Neuromuscular Blockade in ARDS

Reviewed revised 2 August 2014

OVERVIEW

  • The use of neuromuscular blockade in acute respiratory distress syndrome (ARDS) is controversial
  • Renewed interest since the French ACURASYS trial in 2010

RATIONALE

  • benefits of controlled ventilation need to be weighed against the longer term harm from neuromuscular weakness and drug adverse effects

PROS AND CONS

Advantages

  • NNT of 7 for 90d mortality when adjusted for baseline in imbalance in ACURASYS
  • also decreased MV days, less organ failure and more ICU free days
  • less pneumothoraces (barotraumas)
  • no increase in amount of critical illness polyneuropathy in ACURASYS trial
  • cheap
  • simple
  • easy to titrate (neuromuscular monitoring)
  • decreases the amount of sedation required to tolerate ventilation strategy (permissive hypercapnoea)
  • NMBAs are also thought to have an anti-inflammatory effect, including attenuation of interleukin-6 and 8 expression
  • improved ventilator synchrony with decreased ventilator-induced lung injury, and improve oxygenation due to lower oxygen consumption

Disadvantages

  • awareness and increased risk of PTSD (need use of a depth of sedation monitor)
  • extra intervention
  • most beneficial in sickest patients
  • study underpowered as assumed mortality rate was 50% (actually 40% in control group)
  • drug side-effects (e.g. histamine release with hypotension, bronchospasm, urticaria due to cis-atracurium)
  • associated with ICU-acquired weakness in other studies
  • unable to assess neurological status

EVIDENCE

Papazian L. et al Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med. 2010 Sep 16;363(12):1107-16. PMID: 20843245

  • aka ACURASYS trial
  • MC RCT (French study) – 20 ICU’s
  • n = 340
  • cis-atracurim vs placebo in early severe ARDS for 48 hrs
  • inclusion criteria:
    — intubated for hypoxic respiratory failure for less than 48 hours, ARDS (PF ratio < 150)
  • exclusion criteria:
    — age < 18, no consent, already paralysed by infusion, pregnancy, increased ICP, severe COPD, fat, severe liver disease, bone marrow transplantation or chemo induced neutropenia, pneumothorax, expected duration of MV < 48 hrs, withdrawal of care imminent, ‘other reasons’ = 10%
  • primary outcome: 90 day mortality
  • secondary outcomes: 28 day mortality, outside ICU days, organ failure free days, barotraumas, ICU-acquired paresis, ventilator free days, ICU discharge

Strengths of study

-> no significant difference in 90 day mortality (as underpowered)
-> significant difference in mortality when adjusted for the pre-specified covariates of baseline PaO2:FiO2, Simplified Acute Physiology II score, and plateau pressure (NNT = 7)
-> suggestion of increased survival in the patients with lower P:F ratios
-> no difference in 28 day mortality

Cis-atracurium group:

-> had significantly more ventilator free days
-> less organ failure days
-> spend more days outside ICU
-> less pneumothoraces
-> no difference in ICU-acquired paresis!

Weaknesses of study

  • ‘others’ excluded = 10%
  • underpowered given assumed a 50% mortality rate at it was actually 40% in control group
  • used censored 90-d mortality rate (i.e. mortality in hospital within 90 days, not true 90d mortality)
  • weakness was not assessed 1 week post-desedation as described in the pre-existing literature
  • effectiveness of neuromuscular blockade was not confirmed
  • true blinding is unlikely as non-paralysed patients will trigger the ventilator
  • how ventilator dyssyncrony was dealt with was not addressed
  • cannot be certain that the neuromuscular blockade was the factor (other drug effect? e.g. anti-inflammatory)
  • may not be generalisable to other neuromuscular blockers, or to later in the course of illness

CONCLUSION

  • this trial has reawakened the use of neuromuscular blockade in severe the management of ARDS
  • Using NMBs in early, severe ARDS for 48 hours with use of a depth of sedation/anaesthesia monitor appears to be an acceptable, safe and possibly beneficial approach

References and Links

Journal articles

  • Alhazzani W, Alshahrani M, Jaeschke R, Forel JM, Papazian L, Sevransky J, Meade MO. Neuromuscular blocking agents in acute respiratory distress syndrome: a systematic review and meta-analysis of randomized controlled trials. Crit Care. 2013 Mar 11;17(2):R43. PMC3672502.
  • Papazian L, Forel JM, Gacouin A, Penot-Ragon C, Perrin G, Loundou A, Jaber S, Arnal JM, Perez D, Seghboyan JM, Constantin JM, Courant P, Lefrant JY, Guérin C,  Prat G, Morange S, Roch A; ACURASYS Study Investigators. Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med. 2010 Sep 16;363(12):1107-16. PMID: 20843245. [Free Full Text]
  • Price D, Kenyon NJ, Stollenwerk N. A fresh look at paralytics in the critically ill: real promise and real concern. Ann Intensive Care. 2012 Oct 12;2(1):43. PMC3519794.
  • Slutsky AS. Neuromuscular blocking agents in ARDS. N Engl J Med. 2010 Sep 16;363(12):1176-80. doi: 10.1056/NEJMe1007136. PubMed PMID: 20843254.
  • Yegneswaran B, Murugan R. Neuromuscular blockers and ARDS: thou shalt not breathe, move, or die! Crit Care. 2011;15(5):311. PMC3334776.

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Critical Care

Compendium

Chris is an Intensivist and ECMO specialist at the Alfred ICU in Melbourne. He is also the Innovation Lead for the Australian Centre for Health Innovation at Alfred Health and Clinical Adjunct Associate Professor at Monash University. He is a co-founder of the Australia and New Zealand Clinician Educator Network (ANZCEN) and is the Lead for the ANZCEN Clinician Educator Incubator programme. He is on the Board of Directors for the Intensive Care Foundation and is a First Part Examiner for the College of Intensive Care Medicine. He is an internationally recognised Clinician Educator with a passion for helping clinicians learn and for improving the clinical performance of individuals and collectives.

After finishing his medical degree at the University of Auckland, he continued post-graduate training in New Zealand as well as Australia’s Northern Territory, Perth and Melbourne. He has completed fellowship training in both intensive care medicine and emergency medicine, as well as post-graduate training in biochemistry, clinical toxicology, clinical epidemiology, and health professional education.

He is actively involved in in using translational simulation to improve patient care and the design of processes and systems at Alfred Health. He coordinates the Alfred ICU’s education and simulation programmes and runs the unit’s education website, INTENSIVE.  He created the ‘Critically Ill Airway’ course and teaches on numerous courses around the world. He is one of the founders of the FOAM movement (Free Open-Access Medical education) and is co-creator of litfl.com, the RAGE podcast, the Resuscitology course, and the SMACC conference.

His one great achievement is being the father of two amazing children.

On Twitter, he is @precordialthump.

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