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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 inﬂammatory 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, Espósito 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 sufﬁcient
inﬂation pressure to recruit and maintain alveoli in an
inﬂated state while avoiding alveolar overdistension and associated pulmonary and systemic inﬂammation 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 patient’s 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 beneﬁt 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 reﬂexes.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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the Papazian et al study was higher than in any of the high-PEEP RCTs. 100 mm Hg. no longer meeting ARDS criteria) by applying 10 cm H2O PEEP at 24 h and rechecking the Pao2/Fio2.10 and Talmor et al. Important differences exist among nondepolarizing NMBAs.9 Brower et al.5 was not used. more ventilatorand organ failure-free days.5 mg/h) for 48 h without titrating to clinical measures of safety or efﬁcacy. resulting in lower average PEEP values than the low-PEEP arm of all of the RCTs that compared low-PEEP and high-PEEP strategies.6 Aminosteroids are eliminated by CHEST / 144 / 5 / NOVEMBER 2013 1443 Downloaded From: http://journal.5 In their multicenter. Unfortunately. 5 cm H2O and tidal volume of 6 to 8 mL/kg predicted body weight.chestnet. but it is possible that their results are not reproducible with other NMBAs. thus. Both ﬁxed cisatracurium dosing and lack of monitoring were departures from conventional practice. Safe practice emphasizes avoiding unnecessary use of NMBAs and limiting the duration of therapy to avoid these complications. often producing profound weakness that lasts weeks to months. 150 mm Hg while mechanically ventilated with a positive endexpiratory pressure (PEEP) . although the median Medical Research Council muscle strength score and the proportion of patients without ICU-acquired paresis at day 28 and at ICU discharge were similar between the cisatracurium and placebo groups. 40% of patients with ARDS are reclassiﬁed as having a Pao2/Fio2 .13 The clinical picture includes paretic spinal nerve-innervated muscles with sparing of cranial nerve-innervated muscles and intact sensory function and cognition. limiting generalizability related to the numerous exclusions. More importantly. the PEEP strategy that Papazian et al4 used was conservative. The technique of periodically measuring response to peripheral nerve stimulation. and 5% received the respiratory stimulant almitrine.org/ by a St Joseph Hospital User on 11/05/2013 .publications. both regarding selecting their patient population and during management.4 Finally. Papazian et al4 selected cisatracurium as the NMBA to test.9-11 except the French study by Mercat et al8 (Fig 1). and less barotrauma. at least 50% of patients in each study arm received as-needed doses of cisatracurium. only 25% of eligible patients were enrolled. The average PEEP used was far lower than that used in high-PEEP strategies that are associated with lower mortality and shorter length of stay by meta-analysis. including a lower 90-day mortality rate after adjustment for selected baseline variables (but not crude mortality [P 5 . Furthermore. placebo-controlled. randomized controlled trial (RCT) conducted in 340 French patients with severe ARDS. Papazian et al4 reported provocative results after the administration of cisatracurium for 48 h.8 Meade et al. Eligibility criteria were traditional ARDS criteria but required a Pao2/Fio2 ratio .chestnet. particularly when comparing aminosteroidal agents like pancuronium and vecuronium to benzylisoquinolinium drugs like atracurium and cisatracurium. it is important to examine details of the study design and conduct as one considers the strength of evidence as well as generalizability. the barotrauma rate of nearly 12% in the placebo arm of journal. they found no difference in rates of ICU-acquired paresis between groups by Medical Research Council score for muscle strength. other outcome data and safety data for these subpopulations were not reported.4 Cisatracurium was administered at a set dose (37. Twenty percent of patients received continuous IV infusion ketamine in their sedation regimen. Similar to many RCTs. There are additional aspects of patient management in the Papazian et al4 study that may limit generalizability. Average Pao2/Fio2 vs average PEEP on day 3 for subjects from Papazian et al4 and from subjects randomized to the low-PEEP and high-PEEP groups in Mercat et al. which is widely used to test for depth of paralysis and to avoid overdosing with NMBAs. one wonders whether the infrequent case of AQM that can produce prolonged disability and ventilator support was adequately captured with these authors’ approach.corticosteroid. This was not done by Papazian et al4 but could have inﬂuenced patient selection. This threshold for severe ARDS is more consistent with the recent Berlin ARDS criteria that classify severe ARDS as Pao2/Fio2 .11 PEEP 5 positive end-expiratory pressure.8-11 One wonders whether the same beneﬁts found with cisatracurium by Papazian and colleagues would have been observed if a higher PEEP strategy had been used.14 Papazian et al4 used a very conservative approach to PEEP. Data from the post hoc analysis revealed that the survival beneﬁt was limited to the two-thirds of enrolled patients who had a Pao2/Fio2 . Villar et al15 demonstrated that .08]).5 Also of note. Key differences include the process of drug elimination and the presence of active metabolites.org Figure 1. Although the primary results are indeed noteworthy. 120 mm Hg. neither intervention is used in most ICUs.5. potentially clouding the results. Survival was virtually identical for the cisatracurium and placebo groups for Pao2/Fio2 Ն 120 mm Hg.16 Furthermore. 200 mm Hg (and.publications.
Neuromuscular blockade in the intensive care unit. 2011. JAMA. 3. Malhotra A. Ranieri VM.17 In an analysis of prospective trials of NMBAs in ICU patients in which prolonged weakness was actively sought. Severe hypoxemic respiratory failure: part 2—nonventilatory strategies. Cook DJ. An early PEEP/Fio2 trial identiﬁes different degrees of lung injury in patients with acute respiratory distress syndrome. Warr et al6 endorsed the benzylisoquinoliniums over aminosteroids for patients in the ICU with organ dysfunction. 1995. MD.18 In a systematic review. Neuromuscular blockers in early acute respiratory distress syndrome. 11. In summary. et al. both pancuronium and vecuronium have active metabolites. N Engl J Med. and high positive end-expiratory pressure for acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. Sarge T. whereas none of those receiving atracurium or cisatracurium did. Vielle B. Virginia Commonwealth University Health System.359(20):2095-2104. Sessler. George L. MD.299(6): 637-645. FCCP. Semin Respir Crit Care Med. Correspondence to: Curtis N.45(9):1116-1126. Ann Intern Med.642:92-98. Mercat A. 2001. 10. and reduced inﬂammation. The acute respiratory distress syndrome. Papazian L. 299(6):646-655.20 In agreement with Papazian and colleagues. et al. 2008. DOI: 10. Sessler.13-1462 References 1. these studies were performed by the same research group that led the study by Papazian et al4 and focused only on cisatracurium. N Engl J Med.141(6):460-470. Lung. 16. et al. 2004. and clinical considerations of neuromuscular blocking agents for critically ill adults. Chest. VA Afﬁliations: From the Division of Pulmonary and Critical Care Medicine. Crit Care Med. Rose L. Schwartz DA. future studies are needed to replicate and expand these ﬁndings before they can be widely adopted in clinical practice. American College of Chest Physicians.137(5):1203-1216. 17. Mehta S. Prielipp RC. cisatracurium had an average recovery time of 68 min with 9% delayed beyond 2 h.chestnet. Larsson L. Goulet K. Guyatt GH. American Society of Health-System Pharmacists. Esan A. Paresis acquired in the intensive care unit: a prospective multicenter study. FCCP Richmond. Acute quadriplegic myopathy: an acquired “myosinopathy”. I favor modifying the statement that paralyzing agents should be routinely used in severe ARDS to instead say that cisatracurium should be considered for short-term use (. ACURASYS Study Investigators.30(1):142-156. Curtis N. MacIntyre N. Brower RG. 4. Expiratory Pressure (Express) Study Group. Meade MO. Groupe de Réﬂexion et d’Etude des Neuromyopathies en Réanimation. et al. 2012. Thiboutot Z. 2010. 8. 2010. 1444 Point/Counterpoint Editorials Downloaded From: http://journal.288(22):2859-2867. Raoof S. DeBlock H. Pérez-Méndez L. 2010. 9. Comparison of the infusion requirements and recovery proﬁles of vecuronium and cisatracurium 51W89 in intensive care unit patients. e-mail: csessler@vcu. 15. pharmacology. Forel JM.351(4):327-336. Hess DR. ARDS Definition Task Force. Murray MJ. 2004. 14. Positive end-expiratory pressure setting in adults with acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. N Engl J Med. Hess DR. Lung Open Ventilation Study Investigators. Medical College of Virginia Campus.363(12):1107-1116. Higher versus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome. Gehr LC. Although several smaller RCTs have demonstrated beneﬁcial ﬁndings of better oxygenation. trends for lower mortality. Gacouin A. National Heart. whereas vecuronium had an average recovery time of 387 min with 43% delayed beyond 2 h. 5. Piantadosi CA. JAMA.edu © 2013 American College of Chest Physicians. 2007. Villar J. Lanken PN. López J. 2002. 12. 2002. 48 h) in patients with severe ARDS (deﬁned as Pao2/Fio2 . 2. There are few RCTs of aminosteroids and benzylisoquinoliniums in patients in the ICU. Scuderi PE. et al. Meade M. et al. Richard JC. 6. Furthermore. et al. et al.19. whereas atracurium or cisatracurium do not. Sessler CN. Adv Exp Med Biol. JAMA. Ann Pharmacother. the statement that paralytic agents should be routinely used in severe ARDS should be narrowed to focus only on cisatracurium. Briel M. Chest. 7.org/ by a St Joseph Hospital User on 11/05/2013 . Sharshar T. Raoof S. Task Force of the American College of Critical Care Medicine (ACCM) of the Society of Critical Care Medicine (SCCM).303(9):865-873. Reproducibility of results should be considered when stating a strong recommendation. HELP Network. 13. Severe hypoxemic respiratory failure: part 1—ventilatory strategies. Acute respiratory distress syndrome: the Berlin Deﬁnition. Burry LD. 2008. in one small ICU study. about 8% of patients who received aminosteroids had AQM. JAMA. Financial/nonﬁnancial disclosures: The author has reported to CHEST that no potential conﬂicts of interest exist with any companies/organizations whose products or services may be discussed in this article.hepatic and renal mechanisms whereas benzylisoquinoliniums are eliminated by an end organ-independent enzymatic process called Hofmann degradation. Sessler CN. et al. Virginia Commonwealth University Health System. recruitment maneuvers. See online for more details. Warr J.137(6):1437-1448. Higher vs lower positive end-expiratory pressure in patients with acute lung injury and acute respiratory distress syndrome: systematic review and meta-analysis.176(8):795-804. Esan A. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. De Jonghe B. et al. 2008. 2008. and Blood Institute ARDS Clinical Trials Network. However. JAMA. Mechanical ventilation guided by esophageal pressure in acute lung injury. Box 980050. et al. VA 23298. Division of Pulmonary and Critical Care Medicine. Anesth Analg. Coursin DB.1378/chest. 2010. Am J Respir Crit Care Med. Talmor D. 120 mm Hg) until further studies are available. Ventilation strategy using low tidal volumes. Sessler CN.22(2):175-188. Current therapeutic uses.81(1):3-12. Clinical practice guidelines for sustained neuromuscular blockade in the adult critically ill patient. Rubenfeld GD. Because the Papazian et al4 study was conducted with cisatracurium and on considering the potential disadvantages of aminosteroids for critically ill patients. Thompson BT.307(23):2526-2533. Lefaucheur JP. Cowen J. Richmond. Mercat A.publications.
The particulars of NMB administration in the trial. a strong criticism of observer bias likely would have been raised. FCCP Chicago.uchicago. Sessler CN. Neuromuscular blocking agents decrease inﬂammatory response in patients presenting with acute respiratory distress syndrome. and high positive endexpiratory pressure for acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. I agree with Dr Sessler that translation of the results of trials to practice is challenging and must be done carefully.2-6 The relatively low positive end-expiratory pressure (PEEP) levels used in the Papazian et al2 trial do not likely limit the interpretation of beneﬁt because it is not likely that higher PEEP levels would achieve greater patient-ventilator synchrony. FCCP. recruitment maneuvers. MD. Had standard approaches to NMB administration been journal. Meade MO. Financial/nonﬁnancial disclosures: The author has reported to CHEST that no potential conﬂicts of interest exist with any companies/organizations whose products or services may be discussed in this article. DOI: 10. Gacouin A. et al. until additional studies evaluate this approach. Accordingly. as did I. Neuromuscular blockers in early acute respiratory distress syndrome. 2004. Rebuttal From Dr Hall interpretation of the study supporting a role for neuromuscular blockade (NMB) as a therapeutic adjunct during mechanical ventilation of patients with severe ARDS. CHEST / 144 / 5 / NOVEMBER 2013 1445 Downloaded From: http://journal. Pritzker School of Medicine. even in aggregate they do not dissuade me from my initial position. ACURASYS Study Investigators. et al. a ﬁxed dose and lack of peripheral nerve stimulation titration.299(6):646-655. 2008. Pritzker School of Medicine. Richard JC. Marin V. that is. The University of Chicago. This information even suggests that clinicians might use the results of the study to restrict their use of NMB because.299(6):637-645. 19. Dr Sessler also notes. et al.chestnet. as many as 25% to 55% of patients enrolled in modern ARDS trials received NMB. I view this as very helpful information to guide the clinician in the use of NMB in the sickest patients (as measured by this physiologic signal). He points out that there may be a disconnect between the patients reported in the trial and those whom practicing physicians actually care for. Jesse B. 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. 120 mm Hg. Crit Care Med. even in the form of observational data. Higher PEEP levels would not likely result in the observation of lower levels of barotrauma in the treatment group. JAMA. Crit Care Med.bsd.publications. MD. See online for more details. I agree that cisatracurium should be the preferred agent in this setting until studies with other NMB agents are available. Vielle B. e-mail: jhall@medicine. which I believe is a likely mechanism by which this beneﬁt occurs. et al. were necessary study design elements to avoid obvious unblinding of group allocation.126(4):1018-1022. Guyatt GH. from larger patient populations followed for longer periods of time. On this point I am sure that Dr Sessler and I share a desire to have information available. but I will simply note that this was not seen within the limitations of assessment of muscle strength conducted in the trial. 3. I believe that NMB should be considered a beneﬁcial adjunct to our strategies for lung-protective mechanical ventilation. 2008. 2. et al. However. Finally. 4. Hall.34(11):2749-2757. Roch A. Section of Pulmonary and Critical Care Medicine.edu © 2013 American College of Chest Physicians. Ventilation strategy using low tidal volumes. 2010. Chicago.chestnet. Mercat A. The University of Chicago. as Dr Sessler notes.org has provided a number of arguments in DranSessler attempt to counter or at least soften a positive used. Forel JM.1378/chest.13-1461 References 1.1. Forel JM.18. Forel JM. Ste 104. I share the concern for potentiation of ICU-acquired weakness by NMB. Effect of neuromuscular blocking agents on gas exchange in patients presenting with acute respiratory distress syndrome. Counterpoint: should paralytic agents be routinely used in severe ARDS? No. I agree that the results of the Papazian et al2 trial should be considered to address speciﬁcally the use of cisatracurium in patients with severe ARDS receiving mechanical ventilation.363(12):1107-1116. Sessler CN.publications. 2006. 2013. this is the reality of clinical trials and is not different from the usual circumstances of trying to apply evidence from trials to practice.2 Although these arguments are thoughtful and well presented. N Engl J Med. I believe that we are better off with the results of trials conducted under a careful protocol than being limited to observational data from real-world circumstances. Correspondence to: Jesse B. Papazian L. Train-of-four to monitor neuromuscular blockade? Chest. For better or for worse. 924 E 57th St. Lung Open Ventilation Study Investigators. Chest.144(5):1442-1445. IL 60637-5415. 32(1):113-119. Dr Sessler’s observation that the beneﬁts seen in this trial may not be seen with NMB agents other than cisatracurium for the reasons he cites is insightful. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. Gainnier M. JAMA. 2004. Roch A. 20.org/ by a St Joseph Hospital User on 11/05/2013 . Hall. that the post hoc analysis suggested that the treatment effect was limited to the subset of patients with a Pao2/Fio2 ratio . Cook DJ. as suggested by the fact that only 25% of eligible patients were enrolled. IL Afﬁliations: From the Department of Anesthesia & Critical Care and Section of Pulmonary and Critical Care Medicine.