Neuromuscular Blockade in ARDS

Introduction –

Acute respiratory distress syndrome (ARDS) is a life-threatening condition characterized by intense lung inflammation, consolidation, and progressive microatelectasis with refractory acute hypoxemia [1, 2]. Despite advances in technology and sophistication of mechanical ventilators, the mortality of ARDS is still high [3–5]. A multimodal strategy involving non-pharmacologic interventions and pharmacologic interventions is recommended for the management of ARDS. Non-pharmacologic interventions include protective lung ventilation strategies, including low tidal volume and higher positive end-expiratory pressure (PEEP) along with prone positioning. These strategies are accepted because of their beneficial effects on patient outcomes in ARDS [2, 5, 6]. However, the benefit of pharmacologic interventions still remains questionable.

What’s the rationale of using NMB in ARDS?

1. The use of neuromuscular blocking agents (NMBs) may facilitate a lung-protective ventilation strategy.
2. Vigorous spontaneous respiratory efforts may lead to the worsening of lung injury through several mechanisms.
   1. Changes in transpulmonary pressure that predispose to lung injury are similar to spontaneously-generated or ventilator-driven tidal volumes.³ 
   2. Changes in pleural pressure with respiration are transmitted uniformly in normal lungs. However, in the injured lung, the transmission of pleural pressure is non-uniform.
   3. The dependent areas of the lung are in close physical contact with the diaphragm. As the diaphragm contracts forcefully during vigorous spontaneous efforts, the dependent areas of the lung experience a more pronounced negative pleural pressure. The non-uniform distribution of pleural pressure results in air movement from the non-dependent to the dependent lung by the “pendelluft” phenomenon.⁴ This intra-pulmonary movement of air leads to injury to the dependent lung, one of the hallmarks of ARDS. Abolition of vigorous spontaneous efforts may thus prevent damage to the injured lung.³
3. A spontaneous respiratory effort may be triggered at the end of the inspiratory phase of a mechanical breath in some patients, through a phenomenon called “reverse triggering”, leading to patient-ventilator asynchrony.⁵ These harmful effects of spontaneous respiratory efforts in the injured lung are overcome with the use of NMBs.
4. NMBs have been shown to improve oxygenation and reduce the release of inflammatory mediators.^6,7 
5. Abolition of spontaneous respiratory efforts may also reduce the oxygen consumption by decreasing the work of breathing and elimination of the resting muscle tone.⁸ 
6. Improved patient-ventilator synchrony may allow safer, and more precise titration of tidal volumes and ventilation pressures.³

Harms –

1. ICU-acquired muscle weakness is of increasing concern in critically ill patients.
2. Complications related to prolonged immobility resulting from NMB include deep vein thrombosis and ocular complications, including dryness, scarring, and ulceration of the cornea.
3. Awareness can be a significant problem if adequate sedation is not provided during NMB use. 
4. IgE-mediated anaphylaxis is a rare complication of NMB use with Succinylcholine and Rocuronium being the most implicated.

Which NMB agent to use?

The choice of a neuromuscular blocking agent is an important question. The options available to intensivists include vecuronium, pancuronium, atracurium, and cis-atracurium.

 Compared with other neuromuscular blocking agents, cisatracurium has several attractive properties, including elimination independent of renal and hepatic function, no active metabolites, and a short half-life.

Cisatracurium also appears to have direct anti-inflammatory properties, independent of the effect of neuromuscular blockade on ventilator dyssynchrony (6).

However, cisatracurium is more expensive than other neuromuscular blocking agents and similar to many drugs, it has experienced shortages.

Thus, the choice of a neuromuscular blocking agent depends on local availability &/or financial concerns.

What is evidence either in favor or against the routine use of NMB in patients with ARDS?

In one of the early randomized controlled trials (RCT), 56 patients with ARDS with a PaO₂/FiO₂ ratio of less than 150 mm Hg, and a PEEP of 5 cm of H₂O were studied. Patients were randomized to receive cisatracurium as a bolus followed by an infusion and compared with a placebo. Gas exchange was followed up for a period of 120 hours after randomization. There was a significant improvement in the PaO₂/FiO₂ ratio among patients who received cisatracurium at 48, 96, and 120 hrs after randomization. Besides, the use of cisatracurium resulted in a significant reduction of the PEEP level. This study demonstrated that the use of NMBs in early ARDS may result in improved gas exchange and enable reduction of PEEP levels.⁷

Does the use of NMBs result in attenuation of the pulmonary and systemic inflammatory response in patients with ARDS? In a multi-centric French study, 36 patients with ARDS, and PaO₂/FiO₂ ratios of  ≤ 200 on a positive end-expiratory pressure of 5 cm H₂O were studied. Patients were randomly assigned to receive cisatracurium as a loading dose followed by an infusion, or an equivalent placebo within 48 hours of disease onset. Lung-protective ventilation was carried out using tidal volumes of 4–8 ml/kg ideal body weight and a plateau pressure of ≤ 30 cm of H₂O. Serum and bronchoalveolar fluid levels of tumor necrosis factor-alpha, IL-1, IL-6, and IL-8 were determined before randomization and after 48 hours. Early cisatracurium administration during the initial 48-hr period resulted in a significant reduction in the levels of pulmonary and systemic proinflammatory cytokines. Furthermore, a significantly greater improvement in the PaO₂/FiO₂ ratio was observed among patients who received cisatracurium.⁶

The ACURASYS trial was a multi-center RCT among patients with severe ARDS, characterized by a PaO₂/FiO₂ ratio of less than 150 mm Hg while receiving a PEEP level of ³ 5 cm H₂O. Cisatracurium was administered as a bolus followed by a continuous infusion in 178 patients, while 162 patients received a placebo. A lung-protective ventilation strategy was utilized, with tidal volumes of 6–8 ml/kg of predicted body weight. Cisatracurium was administered within 48 hours of the onset of ARDS and continued for 48 hours. The overall in-hospital mortality at 90 days was not significantly different between patients who received cisatracurium compared to those who received a placebo (31.6% vs. 40.7%, p = 0.08). On analysis after adjustment for the baseline PaO₂/FiO₂ ratio, plateau pressure, and the Simplified Acute Physiology II score (SAPS) score, the 90-day mortality was significantly lower in the cisatracurium group (hazard ratio: 0.68; 95% CI: 0.48–0.98; p = 0.04). The number of ventilator-free days at 28 and 90 days was also significantly lower with cisatracurium administration. The incidence of ICU-acquired weakness was similar between groups. 

The ROSE trial was conducted across multiple centers in the US by the National Heart, Lung, and Blood Institute PETAL Clinical Trials Network. Patients with severe ARDS and a PaO₂/FiO₂ ratio of <150 mmHg while receiving a PEEP >8 cm H₂O were included. Study enrolment was carried out within one week of disease onset. In the intervention group, cisatracurium was administered as a bolus followed by a continuous infusion after ensuring deep sedation (Ramsay sedation score: 6). In the control arm, light sedation was administered, titrated to a Ramsay sedation score of 2–3. A lung-protective ventilation strategy was followed in both groups. The study was stopped for futility at the second interim analysis after the enrolment of 1006 patients. There was no difference in the primary endpoint of 90-day all-cause hospital mortality between the cisatracurium and control groups (42.5% vs. 42.8%; p = 0.93). No significant difference was noted in the secondary endpoints, including 28-day mortality, ventilator- or ICU-free days at 28 days, and ICU-acquired weakness. The number of hospital-free days at day 28 and long-term quality of life also remained similar between groups.¹⁵

Prone ventilation has been established to improve mortality in patients with severe ARDS.¹⁶ In the ROSE trial, prone ventilation was carried out only in 16% of patients compared to 50% patients in the ACURASYS trial, which may have impacted outcomes. Besides, 655 of 4848 patients who were screened were already on NMBs, and hence excluded from the study. In contrast to the ACURASYS trial, the ROSE trial was unblinded, which may have resulted in bias. 

The results from the meta-analysis by Hua et al are summarised here – 

Summary –

The use of NMB in patients with severe ARDS has several benefits without proven evidence of increased incidence of ICU-acquired weakness. However, the rational use of NMB agents on a case by case basis is warranted. We suggest their use early in the course of ARDS

1. In patients with P/F ratio <150, with RR> 30/min,
2. Pplat > 30 cm H2O or Pdriving > 15 cm H2O
3. e/o ventilator dyssynchrony and
4. In conjunction with proning.

References –

1. Force ADT, Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E, et al. Acute respiratory distress syndrome: the Berlin Definition. JAMA. 2012; 307:2526–33. pmid:22797452
2. Sweeney RM, McAuley DF. Acute respiratory distress syndrome. Lancet. 2016; 388:2416–30. pmid:27133972
3. Villar J, Blanco J, Kacmarek RM. Current incidence and outcome of the acute respiratory distress syndrome. Curr Opin Crit Care. 2016; 22:1–6. pmid:26645551
4. Bellani G, Laffey JG, Pham T, Fan E, Brochard L, Esteban A, et al. Epidemiology, Patterns of Care, and Mortality for Patients With Acute Respiratory Distress Syndrome in Intensive Care Units in 50 Countries. JAMA. 2016; 315:788–800. pmid:26903337
5. Thompson BT, Chambers RC, Liu KD. Acute Respiratory Distress Syndrome. N Engl J Med. 2017; 377:562–72. pmid:28792873
6. Fan E, Brodie D, Slutsky AS. Acute Respiratory Distress Syndrome: Advances in Diagnosis and Treatment. JAMA. 2018; 319:698–710. pmid:29466596
7. Ashbaugh DG, Bigelow DB, Petty TL, Levine BE. Acute respiratory distress in adults. Lancet Lond Engl. 1967;2(7511):319-323. doi:10.1016/s0140-6736(67)90168-7
8. Acute Respiratory Distress Syndrome Network, Brower RG, Matthay MA, et al. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med. 2000;342(18):1301-1308. doi:10.1056/NEJM200005043421801
9. Brochard L, Slutsky A, Pesenti A. Mechanical Ventilation to Minimize Progression of Lung Injury in Acute Respiratory Failure. Am J Respir Crit Care Med. 2017;195(4):438-442. doi:10.1164/rccm.201605-1081CP
10. Yoshida T, Torsani V, Gomes S, et al. Spontaneous Effort Causes Occult Pendelluft during Mechanical Ventilation. Am J Respir Crit Care Med. 2013;188(12):1420-1427. doi:10.1164/rccm.201303-0539OC
11. Akoumianaki E, Lyazidi A, Rey N, et al. Mechanical Ventilation-Induced Reverse-Triggered Breaths. Chest. 2013;143(4):927-938. doi:10.1378/chest.12-1817
12. Forel J-M, 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. doi:10.1097/01.CCM.0000239435.87433.0D
13. Gainnier M, Roch A, Forel J-M, 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. doi:10.1097/01.CCM.0000104114.72614.BC
14.  deBacker J, Hart N, Fan E. Neuromuscular Blockade in the 21st Century Management of the Critically Ill Patient. Chest. 2017;151(3):697-706. doi:10.1016/j.chest.2016.10.040
15.  Garnacho-Montero J, Madrazo-Osuna J, García-Garmendia JL, et al. Critical illness polyneuropathy: risk factors and clinical consequences. A cohort study in septic patients. Intensive Care Med. 2001;27(8):1288-1296. doi:10.1007/s001340101009
16. Adnet F, Dhissi G, Borron SW, et al. Complication profiles of adult asthmatics requiring paralysis during mechanical ventilation. Intensive Care Med. 2001;27(11):1729-1736. doi:10.1007/s00134-001-1112-6
17. Schakman O, Gilson H, Thissen JP. Mechanisms of glucocorticoid-induced myopathy. J Endocrinol. 2008;197(1):1-10. doi:10.1677/JOE-07-0606
18. Fan E, Dowdy DW, Colantuoni E, et al. Physical complications in acute lung injury survivors: a two-year longitudinal prospective study. Crit Care Med. 2014;42(4):849-859. doi:10.1097/CCM.0000000000000040
19. Wang Z-H, Chen H, Yang Y-L, et al. Bispectral Index Can Reliably Detect Deep Sedation in Mechanically Ventilated Patients: A Prospective Multicenter Validation Study. Anesth Analg. 2017;125(1):176-183. doi:10.1213/ANE.0000000000001786
20. Mertes P-M, Laxenaire M-C, GERAP. [Anaphylactic and anaphylactoid reactions occurring during anesthesia in France. Seventh epidemiologic survey (January 2001-December 2002)]. Ann Fr Anesth Reanim. 2004;23(12):1133-1143. DOI:10.1016/j.annfar.2004.10.013
21. The National Heart, Lung, and Blood Institute PETAL Clinical Trials Network. Early Neuromuscular Blockade in Acute Respiratory Distress Syndrome. N Engl J Med. 2019;380(21):1997-2008. DOI:10.1056/NEJMoa1901686
22. Guérin C, Reignier J, Richard J-C, et al. Prone positioning in severe acute respiratory distress syndrome. N Engl J Med. 2013;368(23):2159-2168. doi:10.1056/NEJMoa1214103.