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Use of neuromuscular blocking agents in acute respiratory distress syndrome.

Acute respiratory distress syndrome (ARDS) was described in 1967 by Dr. Ashbaugh and colleagues as an acute inflammatory response of the lungs with consequent hypoxemia. (1) In 2011, a panel of experts developed the Berlin definition, which defined ARDS as a syndrome occurring within 1 week of a known clinical insult or worsening respiratory symptoms, with evidence of bilateral opacities not fully explained by effusions, lobar/lung collapse, or nodules. The Berlin definition also divided ARDS into three categories based on the degree of hypoxemia but considering the level of positive end-expiratory pressure (PEEP; Table 1)) A landmark study comparing mechanical ventilation with lower tidal volumes (6 cc/kg of predicted body weight) vs traditional tidal volumes (12 cc/kg) showed a reduction in mortality by almost 9% and became the standard of care for the management of ARDS. (2) Many other therapeutic modalities have since been evaluated: high-frequency oscillatory ventilation, (3,4) airway pressure release ventilation, (5) inhaled vasodilators, (6) and extracorporeal membrane oxygenation. (7,8) Two strategies that have gained significant attention after demonstrating improvement in survival are prone positioning and use of neuromuscular blocking agents (NMBAs). (9) Despite its positive effect, prone positioning remains underutilized in clinical practice, because it requires trained and experienced personnel to obtain desirable outcomes. Therefore, the use of continuous infusion of NMBAs may be seen as a valuable strategy in a group of patients with severe ARDS not responding to standard of care therapy. (10) This article reviews the mechanism of action of NMBAs, the evidence for their use in ARDS, and current recommendations.


A neuromuscular junction is composed of a presynaptic motor axon that abuts acetylcholine receptors of skeletal muscle cells. Upon activation, the neuron releases acetylcholine, activating the skeletal muscle cell and thereby allowing the flow of sodium and potassium to trigger a muscle contraction. (11) NMBAs competitively bind to the acetylcholine receptor, preventing activation of the muscle cell by acetylcholine. NMBAs are classified as depolarizing or nondepolarizing agents. Depolarizing agents mimic the effect of acetylcholine at the neuromuscular junction, and these include succinylcholine and decamethonium. Normally, when acetylcholine binds to the acetylcholine receptor on muscle cells, the channel opens for a very short duration because acetylcholinesterase rapidly degrades the transmitter in the perijunctional area. (12) Conversely, depolarizing agents have a biphasic action, because they mimic acetylcholine by causing muscle contractions and, subsequently, they cause paralysis due to decreased susceptibility to degradation by acetylcholinesterase. Nondepolarizing NMBAs are also competitive antagonists at the nicotinic acetylcholine receptor but differ from depolarizing agents because they bind for longer periods of time, preventing acetylcholine from binding. (13) Importantly, these agents are lipophobic, so they do not cross the blood-brain barrier. Among nondepolarizing agents, pancuronium, cisatracurium, and atracurium have all been studied in the ARDS population. Atracurium was developed in 1981 by Stenlake and colleagues. (14) It is a benzylisoquinoline molecule that breaks down irreversibly at physiological pH and temperature based on the principles of Hofmann elimination. (15) This characteristic presents important advantages in critically ill subjects, allowing its utilization in patients with kidney, liver, or multiorgan failure. (16) However, atracurium may cause histamine release with consequent cardiovascular effects, hypotension, cutaneous flushing, and tachycardia. These effects are usually reversible within 5 minutes postadministration. As previously stated, atracurium undergoes Hofmann elimination; one of the metabolites associated with this elimination path is laudanosine, which has been reported to cross the blood-brain barrier and decrease the seizure threshold. Nevertheless, multiple studies demonstrated that concentrations of laudanosine needed to trigger seizures are much higher than those generated by doses of atracurium used in clinical practice. (17) Cisatracurium is an optical isomer of atracurium and is slightly more potent. It also undergoes Hoffman elimination. Because cisatracurium causes less histamine release and concentrations of laudanosine are reportedly lower compared with atracurium, this NMBA presents hypothetical advantages. (18)


The first NMBA reported as a potential treatment for ARDS was pancuronium. Specifically, a report from 1975 described the use of pancuronium in 6 patients with ARDS with a goal to improve patient-ventilator synchrony. (19) Later, in 1984, Bishop reported the use of a single bolus of pancuronium in 9 patients with acute lung injury/ARDS. (20) Nevertheless, no hemodynamic or oxygenation effects were seen in those patients. (20) Interestingly, a survey sent out in 1990 showed that paralytics were already being utilized for ARDS without extensive research to support their benefits. (21) Major studies that have evaluated NMBA in ARDS have been conducted since these early reports. The first prospective randomized control study, which included the use of cisatracurium as an infusion for a period of 2 hours, included 102 patients with ARDS. These patients were randomized to two different levels of paralysis based on train-of-four (TOF) monitoring. No placebo group was included. The study showed improvement of oxygenation and plateau pressures in both groups, showing no differences when aiming for TOF of 0 of 4 or 2 of 4. (11) Another multicenter prospective randomized controlled study, published in 2004, included 56 patients with a partial pressure of arterial oxygen and fraction of inspired oxygen (Pa[O.sub.2]/Fi[O.sub.2]) ratio <150 and PEEP [greater than or equal to] 5 cm [H.sub.2]O. Neuromuscular blockade for 48 hours was utilized vs placebo and resulted in significant improvement in oxygenation, manifested by a higher Pa[O.sub.2]/Fi[O.sub.2] ratio at 48, 96, and 120 hours postrandomization. Furthermore, the level of PEEP required to achieve similar oxygenation compared with the placebo group was reduced. (22) In this study, the proposed mechanism for the improvement in oxygenation was a reduction in proinflammatory cytokines, leading to a decrease in lung permeability and inflammatory response. In a follow-up study published in 2006, Forel and colleagues (23) reviewed the effects of NMBAs on pulmonary and systemic inflammation. The study involved collection of blood samples and bronchoalveolar lavages upon admission with ARDS and 48 hours after NMBA treatment vs control. The authors investigated concentrations of tumor necrosis factor-alpha, interleukin (IL)-1beta, IL-6, and IL-8. Notably, the study found that after 48 hours, pulmonary concentrations of IL-1beta, IL-6, and IL-8 were lower in the neuromuscular blockade group vs the control group. There was a serum decrease in IL-6 and IL-8 as well. Furthermore, this trial confirmed a sustained improvement in the Pa[O.sub.2]/Fi[O.sub.2] ratio with NMBA utilization. (23)

Based on the previously described experiences, Papazian and colleagues investigated the use of NMBAs and their effect in clinical outcomes. (10) Specifically, patients with severe ARDS, defined as Pa[O.sub.2]/Fi[O.sub.2] ratios <150, were randomized to a continuous infusion of cisatracurium vs placebo. Interestingly, the authors found that treatment with cisatracurium for 48 hours improved the adjusted 90-day survival rate with a hazard ratio of cisatracurium compared with placebo of 0.68 (P = 0.04). Furthermore, the cisatracurium group had a higher number of ventilator-free days at 90 days (hazard ratio of 1.41; P = 0.01) and organ failure-free days at 28 days (15.8 days vs 12.2 days in the cisatracurium group vs placebo group, respectively; P = 0.01). Notably, the incidence of intensive care unit (ICU)-acquired paresis at 28 days or upon ICU discharge was not statistically different between groups. (11) A recently published retrospective study compared a continuous infusion of atracurium vs cisatracurium in patients with severe ARDS. There was no difference in oxygenation improvement at 72 hours post-NMBA initiation. Furthermore, ventilator-free days at 28 days, ICU length of stay, and hospital mortality were not different among NMBAs studied. (24)

There is currently an open clinical trial to reevaluate systemic early NMBA with cisatracurium in a randomized, parallel assignment. (25) In addition, there is a second trial evaluating the effects of NMBA on the alteration of transpulmonary pressures in early phase ARDS. (26) The result of these trials may provide further evidence for their clinical utilization.


Given the findings of the previously described trials, the surviving sepsis campaign guidelines recommend a short course of neuromuscular blockade for not longer than 48 hours in patients with early sepsis-induced ARDS and Pa[O.sub.2]/Fi[O.sub.2] <150 mm Hg. (27) Monitoring should include both clinical acumen and TOF. TOF should be titrated aiming at 1 to 2 twitches out of 4 applied stimuli, which equates to approximately 80% to 90% of blocked receptors. (28) The current guidelines make no recommendations regarding use of electroencephalogram-derived parameters as a measure of sedation but recommend using clinical judgment to monitor sedation. (29) In the paralyzed patient, common scales (i.e., the Richmond Agitation and Sedation Scale) are not useful to monitor sedation. Therefore, some institutions still use the Bispectral Index or the Patient State Index to determine levels of sedation in ICU patients. In terms of side effects, studies have not shown an increased risk of ICU-acquired weakness if NMBAs are used for 48 hours. (29) However, current guidelines recommend a structured physiotherapy regimen. (29) Though atracurium may cause histamine release, hypersensitivity reactions are not frequently reported. There are no specific contraindications for NMBA use.

In summary, NMBA became a practical and evidencebased therapy in subjects with severe ARDS not responding to conventional ventilator strategies. Proper selection of blocking agents, as well as training in their use, monitoring, and expected complications, is fundamental to achieve desirable outcomes in this group of patients with already high mortality rates.

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(2.) Ranieri VM, Rubenfeld GD, Thompson BT; ARDS Definition Task Force. Acute respiratory distress syndrome. The Berlin definition. JAMA. 2012; 307:2526-2533.

(3.) Young D, Lamb SE, Shah S, et al. High-frequency oscillation for acute respiratory distress syndrome. N Engl J Med. 2013; 368:806-813.

(4.) Ferguson ND, Cook DJ, Guyatt GH, et al. High-frequency oscillation in early acute respiratory distress syndrome. N Engl J Med. 2013; 368:795-805.

(5.) Maung AA, Kaplan RJ. Airway pressure release ventilation in acute respiratory distress syndrome. Crit Care Clin. 2011; 27:501-509.

(6.) Taylor RW, Zimmerman JL, Dellinger RP, et al. Low-dose inhaled nitric oxide in patients with acute lung injury: a randomized controlled trial. JAMA. 2004; 291:1603-1609.

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(10.) Papazian L, Forel JM, Gaucouin A, et al. Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med. 2010; 363:1107-1116.

(11.) Colquhoun D, Sakmann B. Fast events in single-channel currents activated by acetylcholine and its analogues at the frog muscle endplate. J Physiol. 1985; 369:501-557.

(12.) Martyn J, Durieux M. Succinylcholine new insights into mechanisms of action of an old drug. Anesthesiology. 2006; 104:633-634.

(13.) Paton WD. Mode of action of neuromuscular blocking agents. Br J Anaesth. 1956; 28:470-480.

(14.) Stenlake JB, Waigh RD, Dewar GH. Biodegradable neuromuscular blocking agents. Part 4: atracurium besylate and related polyalkylene diesters. EurJMed Chem. 1981; 16:515-524.

(15.) Stenlake JB, Waigh RD, Urwin J, Dewar GH, Coker GG. Atracurium: conception and inception. Br J Anaesth. 1983; 55:3S-10S.

(16.) Bowman WC. Neuromuscular block. Br J Pharmacol. 2006; 147:S277-S286.

(17.) Fodale V, Santamaria LB. Laudanosine, an atracurium and cisatracurium metabolite. Eur J Anaesthesiol Suppl. 2002; 19:466-473. 1017/S0265021502000777.

(18.) Kisor DF, Schmith VD. Clinical pharmacokinetics of cisatracurium. Clin Pharmacokinet. 1999; 36:27-40. 36010-00003.

(19.) Light RW, Bengfort JL, George RB. The adult respiratory distress syndrome and pancuronium bromide. Anesth Analg. 1975; 54:219-223.

(20.) Bishop MJ. Hemodynamic and gas exchange effects of pancuronium bromide in sedated patients with respiratory failure. Anesthesiology. 1984; 60:369-371.

(21.) Hansen-Flaschen JH, Brazinsky S, Basile C, Lanken PN. Use of sedating drugs and neuromuscular blocking agents in patients requiring mechanical ventilation for respiratory failure: a national survey. JAMA. 1991; 266:2870-2875.

(22.) 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; 32:113-119. CCM.0000104114.72614.BC.

(23.) 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; 34:2749-2757.

(24.) Moore L, Kramer CJ, Delcoix-Lopes S, Modrykamien AM. Comparison of cisatracurium versus atracurium in early ARDS. Respir Care. 2017; 62:947-952.

(25.) Reevaluation of systemic early neuromuscular blockade (ROSE). Accessed January 31, 2018.

(26.) Effects of neuromuscular blocking agents (NMBA) on the alteration of transpulmonary pressures at the early phase of acute respiratory distress syndrome (ARDS). Accessed January 31, 2018.

(27.) Rhodes A, Evans L, Alhazzani W, et al. Surviving sepsis campaign. Crit Care Med. 2017; 45:486-552. 002255.

(28.) Strange C, Vaughan L, Franklin C, Johnson J. Comparison of train-off-our and best clinical assessment during continuous paralysis. Am J Respir Crit Care Med. 1997; 156:1556-1561. 5.9701079.

(29.) Puthucheary A, Rawal J, Ratnayake G, Harridge S, Montgomery H, Hart N. Neuromuscular blockade and skeletal muscle weakness in critically ill patients. Am J Respir Crit Care Med. 2012; 185:911-917. doi. org/10.1164/rccm.201107-1320OE.

G. Tsai-Nguyen, MD, and Ariel M. Modrykamien, MD

Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Baylor University Medical Center, Dallas, Texas

Corresponding author: Ariel M. Modrykamien, MD, Division of Pulmonary and Critical Care Medicine, Baylor University Medical Center at Dallas, 3600 Gaston Ave., Suite 960, Dallas, TX 75246 (e-mail:

Received October 12, 2017; Revised November 3, 2017; Accepted November 7, 2017.
Table 1. Classification of ARDS based on Berlin definition

Type       Description

Mild       Pa[O.sub.2]/Fi[O.sub.2] 201-300 with PEEP or CPAP
           (greater than or equal to) 5 cm [H.sub.2]O

Moderate   Pa[O.sub.2]/Fi[O.sub.2] 101-200 with PEEP
           (greater than or equal to) 5 cm [H.sub.2]O

Severe     Pa[O.sub.2]/Fi[O.sub.2] (left arrow) 100 with PEEP
           (greater than or equal to) 5 cm [H.sub.2]O

ARDS indicates acute respiratory distress syndrome; CPAP, continuous
positive airway pressure; Pa[O.sub.2]-Fi[O.sub.2], ratio of partial
pressure of arterial oxygen to fraction of inspired oxy-gen; PEEP,
positive end-expiratory pressure.
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Author:Tsai-Nguyen, G.; Modrykamien, Ariel M.
Publication:Baylor University Medical Center Proceedings
Article Type:Report
Date:Apr 1, 2018
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