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.