Neuromuscular-blocking agent use in critically ill patients

Shmeylan A Al Harbi; Hind S Almodaimegh; Yaseen M Arabi

doi:10.4103/2543-1854.259477

REVIEW ARTICLE

Year : 2019 | Volume : 3 | 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

Correspondence Address:
Shmeylan A Al Harbi
Department of Pharmaceutical Care, College of Pharmacy, King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Riyadh
Saudi Arabia

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/2543-1854.259477

Abstract

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 2021 Mar 8];3:33-7. Available from: https://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).^[1],[2] Other indications include the management of acute respiratory distress syndrome (ARDS), increased intracranial and abdominal pressure, and prevention of shivering during therapeutic hypothermia.^{[1],[2],[3],[4]} 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.^[1],[2] 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.^[2] Nondepolarizing NMBAs are highly ionized water-soluble compounds, which bind to acetylcholine receptor and act as competitive antagonists.^[1],[3] 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^{[2],[7],[31],[32],[33]} percentages

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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.^[5] Their use has been associated with a lower prevalence of hypoxemia, procedure-related complications, and improved intubating conditions with fewer attempts.^[6] 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.^[8] 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.^[9] Allergy to aminosteroids is the only absolute contraindication for rocuronium.^[10] 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.^[10]

Acute respiratory distress syndrome

Mechanical ventilation remains the basis of supportive treatment for ARDS.^[11],[12] 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.^[13] In 2016, Murray et al. recommended a short course (<48 h) of paralysis for patients with moderate-to-severe ARDS (PaO2/FiO2 ratio <150).^[2],[13] In 2017, the Surviving Sepsis Campaign also recommended a trial of NMBA therapy for severe ARDS.^[5] 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.^[14],[15] 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.^[16]

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.^[1] 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.^[7] 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.^[17],[18]

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.^[15]

Monitoring

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.^[19] 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.^[19]

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).^[20] 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).^[20] 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.^[17],[21]

Complications

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.^[22] 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.^[22],[23] 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.^[24] 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.^[21],[25] 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.^[26] 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.^[27] 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.^[27],[28]

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.^[29]

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.^[30]

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.^{[1],[5],[23],[33]} 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.^[32]

Reversal agents

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.^{[2],[3],[4],[5],[12]} 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.^[33]

Drug–drug interactions

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

Nil.

Conflicts of interest

There are no conflicts of interest.

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