Neuromuscular Blockers in Early Acute Respiratory Distress Syndrome | Review

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23/09/19 Medical Reference this

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Acute Respiratory Distress Syndrome (ARDS) was first defined by the American European Consensus Conference (AECC) as ‘an acute inflammatory syndrome manifesting as diffuse pulmonary oedema and respiratory failure that cannot be explained by, but may co-exist with, left-sided heart failure’ (Bernard GR, 1994). Bernard et al. differentiated Acute Lung Injury (ALI) from ARDS. This Consensus Committee left the term ALI for the least severe cases with an Arterial oxygen Pressure/Fractions of inspired oxygen (Pa02/Fi02) ratio bellow 200mmHg leaving PEEP outside of the oxygenation criteria. The only difference between ALI and ARDS was a cut-off on the Pa02/Fi02 ratio.

However, the term has evolved since then and a new definition was created by a panel of experts in order to facilitate diagnosis, improve patient’s outcomes and promote research. The new Berlin definition for ARDS brought a new categorization determined by the degree of hypoxaemia with a minimum PEEP of +5 base on the Pa02/Fi02 ratio (full definition can be found on Appendix 1). (The ARDS Definition Task Force*, 2012). 

Patients diagnosed with ARDS experience an inflammatory response that increases pulmonary vascular permeability. During this exudative phase, interstitial or alveolar oedema can be found with acute inflammatory cells and erythrocytes being translocated into the alveoli. Both, endothelial and epithelial layers are injured, therefore gas exchange is compromised. (The ARDS Definition Task Force*, 2012). It has been showed that some alveoli fill with fluid, but some do not. When the liquid-filled alveoli shrink, they force mechanical stress in the air-filled alveoli. This stress diminishes compliance of the air-filled alveoli, putting in it at risk of overexpansion and volutrauma. The areas of the lungs filled with fluid are not aerated but they are still perfused, therefore physiological dead space is increased. (Perlman, 2010) It has been established in experimental studies that spontaneous breath can worsen lung injury on ARDS patients during mechanical ventilation (MV). If a patient spontaneously breaths during a ventilator breath the transpulmonary pressure is increased, however the pleural pressure decreases. This will result on a bigger Tidal Volume (VT) that could aggravate the already injured lung. (Yosida, 2016)

Despite the benefits of spontaneous breathing during MV on ARDS (i.e. oxygenation improvement, alveolar recruitment) it has its risks, specially on the acute phase of the disease as it would not be possible to deliver lung protective ventilation. (Bourenne. et al 2017). Lung protective strategies include low plateau pressure (lower than 35 cm of H20), high Positive End Expiratory Pressure (PEEP) and low tidal volumes (6ml/kg of patient’s ideal body weight). It has been demonstrated that these strategies improve oxygenation, with less cases of deaths caused by refractory hypoxemia. (Meade. et al, 2008)

Current ARDS guidelines support the use of lung protective ventilation so using the ventilators settings above mentioned will assure health professionals that the best evidence based care is being delivered to their patients. (Grimshaw, 1993). In order to follow the latest ARDS guidelines and provide patients with these conservative lung strategies, Neuro Muscular Blocking Agents (NMBA) may be useful when sedation is maximised, and patients are not well synchronised with mandatory ventilation.

NMBA use is not recommended by the Guidelines of management of ARDS. However, Cisatracurium Besylate, has been suggested by the same group of experts but only in cases of moderate to severe cases of ARDS on the early stages of the syndrome. (Guidelines of the management of ARDS)

The 12.5% of Intensive Care Unit (ICU) admissions is caused by this syndrome (Yasser Sakr et al. 2005) and is associated with a mortality rate of 40% to 45% depending on the severity of the hypoxia.  (Emanuele Rezoagli, 2017). Due to its high mortality rates it is important to acquired deep knowledge in this condition and its management within ICU.

Given the high incidence rates and mortality, is extremely important to educate ICU nurses on how to early identify this syndrome so early management can be implemented. Signs should be clearly recognised by nursing staff and ventilator asynchrony should be promptly escalated to the medical team so NMBA can be started in the early stages of the syndrome as it has been previously highlighted. Nurses caring for ARDS patients should be aware of NMBA side effects, potential complications and how to assess the efficacy of this group of drugs. (NMC, 2015)

The aim of this paper is to critically analyse the paper written by Papazian et al. “Neuromuscular Blockers in Early Acute Respiratory Distress Syndrome” in 2010. Despite the publication date of this paper is still clinically relevant because the intervention being analysed in the paper is in current use. Therefore, the reasons to choose this paper is to get a better understanding on why NMBA are used as their possible complication in this specific group of patients.



This paper was published on The New England Journal of Medicine. This journal had an impact factor of 79.258 in 2017 and is a peer reviewed journal. According to I. Hames peer reviews ensure research is done without bias and the right methodology is used. It can be assumed that the piece of research being analysed maintains high standards and results are reported as accurate as possible (Hames, 2007).

Researchers’ qualifications are specified and most of them are qualified with a Doctoral Degree, so it could be assumed that the authors are experienced researchers and the would be able to produce good quality research (Bootland, 2007). Papazian is a well experienced researcher in this specific field being the author of papers on the management of ARDS (Coughlan, 2007). However, despite the experience of the authors the quality of this paper must be critically analysed before being applied to patients. (Bootland, 2017).

The title identifies the group of patients that the research is focus on, however is vague as it does not specified the intervention made to the control group or the purpose of the study (Coughlan, 2007). As stated by Bootland et al. the title should give the reader an idea about the research question or the possible study design, however neither of them are specified in the title of this piece of work.

The abstract presents a brief summary of study and it includes methods, results and conclusion. The content in the abstract help the reader to decide whether the study is of interest and relevant for the reader’s practice (Conkin Dale, 2005).


 In the introduction the authors specify a clear background of the problem to study and the importance of the clinical question (Bootland et al. 2017). They base the significance of the research on an intense literature review including previous studies similar to the one performed on this paper.

 At the end of the introduction Papazian et al. clearly present the hypothesis they have decided to test and the methods the will use for it (Greenhalgh, 2014).


 A previous Randomised Controlled Trial (RCT) was performed in 56 patients to evaluate the effects of a 48 hours infusion of NMBA on gas exchange in patient with ARDS. (Gainnier et al. 2004). However, this study was not designed to study mortality or the rate of ICU-acquired paresis. Papazian et al. designed a bigger trial, powered to study mortality in a larger population and with more specific outcomes for the drug being assessed than the Gainnier et al. (Greenhalgh, 2014)

The authors conducted an RCT, the highest level of evidence in the research hierarchy as they are designed to minimised bias and to have less risk of systematic errors (Burns, Rohrich and Chung, 2012). As the authors wanted to compare two different interventions it seems adequate to use an RCT to design the study (Bootland et al. 2017). Papazian et al. compared the use of NMBA and sedation with the use of only sedation on patients mechanically ventilated during the acute phase of ARDS. Patients were randomly distributed to the two arms of the trial using concealed allocation. Randomisation is important as it distributes known or unknown cofounders between the two arms of the trial (Bootland et al. 2017). Randomization was performed following the Consolidated Standards for the reporting of Trials (CONSORT) and a diagram of the randomisation and follow-up of the patients can be found on the paper.

The population being studied is well identified by the researchers. Inclusion and exclusion criteria are specified on the paper. Patients mechanically ventilated, diagnosed with severe to moderate ARDS, PEEP of 5 cm of water or above, and a Vt of 6-8ml per kilogram of ideal body weight were included on the trial. Authors added an eligibility criterion, the absence of left atrial hypertension. This was ruled out by pulmonary-wedge pressure (PWP) or echocardiography, if PWP was not available. The absence of left atrial hypertension was part of the old definition of ARDS (Bernard et al. 1994), however it is included in the current definition of ARDS (The ARDS Definition Task Force*). By inserting a Pulmonary Artery catheter (PAC) to ruled out left atrial hypertension unnecessarily, authors were putting patients at risk as higher mortality on patients undergoing PAC has been demonstrated by several studies (Dalen, 2005).  Exclusion criteria can be found on appendix 2. Baseline characteristics are well defined on tables and appendixes. Patients from both arms of the trial received similar procedures. It is important to highlight, a significant difference between the two groups at baseline. Cisatracurium group had a lower Pa02/FiO2 ratio than the control group. According to the Scottish Intercollegiate Guidelines Network, a study could potentially be downgraded as both groups are no identical in such an important characteristic, essential in the diagnosis of ARDS. However, authors do highlight this difference in the text.

Written informed consent was obtained from patients or legally authorised representative when patients were sedated as they are considered persons with diminished autonomy and it is documented on the paper (Grove, Burns & Gray, 2014). Ethical approval was obtained from the ethical committee of Marseille University Hospital.

Papazian et al. proposed for their study treatment the use of an infusion of Cisatracurium Besylate for 48 hours. The control group received a placebo. Detailed study treatment can be found on appendix 3. Both infusions (treatment and placebo) were prepared in identical vials. Peripheral-nerve stimulators were not allowed. It can be said that blinding in this paper is well done as patients, health care professionals and researchers are not aware of the treatment being infused. This successful blinding will result in less chance of bias (Bootland et al. 2017).

Outcomes were openly specified in the paper. The primary outcome was the 90-day mortality after the study enrolment. Authors presented several secondary outcomes but only the most significant for nursing staff has been included in this critical analysis due to the restrictive word count. The rate of ICU-acquired paresis was assessed with the Medical Research Council (MRC). The definition of ICU-acquired paresis was an MRC score of less than 48. Despite of the use of a validated scale, it can be said that the MRC scale is

Ramsay sedation scale was used to assess sedation score. Ramsay scale is a validated scale and it has shown to have higher validity than other subjective scales like Richmond Agitation-Sedation Scale. Moreover, Ramsay scale has been compared with objective methods showing the highest criterion validity (Dishoeck et al. 2009).

  • The American-European Consensus Conference on ARDS. Definitions, Mechanism, Relevant outcomes and Critical Trial Coordination. Gordon B.Bernard, Antonio Artigas, Kenneth L. Brigham, Jean Carlet, Konrad Falke, Leonard Hudson, Maurice Lamy, Jean Roger Legall, Alan Morris, Roger Spragg, an the Consensus Committee. American Journal of Respiratory and Critical Care Medicine. Vol 149. 1994. 
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Sedation and neuromuscular blocking agents in acute respiratory distress syndrome(2017)Jeremy Bourenne1,2, Sami Hraiech2,3, Antoine Roch2,3, Marc Gainnier1,2, Laurent Papazian2,3, Jean-Marie Forel2,3

  • Ventilation Strategy Using Low Tidal Volumes, Recruitment Maneuvers, and High Positive End-Expiratory Pressure for Acute Lung Injury and Acute Respiratory Distress SyndromeA Randomized Controlled Trial. Maureen O. Meade, MD, MScDeborah J. Cook, MD, MScGordon H. Guyatt, MD, MSc; et al
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