|Year : 2019 | Volume
| Issue : 1 | Page : 33-37
Neuromuscular-blocking agent use in critically ill patients
Shmeylan A Al Harbi1, Hind S Almodaimegh1, Yaseen M Arabi2
1 Department of Pharmaceutical Care, College of Pharmacy, King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Riyadh, Saudi Arabia
2 Department of Intensive Care, College of Medicine, King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Riyadh, Saudi Arabia
|Date of Web Publication||30-May-2019|
Shmeylan A Al Harbi
Department of Pharmaceutical Care, College of Pharmacy, King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Riyadh
Source of Support: None, Conflict of Interest: None
Neuromuscular-blocking agents (NMBAs) are a cornerstone in the management of critically ill patients. There is evidence supporting short course (<48 h) of paralysis for patients with moderate-to-severe acute respiratory distress syndrome with PaO2/FiO2 ratio <150. Proper knowledge of these agents and their evidence-based use is fundamental. Health-care providers can play an important role in the regulation and the use of NMBAs in critically ill patients.
|How to cite this article:|
Al Harbi SA, Almodaimegh HS, Arabi YM. Neuromuscular-blocking agent use in critically ill patients. Saudi Crit Care J 2019;3:33-7
|How to cite this URL:|
Al Harbi SA, Almodaimegh HS, Arabi YM. Neuromuscular-blocking agent use in critically ill patients. Saudi Crit Care J [serial online] 2019 [cited 2020 Sep 20];3:33-7. Available from: http://www.sccj-sa.org/text.asp?2019/3/1/33/259477
| Introduction|| |
Neuromuscular-blocking agents (NMBAs) play an important role in the management of critically ill patients. Their use is common in situ ations where patient paralysis is required like in surgical anesthesia and rapid sequence intubation (RSI)., Other indications include the management of acute respiratory distress syndrome (ARDS), increased intracranial and abdominal pressure, and prevention of shivering during therapeutic hypothermia.,,, NMBAs are classified based on their chemical structures, mechanism of action (depolarizing and nondepolarizing), and pharmacokinetic properties including their duration of action (short, intermediate, and long acting). Depolarizing agents bind and activate nicotinic acetylcholine receptors causing persistent depolarization, which then render muscle fibers resistant to further cholinergic stimulation., Succinylcholine is the only available depolarizing NMBA that is commonly used as the drug of choice for urgent intubation because of its quick onset and short duration. Nondepolarizing NMBAs are highly ionized water-soluble compounds, which bind to acetylcholine receptor and act as competitive antagonists., They can be divided into either aminosteroidial or benzylisoquinolinium nucleus and vary in their onset and duration of action. NMBAs have a different variety of pharmacokinetic profiles that can be utilized depending on the situation. For instance, rapid onset and short duration are of value in RSI. In contrast, those with a longer duration are useful in surgeries. [Table 1] depicts an overview of commonly used NMBAs.
|Table 1: Overview of various neuromuscular-blocking agent,,,, percentages|
Click here to view
| Clinical Usage|| |
Rapid sequence intubation
RSI is used to secure a definitive airway in critically ill patients who are unstable and uncooperative or may be at risk of aspiration. Their use has been associated with a lower prevalence of hypoxemia, procedure-related complications, and improved intubating conditions with fewer attempts. Succinylcholine and rocuronium are commonly used for intubation given the advantage of their short onset and duration of action. A large Cochrane review found succinylcholine (minimum dose, 1 mg/kg) to be superior to rocuronium (minimum dose, 0.6 mg/kg) with regard to favorable intubation conditions. There was no difference in intubation conditions when succinylcholine was compared with higher doses of rocuronium (0.9–1.2 mg/kg), but the shorter duration of action with succinylcholine made it more favorable clinically. However, several important contraindications to its use in critically ill patients with a history of malignant hyperthermia or hyperkalemia made clinicians to prefer rocuronium as a viable option for RSI. Allergy to aminosteroids is the only absolute contraindication for rocuronium. Furthermore, its longer duration of action needs extreme caution in patients with anticipated difficult intubation. Rapid reversal of rocuronium may be achieved with sugammadex, a novel direct-reversal agent.
Acute respiratory distress syndrome
Mechanical ventilation remains the basis of supportive treatment for ARDS., It involves the use of sedation to allow for patient comfort while on the ventilator. In some circumstances, sedation is not sufficient and other adjunct medications are needed. The current evidence investigated the outcomes of using NMBAs in ARDS for a short period of time. A review article by Bourenne et al. illustrated that approximately 25%–45% of ARDS patients require NMBAs for an average of 1 ± 2 days and the main indications for initiating are hypoxemia and need for mechanical ventilation. In 2016, Murray et al. recommended a short course (<48 h) of paralysis for patients with moderate-to-severe ARDS (PaO2/FiO2 ratio <150)., In 2017, the Surviving Sepsis Campaign also recommended a trial of NMBA therapy for severe ARDS. A randomized controlled trial (RCT) by Gainnier et al. demonstrated the benefit of NMBAs, mainly with cisatracurium, on oxygenation for patients with moderate-to-severe ARDS., The outcome of the above-mentioned trials indicates that the use of NMBAs, mainly cisatracurium in severe ARDS as a continuous infusion for 48 h or less, may be beneficial. Furthermore, it is important to realize that their use in ARDS is still considered a last resort and that they are used when adequate sedation and appropriate ventilator adjustments have been done.
Elevated intra-abdominal pressure
NMBAs may be used for preventing abdominal compartment syndrome, which is defined as an elevated intra-abdominal hypertension of 20 mmHg, and ultimately decompressive laparotomy for those patients with elevated intra-abdominal pressures (IAPs) through the reduction of abdominal wall muscle tone.
Elevated intracranial pressure
Routine use of NMBAs in the management of elevated intracranial pressures is not recommended. NMBAs should only be considered in the managements of elevated intracranial pressures when deep sedation is insufficient for controlling the persistent increase in intracranial pressure. NMBAs can either prevent or decrease the sympathetic and reflex response to tracheal suctioning, which would otherwise elevate intracranial pressure. NMBAs help to facilitate mechanical ventilation (carbon dioxide elimination and lower positive end-expiratory pressure), decrease metabolic expenditure, and limit elevations in intracranial pressure after stimulating procedures. They can also decrease respiratory drive and IAP, thus improving cerebral flow both toward and away from the brain. The use of NMBAs in traumatic brain injury has not been demonstrated to improve long-term patient outcomes. In addition, it leads to difficulties in monitoring neurological function and seizure activity.,
Therapeutic hypothermia after cardiac arrest
NMBAs have been used to prevent or treat shivering associated with therapeutic hypothermia. Shivering leads to heat production, inflammation, elevated intracranial pressure, decreased brain tissue oxygen levels, and increased metabolic rate. Retrospective studies showed conflicting data on survival rates and complications that lead the American Heart Association guidelines to recommend the avoidance or minimal use of NMBAs.
NMBA depth of neuromuscular blockade should be evaluated frequently to avoid complications. It is critical that patients are sedated and pain free before initiating NMBAs. Furthermore, NMBAs should be titrated to the lowest effective dose. A prospective, randomized, controlled investigation was conducted in 77 critically ill medical patients to compare outcomes between two different monitoring methods of neuromuscular blockade. Vecuronium doses were individualized by peripheral nerve stimulation (TOF) in the treatment group and by standard clinical assessment in the control group. Although TOF monitoring was performed in the control group, the nursing and house staff were blinded to the results and dosage adjustments were made according to a protocol. The mean TOF value at drug discontinuation was significantly lower in the standard clinical assessment group compared to the TOF group. There was less drug used to achieve 90% blockade (TOF = 1) in the patients monitored by TOF compared to those monitored by standard clinical assessment. The mean infusion rate and cumulative amount of drug used were also significantly lower in the TOF group. Recovery to a TOF of 4 out of 4 twitches and return of spontaneous ventilation were significantly faster in the TOF group. The incidence of prolonged paralysis was significantly higher in the standard clinical assessment group. Overall, 71% of patients (including patients from both groups) had abnormal neurologic examinations following discontinuation of vecuronium.
In another trial, medical intensive care unit (ICU) patients receiving continuous infusions of cisatracurium were randomized to TOF monitoring (n = 16) or clinical assessment (n = 14). Clinical assessment consisted of adjusting the NMBAs based on observed responses of the patient. Specifically, nurses monitored patient-ventilator dyssynchrony defined as signs of “bucking” and elevated mechanical ventilation peak pressures. Total absence of patient-initiated breaths was a goal of clinical assessment only for those patients undergoing inverse-ratio ventilation. Demographics were similar between groups, and there were no differences in the total number of medications or medication type (corticosteroid, aminoglycoside, or clindamycin). In respect to the outcome measures of postparalytic recovery times, total time paralyzed before discontinuation of paralytic, total cisatracurium dose, or episodes of prolonged paralysis, there was no difference between groups. In addition, no cases of prolonged paralysis syndrome or clinical evidence of acute myopathy were noted.,
The use of NMBAs in certain conditions has its benefits; however, there are complications associated with their use that should be considered. Among those are ICU-acquired prolonged weakness. Several studies have investigated associations between the use of NMBAs and prolonged weakness that include myopathy, polyneuropathy, and neuropathy. However, data were inconsistent and not controlled, and the relationship is still controversial. Further studies are needed to clarify the relationship of specific risk factors. A retrospective observational study in severe asthmatics demonstrated an increased incidence (30% vs. 10%) of skeletal myopathy with NMBA administration (mean duration, 3.1 ± 2.3 days), with myopathy only associated with duration of muscle relaxation., Another retrospective study in patients with severe asthma also demonstrated a higher incidence of postextubation skeletal muscle dysfunction, and multiple logistic regression analysis demonstrated that NMBAs were independent predictors of overall morbidity. A prospective study of patients with sepsis demonstrated that NMBAs were an independent risk factor for the development of critical illness polyneuropathy, defined by electrophysiologic testing., In contrast, a prospective study by Fan et al. found that in patients with acute lung injury, the duration of bed rest during critical illness, but not systemic corticosteroid nor use of NMBAs, was independently associated with prolonged muscle weakness. Furthermore, a RCT by Papazian et al. showed no change in muscle strength testing at day or at ICU discharge in patients receiving 48-h cisatracurium infusions compared with placebo. Modern critical care practice moving toward minimizing and interrupting sedation may offer further reductions for the incidence of prolonged muscle weakness in the ICU by decreasing overall immobility.,
Other complications of using NMBAs include the association with risk of thrombosis. One study found NMBA use to be the strongest predictor of deep vein thrombosis (DVT) incidence and encouraged procedures that reduce venous stasis (passive mobilization and elastic compression stockings) to increase the efficacy of pharmacologic DVT prophylaxis in patients who are paralyzed.
Paralysis may result in impaired eyelid closure and loss of corneal reflex, which place the cornea at risk for drying, scarring, ulceration, and infection and may lead to permanent visual loss. An RCT found that applying artificial tears, on a regular set schedule, was more effective than passive eyelid closure alone at reducing the incidence of corneal abrasions.
Skin breakdown, slowed gastrointestinal motility, peripheral muscle weakness, diaphragmatic atrophy, and myositis are other complications of immobility that may be managed with supportive care, changes in position and height of bed, and mobilization.,,, Allergic reaction can occur after the first-dose NMBAs because of the ammonium ions in the NMBAs. They are considered the most common cause of anaphylaxis in anesthesia, with succinylcholine (38%) and rocuronium (26%) being the most frequently culprits, and cross-reactivity between NMBAs is observed in >60% of cases.
To reverse paralysis, agents or infusions are usually discontinued and muscular function is allowed to recover gradually as the NMBAs are metabolized and eliminated. If rapid reversal of nondepolarizing NMBAs is required, anticholinesterase agents, such as edrophonium, neostigmine, pyridostigmine with the use of antimuscarinic agents, as glycopyrrolate, atropine may be used. Drugs, such as edrophonium 0.5–1.0 mg/kg, neostigmine 0.03–0.07 mg/kg, and pyridostigmine 0.1–0.4 mg/kg, are administered with antimuscarinics, such as atropine and glycopyrrolate, to prevent the clinical effects of the parasympathetic activation, including bradycardia, bradyarrhythmias, bronchoconstriction, and excessive airway secretions, caused by acetylcholine increase at autonomic synapse.,,,, Sugammadex acts by forming tight complexes with aminosteroidal NMBAs in the plasma and can provide immediate reversal after rocuronium administration in patients where emergency intubation has failed.
Certain medications may decrease the activity of NMBAs, while others can enhance or prolong their activity. Among medications that decrease NMBAs activity are calcium due its antagonistic effect of magnesium on neuromuscular blockage. Carbamazepine acts as a competitor of acetylcholine receptor. In addition, phenytoin depresses postsynaptic response to acetylcholine. Finally, ranitidine and theophylline can decrease NMBA activities by unknown mechanism.
In contrast, antibiotics, such as aminoglycosides, clindamycin, tetracycline, and vancomycin, potentate NMBA effect by decreasing the prejunctional acetylcholine release with decreased postjunctional acetylcholine receptor sensitivity and block acetylcholine receptors. In addition, cardiac medications such as β-blockers, calcium channel blockers, procainamide, quinidine, and furosemide prolog NMBA activity by decreasing the prejunctional acetylcholine release. Finally, steroids decrease end-plate sensitivity to acetylcholine and cyclosporine inhibits the metabolism of certain NMBAs.
| Conclusion|| |
NMBAs are a cornerstone in the management of critically ill patients. Therefore, proper knowledge of these agents and their evidence-based use is fundamental. Health-care providers can play an important role in the regulation and the use of NMBAs in critically ill patients.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Prielipp RC. Pharmacology, selection and complications associated with neuromuscular blocking drugs in ICU patients. Yale J Biol Med 1998;71:469-84.
Murray MJ, DeBlock H, Erstad B, Gray A, Jacobi J, Jordan C, et al.
Clinical practice guidelines for sustained neuromuscular blockade in the adult critically ill patient. Crit Care Med 2016;44:2079-103.
Warr J, Thiboutot Z, Rose L, Mehta S, Burry LD. Current therapeutic uses, pharmacology, and clinical considerations of neuromuscular blocking agents for critically ill adults. Ann Pharmacother 2011;45:1116-26.
Needham CJ, Brindley PG. Best evidence in critical care medicine: The role of neuromuscular blocking drugs in early severe acute respiratory distress syndrome. Can J Anaesth 2012;59:105-8.
Jaber S, Amraoui J, Lefrant JY, Arich C, Cohendy R, Landreau L, et al.
Clinical practice and risk factors for immediate complications of endotracheal intubation in the intensive care unit: A prospective, multiple-center study. Crit Care Med 2006;34:2355-61.
Wilcox SR, Bittner EA, Elmer J, Seigel TA, Nguyen NT, Dhillon A, et al.
Neuromuscular blocking agent administration for emergent tracheal intubation is associated with decreased prevalence of procedure-related complications. Crit Care Med 2012;40:1808-13.
Greenberg SB, Vender J. The use of neuromuscular blocking agents in the ICU: Where are we now? Crit Care Med 2013;41:1332-44.
Tran DT, Newton EK, Mount VA, Lee JS, Wells GA, Perry JJ. Rocuronium versus succinylcholine for rapid sequence induction intubation. Cochrane Database Syst Rev 2015:CD002788.
Booij L. Appropriate use of muscle relaxants in anaesthesia, intensive and emergency care. J Rom Anest Ter Intensive 2011;18:136-44.
Jones RK, Caldwell JE, Brull SJ, Soto RG. Reversal of profound rocuronium-induced blockade with sugammadex: A randomized comparison with neostigmine. Anesthesiology 2008;109:816-24.
Amato MB, Barbas CS, Medeiros DM, Magaldi RB, Schettino GP, Lorenzi-Filho G, et al.
Effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome. N
Engl J Med 1998;338:347-54.
Acute Respiratory Distress Syndrome Network, Brower RG, Matthay MA, Morris A, Schoenfeld D, Thompson BT, 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;342:1301-8.
Bourenne J, Hraiech S, Roch A, Gainnier M, Papazian L, Forel JM. Sedation and neuromuscular blocking agents in acute respiratory distress syndrome. Ann Transl Med 2017;5:291.
Gainnier M, Roch A, Forel JM, Thirion X, Arnal JM, Donati S, et al.
Effect of neuromuscular blocking agents on gas exchange in patients presenting with acute respiratory distress syndrome. Crit Care Med 2004;32:113-9.
deBacker J, Hart N, Fan E. Neuromuscular blockade in the 21st
century management of the critically ill patient. Chest 2017;151:697-706.
Malbrain ML, Cheatham ML, Kirkpatrick A, Sugrue M, Parr M, De Waele J. Results from the international conference of experts on intra-abdominal hypertension and abdominal compartment syndrome. I. Definitions. Intensive Care Med 2006;32:1722-32.
Rangel-Castilla L, Gopinath S, Robertson CS. Management of intracranial hypertension. Neurol Clin 2008;26:521-41, x.
Hsiang JK, Chesnut RM, Crisp CB, Klauber MR, Blunt BA, Marshall LF, et al.
Early, routine paralysis for intracranial pressure control in severe head injury: Is it necessary? Crit Care Med 1994;22:1471-6.
Rudis MI, Sikora CA, Angus E, Peterson E, Popovich J Jr. Hyzy R, et al.
Aprospective, randomized, controlled evaluation of peripheral nerve stimulation versus standard clinical dosing of neuromuscular blocking agents in critically ill patients. Crit Care Med 1997;25:575-83.
Baumann MH, McAlpin BW, Brown K, Patel P, Ahmad I, Stewart R, et al.
Aprospective randomized comparison of train-of-four monitoring and clinical assessment during continuous ICU cisatracurium paralysis. Chest 2004;126:1267-73.
Hund E. Myopathy in critically ill patients. Crit Care Med 1999;27:2544-7.
Behbehani NA, Al-Mane F, D'yachkova Y, Paré P, FitzGerald JM. Myopathy following mechanical ventilation for acute severe asthma: The role of muscle relaxants and corticosteroids. Chest 1999;115:1627-31.
Puthucheary Z, Rawal J, Ratnayake G, Harridge S, Montgomery H, Hart N. Neuromuscular blockade and skeletal muscle weakness in critically ill patients: Time to rethink the evidence? Am J Respir Crit Care Med 2012;185:911-7.
Adnet F, Dhissi G, Borron SW, Galinski M, Rayeh F, Cupa M, et al.
Complication profiles of adult asthmatics requiring paralysis during mechanical ventilation. Intensive Care Med 2001;27:1729-36.
Garnacho-Montero J, Madrazo-Osuna J, García-Garmendia JL, Ortiz-Leyba C, Jiménez-Jiménez FJ, Barrero-Almodóvar A, et al.
Critical illness polyneuropathy: Risk factors and clinical consequences. A cohort study in septic patients. Intensive Care Med 2001;27:1288-96.
Fan E, Dowdy DW, Colantuoni E, Mendez-Tellez PA, Sevransky JE, Shanholtz C, et al.
Physical complications in acute lung injury survivors: A two-year longitudinal prospective study. Crit Care Med 2014;42:849-59.
Papazian L, Forel JM, Gacouin A, Penot-Ragon C, Perrin G, Loundou A, et al.
Neuromuscular blockers in early acute respiratory distress syndrome. N
Engl J Med 2010;363:1107-16.
Kress JP, Pohlman AS, O'Connor MF, Hall JB. Daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation. N
Engl J Med 2000;342:1471-7.
Boddi M, Barbani F, Abbate R, Bonizzoli M, Batacchi S, Lucente E, et al.
Reduction in deep vein thrombosis incidence in intensive care after a clinician education program. J Thromb Haemost 2010;8:121-8.
Lenart SB, Garrity JA. Eye care for patients receiving neuromuscular blocking agents or propofol during mechanical ventilation. Am J Crit Care 2000;9:188-91.
Peppard WJ, Peppard SR, Somberg L. Optimizing drug therapy in the surgical intensive care unit. Surg Clin North Am 2012;92:1573-620.
Mertes PM, Laxenaire MC; GERAP. Anaphylactic and anaphylactoid reactions occurring during anaesthesia in France. Seventh epidemiologic survey (January 2001-december 2002). Ann Fr Anesth Reanim 2004;23:1133-43.
Abrishami A, Ho J, Wong J, Yin L, Chung F. Sugammadex, a selective reversal medication for preventing postoperative residual neuromuscular blockade. Cochrane Database Syst Rev 2009:CD007362.