Dr. Yegneswaran and Dr. Murugan did an interesting analysis of the ACURASYS trial. Some comments should however be made in order to clarify certain points.
The first point is that we did (and published) two physiological studies prior designing the ACURASYS trial(1,2). There was in both studies a strong tendency toward a better (and unexpected) outcome in the group of patients receiving cisatracurium. These two physiological studies were not designed to evaluate the outcome. For example the management of the patients was standardized only throughout the 120-h period of the studies. It would have however been logical to also include the second physiological study (1) in the metaanalysis. However this metaanalysis did not add useful and new elements because crude mortality at day 28 was significantly reduced in the cisatracurium group in the ACURASYS study (23.7% vs. 33.3%).
Second point, regarding the blinding of the healthcare providers, it must be highlighted that Ramsay score was at 6 when starting infusion of cisatracurium or placebo which precludes any movement of the patient(3). The blinding of all healthcare providers was not applied in our two first previous works(1,2) (only doctors were blinded) but there were some reviewers¿ criticisms regarding the absence of blinding for all health care providers. It was the reason why we planned this study using a double-blind design. Taking into account mortality as the main outcome rather than the duration of mechanical ventilation for example permitted to decrease the risks related to an unsatisfactory blinding. It would have been easier for us to design a study with ventilator-free days as the main outcome in order to show a better outcome effect of cisatracurium. However, the weaning from mechanical ventilation is more subjective and could be influenced by a potential inadequate blinding of the investigators. However we admit and we consider this criticism but we are waiting for some proposition for an alternative design¿.
The primary outcome was the proportion of patients who died before discharge home and within 90 days after study enrolment (day-90 mortality). Patients who were in other types of healthcare facilities and who were able to breathe spontaneously at 90 days were considered discharged home. It means that patients admitted in other types of healthcare facilities were also surveyed until day 90. This definition was also used in previously published studies by the ARDS network including ALVEOLI(4) and LaSRS(5).
The third point stressed by the two readers was the absence of biomarkers determination to explain beneficial effects of cisatracurium. This study has been done before(1). It is the one missed in the metaanalysis. There was a decrease of some pro-inflammatory cytokines in BAL and blood samples when the patients received 2 days of cisatracurium as compared with the placebo group.
In conclusion, it is a little bit reducing to regard the results of the ACURASYS trial as only related to the use of cisatracurium. The use of NMBA was part of a lung-protective policy including the use of low tidal volume, a proactive strategy regarding plateau pressure increases and, major point, a strong incitation to start weaning since day 3 when FiO2 was 0.6. or lower (see Table 1 of the article(3)).
We would like finally to thank Dr. Yegneswaran and Dr. Murugan to give us the opportunity to clarify some interesting points.
Laurent Papazian, Jean-Marie Forel et Antoine Roch
References
1 Forel JM, Roch A, Marin V et al. Neuromuscular blocking agents decrease inflammatory response in patients presenting with acute respiratory distress syndrome. Crit Care Med. 2006; 34(11):2749-2757.
2 Gainnier M, Roch A, Forel JM et al. Effect of neuromuscular blocking agents on gas exchange in patients presenting with acute respiratory distress syndrome. Crit Care Med. 2004; 32(1):113-119.
3 Papazian L, Forel JM, Gacouin A et al. Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med. 2010; 363(12):1107-1116.
4 Brower RG, Lanken PN, MacIntyre N et al. Higher versus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome. N Engl J Med. 2004; 351(4):327-336.
5 Steinberg KP, Hudson LD, Goodman RB et al. Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome. N Engl J Med. 2006; 354(16):1671-1684.
Critical Care
Response of the authors
8 November 2011
Dr. Yegneswaran and Dr. Murugan did an interesting analysis of the ACURASYS trial. Some comments should however be made in order to clarify certain points.
The first point is that we did (and published) two physiological studies prior designing the ACURASYS trial(1,2). There was in both studies a strong tendency toward a better (and unexpected) outcome in the group of patients receiving cisatracurium. These two physiological studies were not designed to evaluate the outcome. For example the management of the patients was standardized only throughout the 120-h period of the studies. It would have however been logical to also include the second physiological study (1) in the metaanalysis. However this metaanalysis did not add useful and new elements because crude mortality at day 28 was significantly reduced in the cisatracurium group in the ACURASYS study (23.7% vs. 33.3%).
Second point, regarding the blinding of the healthcare providers, it must be highlighted that Ramsay score was at 6 when starting infusion of cisatracurium or placebo which precludes any movement of the patient(3). The blinding of all healthcare providers was not applied in our two first previous works(1,2) (only doctors were blinded) but there were some reviewers¿ criticisms regarding the absence of blinding for all health care providers. It was the reason why we planned this study using a double-blind design. Taking into account mortality as the main outcome rather than the duration of mechanical ventilation for example permitted to decrease the risks related to an unsatisfactory blinding. It would have been easier for us to design a study with ventilator-free days as the main outcome in order to show a better outcome effect of cisatracurium. However, the weaning from mechanical ventilation is more subjective and could be influenced by a potential inadequate blinding of the investigators. However we admit and we consider this criticism but we are waiting for some proposition for an alternative design¿.
The primary outcome was the proportion of patients who died before discharge home and within 90 days after study enrolment (day-90 mortality). Patients who were in other types of healthcare facilities and who were able to breathe spontaneously at 90 days were considered discharged home. It means that patients admitted in other types of healthcare facilities were also surveyed until day 90. This definition was also used in previously published studies by the ARDS network including ALVEOLI(4) and LaSRS(5).
The third point stressed by the two readers was the absence of biomarkers determination to explain beneficial effects of cisatracurium. This study has been done before(1). It is the one missed in the metaanalysis. There was a decrease of some pro-inflammatory cytokines in BAL and blood samples when the patients received 2 days of cisatracurium as compared with the placebo group.
In conclusion, it is a little bit reducing to regard the results of the ACURASYS trial as only related to the use of cisatracurium. The use of NMBA was part of a lung-protective policy including the use of low tidal volume, a proactive strategy regarding plateau pressure increases and, major point, a strong incitation to start weaning since day 3 when FiO2 was 0.6. or lower (see Table 1 of the article(3)).
We would like finally to thank Dr. Yegneswaran and Dr. Murugan to give us the opportunity to clarify some interesting points.
Laurent Papazian, Jean-Marie Forel et Antoine Roch
References
1 Forel JM, Roch A, Marin V et al. Neuromuscular blocking agents decrease inflammatory response in patients presenting with acute respiratory distress syndrome. Crit Care Med. 2006; 34(11):2749-2757.
2 Gainnier M, Roch A, Forel JM et al. Effect of neuromuscular blocking agents on gas exchange in patients presenting with acute respiratory distress syndrome. Crit Care Med. 2004; 32(1):113-119.
3 Papazian L, Forel JM, Gacouin A et al. Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med. 2010; 363(12):1107-1116.
4 Brower RG, Lanken PN, MacIntyre N et al. Higher versus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome. N Engl J Med. 2004; 351(4):327-336.
5 Steinberg KP, Hudson LD, Goodman RB et al. Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome. N Engl J Med. 2006; 354(16):1671-1684.
Competing interests
No competing interests