Since the publication of the ARMA trial by the Acute Respiratory Distress Syndrome (ARDS) Network in 2000,(1) lung-protective ventilation has been the standard approach to mechanical ventilation in patients with ARDS. In conjunction with the use of low tidal volume ventilation with an acceptable plateau pressure, several additional strategies have been employed in an attempt to further benefit these patients. Among these approaches is the early use of neuromuscular blockade (NMB).
As reported by Hickling in 1990,(2) the original description of benefit to low tidal volume ventilation entailed the use of permissive hypercapnic ventilation. In the 1990s, the use of NMB to achieve lung protection was not uncommon, even though only a few of Hickling’s patients actually received NMB to achieve lung protection via permissive hypercapnia.
Following the publication of ARMA, in which patients were allowed to breathe up to 35 breaths/minute, and the concern that NMB might be a risk factor for critical illness polyneuropathy,(3) NMB use in the management of ARDS patients fell out of favor. Additionally, the use of NMB precluded the use of increasingly popular spontaneous breathing modes of mechanical ventilation such as airway pressure release ventilation. By 2010, NMB was considered something to be “generally avoided unless a patient continues to fight the ventilator despite all attempts to identify and reverse the cause.”(4)
It was in this clinical environment that the publication of the ACURSYS trial(5) was received. In this multicenter, prospective, randomized trial, patients with severe ARDS (P/F < 150 on at least 5 cm H2O positive end-expiratory pressure [PEEP]) enrolled within the first 48 hours of mechanical ventilation who received 48 hours of NMB had a lower 28-day mortality (23.7%; 95% CI, 18.1–30.5) compared with placebo (33.3%; 95% CI, 26.5–40.9), both groups of whom received lung-protective ventilation (p = 0.05). NMB patients also had lower rates of pneumothorax and barotrauma, suggesting that more equitable distribution of the delivered tidal volume may have also mitigated lung injury by diminishing ventilator asynchrony in the NMB group. The incidence of neuromuscular weakness did not differ between groups. Notably, NMB patients were not more hypercapnic than the placebo group, emphasizing the difference between NMB and permissive hypercapnia, which are sometimes conflated.
Criticisms of this approach include lack of complete blinding, lack of use of peripheral train-of-four nerve stimulators to monitor the depth of paralysis, lack of a standard approach to the measurement of neuromuscular weakness, lack of measurement of ventilator asynchrony, Kaplan-Meier survival curves separated only after day 14, and, perhaps most importantly, the primary end point of the trial, adjustment of 90-day mortality, achieved statistical significance only with acuity adjustment.(6)
Proponents of NMB point to the publication of an earlier biomarker trial by the same group, which showed lower pulmonary levels of inflammatory cytokines such as interleukin (IL)-1ß, IL-6, and IL-8 in the NMB group.(7) Additionally, evidence from an animal model suggests that a distribution of gas away from potentially over-distended, dependent lung zones adjacent to the diaphragm occurs with NMB institution(8) and contradicts those who presume an advantage to diaphragmatic contraction with spontaneous breathing modes such as airway pressure release ventilation.(9)
Six years after publication, these results, which are level II by evidence-based standards, remain controversial. Widespread implementation of this approach has not occurred. Clinicians continue to use NMB as a rescue modality(10) and not early on as routine intervention in such moderate to severe ARDS patients, as defined by the Berlin definition. Perhaps this is due to the above criticisms. Perhaps too, this reflects difficulties regarding implementation. Even lung-protective ventilation, such as that employed in ARMA, still lacks widespread implementation, with a disconnect between what clinicians believe(10) they do and actual practice.(11)
ARDS is a histopathologically heterogenous disease.(12,13) Recruitability of lung tissue with mean airway pressure and PEEP is also heterogenous both between patients and within the lungs of any given patient.(14,15) Therapeutic alterations in the distribution of delivered gas in order to potentially mitigate ventilator-induced lung injury forms the basis of both early NMB and prone ventilation. As with NMB, there is one large positive trial demonstrating benefit of prone ventilation, Proning Severe ARDS Patients (PROSEVA).(16)
Proponents of prone ventilation suggest that the approach taken in PROSEVA was a refinement of technique that finally got it right;(17) detractors suggest that the large treatment effect seen was too good to be true.(18) Yet the critical care community at large seems to accept the validity of prone ventilation (which usually also requires NMB) more than early NMB use. There is no reason that early NMB might not work.
Clearly, additional verification of early NMB is required if widespread implementation is to happen; fortunately this will be forthcoming. The National Institutes of Health Prevention and Early Treatment of Acute Lung Injury (PETAL) Network(19) is currently enrolling in the Reevaluation of Systemic Early Neuromuscular Blockade (ROSE) trial (Disclosure: I am project director at the University of Michigan PETAL site). ROSE is a multicenter, randomized placebo-controlled trial of early NMB in moderate to severe ARDS patients with 90 day all-cause mortality as the primary end point.
ROSE is not an exact replication of ACURASYS, since both groups will receive a high PEEP open-lung ventilation approach. Undoubtedly the distribution of ventilation is different under such circumstances. Nevertheless, a negative result will likely confine the use of NMB to that of a rescue modality or an adjunct to prone ventilation. If ROSE yields a positive result for its primary end point, it will establish early NMB as a standard approach in the treatment of these ARDS patients. Implementation of this strategy will be either helped or hindered by whether neuromuscular weakness is made worse as a result.
1. [No authors listed]. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. N Engl J Med. 2000 May 4;342(18):1301-1308.
2. Hickling KG, Henderson SJ, Jackson R. Low mortality with low volume pressure limited ventilation with permissive hypercapnia in severe adult respiratory distress syndrome. Intensive Care Med. 1990;16(6):372-377.
3. Garnacho-Montero J, Madrazo-Osuna J, Garcia-Garmendia JL, et al. Critical illness polyneuropathy: risk factors and clinical consequences. A cohort study in septic patients. Intensive Care Med. 2001 Aug;27(8):1288-1296.
4. Tobin MJ, Laghi F, Jubran A. Narrative review: ventilator-induced respiratory muscle weakness. Ann Intern Med. 2010 Aug 17;153(4):240-245.
5. Papazian L, Forel JM, Gacouin A, et al; ACURASYS Study Investigators. Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med. 2010 Sep;363(12):1107-1116.
6. Yegneswaran B, Murugan R. Neuromuscular blockers and ARDS: thou shalt not breathe, move, or die! Crit Care. 2011;15(5):311.
7. Forel JM, Roch A, Marin A, et al. Neuromuscular blocking agents decrease inflammatory response in patients presenting with acute respiratory distress syndrome. Crit Care Med. 2006 Nov;34(11):2749-2757.
8. Yoshida T, Torsani V, Gomes S, et al. Spontaneous effort causes occult pendelluft during mechanical ventilation. Am J Respir Crit Care Med. 2013 Dec 15;188(12):1420-1427.
9. Hubmayr RD. Volutrauma and regional ventilation revisited. Am J Respir Crit Care Med. 2013 Dec 15;188(12):1388-1389.
10. Alhurani RE, Oeckler RA, Franco PM, Jenkins SM, Gajic O, Pannu SR. Refractory hypoxemia and use of rescue strategies: a U.S. National Survey of Adult Intensivists. Ann Am Thorac Soc. 2016 Jul;13(7):1105-1114.
11. Bellani G, Laffey JG, Pham T, et al; LUNG SAFE Investigators; ESICM Trials Group. Epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in 50 countries. JAMA. 2016 Feb 23;315(8):788-800.
12. Guerin C, Bayle F, Leray V, et al. Open lung biopsy in nonresolving ARDS frequently identifies diffuse alveolar damage regardless of the severity stage and may have implications for patient management. Intensive Care Med. 2015 Feb;41(2):222-230.
13. Lorente JA, Ballén-Barragán, Herrero R, Esteban A. Acute respiratory distress syndrome: does histology matter? Crit Care. 2015 Sep 15;19:337.
14. Gattinoni L, Caironi P, Cressoni P, et al. Lung recruitment in patients with the acute respiratory distress syndrome. N Engl J Med. 2006 Apr 27;354(17):1775-1786.
15. Terragni PP, Rosboch G, Tealdi A, et al. Tidal hyperinflation during low tidal volume ventilation in acute respiratory distress syndrome. Am J Respir Crit Care Med. 2007 Jan 15;175(2):160-166.
16. Guérin C, Reignier J, Richard JC, et al; PROSEVA Study Group. Prone positioning in severe acute respiratory distress syndrome. N Engl J Med. 2013 Jun 6;368(23):2159-2168.
17. Beitler J, Shaefi S, Montesi SB, et al. Prone positioning reduces mortality from acute respiratory distress syndrome in the low tidal volume era: a meta-analysis. Intensive Care Med. 2014 Mar;40(3):332-341.
18. Tonelli AR, Zein J, Adams J, Ioannidis JP. Effects of interventions on survival in acute respiratory distress syndrome: an umbrella review of 159 published randomized trials and 29 meta-analyses. Intensive Care Med. 2014 Jun;40(6):769-787.