Neuromuscular blocking agents in severe acute respiratory distress syndrome: benefit or harm?

The acute respiratory distress syndrome (ARDS), characterized by hypoxemia and bilateral alveolar infiltrates, was described in 1967 by Ashbaugh et al.¹ Ventilation strategies in ARDS have undergone considerable refinement over the years. A lung-protective ventilation strategy using low tidal volumes may be one of the key interventions to reduce ventilator-induced lung injury (VILI).²

Beneficial effects of neuromuscular blocking agents

The use of neuromuscular blocking agents (NMBs) may facilitate a lung-protective ventilation strategy. Vigorous spontaneous respiratory efforts may lead to worsening of lung injury through several mechanisms. Changes in transpulmonary pressure that predispose to lung injury are similar with spontaneously-generated or ventilator-driven tidal volumes.³ Changes in pleural pressure with respiration are transmitted uniformly in normal lungs. However, in the injured lung, transmission of pleural pressure is non-uniform.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

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. Besides, NMBs have been shown to improve oxygenation and reduce the release of inflammatory mediators.^6,7 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 Besides, improved patient-ventilator synchrony may allow safer, and more precise titration of tidal volumes and ventilation pressures.³

Possible harm from NMBs

ICU-acquired muscle weakness is of increasing concern in critically ill patients. Hence, the appropriate use of NMBs is of crucial importance. Studies in septic⁹ and asthmatic patients¹⁰ who were administered NMBs have revealed an increased incidence of skeletal muscle dysfunction-related morbidity. However, a direct cause and effect relationship attributable to NMBs and functional outcomes has not been demonstrated. Corticosteroids, often used in combination with NMBs have also been implicated in the causation of ICU-acquired muscle weakness.¹¹ Fan et al. conducted an epidemiological study on muscle weakness and health-related quality of life among survivors from acute lung injury. They observed that over the study period, skeletal muscle weakness was not associated with the cumulative dose of NMBs and corticosteroids.¹²Other complications related to prolonged immobility resulting from NMB include deep vein thrombosis and ocular complications, including dryness, scarring, and ulceration of the cornea. Awareness can be a significant problem if adequate sedation is not provided during NMB use. Continuous monitoring of awareness using bispectral index may enable early identification of awareness.¹³ IgE-mediated anaphylaxis is a rare complication of NMB use with succinylcholine and rocuronium being the most implicated.¹⁴

Evidence for NMB use in 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 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 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 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 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. 

Summary 

• The putative benefits of neuromuscular blockade in ARDS include elimination of patient-ventilator asynchrony, mitigation of lung injury from vigorous spontaneous respiratory efforts, reduction in the pulmonary and systemic inflammatory response, and improvement in arterial oxygenation. 
• These potential advantages may be offset by a higher incidence of neuromuscular weakness, complications related to prolonged immobility, and the need for deep sedation to prevent awareness. 
• A consistent improvement in PaO₂/FiO₂ ratios has been demonstrated with the early administration of neuromuscular blocking drugs in ARDS. 
• The impact of NMB usage on clinical outcomes, including mortality remain inconclusive from the evidence available so far.
• However, there is a likely role for the early administration of NMBs among patients with severe ARDS to enable lung-protective ventilation, reduce patient-ventilator asynchrony, allow prone ventilation, and mitigate arterial hypoxemia. Needless to say, a patient-centered approach is pivotal to guide the appropriate use of NMBs among mechanically ventilated patients with severe ARDS. 

References

1.         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

2.         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

3.         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

4.         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

5.         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

6.         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

7.         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

8.         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

9.         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

10.       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

11.       Schakman O, Gilson H, Thissen JP. Mechanisms of glucocorticoid-induced myopathy. J Endocrinol. 2008;197(1):1-10. doi:10.1677/JOE-07-0606

12.       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

13.       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

14.       Mertes P-M, Laxenaire M-C, GERAP. [Anaphylactic and anaphylactoid reactions occurring during anaesthesia 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

15.       The National Heart, Lung, and Blood Institute PETAL Clinical Trials Network. Early Neuromuscular Blockade in the Acute Respiratory Distress Syndrome. N Engl J Med. 2019;380(21):1997-2008. doi:10.1056/NEJMoa1901686

16.       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