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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
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 inﬂammatory 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 ﬁnding 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 speciﬁc PEEP strategy that improves mortality has not been identiﬁed.4-6 Even with these substantial improvements in ventilation strategy, mortality and morbidity remain unacceptable.
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 beneﬁts 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 ﬂow 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 ﬁrst 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 (Յ 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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chestnet. it is worth observing that a prerequisite for recovering from ARDS itself and the complication of ICU-AW is survival. et al. 56 and 36 patients with ARDS. yet these very differences were predeﬁned by the investigators and are known to be associated with outcomes from ALI/ARDS.16 it is greatly enhanced by liberation from mechanical ventilation. 2. FCCP. offering proof of principle that NMB administration could potentiate the beneﬁts sought from a lung-protective ventilation strategy. This was a single study that has not yet been duplicated.edu © 2013 American College of Chest Physicians. By post hoc analysis. one would assume that the results would have been less impressive.chestnet. 2005.1(1):28-43. Jesse B.org/ by a St Joseph Hospital User on 11/05/2013 . 120). thus. and the increased number of ventilator-free days in the patients undergoing NMB suggests a greater window of opportunity for their rehabilitation. In addition.12 In both studies. the incidence of ICU-AW at 28 days and at hospital discharge was similar. ventilator-free days. to the extent that some fraction of the patients did not achieve complete paralysis. There were signiﬁcantly more ventilator-free days in the group undergoing NMB in the intervals of 1 to 28 days and 1 to 90 days. although physical therapy can certainly occur while patients are receiving mechanical ventilation. the beneﬁt of NMB appeared to be present primarily in the patients with the most severely impaired physiology (defined as P/F ratio . When the results of this multicenter study were combined with the results of the two pilot studies for the purpose of meta-analysis. Caldwell E. and the incidence of ICU-AW. IL Afﬁliations: From the Department of Anesthesia & Critical Care and Section of Pulmonary and Critical Care Medicine.bsd. In addition. and this improvement in gas exchange persisted beyond the period of paralysis. DOI: 10. The results of the study were striking.11. MD. There was no difference between the groups in MRC scores. such as the use of journal. 150 on Ն 5 cm H2O PEEP) were randomized to receive either a 48-h infusion of cisatracurium or placebo. Ste 104.org early goal-directed therapy for sepsis.13 In this trial. 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. Sedation was titrated to a deep level (Ramsay score. Patients were enrolled within 48 h of receiving a diagnosis of ARDS.05) favoring NMB was observed. 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. Incidence and outcomes of acute lung injury. de Prost N. it could be argued that adjustment of the ventilator rather than pharmacologic adjustment of the patient is preferable.1378/chest. While true. and receiving lung-protective ventilation were randomized to receive 48 h of NMB with cisatracurium vs placebo. Correspondence to: Jesse B. 6) in both groups before initiation of treatment. Section of Pulmonary and Critical Care Medicine. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. Finally. the rate of pneumothorax was signiﬁcantly less (4%) in patients receiving NMB than in those receiving placebo (11%). FCCP Chicago.2004 and 2006. End points for the study included mortality. Importantly.08) when adjusted by Cox regression for signiﬁcant predeﬁned parameters known to inﬂuence outcome in patients with ARDS. MD. 924 E 57th St. limitations to the study should be noted. The University of Chicago.publications. the beneﬁts of improved mortality and increased ventilator-free days with NMB persisted. Saumon G. Pritzker School of Medicine. no clear ventilator approaches have been described to effectively eliminate patientventilator asynchrony in this context. The University of Chicago. See online for more details. Rubenfeld GD. full paralysis could not be confirmed by TOF determination because use of TOF itself would break blinding. N Engl J Med. e-mail: jhall@medicine. IL 60637-5415. This problem is inherent in any study of NMB. the elevation of proinﬂammatory cytokines measured from BAL samples was signiﬁcantly less in patients receiving NMB.15 If NMB confers beneﬁt to patients by eliminating patient-ventilator asynchrony early in the course of ARDS. While true. respectively.uchicago. Ann Intensive Care. However. Hall.publications. Unfortunately.353(16): 1685-1693. Hall. CHEST / 144 / 5 / NOVEMBER 2013 1441 Downloaded From: http://journal. Peabody E.14 Although these results are impressive. After the period of infusion. Level of paralysis was not followed by train-of-four (TOF) testing to avoid unblinding. 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. 2011. a signiﬁcant difference (P 5 . patients with severe ARDS (deﬁned as a P/F ratio of . patients were followed for neuromuscular weakness by the Medical Research Council (MRC) score. Additionally. the oxygenation index (as judged by the Pao2/Fio2 [P/F] ratio) was improved by NMB. Ricard JD. 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. Although the crude 90-day mortality did not differ between the two groups (P 5 . Ventilatorinduced lung injury: historical perspectives and clinical implications. Dreyfuss D. Pritzker School of Medicine. Chicago. and hence. It might also be argued that mortality difference was signiﬁcant only when adjusted for differences between the patient groups.13-1460 References 1. These important studies set the stage for a multicenter prospective randomized trial published in the New England Journal of Medicine in 2010.
Furthermore. Schweickert WD. 6. Rivers E. N Engl J Med. Pohlman MC. et al. Raps EC. Crit Care Med. 2008. ACURASYS Study Investigators. 2001. Early GoalDirected Therapy Collaborative Group. JAMA. impaired communication. Espósito DC. patient awareness and pain while paralyzed. Gainnier M. 12. and the reproducibility and generalizability of the supporting results. Forel JM. Lung Open Ventilation Study Investigators. Crit Care Med. Briel M.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. 11. it is important to weigh the strength of the evidence. corneal ulcers. et al. the risk and beneﬁt of the intervention. the key components of the question should be carefully examined. N Engl J Med. George RB. Forel JM. nerve compression. Meade M. et al. Bengfort JL. Hall JB. compromised skin integrity. et al. and high positive end-expiratory pressure for acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. Pohlman AS. Lancet. Richard JC. Ressler J. and severe ARDS.34(11):2749-2757. Crit Care Med. 299(6):646-655. McCallister KE.org/ by a St Joseph Hospital User on 11/05/2013 . 16. The Acute Respiratory Distress Syndrome Network. Neto AS .2(1):33-38. Potential consequences of widespread muscular paralysis include VTE. 1993. typically following the concomitant use of an NMBA and Point/Counterpoint Editorials Downloaded From: http://journal. Chest. 14. Pereira VGM. Effect of neuromuscular blocking agents on gas exchange in patients presenting with acute respiratory distress syndrome. However. 32(1):113-119.2. Marin V. N Engl J Med. 2004. Excessive tidal volume from breath stacking during lung-protective ventilation for acute lung injury.373(9678):1874-1882.5-7 Guidelines published in 2001 support the use of NMBAs to facilitate mechanical ventilation when sedation alone is inadequate. Forel JM. et al. The adult respiratory distress syndrome and pancuronium bromide. Nguyen B.5 In fact. 2010. Guyatt GH. is a frequent cause of death. Higher vs lower positive end-expiratory pressure in patients with acute lung injury and acute respiratory distress syndrome: systematic review and meta-analysis. Ventilation strategy using low tidal volumes.147(1):234-236. Mercat A. 8. Cowen J. Damasceno MC. et al. NMBAs were administered to 25% to 55% of patients enrolled in modern ARDS clinical trials. producing paralysis of skeletal muscles. 5. 9. 2009.chestnet. including the use of neuromuscular blocking agents (NMBAs). Gacouin A. 2000. 2008. Pohlman MC.4 To consider this question of clinical decision-making.publications. Severe ARDS is characterized by profound hypoxemia that often is refractory to traditional management and. Early goal-directed therapy in the treatment of severe sepsis and septic shock. along with multiple organ failure. et al. 4. More than we bargained for.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. Neuromuscular blockers in early acute respiratory distress syndrome. Expiratory Pressure (Express) Study Group. impaired cough. 2012. Am Rev Respir Dis. results from a placebocontrolled trial in which patients with severe ARDS randomized to receive the NMBA cisatracurium had superior outcomes have prompted this debate. including paralytic agents.5-7 Additionally.1 A variety of ventilatory and nonventilatory interventions have been used to improve oxygenation in severe ARDS.36(11): 3019-3023. Roch A. 2006. 2008. Hansen-Flaschen J. 2010. Light RW.345(19):1368-1377. Schultz MJ. Meade MO. Early physical and occupational therapy in mechanically ventilated. Vielle B. 1975.131(5):1541-1549. 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 1442 inﬂation pressure to recruit and maintain alveoli in an inﬂated state while avoiding alveolar overdistension and associated pulmonary and systemic inﬂammation and barotrauma. Mercat A. JAMA. JAMA. Havstad S.363(12):1107-1116. critically ill patients: a randomised controlled trial. Cook DJ. whether they should be routinely used. Neuromuscular blocking agents in patients with acute respiratory distress syndrome: a summary of the current evidence from three randomized controlled trials. Papazian L. Schweickert WD. 15.8-11 A key question is whether all patients with severe ARDS should be treated with NMBAs or whether this treatment should be individualized. 10. Schweickert WD. particularly in patients with severe gas exchange impairments.303(9):865-873.342(18):1301-1308. Neuromuscular blocking agents decrease inﬂammatory response in patients presenting with acute respiratory distress syndrome. 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. recruitment maneuvers. 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). and elimination of protective reﬂexes. and perhaps from myonecrosis. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. Nondepolarizing NMBAs act by competing with acetylcholine for binding at the nicotinic receptor of the motor end plate. 2007. 7.299(6): 637-645. et al. Roch A. ICU-acquired weakness. Neuromuscular blockade in the intensive care unit.3. 13. Positive end-expiratory pressure setting in adults with acute lung injury and acute respiratory distress syndrome: a randomized controlled trial.54(2):219-223. Ann Intensive Care. et al. Anesth Analg.
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