Clinical trial NCT02554487: Early Sleep Apnea Treatment in Stroke
Official title: Early Sleep Apnea Treatment in Stroke: A Multicenter, Randomized, Rater-Blinded, Clinical Trial of Adaptive Servo-Ventilation
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Sleep Apnea, Obstructive
Sleep Apnea, Central
Stroke
Keywords: stroke
sleep disordered breathing
sleep apnea
infarct volume
penumbra
Lead sponsor: Insel Gruppe AG, University Hospital Bern
Sponsor class: OTHER
Collaborators: name: Swiss National Science Foundation
name: TROPOS Stiftung für Humane Verhaltensforschung
First posted: 2015-09-18
Enrollment: 201
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Investigating the interrelation of stroke and sleep-disordered breathing (SDB) is of major importance. First because of the high occurrence rate of stroke and the fact that it is a frequent cause of long-term disability in adulthood. Second because SDB (obstructive, central and mixed forms) affects more than 50% of stroke survivors and has a detrimental effect on clinical stroke outcome. Third, spontaneous and learning-dependent sleep-associated neuroplasticity may be affected by SDB following stroke worsening stroke rehabilitation. Therefore, it is crucial to investigate whether early treatment of SDB with Adaptive Servo-Ventilation (ASV), the treatment device of choice to treat obstructive, central and mixed forms of SDB, has a beneficial effect on the evolution of the lesion volume and on clinical stroke outcome.

To this end, the investigators recruit and prospectively follow 3 groups of patients with ischemic stroke over 1 year. During the first night after hospital admission due to acute stroke, nocturnal breathing is assessed by means of a respiratory polygraphy. Patients with significant sleep disordered breathing, defined as an Apnea-Hypopnea-Index (AHI) \> 20/h, are randomized to ASV treatment or no treatment (sSDB ASV+ or sSDB ASV-). ASV treatment starts the second night following hospital admission and ends 90 days later. Stroke patients without SDB (AHI \< 5 / h) serve as a control group (no SDB) to observe the evolution of the lesion volume and stroke outcome without the additional burden of SDB.

Lesion volume one day after hospital admission due to acute stroke (after potential lysis therapy) measured by Diffusion Weighted Imaging will be subtracted from lesion volume measured by T2-weighted volumetry assessed 90(+/-7) days following stroke and compared between patients with and without ASV treatment (sSDB ASV+ and sSDB ASV-) as well as patients without SDB (no SDB). Short- and long-term clinical stroke outcomes are assessed by clinical scales and questionnaires 4 to 7 days, 3 months and 1 year following stroke. Cognitive outcome is assessed during hospitalization (within the first week following stroke) and after the treatment period of 90 days by neuropsychological tests assessing attention and memory. In addition, baseline assessment of physiological parameters such as blood pressure and endothelial function/arterial stiffness are assessed during the first weeks following stroke and at the end of the treatment period, i.e. approximately 90 days following stroke.

Detailed description: Background

Investigating the interrelation of stroke and sleep-disordered breathing (SDB) is of major importance. Stroke affects 2-3 individuals per 1000 a year and is the most common neurological cause of hospitalization and long-term disability in adulthood. SDB, i.e., obstructive, central and mixed forms of sleep apnea syndrome, is highly prevalent after acute stroke, affecting approximately over 50% of stroke patients. It is also a significant risk factor for stroke. Beside the high prevalence, SDB negatively influences stroke outcome. SDB after stroke has been found to be associated with a faster progression of stroke severity, higher blood pressure levels and longer hospitalization in the acute phase. Chronically, stroke patients with SDB exhibit worse functional outcome and a higher mortality. The mechanisms leading to the detrimental effects of SDB on stroke outcome are multiple and include changes of cerebral hemodynamics and brain oxygenation as well as a number of humoral and systemic changes. Frequent arousals during sleep and interruptions of deep sleep and sleep continuity may also negatively influence sleep-associated neuroplasticity.

Adaptive Servo-Ventilation (ASV) is the treatment of choice in mixed and complex sleep apnea syndrome, consisting of the coexistence of obstructive sleep apnea/hypopnea and central events. Pressure support is adjusted based on the patient's recent minute ventilation and respiratory rate, which means that ventilation can vary gradually and naturally over the course of the night and is continuously adjusted to the patient's need.

Due to the high prevalence of SDB following stroke and its detrimental effects on stroke outcome, it is crucial to investigate whether early treatment of central, obstructive and mixed forms of SDB with Adaptive Servo-Ventilation (ASV) has a beneficial effect on the evolution of the lesion volume and on clinical stroke outcome.

Objective

The primary objective of the present trial is to assess whether an immediate onset of ASV treatment in ischemic stroke patients with significant SDB (sSDB, Apnea-Hypopnea-Index (AHI) \> 20/h) has a favorable effect on infarct growth assessed as the difference in lesion volume before and 90 days after treatment start. The potential reduction in infarct growth should also result in a better clinical stroke outcome.

One of the secondary objectives of the trial is therefore to assess whether an immediate onset of ASV treatment in stroke patients with SDB improves clinical outcome and is tolerated and associated with good treatment compliance. Moreover, it will be investigated whether it improves cognitive outcome as well as short and long-term cortical reorganization assess by functional resting state imaging. The investigators are also interested whether ASV treatment improves physiological parameters such as blood pressure and endothelial function/arterial stiffness.

Methods

3 groups of patients are prospectively followed over 1 year. ASV treatment starts the second night following hospital admission due to acute ischemic stroke and ends 90 days later. Group assignment takes place the day following stroke after the assessment of SDB by respiratory polygraphy. Patients with an AHI \> 20/h are randomized to ASV treatment or no treatment (sSDB ASV+ or sSDB ASV-). Stroke patients without SDB (AHI \< 5 / h) serve as a control group (no SDB) to observe the evolution of the lesion volume and stroke outcome without the additional burden of SDB.

Evolution of lesion volume from the first to the 90st day following stroke and clinical (including cognitive) outcome 90 days after stroke will be compared between stroke patients with sSDB that receive ASV treatment (sSDB ASV+) versus no treatment (sSDB ASV-) and stroke patients without SDB (no SDB, AHI \< 5 / h).

Eligibility criteria: Inclusion Criteria:

* Informed consent as documented by signature
* Admission to one of the participating centers
* Age 18-85 years
* Ischemic stroke detectable by neuroimaging, affecting internal carotid artery, anterior cerebral artery (ACA), middle cerebral artery (MCA), posterior cerebral artery (PCA) and/or branches thereof
* Symptom onset to admission \< 24 hours
* AHI \> 20/h or \< 5/h

Exclusion Criteria

* Primary hemorrhagic stroke
* Secondary parenchymal haemorrhage (PH 1 and PH 2 according to ECASS; secondary haemorrhagic infarction HI 1 and HI 2 can be included)
* Small strokes (diameter \< 1.5cm)
* Coma/Stupor
* Intubation
* Clinically unstable or life threatening condition (oxygen-dependent pulmonary disease or severe pulmonary complications, severe renal or liver insufficiency, agitated patient, patients under blood pressure-elevating substances \>24h after stroke, patients that need decompressive craniectomy )
* Heart failure defined as known congestive heart failure (CHF) functional class NYHA III-IV (New York Heart Association) OR CHF NYHA II and hospitalization caused by CHF in the preceding 24 months
* OR left ventricular ejection fraction lower or equal 45% either known from preceding imaging method or found at the routine examination (echocardiography) during hospitalization
* Oxygen supply \> 2 l/min during day and night
* Intermediate AHI value: ≥ 5/h and ≤ 20/h
* Known progressive neurological diseases (such as dementia, Parkinson's disease or multiple sclerosis)
* Drug or alcohol abuse (\>14 units alcohol / week for males, \>7 units alcohol / week for females)
* Inability to follow study procedure
* Pregnancy
* Any given contraindications to MRI or MRI-contrast agent (allergy or severe renal impairment)
* Any given contraindications to ASV treatment
* Patients with clinical symptoms of COVID-19 infection during initial hospitalization

Primary outcomes:
measure: Infarct growth from baseline to 90 day following stroke: difference in lesion volume [ccm] assessed by Diffusion Weighted Imaging (DWI) at baseline and T2-weighted imaging at day 90 following stroke
timeFrame: The day after admission and potential lysis therapy, at 4 to 7 days following stroke and 90 (+/-7 ) days following stroke
Secondary outcomes:
measure: Relative salvage of the penumbra volume from the day after lysis therapy to day 4-7 following stroke will be compared between the three patients groups (sSDB ASV+, sSDB ASV-, no SDB)
timeFrame: The day after admission/potential lysis therapy and at 4 to 7 days following stroke
measure: Differences in spatial/temporal dynamics of resting state connectivity between the three patients groups: sSDB ASV+, sSDB ASV-, no SDB
timeFrame: The day after admission/potential lysis therapy, at day 4-7 and day 90 following stroke
measure: Differences in clinical outcome between the three patients groups, sSDB ASV+, sSDB ASV- and no SDB, assessed by the NIHSS, Barthel Index and the modified Rankin scale
timeFrame: Pre-stroke assessment during hospitalization and post-stroke assessments at day 90 and 1 year following stroke
measure: Differences in blood pressure measurements (absolute values and variability) during hospitalisation, during a 3-week period following dismissal and during a 3-week period 90-days following stroke.
timeFrame: 3 weeks following hospital discharge (baseline) and 3-weeks before end of intervention period (~day 69-90).
measure: Differences in endothelial functioning/arterial stiffness at day 2 (baseline) and at 90 days following stroke
timeFrame: 3 weeks following hospital discharge (baseline) and 3-weeks before end of intervention period (~day 69-90).
measure: Stroke patients' tolerance of and compliance to the ASV intervention during the acute (within the first week following stroke) and subacute to chronic phase (within the first 3 months following stroke)
timeFrame: Tolerance and compliance are assessed during hospitalization (between 2 and 7 following stroke), at a follow-up control visit (between day 28-42) and at the end of the treatment period (day 83-97).
Other outcomes:
Locations:
city: Grenoble
country: France
facility: Clinic universitaire de physiologie, sommeil et exercice, Centre Hospitalier Universitaire (CHU) de Grenoble
city: Berlin
country: Germany
facility: Department and Out-Patient Care of Neurology, Charité Center Neurology, Neurosurgery and Psychiatry CC 15, Department of Neurology with Experimental Neurology, Center for Stroke Research Berlin (CSB)
city: Mainz
country: Germany
facility: Universitätsmedizin der Johannes Gutenberg-Universität Mainz, HNO-Universitätsklinik, Klinik und Poliklinik für Neurologie
city: Saint Petersburg
country: Russian Federation
facility: Federal State Budgetary Institution "Almazov National Medical Research Centre" of the Ministry of Health of the Russian Federation
city: Bern
country: Switzerland
facility: Department of Neurology, Pulmonary Medicine and Institute of Diagnostic and Interventional Neuroradiology, Bern University Hospital
city: St.Gallen
country: Switzerland
facility: Neurology Department, Cantonal Hospital St.Gallen
Study officials:
affiliation: Department of Neurology, Bern University Hospital, 3010 Bern, Switzerland
name: Claudio L Bassetti
role: PRINCIPAL_INVESTIGATOR
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