12 Silva Alves E, et al. Low grade inflammation and spinal cord injury: exercise as therapy? Mediators Inflamm. 2013;2013:971841. 13 Morse LR, at al. Association between mobility mode and C-reactive protein levels in men with chronic spinal cord injury. Arch Phys Med Rehabil 2008;89:726-31. 414 14 Powell, F. Mini review: Physiological effects of intermittent hypoxia. High Altitude Medicine & Biology. 2000; 1(2): 125-136 15 Shatilo, V.B. Effects of intermittent hypoxia training on exercise performance, hemodynamics, and ventilation in healthy senior men. High Altitude Medcicine & Biology. 2008; 9(1): 43-52. 16 Kopp MA, et al. Small-molecule-induced Rho-inhibition: NSAIDS after spinal cord injury. Cell Tissue Res 2012;349:119-132.

  15. Questions

  16. Results: hemodynamics

  17. What is Acute Intermittent Hypoxia (AIH)? • AIH restores breathing capacity in rats with high cervical spinal hemisection3 • Strengthening of phrenic nerve synapses via long-term potentiation4 • Similar findings seen in non-respiratory somatic motor nuclei5 • In humans with chronic incomplete SCI, when compared to sham normoxia breathing treatment, AIH: • Promotes lower extremity motor output as assessed by ankle plantar flexion torque6 • Improves walking speed and endurance when combined with PT7

  18. Why Ibuprofen? • In rats: • CNS inflammation & cytokine release impairs AIH-induced phrenic nerve long-term potentiation10 • Pre-treatment with the NSAID ketoprofen restores this long-term potentiation10 • Systemic administration of ibuprofen enhances neuroplasticity and locomotor recovery following spinal contusion via RhoA inhibitory pathways16 • Effects of non-ibuprofen NSAIDs not as robust16 • In humans with chronic SCI: • Low-grade inflammation exists in the absence of active infection or wounds11-13

  19. Additional discussion points • Individuals with incomplete SCI likely recruit muscles in different patterns in order to produce resultant torque • No sham breathing treatment • Study intended to be a pilot to investigate the effects of ibuprofen, not a proof-of-concept study for AIH • Imperative that AIH protocols be chosen above the threshold to elicit neuroplasticity, but below threshold for serious morbidity

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