Long-term facilitation of ventilation in humans with chronic spinal cord injury

Abstract

Rationale: Intermittent stimulation of the respiratory system with hypoxia causes persistent increases in respiratory motor output (i.e., long-term facilitation) in animals with spinal cord injury. This paradigm, therefore, has been touted as a potential respiratory rehabilitation strategy.

Objectives: To determine whether acute (daily) exposure to intermittent hypoxia can also evoke long-term facilitation of ventilation after chronic spinal cord injury in humans, and whether repeated daily exposure to intermittent hypoxia enhances the magnitude of this response.

Methods: Eight individuals with incomplete spinal cord injury (>1 yr; cervical [n = 6], thoracic [n = 2]) were exposed to intermittent hypoxia (eight 2-min intervals of 8% oxygen) for 10 days. During all exposures, end-tidal carbon dioxide levels were maintained, on average, 2 mm Hg above resting values. Minute ventilation, tidal volume, and breathing frequency were measured before (baseline), during, and 30 minutes after intermittent hypoxia. Sham protocols consisted of exposure to room air and were administered to a subset of the participants (n = 4).

Measurements and main results: Minute ventilation increased significantly for 30 minutes after acute exposure to intermittent hypoxia (P < 0.001), but not after sham exposure. However, the magnitude of ventilatory long-term facilitation was not enhanced over 10 days of intermittent hypoxia exposures.

Conclusions: Ventilatory long-term facilitation can be evoked by brief periods of hypoxia in humans with chronic spinal cord injury. Thus, intermittent hypoxia may represent a strategy for inducing respiratory neuroplasticity after declines in respiratory function that are related to neurological impairment. Clinical trial registered with www.clinicaltrials.gov (NCT01272011).

Figures

Figure 1.

Schematic diagram of experimental design and protocols. (A) All participants underwent an initial visit to determine eligibility (visit 1) and 10 days of exposure to intermittent hypoxia (IH). Pulmonary function was tested immediately before and after the first and tenth exposure to IH. Two sham sessions used for control comparisons (one before [Pre-IH Sham] and one after [Post-IH Sham] the 10 d of IH) were completed in a subset of the participants to demonstrate that observed outcomes were associated with exposure to IH, and not placebo or chance. (B) IH and sham protocols are outlined (see Methods for details). AIS = American Spinal Injury Association Impairment Scale; PetCO2 = end-tidal partial pressure of carbon dioxide; PetO2 = end-tidal partial pressure of oxygen; PFT = pulmonary function test.

Figure 2.

Effect of carbon dioxide on minute ventilation. Responses in ventilation to the increase in carbon dioxide during baseline (from B1 to B2) were used to generate a linear equation (with slope representing ventilatory sensitivity) to determine predicted values of minute ventilation during the end-recovery (ER) period. B1 = eupneic baseline; B2 = baseline with elevated carbon dioxide.

Figure 3.

Ventilatory long-term facilitation was detected post–spinal cord injury (SCI), during initial (i.e., Days 1 and 2) and final (i.e., Days 9 and 10) days of the intermittent hypoxia (IH) protocol. Shown are breath-to-breath measures of minute ventilation and end-tidal partial pressures of oxygen (PetO2) and carbon dioxide (PetCO2) (top to bottom) recorded from one participant (participant 6) with SCI before, during, and after (1) exposure to IH on initial (black, A–C) and final (gray, D–F) days of the protocol and (2) exposure to sham conditions (G–I). Measures from normoxic and isocapnic baseline (B1, eupnea) are graphed before the step increase in carbon dioxide, initiated during B2 (baseline with elevated carbon dioxide). Carbon dioxide was elevated and sustained until the end of the protocols. (A and D) Note that minute ventilation during the end-recovery (ER) period was greater than either baseline (B1, eupnea and B2, elevated carbon dioxide) after exposure to IH. (G) Data from a representative sham session show that this increase in minute ventilation was absent without hypoxic exposure during the sham protocols.

Figure 4.

(A–C) Acute and cumulative responses resulting from daily and repeated exposure to intermittent hypoxia (IH), compared to sham. Minute ventilation (top), tidal volume (middle), and breath frequency (bottom) during the end-recovery (ER) period at initial (i.e., Days 1 and 2, initial ER period) and final (i.e., Days 9 and 10, final ER period) days of the IH protocol were normalized to values from baseline with elevated carbon dioxide (B2) within each individual session to characterize daily effects of exposure to IH at the beginning and end of treatment. Data from initial and final sham sessions were normalized in the same way, and averaged because no statistically significant differences between the one sham session immediately preceding (pre-IH-sham) and one sham session immediately after (post-IH sham) the 10 days of hypoxic exposure were detected. (D–F) Values from baseline with elevated carbon dioxide and the ER period during the final days of the protocol (final B2 and final ER period, respectively) also were normalized to elevated carbon dioxide baseline during initial days of the protocol (initial B2) to describe the cumulative effects of repeated exposure to IH. Individual data points are graphed and outliers are identified with diagonal lines through data points. Open circles represent individuals who were exposed to both the IH and sham protocols, and solid circles represent individuals exposed only to the IH protocol. Histograms represent means, and error bars represent 95% confidence intervals. In all graphs, 1.0 represents the baseline to which all data were normalized and compared. *Significantly different from within-session B2 values; †significantly different from values after IH exposure.