LOWER EXTREMITY MOTOR FUNCTION IN CHRONIC SPINAL CORD INJURY AFTER EXPOSURE TO IBUPROFEN & INTERMITTENT HYPOXIA A RANDOMIZED TRIAL Meaghan Lynch, MD; Sudarshan Srivatsan, BS; Kelly Deatsch, DPT; Lynsey Duffell, PhD; Allison Kessler, MD; Arun Jayaraman, PhD, PT; William Zev Rymer, MD, PhD AAP&MR November 2014

BACKGROUND  Majority of new traumatic SCI are incomplete, and the extent of spontaneous neurological recovery is limited 1,2  Acute intermittent hypoxia (AIH) strengthens spared neural pathways 3-5 and potentiates functional motor output in chronic incomplete SCI 6,7 Serotonin mediated 8,9 Inhibited by inflammation 10  Elevated circulating cytokines persist in chronic SCI in the absence of infection or wounds 11-13

BACKGROUND continued  AIH… Periodic hypoxia alternating with normoxia Promotes lower extremity strength in chronic SCI compared to sham 6 Improves walking speed and endurance when combined with PT 7 Safe in humans, first utilized in altitude training 14,15

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

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

METHODS: design  Double blinded  Randomized  Placebo controlled  Cross-over

METHODS: outcome measures  Primary: lower extremity strength Maximum torque during isometric ankle plantar flexion  Secondary: surface EMG Medial gastroc, soleus, tibialis anterior

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

RESULTS: % change from baseline

RESULTS: EMG activity  Significant association between torque and EMG activity in gastroc (p<0.005) and soleus (p<0.005). No association with tibialis anterior  No significant effect of drug administration on EMG activity

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

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

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.

REFERENCES  1 Devivo MJ. Epidemiology of traumatic spinal cord injury: trends and implications. Spine Cord 2012;50:  2 Shin JC, et al. Epidemiology change of patients with spinal cord injury. Ann Rehabil Med 2013;37:  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:  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:  5 LovetteBarr MR, et al. Repetitive intermittent hypoxia induces respiratory and somatic motor recovery after chronic cervical spinal cord injury. J Neurosci 2012;32:  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:  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:  9 Kinkead R, et al. Plasticity in respiratory motor control: intermittent hypoxia and hypercapnia activate opposing serotonergiv and noradreniergic modulatory systems. Comp Biochem Physiol A Mol Integr Physiol 2001;130:  10 Huxtable AG, et al. Systemic LPS induces spinal inflammatory gene expression and impairs phrenic long-term facilitation following acute intermittent hypoxia. J Appl Physiol 2013;114:  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:  12 Silva Alves E, et al. Low grade inflammation and spinal cord injury: exercise as therapy? Mediators Inflamm. 2013;2013:  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:  14 Powell, F. Mini review: Physiological effects of intermittent hypoxia. High Altitude Medicine & Biology. 2000; 1(2):  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):  16 Kopp MA, et al. Small-molecule-induced Rho-inhibition: NSAIDS after spinal cord injury. Cell Tissue Res 2012;349:

QUESTIONS

RESULTS: HEMODYNAMICS

WHAT IS ACUTE INTERMITTENT HYPOXIA (AIH)?  AIH restores breathing capacity in rats with high cervical spinal hemisection 3  Strengthening of phrenic nerve synapses via long-term potentiation 4  Similar findings seen in non-respiratory somatic motor nuclei 5  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 torque 6  Improves walking speed and endurance when combined with PT 7

WHY IBUPROFEN?  In rats:  CNS inflammation & cytokine release impairs AIH- induced phrenic nerve long-term potentiation 10  Pre-treatment with the NSAID ketoprofen restores this long-term potentiation 10  Systemic administration of ibuprofen enhances neuroplasticity and locomotor recovery following spinal contusion via RhoA inhibitory pathways 16  Effects of non-ibuprofen NSAIDs not as robust 16  In humans with chronic SCI:  Low-grade inflammation exists in the absence of active infection or wounds 11-13

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