ACURASYS

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Papazian L, et al. "Neuromuscular blockers in early acute respiratory distress syndrome". The New England Journal of Medicine. 2010. 363(12):1107-1116.
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Clinical Question

Does administration of cisatracurium improve survival when compared to placebo in ICU patients undergoing mechanical ventilation for early severe ARDS?

Bottom Line

Paralysis with cisatracurium for 48 hours in patients with early severe ARDS improves 90 day survival and increases ventilator-free days.

Major Points

The high mortality of ARDS -- up to 46% at 60 days[1] -- has been improved upon by only a few interventions, most notably the ARDSNet (2000) low tidal volume protocol. Therapeutic paralysis has been used in synergy with sedation to improve mechanical ventilation. However, its role as a treatment modality for ARDS was unclear.

The 2010 ARDS et Curarisation Systematique (ACURASYS) trial (sometimes referred to as the Papazian trial) randomized 340 intubated patients with early severe ARDS in French ICUs to cisatracurium-induced paralysis or placebo for 48 hours. The intervention group was associated with a 9% absolute reduction in mortality at discharge or 90 days (31.6% vs. 40.7%; P=0.04; NNT=11). Paralysis was also associated with a reduction in barotrauma (5.1% vs. 11.7%; P=0.03), pneumothorax (4.0% vs. 11.7%; P=0.01), days out of the ICU (47.7 vs. 39.5 days; P=0.03), and days not on the ventilator (53.1% vs. 44.6%; P=0.03).

Guidelines

Surviving Sepsis Campaign severe sepsis and septic shock (2016, adapted)[2]

  • Suggest using a neuromuscular blockade agent for ≤48 hours in adults with ARDS from sepsis and PaO2/FIO2 ratio <150 mm Hg (weak recommendation, moderate quality of evidence)

Design

  • Multicenter, double-blinded, placebo-controlled trial
  • N=340
    • Cisatracurium (n=178)
    • Placebo (n=162)
  • Setting: 20 ICUs in France
  • Enrollment: 2006-2008
  • Follow-up: 90 days
  • Analysis: Intention-to-treat
  • Primary outcome: Mortality before discharge or 90 days

Population

Inclusion Criteria

  • Acute respiratory failure and intubated with all of the following for <48h:
    • PaO2:FiO2 <150
    • PEEP of 5 cm H2O or greater
    • TV of 6-8 ml/kg predicted body weight
    • Bilateral pulmonary infiltrates consistent with edema
    • Absence of left atrial hypertension determined by:
      • PCWP <18 mmHg
      • Echocardiography if no PCWP and h/o ischemic heart disease or had crackles on auscultation.

Exclusion Criteria

  • Age <18 years
  • Lack of consent
  • Continuous infusion of neuromuscular blocking agent at enrollment
  • Known pregnancy
  • Enrollment in another trial within previous 30 days
  • Increased ICP
  • Severe chronic respiratory disease requiring either:
    • Long-term home O2 therapy
    • Home mechanical ventilation
  • Actual body weight >1kg/1cm of height
  • Severe chronic liver disease (Child-Pugh class C)
  • Bone marrow transplant or chemo-induce neutropenia
  • Expected duration of mechanical ventilation of <48hrs
  • Decision to withhold life-sustaining treatment
  • Time window missed
  • Other reason

Baseline Characteristics

Derived from the cisatracurium group.

  • Mean age: 58 years
  • VT: 6.55 mL/kg of predicted body weight
  • Minute ventilation: 10.0 L/min
  • PEEP applied: 9.2 cm H2O
  • Plateau pressure: 25.0 cm H2O
  • Respiratory system compliance: 31.5 mL/cm H2O
  • FiO2: 0.79
  • PaO2:FiO2: 106
  • pH: 7.31
  • PaO2: 80 mmHg
  • PaCO2: 47 mmHg
  • Prone position or inhaled NO or almitrine mesylate: 33%
  • SAPS II score:[3] 50 (out of 163, higher indicates increased mortality risk)
  • Reason for ICU admission:
    • Medical: 72.0%
    • Surgical, emergency: 15.3%
    • Surgical, scheduled: 11.9%
  • Corticosteroids for septic shock: 39.5%
  • Direct lung injury: 80.2%

Interventions

  • Patients were sedated to a Ramsay sedation score of 6 then were infused the study drug
    • Cisatracurium - 15 mg IV once then 37.5 mg/hr for 48 hours
    • Placebo
  • Of note, peripheral nerve stimulators were disallowed
  • Ventilators placed on assist control (AC) with VT of 6-8 mL/kg with modification of FIO2 and PEEP to reach goal SpO2 88-92% or PaO255-80 mmHg
  • An open-label injection of up to two administrations cisatracurium 20 mg IV were allowed in all patients if the end-inspiratory plateau pressure remained ≥32 cm H2O for ≥10 minutes with increasing sedation and decreasing VT and PEEP

Outcomes

Comparisons are cisatracurium vs. placebo.

Primary Outcomes

Mortality before discharge or 90 days
31.6% vs. 40.7% (RR 0.68; 95% CI 0.48-0.98; P=0.04; NNT=11)

Secondary Outcomes

28-day mortality
23.7% vs. 33.3% (RR 0.71; 95% CI 0.51-1.00; P=0.05)
Number of days outside of ICU
Day 1-28: 6.9 days vs. 5.7 days (P=0.16)
Day 1-90: 47.7 days vs. 39.5 days (P=0.03)
Number of days without organ or system failure, days 1-28
15.8% vs. 12.2% (P=0.01)
Rate of barotrauma
5.1% vs. 11.7% (RR 0.43; 95% CI 0.20-0.93; P=0.03; NNT=15)
Rate of ICU-acquired paresis by time of ICU discharge
64.3% vs. 68.5% (P=0.51)
MRC scores at time of ICU discharge
55 vs. 55
Number of ventilator-free days
Day 1-28: 10.6% vs. 8.5% (P=0.04)
Day 1-90: 53.1% vs. 44.6% (P=0.03)
Pneumothorax
4.0% vs. 11.7% (P=0.01; NNT=13)

Subgroup Analysis

  • Use of corticosteroids, prone position, use of inhaled NO, or IV almitrine mesylate did not affect the 90 day mortality
  • Most of the mortality benefit was in the patients with a PaO2:FIO2 ratio ≤120

Adverse Events

One patient in the cisatracurium group experienced bradycardia.

Criticisms

  • Outcome may not apply to other neuromuscular blocking agents
  • Unknown if later initiation of cisatracurium provides benefit
  • Unknown if conditions affecting neuromuscular blockade would contribute
  • Lower-than-expected mortality rate means that the study was underpowered
  • True blinding is unlikely since unparalyzed patients will trigger a breath on a ventilator[4]
  • Management of ventilator dyssynchrony was not addressed and may have contributed to poor outcomes in the placebo group[4]
  • Efficacy of paralysis was not studied with a train-of-four stimulation and, therefore, effective paralysis cannot be confirmed[4]
  • ICU paresis was not tested a week after awakening per the original publications on this topic had described[4]
  • Unclear if paralysis or another effect (i.e. anti-inflammatory) accounts for the mortality benefit[5]

Funding

  • Study drugs provided by GlaxoSmithKline France, the makers of Nimbex, the brand name of cisatracurium
  • Supported by the Assistance Publique--Hôpitaux de Marseille and a grant from the Ministère de la Santé (Programme Hospitalier de Recherche Clinique Régional 2004-26).

Further Reading

  1. Gong MN et al. "Clinical predictors of and mortality in acute respiratory distress syndrome: potential role of red cell transfusion." Critical care medicine (2005): 1191-1198.
  2. Rhodes A, et al. "Surviving Sepsis Campaign: International guidelines for management of sepsis and septic shock: 2016." Critical Care Medicine. 2017;45(3)1-67.
  3. Le Gall JR et al. "A new simplified acute physiology score (SAPS II) based on a European/North American multicenter study." JAMA. 1993;270(24):2957-2963.
  4. 4.0 4.1 4.2 4.3 Multiple authors. "Correspondence: Neuromuscular blockers and ARDS." The New England Journal of Medicine. 2010;363(26):2562-2564.
  5. Concurrent editorial - Slutsky AS. "Neuromuscular blocking agents in ARDS." The New England Journal of Medicine. 2010;363(12):1176.