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Positive airway pressure for sleep-disordered breathing in acute quadriplegia: a randomised controlled trial

Rationale Highly prevalent and severe sleep-disordered breathing caused by acute cervical spinal cord injury (quadriplegia) is associated with neurocognitive dysfunction and sleepiness and is likely to impair rehabilitation. Objective To determine whether 3 months of autotitrating CPAP would improve neurocognitive function, sleepiness, quality of life, anxiety and depression more than usual care in acute quadriplegia. Methods and measurements Multinational, randomised controlled trial (11 centres) from July 2009 to October 2015. The primary outcome was neurocognitive (attention and information processing as measure with the Paced Auditory Serial Addition Task). Daytime sleepiness (Karolinska Sleepiness Scale) was a priori identified as the most important secondary outcome. Main results 1810 incident cases were screened. 332 underwent full, portable polysomnography, 273 of whom had an apnoea hypopnoea index greater than 10. 160 tolerated at least 4 hours of CPAP during a 3-day run-in and were randomised. 149 participants (134 men, age 46±34 years, 81±57 days postinjury) completed the trial. CPAP use averaged 2.9±2.3 hours per night with 21% fully ‘adherent’ (at least 4 hours use on 5 days per week). Intention-to-treat analyses revealed no significant differences between groups in the Paced Auditory Serial Addition Task (mean improvement of 2.28, 95% CI −7.09 to 11.6; p=0.63). Controlling for premorbid intelligence, age and obstructive sleep apnoea severity (group effect −1.15, 95% CI −10 to 7.7) did not alter this finding. Sleepiness was significantly improved by CPAP on intention-to-treat analysis (mean difference −1.26, 95% CI −2.2 to –0.32; p=0.01). Conclusion CPAP did not improve Paced Auditory Serial Addition Task scores but significantly reduced sleepiness after acute quadriplegia. Trial registration number ACTRN12605000799651.


Study design and governance
The Institute for Breathing and Sleep at Austin Health in Melbourne, Australia oversaw the trial, managed the study database, trained data collection staff at each site, conducted annual site audits, and staged, scored and reported all sleep studies using standard criteria. 1 An independent data and safety monitoring board reviewed safety and trial data.

Sleep studies
All consented participants underwent a full, unattended, portable sleep study in their At trial conclusion, the sleep study was repeated. Those randomized to control had a repeat diagnostic sleep study performed to determine the presence and severity of any sleep disordered breathing (SDB). Those randomised to CPAP had a sleep study performed on their auto-titrating CPAP. If CPAP was not tolerated for the full night on the final study, summary indices were generated for the proportion of the night when the pressure trace was visible. Participants who declined to have the final study on CPAP underwent a repeat diagnostic.
Heart rate variability (HRV) indices were calculated from a five minute portion of each PSG electroencephalogram trace taken during quiet resting (prior to sleep onset).
The data were selected in the Compumedics PSG (analysis) software, exported as an European data format (EDF) file, imported into the Compumedics Somte analysis software and the automated HRV analyses applied. Studies where it was not possible to sample five minutes of quiet resting electroencephalogram trace data free from movement artefact were excluded from further analyses. Only those with complete data from the baseline and final sleep studies were analysed. Student t-tests assessed between group differences in change in SDANN (standard deviation of the average normal-to-normal sinus intervals) and HF/LF ratio (high frequency to low frequency ratio). These two summary variables summarize aspects of HRV in the time (SDANN) and frequency (LF/HF ratio) domains.

Pre-randomisation procedure
All subjects who fulfilled the inclusion, exclusion criteria, consented to participate and who were classified as positive SDB cases, were trialled on auto titrating CPAP (S8 and S9. Resmed Autoset, San Diego USA) for up to three nights. When the study commenced, the S8 device was in use commercially. This was replaced by the S9 in July 2012.
Subjects who were able to use the CPAP for at least four hours on any night, were randomised into either the treatment or usual care group. If four hours were tolerated on the first night, they were randomised at this time. Those who did not use the CPAP for four hours on any of the three nights ceased trial participation. The four-hour cut off was derived from the feasibility trial where those who were unable to achieve this time were not likely to be adherent in an ongoing way. 3 The decision to only randomize those who were likely to be adherent with CPAP was the most significant study design modification to arise from the feasibility study. A rate of non-adherence of 50%, as was observed in the feasibility study, would render this study unfeasible. Pre-randomization selection potentially limits the study generalisability to those who are tolerant of CPAP, although it accurately reflects clinical practice (you would never "force" a patient to use a therapy they did not accept). This approach was strongly supported by the Australasian Sleep Trials Network, is a similar protocol to that employed in the multi-national The Sleep Apnoea Cardiovascular Endpoints (SAVE) study 4 and significantly increased the project feasibility by reducing the numbers of subjects, the timeframe and the associated staff cost.

Site training and CPAP equipment
As detailed in the protocol paper, 5 participants were fitted with masks as per local practice at each site. All sites were large, specialised spinal cord management centres and as such all had previous clinical experience with the application of non-invasive positive pressure for sleep apnoea or respiratory support in the study population. Sites were thus were well aware of and had strategies to address the "spinal-specific" useability issues such as limited hand function that could potentially add to the burden of CPAP use. To ensure a consistent approach to therapy throughout the trial, all sites received extensive face-to-face training prior to participant enrolment from the central coordinating team. Site coordinator teleconferences occurred approximately three monthly throughout the study and site visits were undertaken at least annually by the coordinating centre. ResMed nasal pillows, face and oro-nasal masks were all available at each site and masking choice individualised to ensure fit, comfort and to minimise leak. The local treating team could transition participants from CPAP to bilevel support if indicated.

Sample size estimation
The specific neurocognitive test best characterized in both the spinal population and obstructive sleep apnoea (OSA) is the PASAT. Lower (worse) PASAT scores correlate with sleep fragmentation severity in the able-bodied 6 and OSA severity in quadriplegia. 7 Lower PASAT scores are associated with diminished frontal lobe function 8 and a mean difference in PASAT scores of seven discriminates between those with and without cognitive impairment in multiple sclerosis. 9 In the able-bodied with OSA, those adherent to CPAP over three months have an 18 unit (standard deviation of 33) higher PASAT score than those who are not. 10

Analyses
Previous research which examined the relationship between the OSA severity and neurocognitive dysfunction in acute quadriplegia controlled for age, sex, medications (baclofen, opiates, benzodiazepines and other potentially sedating medications), days since injury, body mass index (BMI), pre-morbid intelligence (NAART) and pre-injury apnoea symptom frequency. 11 Only age and pre-morbid intelligence consistently contributed and as such were controlled for at baseline in the linear regression modelling of the effect of CPAP on change in neuropsychological function.

Alterations to trial protocol
The age of people experiencing a SCI has rapidly increased alongside an ageing population and an associated increase in injurious falls. 12 The initial exclusion of those over 70 years of age was considered to be compromising trial generalizability and completion, and therefore removed on 30th June 2011. No other protocol alterations were made.

Age distribution
The average participant age was 46.7(15). As illustrated in Figure E1, the distribution was bimodal with a median age of 48 years, an inter-quartile range of 33 to 59. Two peak incidence ranges can be observed; from 20 to the mid-30s and another from 40 to the mid-50s.

Respiratory function
The

CPAP adherence
The pattern of use across all those randomized to auto-titrating CPAP is illustrated in Figure E2 and overall CPAP adherence averaged 2.9 (SD=2.3) hours per night. Figure   E2 illustrates that in contrast with the non-disabled, adherence in the first week was not always predictive of continued use and that a number of participants fell in and out of the "adherent" group as classified by five out of seven nights of at least four hours of use over the trial duration. Despite tolerating therapeutic CPAP for at least four hours during the run-in phase, many participants had less than 4 hours per night on 5 nights per week after randomization. Adherence, leak and pressure information (95 th centile, etc.) was downloaded weekly and available to clinical research staff to assist with CPAP troubleshooting and optimisation.

Adverse events
No differences were observed in the frequency of autonomic dysreflexia events per week between those randomised to auto-titrating CPAP (mean=0.   Data are expressed as the percentage correct from a total possible score of 240.
Comparison data are taken from Tombaugh 13 and Schembri 11