Research summary – Reef Ronel

Neuromuscular electrical stimulation to improve exercise capacity in patients with severe COPD: a randomised double-blind, placebo-controlled trial

Matthew Maddocks, Claire M. Nolan, William D-C. Man, Michael I. Polkey, Nicholas Hart, Wei Gao, Gerrard F. Rafferty, John Moxham, Irene J. Higginson

Published in the journal Lancet Respiratory Medicine, published online December 14th 2015

Patients with severe COPD often have weak legs as breathlessness can limit their ability to be active. Normally, to combat this and other symptoms of COPD, exercise classes called Pulmonary Rehabilitation (PR) are carried out. However, more severely affected patients may struggle to do PR.

An alternative therapy was introduced, neuromuscular electrical stimulation (NMES), to COPD patients with more severe symptoms. NMES is when electricity is used to create muscle contractions, in this case in the thigh muscles. While NMES has been used to strengthen muscles in previous research, this trial is the first to explore the impact on daily activities and the first to investigate the longer-term impact of the treatment.

52 participants with very severe COPD took part in this trial over two years. Participants received 30 minutes of NMES to both sets of thigh muscles daily for 6 weeks; 27 were placebo (‘sham’ stimulation) and 25 received active NMES. The aim: to assess the effectiveness of NMES, as a therapy to be conducted unsupervised at home, and at aiding daily activities. The main measure of effectiveness in this trial was a test of how far participants could walk in 6 minutes.

The results of the walk tests strongly support the use of NMES for severe COPD patients, with the patients who received the active NMES being able to walk substantially further. During interviews active NMES participants expressed a greater ease in everyday tasks (such as climbing the stairs) and stated that they could carry out physical activities for longer. No participants reported any negative views. Unfortunately, the improvement provided by NMES quickly waned after the treatment had stopped. Therefore, all existing evidence suggests that NMES should not be considered a replacement for PR. NMES can be used as an extension to PR, and could be used when patients are unable to take part in PR programmes. In addition, the short duration of effect suggests that longer programmes need to be investigated. Nonetheless, this trial has shown that NMES is a practical home-based therapy, suited to patients with more severe symptoms and has gives suggestions for future research.

This summary was produced by Reef Ronel, Year 12 student from JFS School, as part of our departmental educational outreach programme.

Chris starts his study

Chris Harris, one of our neonatal research colleagues, has recently started measuring patients for his major study comparing the effects of two types of ventilation for babies born prematurely.  The United Kingdom Oscillation Study started in 1998 and recruited over 300 babies who were born 12-17 weeks early and needed help with their breathing from a ventilator.  All of the babies were given one of two types of breathing support – normal ventilation, where air is pushed into the lungs at a rate and depth about the same as they would do on their own, or ‘high-frequency oscillation ventilation’ or HFOV, where the lungs are inflated and then small amounts of air vibrated, or oscillated, in and out of the lungs at a very fast rate.  The idea of the HFOV is that it doesn’t involve the same amount of stretch to the lungs as normal ventilation, possibly preventing some of the damage that can occur to premature babies’ delicate lungs during the crucial weeks after birth while so much lung growth and development is taking place.  Chris is also doing some cellular biology as part of his PhD, stretching lung cells in the lab and seeing what inflammatory chemicals are released.  This will help give a more complete picture of why HFOV may (or may not) be beneficial.

The UKOS participants were last studied at 11-14 years of age; the results then showed that HFOV seemed to have protected the lungs somewhat, particularly the smaller airways further down in the lungs.  These airways are particularly prone to damage as they are still forming during the stage at which these babies were born, and the HFOV perhaps allowed those parts of the lung to continue developing more normally, as they would have done were the babies still in the womb.

The current stage of the research will make detailed lung function measurements again in as many of the participants who are able to come back for more testing, and again compare the children who received HFOV to those who received normal ventilator support.  The UKOS “babies” are now young adults, aged 16-18, and so have probably grown a huge amount since their last tests; this growth will have affected their lung function so that’s why it’s important to see how they’re getting on now.  Chris has had four patients participate so far and all has gone well thanks to their brilliant efforts, so we’re looking forward to seeing the data come in!

 

Research summary – David Launer

Pulmonary function, CT and echocardiographic abnormalities in sickle cell disease

Alan Lunt, Sujal Desai, Athol Wells, David Hansell, Sitali Mushemi, Narbeh Melikian, Ajay Shah, Swee Lay Thein, Anne Greenough

Published in the journal Thorax, August 2014

Sickle Cell Disease (SCD) is amongst the most prevalent genetic diseases worldwide. Only being inherited if both of one’s parents carry a ‘faulty’ gene in their DNA, SCD affects the Haemoglobin molecules that carry oxygen in the blood, distorting the shape of the red blood cells into so-called crescent shaped ‘sickles’.

It has been shown previously that the majority of adults with SCD have changes in their lungs that can be found on a CT scanner, a high powered X-ray scanner that can create a detailed 3D image of the lungs, including airways and blood vessels.

This study showed that findings like particularly large blood vessels in the lung were linked to reduced lung function. This study aimed to show a link between these changes in the lung and the resulting changes in heart function that one can view on an ‘echocardiogram’ in the same group of patients. An ‘echocardiogram’ is a scanner used to observe the way in which the heart functions, from ultrasound waves ‘bouncing’ off the heart. It can view the structure of the heart and vessels, as well as blood flow. In SCD the heart has to pump more blood through the lungs in order to deliver enough oxygen to the tissues.

Adults with SCD were assessed using CT, echocardiography, and other lung function tests such as lung capacity, between the years 2009-2013. This same group of adults had previously been shown to have lung changes on CT scans between 2003-2005.

Whilst there was a large variety in the lung function of the 28 patients with altered lung features, it was demonstrated that lung structure changes seen on CT scans was related to the patients’ decline in lung function, and changes in the function of the heart displayed on echocardiogram tests. Importantly, the results of the study suggest that some of the changes found in the blood vessels between the heart and lungs may be able to explain the differences in the lungs found on CT scan and the decline in lung function. The results of this study help us to understand the complex relationships between heart, lung and blood vessel function in SCD.

This summary was produced by David Launer, Year 12 student from JFS School, Harrow, as part of our departmental educational outreach programme.

Research summary – Ashleigh Francis

Airway and alveolar nitric oxide production, lung function and pulmonary blood flow in sickle cell disease
Alan Lunt, Na’eem Ahmed, Gerrard F. Rafferty, Moira Dick, David Rees, Sue Height, Swee Lay Thein, Anne Greenough
Published in the journal Pediatric Research, March 2016

Patients with Sickle Cell Disease (SCD) are often assumed to have asthma because they have ‘airflow obstruction’, which is when airways become narrowed and air is not able to move out of the lungs as quickly or easily as in healthy lungs.
Inflammation in the airways is one of the main features of asthma. Nitric Oxide (NO) is a substance that is produced by the airways when they are inflamed, so therefore can be used to measure the severity of asthma in a patient and find out how inflamed their airways are.
As well as being produced in the airways, NO is also produced in blood vessels, and helps to widen blood vessels.
People with SCD are anaemic, meaning they have less haemoglobin (a protein in the body that carries oxygen) so their cells cannot carry as much oxygen. In order to compensate for this, the heart beats faster and with more power to make sure enough oxygen is picked up from the lungs and delivered to the body.
This study looked at measurements of NO from the airways (representative of asthma) and the alveoli (representative of blood vessel widening), and compared it to lung function tests (to look at airway narrowing) and measures of pulmonary blood flow (how fast blood was circulating around the lungs).
The results showed that the airway NO was not raised, but that there was still airway narrowing occurring.  There was a relationship between how fast blood was circulating through the lungs and NO from the alveoli. This might suggest that previous findings of high NO and airway narrowing resulted in a false assumption that SCD patients’ airway narrowing was down to asthma. This study suggests that the changes in heart and blood vessel function in SCD may have an effect on the airways.
This study was relevant in terms of contributing to medical research because it shows the airway narrowing in SCD patients may not always be down to asthma, so it therefore allows us to target other root causes of the problem.

This summary was produced by Ashleigh Francis, Year 13 student from Harris City Academy Crystal Palace, as part of our departmental educational outreach programme.

Research paper summary – Casril Liebert

Ankle dorsiflexor muscle size, composition and force with ageing and chronic obstructive pulmonary disease

Matthew Maddocks, Matthew Jones, Thomas Snell, Bronwen Connolly, Susanne de Wolf-Linder, John Moxham, Gerrard F. Rafferty

Published in the journal Experimental Physiology, June 2014

Chronic obstructive pulmonary disease (COPD) is the name for a group of lung diseases that cause breathing problems. COPD patients often find it hard to do exercise because their muscles may be slightly weaker compared to a healthy person. The ankle dorsiflexor muscle, at the front of the shin, is used for balance and walking. This research looked at how the ankle dorsiflexor muscles were different between 20 young healthy people, 18 healthy elderly people and 17 people with COPD. This allows us to see how COPD affects the normal ageing process of the muscle.

Firstly, we took scans of the muscle to see what it is made of. We also measured the size of the muscle. The scans showed that the COPD patients had a lot of non-useful tissue in the muscle that doesn’t help the muscle work normally. The strength of the muscle was also measured. This was done by passing electricity into the nerve to the side of the knee that supplies the dorsiflexor muscle. This caused the nerves to react and tense the muscle.

The results showed that patients with severe COPD have ankle weakness. This means that their muscles are not as strong as a healthy person and it is harder to do certain tasks that require strength. The scans also revealed that a greater muscle size was associated with a greater muscle strength, and also that tissue in the muscle without a function is a major cause of muscle weakness. The muscle composition scan discovered that fat and fluid in the muscle was often found in COPD patients. This tissue that isn’t useful creates problems which affect exercise performance and postural control, causing impaired balance and walking abnormalities. The discoveries within this study have allowed us to better understand why muscle strength in COPD patients decreases much more than seen with normal ageing.

This summary was produced by Casril Liebert, Year 12 student from JFS School, Harrow, as part of our departmental educational outreach programme.

Research paper summary – David Launer

Longitudinal Assessment of Lung Function in Children With Sickle Cell Disease
Alan Lunt, Emily McGhee, Karl Sylvester, Gerrard F. Rafferty, Moira Dick, David Rees, Sue Height, Swee Lay Thein, Anne Greenough

Published in the journal Pediatric Pulmonology, December 2015

Sickle Cell Disease (SCD) is amongst the most prevalent genetic conditions worldwide. Only being inherited if both one’s parents carry a ‘faulty’ gene in their DNA, SCD affects the Haemoglobin molecules that carry Oxygen in the blood, changing the shape of the red blood cells into so-called crescent shaped ‘sickles’. Despite its commonness, with over 300,000 babies being born with SCD worldwide every year, a clear and consistent picture of how SCD affects the lungs of children with SCD had not yet been researched. This study aimed to research the lung function of children affected by the disorder over time, observing how this changed in early and later childhood, and how this was affected by episodes of ACS (Acute Chest Syndrome) in early childhood, when the sickle-shaped red blood cells can block blood vessels and lead to various different injuries.

Two groups of children were tested. The first, who were slightly younger on average, were
measured twice for their lung function over an average of 2 years, while the second group were measured twice over approximately 10 years. A number of methods were used to test each person’s lung function, including ‘spirometry’ in which the quantity of air one can force out the lungs is measured, among other values like lung capacity. These measurements were then compared to a ‘control’ group of healthy children without SCD at a similar age, to give a normal level of lung function to compare against the SCD patients’.

In both groups of children with SCD, a reduction in lung function over time was seen when compared to the groups of children without SCD. However, the lung function of those in the first, younger, group decreased at a faster rate.

The results suggest that the fastest period of deterioration in lung function takes place in early childhood. Indeed, having an episode of ACS in young childhood was the only factor found that increased the likelihood of worse overall lung function later on. This could explain the faster decline of the younger group, as ACS is more common in younger children. This would seem to conclude that a focus should be placed on preventing ACS in young children as a strategy to improve the general lung function later on of those with SCD.

This summary was produced by David Launer, Year 12 student from JFS School Harrow, as part of our departmental educational outreach programme.

Research paper summary – Lily Groom

Understanding Heroin Overdose: A Study of the Acute Respiratory Depressant Effects of Injected Pharmaceutical Heroin  Caroline J. Jolley, James Bell, Gerrard F. Rafferty, John Moxham, John Strang

Published in PLoS One, October 2015

Opioids are a class of drug which act by attaching to opioid receptors, found in the brain and spinal cord, reducing the perception of pain. For this reason, opioids are often prescribed for pain relief. When people misuse opioids, they are often unaware of the dangerous side effects that come with them. For example, they are respiratory depressants, meaning they can reduce the breathing rate, which can be fatal. Many of the current methods of measuring respiratory depression under-estimate the true effect these drugs have on the body (especially the breathing rate), which is why this study was undertaken. Respiratory depression is a major cause of overdose and if you cannot detect when it is happening effectively, you have less chance of helping someone suffering from it.

The participants in this study were monitored over a course of 150 minutes, after they had been given their usual opioid dose. This was done using EMGpara (a tool which assesses how hard the breathing muscles are working), pulse oximetry (measuring the blood’s oxygen levels), and measurement of carbon dioxide levels in exhaled breath. The participants were asked to rate how much they felt the drug’s effect at three minutes prior to the drug being given, and then at regular intervals afterwards. Staff ratings of intoxication and level of consciousness were also given. Pulse oximetry and observer ratings are the more commonly used methods of observing patients’ breathing currently.

However, this study found that there was an increase in the level of carbon dioxide per breath in eight of the ten participants and a low blood oxygen level in only four out of the ten patients. The difference in results shows that the traditional approach of measuring the blood’s oxygen level is not as sensitive a method to detect respiratory depression after taking an opioid. There were varying degrees of respiratory depression found in all patients. However, the pulse oximetry only picked up four of these. The study also found that just talking to a patient helped to mask episodes where they were breathing unusually slowly. This means that it is very easy to miss a potentially dangerous symptom.

The findings of this study therefore suggest that we should change the way we test for respiratory depression in clinical settings, to help identify, treat and prevent it in patients taking opioids.

This summary was produced by Lily Groom, Year 13 student from Graveney School, Tooting, as part of our departmental educational outreach programme.

Research paper summary – Lottricia Millett

Parasternal Intercostal Electromyography: a Novel Tool to Assess Respiratory Load in Children Victoria MacBean, Caroline J. Jolley, Timothy G. Sutton, Akash Deep, Anne Greenough, John Moxham, Gerrard F. Rafferty

Published in the journal Pediatric Research, May 11th 2016

Parasternal intercostal electromyography (EMGpara) is a new way to measure breathing difficulty. Research needs to be carried out because body parts used in breathing, like the lungs, need to be properly checked over for breathing problems to be managed, but the testing methods aren’t always suitable for children who are very young or ill. The parasternal intercostal muscles are muscles that move at the same time as the diaphragm (a thin sheet of muscle under the lungs) when you breathe in and out. EMGpara measures signals from the brain which are sent to these muscles without putting any instruments into the body, so it is ideal for children.

EMGpara was measured using stickers on the front of the chest while the participants (92 healthy, 20 wheezy and 25 with a machine (ventilator) to help them breathe) were breathing in and out in a resting state. For the wheezy children, measurements were taken before and after a substance to widen air passages (reliever inhaler, or bronchodilator) was used; for the critically ill children, these were taken during ventilator-assisted breathing, then with just mild air pressure to keep the airways open (continuous positive airways pressure).

It was found that as age, weight and height increased, EMGpara decreased. This is because when children are growing up, big changes take place in the respiratory system, decreasing the effort needed for breathing. EMGpara in the healthy children was the lowest; in the wheezy children it was higher before the bronchodilator was used, dropping to similar levels to the healthy children afterwards. In the critically ill children, EMGpara was higher than in the wheezy children when the ventilator was used, and even higher with continuous positive airways pressure when they were having to breathe without support.

This study has shown that measuring EMGpara is possible in children of a range of ages and levels of health. The results from the healthy children have shown important age-related changes in EMGpara, and those from the wheezy and critically ill children have shown that EMGpara is affected by changes in how hard the breathing muscles have to work because of different diseases and treatments. EMGpara could be a really helpful method in testing the breathing ability of patients who are usually difficult to assess.

This summary was produced by Lottricia Millett, Year 12 student from Burntwood School, Wandsworth, as part of our departmental educational outreach programme.

A summer with the King’s Muscle Lab

Sasha is a KCL student who is working with Dr Joerg Steier, a former King’s Muscle Lab researcher who is still part of our wider research group.  Here she tells us how she has found her research ‘taster’ summer so far…

My name is Sasha and I am a 2nd year Neuroscience student at KCL. The Neuroscience course,Sasha much like other Biomedical Science courses at King’s, aims to coach you in to a research career. For ages I was never really sure whether I wanted to pursue a career in research. I couldn’t see myself stuck in a lab with pipettes in a white coat, but after a few months of working as a summer student alongside researchers, I have learnt research is nothing like that at all!

I decided to get work experience over the summer because I knew I wouldn’t be sure to pursue a career in research unless I actually had some experience of doing the job. I saw a project online through King’s called ‘the Multiple Dimensions of Sleepiness’ and after having a few lectures on sleep physiology and medicine and thoroughly enjoying them, I decided to email the supervisor, Dr Steier, and share my interest in his project. It was agreed that I would help Dr Steier throughout the summer in collecting and analysing data, attending research meetings, and writing up the paper.

On the first day of helping Dr Steier I was super nervous – I really wanted to make a good impression! We were meeting at his office at 11am so I got there at 10.40am with plenty of time to spare. I knocked on the door and there was no answer. Not to worry I thought – it’s just because I’m early. I stood outside the office for 45 minutes with no one answering the door. I decided at this point to email Dr Steier as maybe he had forgotten we were meeting. He speedily replied saying “Ah I wondered where you were, today I am at my other office in the Lane Fox Unit (Westminster) not at Nuffield house (London Bridge).” So I spent my first day on the job running across London to the other campus arriving sweaty and breathless. Already I had learnt something very important – researchers may have multiple offices in different locations (and I must check beforehand which office I need to go to)!

The next few weeks went smoothly, I attended research meetings where researchers of the King’s Muscle Lab shared their ups and downs of their projects. From these meetings it became clear that research isn’t always smooth sailing, there are set backs and hurdles you need to get through but you have your colleagues, who have often been through the same thing, to support you. Attending these meetings I gained a really good insight in to the different projects that take place in the King’s Muscle Lab. At first it was difficult as I noticed researchers seems to abbreviate EVERYTHING, they are either discussing what happened in ICU or they’re gathering data from EEG’s, MSLT’s and PSG’s… It took me a few meetings to get the hang of it but after that there is nothing cooler than abbreviating everything and having your housemates think you’re an actual genius!

So far, my favourite part about helping on the project has been the data collection. This is because our data is questionnaire based so I have been able to interview patients from the sleep clinic. I have really taken to patient contact and I feel that it is the best way to really get down to the problem you are researching. It’s also really helped with my confidence and I have learnt to approach different patients in different ways based on their needs.

After data collection was completed, we needed to do some analysing. This was done using SPSS [statistical software]. Having never using this software before I was a bit overwhelmed. It seemed so confusing and Dr Steier could do everything on it so quickly. I honestly thought I would never get the hang of it. But after several YouTube videos and a couple of hours in the library I seemed to be producing means, standard deviations, correlations and linear regressions with ease! Alike to the abbreviations, it was tough at the beginning but it felt so good to actually understand how it worked.

We are now at a point in our project where we have sent off an abstract to a journal and we are waiting for it to be accepted. I have prepared myself to not be too disgruntled if it doesn’t get accepted because, like I said, there are many setbacks in research – you just need to let your passion for the subject keep you going. In only a couple of months I have learnt so many research skills that will help me in my career, but I think most importantly I have learnt many skills that will help me through life. I would say the TOP career skills I have learnt are to be a Team player, be Open minded and to Persevere!

Lung function in dolphins!

Dan came across a research paper the other day that was all about measuring respiratory function in dolphins – and it turns out that dolphins have pretty fascinating respiratory systems so we thought it worth sharing.  Obviously measuring lung function in any animal is tricky, but when they live in water…  We’re pretty impressed with the data these researchers managed to get, given that we often struggle with adult humans.  One good thing is that dolphins are so smart that the research team were actually able to train them to perform specific respiratory manoeuvres (“chuffs”) so that they could compare normal dolphin breathing to these effortful breaths.  The researchers also emphasised that the dolphins were free to swim away or resist the measurements if they wished, so actually they ‘gave consent’ for the study in their own way (tricky to sign a consent form when you’ve only got flippers).

Dolphins’ lungs get exposed to a much wider range of pressures than animals who live on the ground, as they have to be able to breathe at the surface but also cope with the increasing pressure as they dive.  It has been thought for some time that diving mammals probably have much floppier small airways and alveoli in order to allow these parts of the lungs to collapse when under pressure during dives, and then re-expand easily when they re-surface.  In this study, the researchers passed small tubes with pressure sensors down into the dolphins’ stomachs so that they could measure the pressure being generated by the dolphins’ respiratory muscles.  This is the same as we do in our studies – though probably a bit harder to do…  This showed that dolphins’ lungs are about four times ‘stretchier’ than human lungs, in line with the researchers’ hypothesis.

F1.largeThe researchers also used a very large flow sensor over the dolphins’ blowholes to measure how much and how fast they were breathing, along with the concentrations of oxygen and carbon dioxide in the air.  Dolphins only breathe about 3 or 4 times per minute (compared to 12-15 breaths per minute in an adult human), but when they do take a breath they have to exchange a huge amount of air very quickly (their total time to breathe in and out is only about 0.7 seconds).  This study showed that even during a normal breath, air moves out of the blowhole at a rate of over 2,600 litres per minute, which is almost four times higher than the fastest human cough we’ve ever measured in our lab!  During a “chuff”, the highest flow recorded in this study was 8,400 litres per minute – that would be 84 bathtubs full of air over a minute!  During a normal breath the dolphins tended to take breaths of about 5-6 litres (which is about the total lung size in adult humans), but this went up as high as 18 litres during chuffs.  They also absorb more oxygen than humans do from the air they breathe – air contains 21% oxygen.  Exhaled breath from a human is normally about 17% oxygen, but dolphins get quite a lot more from it and breathe out gas at only 12.3% oxygen.  They also breathe out a bit more carbon dioxide than us (7% compared to 5% for humans).

So, in summary…  Dolphins:  big lungs, fast lungs, effective lungs.  We are in awe of the research team for what looks like an exceptionally challenging study, with fascinating results!