Muscle wasting in critical illness

A session blog from Day 2 of State of the Art, London December 2015. See the full list

 

Blogger – Andy Martin @andymartin5

Patient experience: Setting the scene

The session started with a video of a 73-year-old patient who had been admitted to intensive care following pneumonia. She remained there for 3-4 weeks, receiving a tracheostomy and was obviously very weak by this stage. Events followed her as she underwent strengthening exercises, using various aids as she learnt how to stand and walk again. At one point she was even using a Nintendo wii for exercise. Initial rehabilitation took around 6 weeks before she another 2 weeks in acute rehab before going home.

An interesting start to proceedings with a case I am sure we can all relate to.

Scientific background: the known unknowns

Zudin Puthucheary

Summary/ Key Messages

Zudin then came to the stage to begin by outlining what we know about ICU-Acquired Weakness (ICU-AW) and the areas that we are still not clear about.

  • Although ICU mortality is dropping, the rapid rise in admission rates still comes at a cost – Of patients admitted of working age, 50% will not be at work 1 year after discharge, while 30% still need assistance with ADLs (NEJM). The majority of ICU survivors are also classified as sedentary according to the WHO classification.
  • Muscle weakness and wasting is the greatest contributor to this phenomenon – The 2nd greatest complication of ICU admission.
  • Despite its incidence, we still don’t know much about ICU-AW pathophysiology and thus, don’t know the best ways to rehabilitate after weakness develops or how to prevent it.
  • Similarly, the number of publications in the last year on this topic remains small in comparison to ARDS for example.
  • The reason the evidence base is not there (despite there being grade 1 evidence for rehabilitation in chronic disease states not replicated in ICU) may be due to
    • The heterogenicity of the patient population and disease states.
    • The varied patient outcome measures used – Do we need to consider a novel outcome measure?
  • Maybe some patients just can’t be rehabilitated – Up to 40% of patients with multi-organ failure have myofibre necrosis – Maybe there is a biological response preventing its repair.
  • What we do know is that critical illness leads to a breakdown in the balance of protein homeostasis – Reduced synthesis and increased destruction.
  • For protein synthesis to occur, we know that we need amino acids, exercise and energy – It is difficult to provide all 3 in illness with exercise being the most obvious flaw
    • This has been challenged with the use of neuromuscular electrical stimulation although clinically significant improvements weren’t seen.
    • May be this is because it is not just stimulation the muscles need but a resistance stimulus to be provided
      • This has led to the use of electrical stimulation assisted cycling
    • Perhaps it is that we don’t know how to feed our patients
      • Studies from the 1970s showed that after 2 hours of being continuously fed, protein uptake by muscles is shut off.
      • We await the results of the IVC study – An RCT looking at the effects of intermittent vs continuous enteral feeding in ICU
    • Ultimately, it is important to not class ICU-AW as a disease but consider it as a syndrome.
    • There are several upcoming studies look into this in more detail
      • MSK USS Study in critical care
      • Muscle II – The Ripped Protocol

References/Further reading

 

The basic science – what do we know?

Brijesh Patel

Following that fantastic introduction to the topic, Brijesh came to the stage to tell us in more detail some of the potential pathophysiological features that ICU-AW involves.

Summary/Key messages

  • What is ICU-AW
    • A combination of CIP/ CIM/ SIM/ SDM.
  • How does muscle wasting occur
    • Difficult to illicit one pathway due to the heterogenous group of patients we encounter.
    • It is difficult o reproduce circumstances in animal models.
    • Oliver Friedrich was one of the first to introduce us to the relevant elements of muscle wasting.
    • What we do know that happens
      • Severe muscle atrophy occurs.
      • That the sicker you are, the worse it is.
      • Both acute and long-term states with impact on length of stay.
      • Inflammation drives myosin loss.
      • TNF – Also called cachexin
        • Works via 2 receptors
        • TNF1/p55 receptor – Involved in Apoptosis signalling and drives catabolic action.
        • Upregulation of system driving protein breakdown – Ubiquitin-proteosome complex.
      • Caspase activation involved in diaphragm weakness and muscle dysfunction.
    • There is a Lung-muscle relationship.
      • Particularly in ARDS.
      • If the PF ratio bad at 24 hours – more likely to have muscle break down at 10 days.
      • Macrophage infiltrate into muscle – Is this a repair mechanism rather than a driving force?
    • How can we potentially enhance recovery
      • We know that 5 years down line patients still have significant deficit.
      • Satellite cells may be relevant
        • They are stem cells in muscle itself.
        • Their function changes depending on the age of the patient (young vs old).
        • They may be the difference between regeneration of muscle fibres vs aberrant activation and muscle fibrosis.
      • Increase anabolism
        • IGF1 drives this – affected by myostatin in catabolism.
        • Myostatin inhibition already present in nature – you can even get tablets over the internet (see body builders)!

References/Further reading

Translational research – where are we heading?

Claudia dos Santos

Lastly Claudia took to the stage having travelled all the way from Toronto to talk to us about some of their current research within this topic.

Summary/Key messages

  • We know that there is an Early and a Late phase to ICU-AW – The Late phase is actually more than 3-6 months after ICU.
  • Persistent ICU-AW involves
    • Atrophy of fast twitch muscle fibres with selective loss of myosin.
    • There is a both a Functional (loss of contractility ability) and Structural (loss of muscle mass) change to muscle tissue.
    • Patients plateau recovery at 6 months – Thus, any potential intervention must be before 6 months, otherwise damage likely to be permanent from then due to the fibrosis.
  • MEND-ICU Program
    • A study looking at the mechanisms that underlie persistent ICU-AW.
    • Aim to better identify those at risk for long term irreversible sequelae and inform elective interventions.
    • Also to identify risk factors for failure of muscle repair/ recovery.
    • They looked at the degree of skeletal muscle atrophy and functional impairment at 7 days and then at 6 months with an associated muscle biopsy.
    • Recruitment proved very difficult, with many lost during follow-up with a reluctance for further invasive procedures shown.
    • The results showed
      • Persistent muscle atrophy at 6 months.
      • Dissociation between persistent loss of muscle mass and contractility
        • Mass recovered but contractility remained poor.
      • Sarcomeres looked normal at 6 months vs poor differentiation at 7 days.
      • No persistent defects in mitochondria size or number although their function was not assessed.
      • Genes showed a difference in acute and chronic states.
      • A reduced number of satellite cells may affect recovery.
    • These results help to inform about the potential causes of ICU-AW and will help lead further research into this area.

 

References/Further reading

 

Q&A

After some fascinating talks, throwing up plenty of areas for more thought, there were plenty of questions taken from the floor and from twitter.

These included –

  • What is the practical basis for this information – When should we mobilise our patients and how should we do it?
    • The answer revolved around what your units practice involved, for example did it practice a heavy or light sedation protocol as this will influence when patients can be mobilised.
    • Best practice would suggest mobilising at 48 hours after admission if possible with early physio input.
    • But ultimately we just don’t know what mobilisation is beneficial – it may be the overall package that is relevant.
  • What should the standards be for helping to prevent ICU-AW?
    • The consensus was to minimise sedation and aim to mobilise to a chair for a short period of time by 48 hours after admission.
    • Although we then don’t know if it is the lack of sedation or the early mobilisation that accounts for any improvement – This probably doesn’t matter.
  • Mervyn Singer then asked that even though recovery of many aspects of muscle structure occurs, functional recovery often still does not happen – why?
    • We just don’t know.
    • We don’t know what mobilisation does to patient’s biology – until we know this in more detail we can’t work out what treatment will cause improvements.
  • Is weakness an inherent problem we cannot resolve? Is the catabolic response something that is a normal response? Where do we move from normal to abnormal muscle breakdown?
    • How do we know when immune response bad? – We don’t know that yet.
    • Processes that drive repair occur in hours of initial insult – there are mediators, which dampen response for some reason not elucidated yet.
    • Is there a systemic switch, which stops proteolysis and until we know this there is no point focusing on altering muscle processes.
  • How can we detect muscle wasting and what do we do if we have?
    • Detecting ICU-AW is easy – What to do with it is hard.
    • Functional testing is an important feature – sit to stand a powerful predictive tool of likelihood of being independent afterwards.
    • Ensure there is a rehabilitation transition for patients to pass through when discharged from ICU.

 

 

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s