CHEST

Point: Should Paralytic Agents Be Routinely Used in Severe ARDS? Yes

Abbreviations: ALI 5 acute lung injury; AQM 5 acute quadriplegic myopathy; ICU-AW 5 ICU-acquired weakness; NMB 5 neuromuscular blockade; NMBA 5 neuromuscular blocking agent; PEEP 5 positive end-expiratory pressure; P/F 5 Pao2/Fio2; RCT 5 randomized controlled trial; TOF 5 train-of-four

Point/Counterpoint Editorials

health burden in the United States and worldwide.1 Importantly, the health consequences of ARDS have been shown to persist in many patients up to 5 years after discharge from the ICU, if not permanently. The need for improvement in the care and outcomes for these patients is clear. Cell and animal model investigations coupled with translational studies in patients undergoing mechanical ventilation for ALI/ARDS have greatly extended our knowledge about the interaction of the injured lung and the ventilator.2 Much evidence supports the concepts that both overdistension of the lung and repetitive opening and closing of alveoli can result in lung injury and even the generation of inammatory mediators by the lung that can have both local and systemic adverse effects. Accordingly, patients with ALI/ARDS can sustain further lung damage through ventilator-induced lung injury mechanisms that confounds their ability to recover from initial lung insults. These understandings have led to the notion of the use of lung-protective ventilation strategies for patients with ALI/ARDS. In a landmark trial comparing tidal volumes of 6 to 12 mL/kg ideal body weight for the management of this syndrome, a 22% relative reduction in mortality was observed in the low tidal volume group, a nding consistent with the notion of limiting lung stretch during ventilator management.3 Trials of high and low levels of positive end-expiratory pressure (PEEP) have also been performed, but to date, a specic PEEP strategy that improves mortality has not been identied.4-6 Even with these substantial improvements in ventilation strategy, mortality and morbidity remain unacceptable.
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ICU syndrome of acute lung injury (ALI) and its The more severe subset, ARDS, results in an enormous

There is at least one potential explanation for the benets of lung-protective ventilation not being fully realized. Simply, setting the ventilator to a desired tidal volume and PEEP level does not guarantee that this volume and end-expiratory pressure will be reliably delivered to the patient. Clinicians have long recognized that patients with ALI/ARDS exhibit a high degree of asynchrony with the ventilator despite the use of high inspiratory ow rates and administration of analgesics and sedatives to blunt both anxiety and respiratory drive. In one study of the breathing pattern of patients with ALI/ARDS undergoing low tidal volume lung-protective ventilation, a majority of patients exhibited periods of breath stacking during the rst 72 h of ventilator support.7 When an additional breath was triggered before full exhalation, the patient received up to two times the set tidal volume ( 6 mL/kg ideal body weight). The calculated average tidal volume during breath stacking exceeded 10 mL/kg ideal body weight. Given this problem of asynchrony, neuromuscular blockade (NMB) in addition to generous sedation was recommended by some authors and used by many clinicians as a pharmacologic adjunct to ventilator management.8 Although this represented an effective means of ensuring patient-ventilator synchrony, reasonable concerns were raised about NMB,9 including the loss of a reliable physical examination and the possibility that long-term paralysis could result in ICU-acquired weakness (ICU-AW), a common concomitant condition with critical illness that often persists months to years after recovery.10 As a consequence, expert opinion shifted to caution in the use of NMB. Nonetheless, the use of NMB continued in more severely ill patients with ALI/ARDS. It is notable that in trials of PEEP strategies published in 2008, approximately one-half of the patients underwent NMB at some point during their course of mechanical ventilation.4,5 Given these circumstances, the critical care community could have been deemed to be in equipoise regarding the use of NMBs in the treatment of ARDS. In such circumstances, there is an obvious need for prospective randomized trials to better inform practice. Fortunately, several such trials have now been published, and the data supporting the use of NMB in properly selected patients are robust. In trials published in
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2004 and 2006, 56 and 36 patients with ARDS, respectively, and receiving lung-protective ventilation were randomized to receive 48 h of NMB with cisatracurium vs placebo.11,12 In both studies, the oxygenation index (as judged by the Pao2/Fio2 [P/F] ratio) was improved by NMB, and this improvement in gas exchange persisted beyond the period of paralysis. Importantly, the elevation of proinammatory cytokines measured from BAL samples was signicantly less in patients receiving NMB, thus, offering proof of principle that NMB administration could potentiate the benets sought from a lung-protective ventilation strategy. These important studies set the stage for a multicenter prospective randomized trial published in the New England Journal of Medicine in 2010.13 In this trial, patients with severe ARDS (dened as a P/F ratio of , 150 on 5 cm H2O PEEP) were randomized to receive either a 48-h infusion of cisatracurium or placebo. Patients were enrolled within 48 h of receiving a diagnosis of ARDS. Sedation was titrated to a deep level (Ramsay score, 6) in both groups before initiation of treatment. Level of paralysis was not followed by train-of-four (TOF) testing to avoid unblinding. After the period of infusion, patients were followed for neuromuscular weakness by the Medical Research Council (MRC) score. End points for the study included mortality, ventilator-free days, and the incidence of ICU-AW. The results of the study were striking. Although the crude 90-day mortality did not differ between the two groups (P 5 .08) when adjusted by Cox regression for signicant predened parameters known to inuence outcome in patients with ARDS, a signicant difference (P 5 .05) favoring NMB was observed. There were signicantly more ventilator-free days in the group undergoing NMB in the intervals of 1 to 28 days and 1 to 90 days. In addition, the rate of pneumothorax was signicantly less (4%) in patients receiving NMB than in those receiving placebo (11%). There was no difference between the groups in MRC scores, and hence, the incidence of ICU-AW at 28 days and at hospital discharge was similar. By post hoc analysis, the benet of NMB appeared to be present primarily in the patients with the most severely impaired physiology (defined as P/F ratio , 120). When the results of this multicenter study were combined with the results of the two pilot studies for the purpose of meta-analysis, the benets of improved mortality and increased ventilator-free days with NMB persisted.14 Although these results are impressive, limitations to the study should be noted. This was a single study that has not yet been duplicated. While true, it is worth noting that it was a high-level study published in a high-impact journal and is no less assailable a study than others that have dramatically changed clinical practice in critical care medicine, such as the use of
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early goal-directed therapy for sepsis.15 If NMB confers benet to patients by eliminating patient-ventilator asynchrony early in the course of ARDS, it could be argued that adjustment of the ventilator rather than pharmacologic adjustment of the patient is preferable. Unfortunately, no clear ventilator approaches have been described to effectively eliminate patientventilator asynchrony in this context. It might also be argued that mortality difference was signicant only when adjusted for differences between the patient groups, yet these very differences were predened by the investigators and are known to be associated with outcomes from ALI/ARDS. The blinding of the study was likely not complete given clinical differences that might have existed between the patients receiving NMB and those simply receiving heavy sedation. This problem is inherent in any study of NMB. Additionally, full paralysis could not be confirmed by TOF determination because use of TOF itself would break blinding. However, to the extent that some fraction of the patients did not achieve complete paralysis, one would assume that the results would have been less impressive. Finally, the end point for ICU-AW (MRC score at 28 days) may not speak to differences between the groups during the more protracted period of recovery from ARDS. While true, it is worth observing that a prerequisite for recovering from ARDS itself and the complication of ICU-AW is survival. In addition, although physical therapy can certainly occur while patients are receiving mechanical ventilation,16 it is greatly enhanced by liberation from mechanical ventilation, and the increased number of ventilator-free days in the patients undergoing NMB suggests a greater window of opportunity for their rehabilitation. Jesse B. Hall, MD, FCCP Chicago, IL
Afliations: From the Department of Anesthesia & Critical Care and Section of Pulmonary and Critical Care Medicine, Pritzker School of Medicine, The University of Chicago. Financial/nonnancial disclosures: The author has reported to CHEST that no potential conicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Correspondence to: Jesse B. Hall, MD, FCCP, Section of Pulmonary and Critical Care Medicine, Pritzker School of Medicine, The University of Chicago, 924 E 57th St, Ste 104, Chicago, IL 60637-5415; e-mail: jhall@medicine.bsd.uchicago.edu 2013 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.13-1460

References
1. Rubenfeld GD, Caldwell E, Peabody E, et al. Incidence and outcomes of acute lung injury. N Engl J Med. 2005;353(16): 1685-1693. 2. de Prost N, Ricard JD, Saumon G, Dreyfuss D. Ventilatorinduced lung injury: historical perspectives and clinical implications. Ann Intensive Care. 2011;1(1):28-43.
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3. The Acute Respiratory Distress Syndrome Network. 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. 4. Meade MO, Cook DJ, Guyatt GH, et al; Lung Open Ventilation Study Investigators. Ventilation strategy using low tidal volumes, recruitment maneuvers, and high positive end-expiratory pressure for acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. JAMA. 2008;299(6): 637-645. 5. Mercat A, Richard JC, Vielle B, et al; Expiratory Pressure (Express) Study Group. Positive end-expiratory pressure setting in adults with acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. JAMA. 2008; 299(6):646-655. 6. Briel M, Meade M, Mercat A, et al. Higher vs lower positive end-expiratory pressure in patients with acute lung injury and acute respiratory distress syndrome: systematic review and meta-analysis. JAMA. 2010;303(9):865-873. 7. Pohlman MC, McCallister KE, Schweickert WD, et al. Excessive tidal volume from breath stacking during lung-protective ventilation for acute lung injury. Crit Care Med. 2008;36(11): 3019-3023. 8. Light RW, Bengfort JL, George RB. The adult respiratory distress syndrome and pancuronium bromide. Anesth Analg. 1975;54(2):219-223. 9. Hansen-Flaschen J, Cowen J, Raps EC. Neuromuscular blockade in the intensive care unit. More than we bargained for. Am Rev Respir Dis. 1993;147(1):234-236. 10. Schweickert WD, Hall JB. ICU-acquired weakness. Chest. 2007;131(5):1541-1549. 11. 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(1):113-119. 12. Forel JM, Roch A, Marin V, et al. Neuromuscular blocking agents decrease inammatory response in patients presenting with acute respiratory distress syndrome. Crit Care Med. 2006;34(11):2749-2757. 13. Papazian L, Forel JM, Gacouin A, et al; ACURASYS Study Investigators. Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med. 2010;363(12):1107-1116. 14. Neto AS , Pereira VGM, Espsito DC, Damasceno MC, Schultz MJ. Neuromuscular blocking agents in patients with acute respiratory distress syndrome: a summary of the current evidence from three randomized controlled trials. Ann Intensive Care. 2012;2(1):33-38. 15. Rivers E, Nguyen B, Havstad S, Ressler J, et al; Early GoalDirected Therapy Collaborative Group. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001;345(19):1368-1377. 16. Schweickert WD, Pohlman MC, Pohlman AS, et al. Early physical and occupational therapy in mechanically ventilated, critically ill patients: a randomised controlled trial. Lancet. 2009;373(9678):1874-1882.

Counterpoint: Should Paralytic Agents Be Routinely Used in Severe ARDS? No

cornerstone of ARDS management is the delivThe ery of positive pressure ventilation with sufcient
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ination pressure to recruit and maintain alveoli in an

inated state while avoiding alveolar overdistension and associated pulmonary and systemic inammation and barotrauma. Severe ARDS is characterized by profound hypoxemia that often is refractory to traditional management and, along with multiple organ failure, is a frequent cause of death.1 A variety of ventilatory and nonventilatory interventions have been used to improve oxygenation in severe ARDS, including the use of neuromuscular blocking agents (NMBAs).2,3 Such measures are typically applied on the basis of the patients severity of gas exchange derangement and other individualized factors rather than routinely administered. However, results from a placebocontrolled trial in which patients with severe ARDS randomized to receive the NMBA cisatracurium had superior outcomes have prompted this debate.4 To consider this question of clinical decision-making, it is important to weigh the strength of the evidence, the risk and benet of the intervention, and the reproducibility and generalizability of the supporting results. Furthermore, the key components of the question should be carefully examined, including paralytic agents, whether they should be routinely used, and severe ARDS. NMBAs have been used for decades in the management of patients in the ICU with respiratory failure primarily due to ARDS or status asthmaticus to permit passive ventilation by eliminating active inspiratory and expiratory efforts that can impair gas exchange and increase the risk for barotrauma.5-7 Guidelines published in 2001 support the use of NMBAs to facilitate mechanical ventilation when sedation alone is inadequate, particularly in patients with severe gas exchange impairments.5 In fact, NMBAs were administered to 25% to 55% of patients enrolled in modern ARDS clinical trials.8-11 A key question is whether all patients with severe ARDS should be treated with NMBAs or whether this treatment should be individualized. Nondepolarizing NMBAs act by competing with acetylcholine for binding at the nicotinic receptor of the motor end plate, producing paralysis of skeletal muscles. Potential consequences of widespread muscular paralysis include VTE, compromised skin integrity, corneal ulcers, nerve compression, impaired communication, patient awareness and pain while paralyzed, impaired cough, and elimination of protective reexes.5-7 Additionally, protracted weakness is described following NMBA administration as a result of either prolonged receptor blockade due to reduced elimination of parent drug and active metabolites or acute quadriplegic myopathy (AQM).5 One of a number of forms of ICU-acquired paresis,12 AQM is believed to arise from the loss of myosin and myosin-associated proteins, and perhaps from myonecrosis, typically following the concomitant use of an NMBA and
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