LOWER EXTREMITY MOTOR FUNCTION IN CHRONIC SPINAL CORD INJURY AFTER EXPOSURE TO IBUPROFEN & INTERMITTENT HYPOXIAA 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 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

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

• Safe in humans, first utilized in altitude training14,15

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.

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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 Biochem Physiol A Mol Integr Physiol 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 Appl Physiol 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.

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132.

QUESTIONS

RESULTS: HEMODYNAMICS

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

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

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