Archive: Feb 2021

Study protocol randomised controlled trial evaluating exercise therapy as a supplemental treatment strategy in early multiple sclerosis the Early Multiple Sclerosis Exercise Study (EMSES)

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Abstract

Introduction

In the relapsing remitting type of multiple sclerosis (MS) reducing relapses and neurodegeneration is crucial in halting the long-term impact of the disease. Medical disease-modifying treatments have proven effective, especially when introduced early in the disease course. However, patients still experience disease activity and disability progression, and therefore, supplemental early treatment strategies are warranted. Exercise appear to be one of the most promising supplemental treatment strategies, but a somewhat overlooked ‘window of opportunity’ exist early in the disease course. The objective of this study is to investigate exercise as a supplementary treatment strategy early in the disease course of MS.

Methods and analysis

The presented Early Multiple Sclerosis Exercise Study is a 48-week (plus 1-year follow-up) national multicentre single-blinded parallel group randomised controlled trial comparing two groups receiving usual care plus supervised high-intense exercise or plus health education (active control). Additionally, data will be compared with a population-based control group receiving usual care only obtained from the Danish MS Registry. The primary outcomes are annual relapse rate and MRI derived global brain atrophy. The secondary outcomes are disability progression, physical and cognitive function, MS-related symptoms, and exploratory MRI outcomes. All analyses will be performed as intention to treat.

Figure 1 a: Primary outcome, b: Part of the Multiple Sclerosis Functional Composite, c: Outcomes available in the population based registry database.

Participants

Recruitment and eligibility

Patients with MS will be recruited via six Danish regional MS clinics (Aarhus University Hospital, Odense University Hospital, Clinics of Southern Denmark (Sønderborg, Esbjerg, Kolding), and Hospital Unit of Western Denmark), or via social media groups and events related to the Danish MS Society. In all cases, patients will be supplied with a leaflet explaining the rationale, design and content of the study and inviting them to participate. Those interested in participation will receive detailed written information as well as a leaflet from the National ethical committee explaining their rights as a participant in a health science research project. Furthermore, the project coordinator will contact participants by phone to explain the study, give the opportunity to ask questions, and to screen according to the inclusion criteria. Specifically, patients have to fulfil the following: (1) 18–60 years of age, (2) ≤2 years since clinical diagnosis with relapsing remitting MS and (3) no relapses or changes in medication ≤8 weeks prior to inclusion. Patients will be excluded if they: (1) are pregnant, or (2) have comorbidities or other issues thought to hinder participation in high intensity exercise activities. Finally, project nurses from the regional MS clinics confirm eligibility based on the patients’ medical records, and patients sign informed consent (standard formula from the Danish National Research Ethics Committee, see online supplemental material before inclusion.

Table 1 Summary of the supervised exercise therapy intervention

Primary outcomes

The overall primary outcomes of the study are annual relapse rate and MRI-derived annual global brain atrophy rate.

Relapse rate

The number of relapses in the study period is obtained from the medical records of the included patients. This will be done in collaboration with the respective MS clinics, and all relapses will be confirmed by a neurologist. According to the Danish national neurological association, a relapse is defined as new symptoms or worsening of existing symptoms, causing neurological dysfunction for a minimum of 24 hours without any signs of infection or fever. This exacerbation must be preceded by a stable 4-week period. The annual relapse rate is calculated for each patient by dividing 365 days with the number of days in the study and multiplying by the number of relapses in the study period. Due to the clinically meaningful definition of this outcome any potential changes in the relapse rate will be considered clinically meaningful.

Secondary outcomes

Disability progression

Neurological impairments in MS can be assessed by grading the impairment of eight different functional systems (pyramidal, cerebellar, brain stem, sensory, bowel and bladder, visual, cerebral, other) to rate the total EDSS score. The EDSS score is considered the gold standard when assessing disability and disease progression in MS and it is used routinely as a clinical endpoint in trials of DMTs. In this study, the EDSS score will be determined for each participant by trained neurologists at the six collaborative MS clinics during routine clinical visits. Therefore, the EDSS score nearest to the date of inclusion, to the date of completion, and to the date of 1 year since completion will be used to assess the progression of disabilities. However, recent studies have pointed out limitations in the EDSS score such as insufficient inter-rater and intrarater reproducibility and a low responsiveness—especially at the lower end of the scale. Therefore, the main measure of disability progression will be the Multiple Sclerosis Functional Composite (MSFC).

Inflammatory and neurodegenerative biomarkers

Blood samples will be collected in resting state at baseline, after 24 weeks, after 48 weeks, and again at 1-year follow-up. Patients will be allowed a minimum of 5 min supine rest before blood collection from the antecubital vein. Blood samples will be collected in ethylenediaminetetraacetic acid-treated tubes, resting for 90 min, and subsequently centrifuged at 1200 g for 10 min. Thereafter serum will be extracted and divided into five aliquots and stored at −80°C until further analyses.

Analysis of blood samples will be exploratory and aim to investigate the effects of exercise on relevant biomarkers, such as Glial Fibrillar Acid Protein, proinflammatory and anti-inflammatory markers (eg, interleukin-6, interleukin-10, interleukin-17, tumour necrosis factor-α) as well as neurodegenerative (eg, neurofilament light chain) and neurotrophic markers (eg, brain-derived neurotrophic factor, insulin-like growth factor).

Table 2 Overview of assessments and the order of testing at different time points

DISCUSSION AND PERSPECTIVES

The presented study seeks to investigate supervised exercise as a supplemental treatment strategy early in the disease course of relapsing remitting MS. Effects of the
intervention will primarily be investigated on measures of disease activity and neurodegeneration, and secondarily on measures of disability progression, cognitive and physical function, and symptoms of fatigue. Efforts investigating the effects of exercise beyond rehabilitation (eg, as a supplemental disease-modifying strategy) are warranted and an overlooked ‘window of opportunity’ early in the disease course for MS exercise therapy have previously been identified. Importantly, the present study addresses both of these issues making the approach novel and innovative. Furthermore, the present study complies with the recommendations from
recent publications guiding the field of MS rehabilitation and exercise aligning the methodology with the current stage of the literature. Specifically, the study has
clearly defined primary outcomes and sample size calculations based hereupon (resulting in a large-scale exercise study), includes a rather long-term supervised exercise intervention and a well-monitored active control group (eg, importantly controlling the physical activity level of participants).

In summary, this is the first-ever study to investigate the effects of exercise in the very early stages of MS and thereby taking a more preventive approach aiming at lowering the disease activity more than medical DMTs alone aiming at maintaining (or even improving) functional and neurological reserve capacity. We expect the present study to hold the potential to change the current clinical practice regarding exercise therapy with MS. In particular, the present study may provide the first data supporting a warranted shift of paradigm where exercise will be considered a supplemental treatment strategy from an early timepoint in the disease course of MS. If these early exercise efforts show additional disease-modifying and neuroprotective effects, this is inherently of major interest to the individual MS patient, yet also to the healthcare system. While medical DMTs constitute the majority of healthcare costs for patients with mild MS early exercise efforts
may be a cost-effective supplemental treatment strategy to minimise disability progression and the huge-related costs. Another highly important perspective of early
exercise efforts as a supplemental treatment strategy in MS is the improvement of general health of the patients and the derived reduction in the increased risk of lifestyle-related comorbidities observed in patients with MS.

                 

Exercise Biology, Department of Public Health, Aarhus University, Aarhus, Denmark
Exercise Biology, Department of Public Health, Aarhus University, Aarhus, Denmark.
3 The MR Research Centre, Aarhus University Hospital, Aarhus N, Denmark.
4 Center of Functionally Integrative Neuroscience, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
5 The Multiple Sclerosis Clinic, Department of Neurology, Aarhus University Hospital, Aarhus, Denmark.
6 Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark.

11 Jan 2021, 11(1):e043699

Efficacy and safety of oxygen-sparing nasal reservoir cannula for treatment of pediatric hypoxemic pneumonia in Uganda: a pilot randomized clinical trial

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Abstract

Background: Oxygen is an essential therapy for hypoxemia but is scarce in low-income settings. Oxygen conserving devices optimize delivery, but to date have been designed for adults in high-income settings. Here we present the development and clinical pilot study of an oxygen-sparing nasal reservoir cannula (OSNRC) for pediatric use in low-income settings.

Methods

(1) Pre-clinical development of a novel OSNRC using a simulated respiratory circuit with metabolic simulator and anatomically accurate face-airway models. Simulated breathing waveforms were designed based on airway resistance, lung compliance, respiratory rate, and tidal volume of spontaneous breathing for three disease conditions.
(2) Pilot, randomized, controlled, non-blinded, cross-over study of the OSNRC vs standard nasal cannula (SNC) among children hospitalized with hypoxemic pneumonia in Uganda. Eight children were randomized to OSNRC followed by SNC, and eight were randomized to SNC followed by OSNRC.

Results

The laboratory simulation showed that the OSNRC provided the same or higher fraction of inspired oxygen at approximately 2.5-times lower flow rate compared to SNC. The flow savings ratio exhibited a linear relationship with the OSNRC volume to tidal volume ratio with a slope that varied with breathing waveforms. The range of performance from different breathing waveforms defined a performance envelope of the OSNRC. Two mask sizes (30 mL and 50 mL) provided sufficient coverage for patients between the 3rd and 97th percentile in our targeted age range. In the clinical pilot study, the rise in capillary blood pCO2 was similar in the OSNRC and SNC groups, suggesting that the OSNRC was not associated with CO2 retention. There were no significant differences between OSNRC and SNC with respect to clinical adverse events, lactate levels, pH, and SpO2. The OSNRC group had a higher mean SpO2 than the SNC group (adjusted mean difference, 1.4, 95% confidence interval 1.1 to 1.8), showing oxygen delivery enhancement.

Conclusion

The OSNRC enhances oxygen delivery without causing CO2 retention and appears to be well-tolerated by pediatric patients. If safety, efficacy and tolerability are confirmed in larger trials, this device has the potential to optimize oxygen delivery in children in low-resource settings, reducing the global burden of pediatric pneumonia.

Authors: Jerry Mulond1 , Stella Maleni1, Hellen Aanyu-Tukamuhebwa2, Ezekiel Mupere2,3, Alfred Onubia Andama4, Chin Hei Ng5, Stephen Burkot5, Ella M. E. Forgie6, Qaasim Mian6, Christine M. Bachman5, Gerard Rummery7, Daniel Lieberman5, David Bell5,8, Michael T. Hawkes6,9,10,11,12*† and Akos Somoskovi5†

1 Infectious Diseases Research Collaboration, Kampala, Uganda.
2 Department of Pediatrics and Child Health, Mulago National Referral Hospital and Makerere University, Kampala, Uganda.
3 Department of Pediatrics, Makerere, University College of Health Sciences, Kampala, Uganda.
4 Department of Medicine, Makerere University College of Health Sciences, Kampala, Uganda.
5 Intellectual Ventures, Global Good Fund, Bellevue, WA, USA.
6 Department of Pediatrics, University of Alberta, 3-588D Edmonton Clinic Health Academy, 11405 87 Ave NW, Edmonton, Alberta T6G 1C9, Canada.
7 ResMed Ltd., Bella Vista, Australia.
8 Present address: Issaquah, USA.
9 Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Canada.
10 School of Public Health, University of Alberta, Edmonton, Canada.
11 Stollery Science Lab, Edmonton, Canada.
12 Women and Children’s Health Research Institute, Edmonton, Canada

* Correspondence: mthawkes@ualberta.ca †
Michael T. Hawkes and Akos Somoskovi contributed equally to this work

           

Article published in: BMC Pulmonary Medicine volume 20, Article number: 230 (2020)

Efficacy and safety of oxygen-sparing nasal reservoir cannula for treatment of pediatric hypoxemic pneumonia in Uganda: a pilot randomized clinical trial