Investigating the effect of therapeutic acute intermittent hypoxia on upper limb and respiratory function in people more than one year post spinal cord injury: The AERO-SCI trial

INTERVENTION: The intervention will involve the implementation of therapeutic acute intermittent hypoxia (AIH) alone or AIH in combination with task‐specific training. Participants will be randomly allocated to one of two intervention arms in this Bayesian Optimal Phase II design. These will comprise either: • Acute intermittent hypoxia • Acute intermittent hypoxia + task‐specific training (upper limb and respiratory muscle training) Participants will be asked to undertake 10 intervention sessions over a 2‐week period, in the presence of an experienced physiotherapist (5 consecutive days x 2 consecutive weeks). Sessions will be conducted on‐site (hospital, university or research institute location), or in the participant s home if feasible. In both trial arms, acute intermittent hypoxia will be generated via a Hypoxico‐123 air generator device (Hypoxico Altitude Training Systems Inc, New York, USA, 10001). The AIH protocol for each intervention session will comprise 15 periods (repetitions) of: 60 seconds in which participants breathe air with 9% fraction of inspired oxygen (FiO2) (equivalent to low 80%’s oxygen saturation (SpO2)), followed by 60 seconds of breathing medical‐grade room air ( 21% FiO2). This AIH protocol is estimated to take a total of 30 minutes per session. In the acute intermittent hypoxia + task‐specific training arm, the upper limb and respiratory training will be standardised and delivered by the same experienced physiotherapist, following each AIH component. Tasks will include 3 sets of 8‐10 handgrips, wrist contractions and breaths through an inspiratory muscle training device (such as a Philips Threshold IMT or similar) at 70% of the maximal voluntary contraction each session. A dexterity task using pegs and holes will al CONDITION: Spinal cord injury (chronic: > 1‐year post impairment) with incomplete paralysis in target muscle groups; ; Spinal cord injury (chronic: > 1‐year post impairment) with incomplete paralysis in target muscle groups Neurological ‐ Other neurological disorders SECONDARY OUTCOME: Forced expiratory volume in 1 second (FEV1): ; Participants will be asked to rate their level of satisfaction with the intervention from a function and time‐burden perspective on a 5‐point Likert scale from ‘very satisfied’ to ‘very dissatisfied’. [Follow‐up (conducted at the completion of the 2‐week intervention period, within 5 days of the final intervention session).] Peak expiratory flow (PEF): ; Measured by spirometry, according to standardised respiratory function testing published guidelines.[Baseline and Follow‐up (conducted at the completion of the 2‐week intervention period, within 5 days of the final intervention session).] Sniff nasal inspiratory pressure (SNIP): ; SNIP is a standard test of respiratory muscle strength. This test will be performed according to standardised respiratory function testing published guidelines.[Baseline and Follow‐up (conducted at the completion of the 2‐week intervention period, within 5 days of the final intervention session).] Upper limb strength: pinch grip dynamometer ; Pinch grip strength, measured using a dynamometer, is a quantitative and objective measure of isometric muscular strength of the hand. This test will be performed according to a standardised procedure for key (lateral) pinch test, using the dominant hand [Baseline and Follow‐up (conducted at the completion of the 2‐week intervention period, within 5 days of the final intervention session).] Brain‐derived neurotrophic factor (BDNF) via salivary sample. ; Measured via pulse oximeter[Monitored continuously during each AIH intervention session] Inspired flow ; Measured using a pneumotachograph in the AIH breathing circuit ; [Monitored continuously during each AIH intervention session conducted in the laboratory. ] Maximal expiratory pressure (MEP): PRIMARY OUTCOME: This Bayesian Optimal Phase II Design trial has a single binary composite primary outcome, where good outcome (or "signal of benefit”) is defined by achieving BOTH:; ; A) Binary outcome: Improvement (increase) above baseline value that is equal or more than the predefined outcome‐specific stated threshold (below), on at least ONE priority outcome; B) Binary outcome: No deterioration (decline) below baseline value that is equal or more than the predefined outcome‐specific stated threshold (below), on ANY of the priority outcomes; ; The set of priority outcomes and corresponding, predefined outcome‐specific thresholds are:; 1) Box and block test (BBT): The Box and Block test is a measure of gross unilateral upper limb dexterity and function. This test will be completed using the dominant hand. Predefined threshold is 5.5 blocks; 2) Hand grip dynamometer: Grip strength, measured using a hand‐held dynamometer, is a quantitative and objective measure of isometric muscular strength of the hand. This test will be performed according to a standardised procedure. Predefined threshold is 5.0 kg; 3) Maximal inspiratory pressure (MIP): Maximal inspiratory pressure sustained at the mouth for 1 second is a standard test of respiratory muscle strength. This test will be performed according to a standardised procedure. Predefined threshold is 10 cmH2O[Each priority outcome will be assessed at Baseline and the Follow‐up Assessment (conducted at the completion of the 2‐week intervention period, within 5 days of the final intervention session).; ; ] ; Measured by spirometry, according to standardised respiratory function testing published guidelines. [Baseline and Follow‐up (conducted at the completion of the 2‐week intervention period, within 5 days of the final intervention session).] Participant perceived benefit ‐ hand grip strength: Assessed using an "anchor‐based method". At the time of the follow‐up assessment (immediately after performing the test), participants will be asked to estimate a global rating of change. Participants will be asked, “Has there been any change in your test since you started the research trial?” Responses will be made on a Likert scale, with a score of 0 indicating no change, positive scores indicating improvement, and negative scores indicating worsening. Change will be scored as follows: 1—almost the same, hardly any better at all; 2—a little better; 3—somewhat better; 4—moderately better; 5—a good deal better; 6—a great deal better; and 7—a very great deal better. Similar assessments were made for deterioration, substituting “worse” for “better.”[Immediately after performing the test at the follow‐up assessment (conducted at the completion of the 2‐week intervention period, within 5 days of the final intervention session).] Participant satisfaction: ; A buccal swab (salivary) sample will be taken from participants. Participants will be instructed to wash their mouths out with a standardised solution prior to the swab being taken. Samples will be stored appropriately at each laboratory. Analysis will be performed at the Australian Genetics once all swabs are collected. These samples will be analysed for BDNF levels. [Baseline and Follow‐up (conducted at the completion of the 2‐week intervention period, within 5 days of the final intervention session).] Fraction of inspired oxygen (FiO2): ; Measured via pulse oximeter[Monitored continuously during each AIH intervention session] Participant perceived benefit ‐ ARAT: Assessed using an "anchor‐based method". At the time of the follow‐up assessment (immediately after performing the test), participants will be asked to estimate a global rating of change. Participants will be asked, “Has there been any change in your test since you started the research trial?” Responses will be made on a Likert scale, with a score of 0 indicating no change, positive scores indicating improvement, and negative scores indicating worsening. Change will be scored as follows: 1—almost the same, hardly any better at all; 2—a little better; 3—somewhat better; 4—moderately better; 5—a good deal better; 6—a great deal better; and 7—a very great deal better. Similar assessments were made for deterioration, substituting “worse” for “better.”[Immediately after performing the test at the follow‐up assessment (conducted at the completion of the 2‐week intervention period, within 5 days of the final intervention session).] Participant perceived benefit ‐ box and block test: Assessed using an "anchor‐based method". At the time of the follow‐up assessment (immediately after performing the test), participants will be asked to estimate a global rating of change. Participants will be asked, “Has there been any change in your test since you started the research trial?” Responses will be made on a Likert scale, with a score of 0 indicating no change, positive scores indicating improvement, and negative scores indicating worsening. Change will be scored as follows: 1—almost the same, hardly any better at all; 2—a little better; 3—somewhat better; 4—moderately better; 5—a good deal better; 6—a great deal better; and 7—a very great deal better. Similar assessments were made for deterioration, substituting “worse” for “better.”[Immediately after performing the test at the follow‐up assessment (conducted at the completion of the 2‐week intervention period, within 5 days of the final intervention session).] Participant perceived benefit ‐ MIP: Assessed using an "anchor‐based method". At the time of the follow‐up assessment (immediately after performing the test), participants will be asked to estimate a global rating of change. Participants will be asked, “Has there been any change in your test since you started the research trial?” Responses will be made on a Likert scale, with a score of 0 indicating no change, positive scores indicating improvement, and negative scores indicating worsening. Change will be scored as follows: 1—almost the same, hardly any better at all; 2—a little better; 3—somewhat better; 4—moderately better; 5—a good deal better; 6—a great deal better; and 7—a very great deal better. Similar assessments were made for deterioration, substituting “worse” for “better.”[Immediately after performing the test at the follow‐up assessment (conducted at the completion of the 2‐week intervention period, within 5 days of the final intervention session).] Participant perceived benefit ‐ pinch strength: Assessed using an "anchor‐based method". At the time of the follow‐up assessment (immediately after performing the test), participants will be asked to estimate a global rating of change. Participants will be asked, “Has there been any change in your test since you started the research trial?” Responses will be made on a Likert scale, with a score of 0 indicating no change, positive scores indicating improvement, and negative scores indicating worsening. Change will be scored as follows: 1—almost the same, hardly any better at all; 2—a little better; 3—somewhat better; 4—moderately better; 5—a good deal better; 6—a great deal better; and 7—a very great deal better. Similar assessments were made for deterioration, substituting “worse” for “better.”[Immediately after performing the test at the follow‐up assessment (conducted at the completion of the 2‐week intervention period, within 5 days of the final intervention session).] Peak cough flow (PCF): ; Measured using a pneumotachograph. The participant will be asked to take a deep breath in and cough as forcibly as possible into a facemask (i.e., cough from the maximum, unassisted inspiratory volume)[Baseline and Follow‐up (conducted at the completion of the 2‐week intervention period, within 5 days of the final intervention session).] Safety of the AIH intervention will be determined by recording the incidence of adverse events throughout the intervention sessions, assessed by participant self‐report and/or physical examination by supervising clinician. Adverse events include but are not limited to: light‐headedness, dizziness, headaches, altered vision, respiratory distress, cyanosis, spasticity, autonomic dysreflexia, cardiopulmonary instability or worsening sensory or motor function i.e. below the baseline level.[Collected during each intervention session and collated at Study completion] Participant perceived benefit ‐ 9‐hole peg test: Assessed using an "anchor‐based method". At the time of the follow‐up assessment (immediately after performing the test), participants will be asked to estimate a global rating of change. Participants will be asked, “Has there been any change in your test since you started the research trial?” Responses will be made on a Likert scale, with a score of 0 indicating no change, positive scores indicating improvement, and negative scores indicating worsening. Change will be scored as follows: 1—almost the same, hardly any better at all; 2—a little better; 3—somewhat better; 4—moderately better; 5—a good deal better; 6—a great deal better; and 7—a very great deal better. Similar assessments were made for deterioration, substituting “worse” for “better.”[Immediately after performing the test at the follow‐up assessment (conducted at the completion of the 2‐week intervention period, within 5 days of the final intervention session).] Participant perceived benefit ‐ FVC: Assessed using an "anchor‐based method". At the time of the follow‐up assessment (immediately after performing the test), participants will be asked to estimate a global rating of change. Participants will be asked, “Has there been any change in your test since you started the research trial?” Responses will be made on a Likert scale, with a score of 0 indicating no change, positive scores indicating improvement, and negative scores indicating worsening. Change will be scored as follows: 1—almost the same, hardly any better at all; 2—a little better; 3—somewhat better; 4—moderately better; 5—a good deal better; 6—a great deal better; and 7—a very great deal better. Similar assessments were made for deterioration, substituting “worse” for “better.”[Immediately after performing the test at the follow‐up assessment (conducted at the completion of the 2‐week intervention period, within 5 days of the final intervention session).] Participant perceived benefit ‐ PCF: Assessed using an "anchor‐based method". At the time of the follow‐up assessment (immediately after performing the test), participants will be asked to estimate a global rating of change. Participants will be asked, “Has there been any change in your test since you started the research trial?” Responses will be made on a Likert scale, with a score of 0 indicating no change, positive scores indicating improvement, and negative scores indicating worsening. Change will be scored as follows: 1—almost the same, hardly any better at all; 2—a little better; 3—somewhat better; 4—moderately better; 5—a good deal better; 6—a great deal better; and 7—a very great deal better. Similar assessments were made for deterioration, substituting “worse” for “better.”[Immediately after performing the test at the follow‐up assessment (conducted at the completion of the 2‐week intervention period, within 5 days of the final intervention session).] Participant perceived benefit ‐ SNIP: Assessed using an "anchor‐based method". At the time of the follow‐up assessment (immediately after performing the test), participants will be asked to estimate a global rating of change. Participants will be asked, “Has there been any change in your test since you started the research trial?” Responses will be made on a Likert scale, with a score of 0 indicating no change, positive scores indicating improvement, and negative scores indicating worsening. Change will be scored as follows: 1—almost the same, hardly any better at all; 2—a little better; 3—somewhat better; 4—moderately better; 5—a good deal better; 6—a great deal better; and 7—a very great deal better. Similar assessments were made for deterioration, substituting “worse” for “better.”[Immediately after performing the test at the follow‐up assessment (conducted at the completion of the 2‐week intervention period, within 5 days of the final intervention session).] Upper limb dexterity and function measure: Action research arm test (ARAT) ; Measured using an oxygen analyser in the AIH breathing circuit[Monitored continuously during each AIH intervention session conducted in the laboratory. ] Participant perceived benefit ‐ MEP: Assessed using an "anchor‐based method". At the time of the follow‐up assessment (immediately after performing the test), participants will be asked to estimate a global rating of change. Participants will be asked, “Has there been any change in your test since you started the research trial?” Responses will be made on a Likert scale, with a score of 0 indicating no change, positive scores indicating improvement, and negative scores indicating worsening. Change will be scored as follows: 1—almost the same, hardly any better at all; 2—a little better; 3—somewhat better; 4—moderately better; 5—a good deal better; 6—a great deal better; and 7—a very great deal better. Similar assessments were made for deterioration, substituting “worse” for “better.”[Immediately after performing the test at the follow‐up assessment (conducted at the completion of the 2‐week intervention period, within 5 days of the final intervention session).] Upper limb dexterity and function measure: 9 Hole peg test ; The 9‐hole peg test is a test of upper limb dexterity and function. This test will be undertaken using the dominant hand. This test involves a participant taking pegs from a container, one by one, and placing them into holes on a board as quickly as possible. The pegs are then transferred back to the container one by one. Shorter time required to complete the task indicates better dexterity. If a participant is unable to complete the test, the score will be recorded as 120 seconds. [Baseline and Follow‐up (conducted at the completion of the 2‐week intervention period, within 5 days of the final intervention session).] Blood pressure: ; Measured using a sphygmomanometer[Measured on a single occasion prior to and following each AIH intervention session] Feasibility of the intervention will be assessed based on the proportion of the sample that could complete the intervention period. In participants who are not able to complete the intervention in its entirety, reasons and supporting information will be collected (i.e. from therapy logs and research notes after each session). [Study conclusion] Heart rate: ; Maximal expiratory pressure sustained at the mouth for 1 second is a standard test of respiratory muscle strength. This test will be performed according to standardised respiratory function testing published guidelines.[Baseline and Follow‐up (conducted at the completion of the 2‐week intervention period, within 5 days of the final intervention session).] Forced vital capacity (FVC): ; Measured by spirometry, according to standardised respiratory function testing published guidelines.[Baseline and Follow‐up (conducted at the completion of the 2‐week intervention period, within 5 days of the final intervention session).] Oxygen saturation levels (SpO2): ; The ARAT is a comprehensive test of upper limb function. The test involves 19 tasks used to assess grasp, grip, pinch and gross movement. Equipment such as wood blocks, a cricket ball, a stone, a jug, a glass, a tube, a washer and bolt, a ball bearing, a marble, a chair with no arm rests, a table, a plant and tin lid are required. The participant is asked to complete the first (and most complex) task of each domain. If they are able to complete the task in its’ entirety, they are scored top marks (i.e. ‘performs test normally’) and they move onto the next section. If the participant is not able to undertake the first task, they are scored according to the following criteria: ‘completes test but takes abnormally long or has great difficulty’, ‘performs test partially', ‘can perform no part of the test’. The second task of each section is the easiest. If the participant is unable to complete this task, they are given a score of zero for the whole section. Participants are given a final score between 0 and 57. The test takes 5 to 15 minutes to complete.[Baseline and Follow‐up (conducted at the completion of the 2‐week intervention period, within 5 days of the final intervention session).] INCLUSION CRITERIA: ‐ Young adults (aged 18 to 50 years) ‐ Independently ventilating with a history of chronic SCI (>1 year post‐injury or impairment onset. American Spinal Injury Association Impairment Scale [ASIA] A to D; with incomplete paralysis in target muscle groups) ‐ Able to perform one block on the Box and Block Test ‐ Medically stable ‐ Ability to follow verbal and visual commands ‐ Ability to provide informed consent