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Effects of non-invasive ventilation on survival and quality of life in patients with amyotrophic lateral sclerosis: a randomised control trial

Bourke, SC; Tomlinson, M; Williams, TL; Bullock, RE; Shaw, PJ; Gibson, GJ. Effects of non-invasive ventilation on survival and quality of life in patients with amyotrophic lateral sclerosis: a randomised control trial. Lancet Neurology. 2006; 5: 140-147

BackgroundFew patients with amyotrophic lateral sclerosis currently receive non-invasive ventilation (NIV), reflecting clinical uncertainty a bout the role of this intervention. We aimed to assess the effect of NIV on quality of life and survival in amyotrophic lateral sclerosis in a randomised controlled trial.Methods92 of 102 eligible patients participated. They were assessed every 2 months and randomly assigned to NIV (n=22) or standard care (n=19) when they developed either orthopnoea with maximum inspiratory pressure less than 60% of that predicted or symptomatic hypercapnia. Primary validated quality-of-life outcome measures were the short form 36 mental component summary (MCS) and the sleep apnoea quality-of-life index symptoms domain (sym). Both time maintained above 75% of baseline (T iMCS and Tisym) and mean improvement (µMCS and µsym) were measured.

FindingsNIV improved TiMCS, Tisym, µMCS, µsym, and survival in all patients and in the subgroup with better bulbar function (n=20). This subgroup showed improvement in several measures of quality of life and a median survival benefit of 205 days (p=0·006) with maintained quality of life for most of this period. NIV improved some quality-of-life indices in those with poor bulbar function, including µsym (p=0·018), but conferred no survival benefit.InterpretationIn patients with amyotrophic lateral sclerosis without severe bulbar dysfunction, NIV improves survival with maintenance of, and improvement in, quality of life. The survival benefit from NIV in this group is much greater than that from currently available neuroprotective therapy. In patients with severe bulbar impairment, NIV improves sleep-related symptoms, but is unlikely to confer a large survival advantage.

Abstract

Intro/Background

• Vital capacity was measured with a flow turbine spirometer. P Imax, PEmax, and sniff nasal inspiratory pressure were measured with a handheld meter. Daytime sleepiness was assessed with the Epworth Sleepiness Scale.

• Bulbar function was assessed as normal to moderate bulbar impairment (score 4–6) and severe bulbar impairment (score 0–3).

• The prognostic variables were: bulbar function; vital capacity; age; body-mass index; and linear estimate of disease progression.

• Repeated measures of symptoms, lung function, and quality of life were assessed. • Quality of life assessments were the generic SF36, the sleep related SAQLI, and

the chronic respiratory disease questionnaire (CRQ). Procedures• NIV settings, interfaces, and inspiratory and expiratory airway pressures were

adjusted for optimum nocturnal oximetry breathing room air, daytime ABG’s, and NIV use.

• Interfaces included nasal and oronasal masks, total face mask, and a mouthpiece with and without a lipseal.

Statistical Analysis• The primary QOL outcome measures were the SF36 mental component summary

and the SAQLI symptoms domain. • All outcome measures were assessed in the subgroups of subjects with and

without severe bulbar impairment, as well as in the whole cohort. • An 80% chance of detecting the expected QOL benefit at the 0.05 significance

level required 40 randomized people with at least 18 with normal or moderately impaired bulbar function for subgroup analysis.

• The trial was not powered for the subgroup with severe bulbar impairment. • The duration that the SF36 mental component summary (T iMCS) and SAQLI

symptoms domain (Tisym) were maintained above 75% of baseline (randomization) score was calculated.

• Survival and the duration that QOL was maintained was analyzed using the generalized Wilcoxon test. Bulbar function was included as a covariate in the analyses.

• The time weighted mean improvement in quality of life was compared for each quality of life domain compared with the Mann Whitney U test.

Methods

Patients with severe bulbarimpairment using NIV showed some QOL benefits but had no QOL benefits when assessed by the SF36 MCS.

In the total population, patients receiving NIV had greater mean improvements in the SF36 mental health, energy vitality, and general health perception domains, and in all domains of the CRQ and SAQLI.

Results

Article OnePiepers, S; Van Den Berg, J; Kalmijn, S et al. Effect of non-invasive ventilation on survival, quality of life, respiratory function and cognition: A review of the literature. Amyotrophic Lateral Sclerosis. 2006; 7: 195-200.Study Description• Databases: Medline, Pubmed, Cochrane Controlled Trial Register• Two reviewers screened abstracts using inclusion criteria• Disagreement on including studies was resolved by discussion of reviewers• 12 articles – 1 RCT, 11 observational with 4 retrospective, 7 prospectiveFindings• These studies suggest improved survival, QOL, no decline in respiratory

function, less respiratory symptoms, and improved cognition. • No metaanalysis could be conducted.• Other studies have shown negative effects of NIV but did not meet criteria.

Article Two

SummaryNIV has been shown to improve survival, QOL, respiratory function, and cognition in ALS patients. Furthermore, a significant increase in survival was found when NPPV was introduced early (FVC<75%). Although these findings support the use of NIV in patients with ALS, these studies have flaws and other studies have shown negative effects associated with NIV, creating the need for further research on this treatment. As physical therapy seeks to improve patient QOL, understanding the effects of NIV on ALS patients can better prepare physical therapists when treating this patient population.

Amyotrophic lateral sclerosis (ALS) is one of the most common neurodegenerative conditions of adult life. Progressive weakness of limb, axial, bulbar, and respiratory muscles due to motor neuron injury and eventual cell death results in disability and ultimately death, usually within 3 years of onset. Respiratory muscle function is a strong predictor of quality of life (QOL) and survival. Although death is usually due to respiratory failure, most patients in Europe and the USA do not receive non-invasive ventilation (NIV), reflecting clinical uncertainty about its role in this condition. NIV has not been shown to improve QOL or survival in a randomized controlled trial, but people with ALS who use NIV survive longer than those who are intolerant of or decline treatment or non-randomized controls. Small prospective studies of NIV have established improvement in various domains of QOL, but none included a contemporaneous and well-matched control group, and only a few people had bulbar weakness, suggesting that only selected patients with ALS were included. In our uncontrolled pilot study, NIV was associated with improved QOL as assessed by several instruments. The mental component summary of the short form 36 (SF36) and the symptoms domain of the sleep apnea quality-of-life index (SAQLI) were the most responsive to intervention with NIV. Of five different criteria for initiation of NIV, orthopnea was the best predictor of QOL benefit and adherence to treatment.

PurposeThis study aimed to determine the effect of NIV on quality of life and survival in a typical population of patients attending a single regional centre. The study was designed to assess the general applicability of NIV across the clinical spectrum of patients with ALS.

DiscussionOverall, the quality-of-life benefits exceeded the improvement in survival, with the greatest improvements in domains assessing problems related to sleep. Improvement in Similar domains of quality of life has been documented in non-randomied studies. In patients with normal or only moderately impaired bulbar function, the improvement in median survival was large, and much greater. Patients with severe bulbar impairment had no survival benefit with NIV, but quality of life improved. This study was not adequately powered to detect the minimum clinically significant improvement in quality of life or survival in patients with severe bulbar impairment. The role of NIV in patients with severe bulbar impairment is not well understood, requiring the need for further studies.

Clinical SignificancePhysical therapy seeks to improve the impairments, functional limitations, and quality of life of patients. This study demonstrates that patients with ALS who do not receive NIV have a decreased quality of life when compared to those who do. Knowing information such as this, physical therapists will be able to better understand ALS patients and improve their physical therapy interventions.

ConclusionsIn patients with amyotrophic lateral sclerosis with respiratory compromise and normal or only moderately impaired bulbar function, NIV improves survival with maintenance of, and improvement in, quality of life. In this group of patients, the survival benefit was much greater than the extension of life offered by the only licensed neuroprotective drug for amyotrophic lateral sclerosis, riluzole. This study provides strong evidence in support of equity of access to NIV services for patients with amyotrophic lateral sclerosis. In patients with severe bulbar impairment, NIV improves sleep related symptoms, but is unlikely to confer a large survival advantage.

Carratu, P; Spicuzza, L; Cassano, A. Early treatment with noninvasive positive pressure ventilation prolongs survival in Amyotrophic Lateral Sclerosis patients with nocturnal respiratory insufficiency. Orphanet Journal of Rare Diseases. 2009; 4:10Study Description• Retrospective analysis of 72 consecutive ALS patients from 2 university labs.• 44 Patients with FVC>75% served as control group • 28 Patients with FVC<75% , 16 received NPPV, 12 were treated without NPPVFindings• A significant increase in survival at 1 year in FVC<75% patients with NPPV

compared to FVC<75% without NPPV. Median rate of decline was also slower.• No significant difference was found between FVC>75% patients and FVC<75%

patients receiving NPPV treatment• Suggests early NPPV treatment prolongs survival , reduces FVC% decline in

patients with ALS and NPPV should be used when FVC<75% instead of FVC<50%.

Presented by Craig Satterley, DPT Student

Trial Design and Participants

Exclusion Criteria: Current or previous use of NIV, life-threatening comorbidity, age > 75 years, or inability to complete the quality of life assessment because of cognitive impairment or inability to communicate by speech or lightwriter.

Patients were subsequently randomly assigned using minimization to NIV or standard care only if and when they met one or both predefined criteria: orthopnoea with PImax less than 60% of that predicted or symptomatic daytime hypercapnia.

Patients and investigators were not masked because sham ventilation was considered ethical.

All NIV patients had large improvements in the duration QOL remained above 75% of baseline and in the time weighted mean improvement in QOL. They also showed a modest improvement in survival.

In the normal and moderate bulbar impairment subgroup, NIV was associated with large benefits in QOL and survival. The duration the primary QOL measures were maintained above 75% of baseline was substantially longer for patients treated with NIV. The time weighted mean improvement in QOL measures also improved significantly with NIV.