Continuing Education Activity

Rocuronium is a non-depolarizing neuromuscular blocker widely used to produce muscle relaxation to help facilitate surgery and ventilation of the lungs in elective and emergent situations. It is one of the many non-depolarizing neuromuscular blockers that is used but has the distinct advantage of being fast-acting and reversible. This activity outlines the indications, mechanism of action, methods of administration, significant adverse effects, contraindications, toxicity, and monitoring, of rocuronium, so providers can direct patient therapy in anesthesia where it is indicated, as part of the interprofessional team.

Objectives:

• Identify the mechanism of action of rocuronium.
• Summarize the indications for using rocuronium as an anesthesia agent.
• Review the adverse effects of rocuronium.
• Outline the contraindications to using rocuronium.

Indications

Rocuronium is a non-depolarizing neuromuscular blocker widely used to produce muscle relaxation to help facilitate surgery and ventilation of the lungs in elective and emergent situations. It is one of the many non-depolarizing neuromuscular blockers used but has the distinct advantage of being fast-acting and reversible. The major indications for its use are:

• Provide airway muscle paralysis to facilitate endotracheal intubation in elective as well as emergent conditions
• Provide surgical paralysis to facilitate surgery
• Provide chest wall relaxation to facilitate mechanical ventilation in critically ill patients who are under adequate sedation
• Provide a defasciculating dose to prevent fasciculations during depolarizing muscle paralysis to prevent myalgias. (off-label)
• Prevent shivering in patients post cardiac resuscitation after the return of spontaneous circulation during therapeutic hypothermia (off-label)

It is vital to ensure that the patients who receive a muscle relaxant like rocuronium are adequately sedated to prevent the risk of awareness. A patient can be paralyzed but awake and cannot show the motor signs of awareness.

Mechanism of Action

Non-depolarizing neuromuscular blockers work at the site of nicotinic neuromuscular junction by acting on the synapse. A synapse is a specialized area where the prejunctional nerve ending interacts with a highly folded postjunctional part of the skeletal membrane. Both of these pre and post-junctional sites have a higher concentration of acetylcholine (Ach) and nicotinic acetylcholine receptors (nAchR), respectively. Normally when an electrical impulse reaches the prejunctional nerve terminal, calcium influx causes a release of Ach ligands, which then interacts at the nicotinic acetylcholine receptors located at the postjunctional membrane to cause changes in the electrical permeability of the membrane, specifically sodium and potassium. This rapid movement of ions causes a decrease in the transmembrane potential to reach threshold potential leading to the generation of an action potential that travels across the muscle membrane and causes muscular contraction.

Administration

Nondepolarizing drugs like rocuronium are quaternary ammonium compounds, which are intermediately acting, highly ionized drugs administered intravenously under controlled conditions by anesthesiologists and other critical care providers after ensuring that the patient is under the effects of anesthesia. The dose of administration can be decided based on the clinical indication versus patient characteristics. Rocuronium does not undergo metabolism into active metabolites and has very limited lipid solubility. Therefore these drugs do not pass the blood-brain barrier, placental barrier, and other lipid membrane barriers. Thus, rocuronium has no effects on the central nervous system, impact on the fetus, minimal renal reabsorption, and ineffective absorption if given orally. Rocuronium is largely excreted unchanged in bile and has around 30 % renal excretion. Factors like hypothermia, hypovolemia, concomitant volatile agents, and renal and hepatic diseases prolong the effects of rocuronium.

Rocuronium is an intermediate-acting nondepolarizing neuromuscular blocker with ED95 of 0.3 mg/kg. At a dosing range of 0.6 to 1.2 mg/kg, intubating conditions can be reached in 1 to 2 minutes, with effects lasting until 20 to 35 minutes. Higher doses, like 1.0 to 1.2 mg/kg, can be used to provide intubating conditions similar to succinylcholine with a short onset time of approximately 1 minute. However, that comes with a duration of action similar to longer-acting nondepolarizing drugs like pancuronium.

Adverse Effects

Allergic reactions: Although there have been reports of cardiovascular side effects with the use of non-depolarizing neuromuscular agents like mivacurium and atracurium, rocuronium has been shown to be very cardiac stable and has no effects on heart rate or blood pressure. Rocuronium has been implicated in multiple IgE-induced anaphylaxes in the perioperative setting, and one paper cites the incidence of around 1 in 2500 patients.[1] After rocuronium administration, any patient who develops sudden cardiovascular collapse along with cutaneous symptoms of allergic reactions should come under suspicion for anaphylaxis.

Residual neuromuscular weakness: Residual neuromuscular blockade is a condition where the effects of the neuromuscular blocks do not completely reverse. The adverse effects of the residual neuromuscular blockade have been proven beyond doubt to increase postoperative morbidity and mortality.[2] The inability to completely reverse the effects of the neuromuscular blockade can result in increased risks of postoperative respiratory dysfunction, including hypoxia, the need for mechanical ventilation, and increasing the length of hospital stay.[3]

Critical illness myopathy and polyneuropathy: Prolonged infusion of neuromuscular blockers can prolong skeletal muscle weakness due to the myopathy induced by critical illness in a subset of patients on steroids or who have multiple organ failure. It is advised to keep the duration of paralysis to less than 48 hrs to prevent this complication.[4]

Contraindications

The absolute contraindication to using rocuronium would be a documented allergic reaction to the drug. Rocuronium should also not be given to any patient who is not sedated or not under the influence of anesthesia to avoid the risk of awareness. It is advisable not to use rocuronium as an infusion to prevent critical illness myopathy and polyneuropathy. Rocuronium should not be used in patients with renal or hepatic dysfunction as it will prolong its effects by delaying elimination. Although with the use of sugammadex, rocuronium can also be used cautiously in these clinical situations.

Monitoring

The effects of the neuromuscular blockade are assessable by evaluating a mechanically evoked response to an electrical stimulation using a peripheral nerve stimulator. Routine use of peripheral nerve stimulators is strongly encouraged by the Anesthesia Patient Safety Foundation (APSF) to monitor the depth of neuromuscular blockade during surgery and after reversal by the reversal agent to confirm and rule out any residual neuromuscular blockade.[5]

Routinely two sites are used for peripheral nerve stimulation - the distal forearm where the ulnar nerve is stimulated using two electrodes placed on the anatomical path of the ulnar nerve to stimulate the adductor pollicis muscle of the hand and around the eyes on the forehead to stimulate the facial nerve and orbicularis oculi muscle. The peripheral nerve stimulator can provide an electrical current of specific strength and duration to create a pattern of stimulation. A train of four (TOF) is most commonly used to evaluate the amount of muscle contraction. Other types of stimulation include a single twitch response, double burst stimulation, tetany, and post-tetanic stimulation. In a TOF stimulation, four electrical stimulations at 2Hz are delivered every 0.5 sec, and the twitch height response of the fourth twitch is compared to the first twitch. In patients under the effect of rocuronium and other nondepolarizing neuromuscular blocking drugs, the fourth twitch response is smaller than the first due to the depletion of Ach released on successive stimulation. This leads to the calculation of the TOF ratio and fade and is a hallmark of nondepolarizing neuromuscular blockade. Loss of 2 twitches out of four is considered adequate for surgical anesthesia, and if all four twitches are lost, one should not administer any more muscle relaxant until there is a recovery of some twitches. A TOF ratio of >0.7-0.9 is considered adequate for complete reversal.[6]

Toxicity

Reversal of rocuronium-induced paralysis is possible with the use of two subgroups of drugs.[7]

• Anticholinesterases - Drugs like neostigmine and rarely edrophonium and pyridostigmine have been the cornerstone of the reversal of neuromuscular blockade. Neostigmine is an anticholinesterase drug that prevents the metabolism of Ach in the synapse by blocking the action of cholinesterase, increasing the level of Ach in the synaptic cleft, and overcomes the neuromuscular blockade of non-depolarizing drugs like rocuronium. The typical dosing depends on the amount of neuromuscular blockade monitored by the TOF response to the peripheral nerve stimulator. If there are no twitches visible in response to TOF, the administration of neostigmine is not recommended. It is advisable to wait for the twitch response to occur before administering neostigmine. If there are less than two twitches present, 0.07 mg/kg of neostigmine is recommended along with an anticholinergic to prevent the cholinergic side effects like glycopyrrolate or atropine. If 3 or 4 twitches are present, 0.04 mg/kg of neostigmine is recommended with appropriate anticholinergic drugs.
• Sugammadex - A novel gamma-cyclodextrin molecule that works by encapsulating steroidal neuromuscular blockers like rocuronium and vecuronium has been extensively used in Europe before being approved recently in the US. Its novel mechanism of action produces a complete reversal of neuromuscular blockade by encapsulating rocuronium and preventing the interaction of rocuronium at the neuromuscular junction. Suggamedex additionally has some affinity in reversing Vecuronium and Pancuronium. Since it does not work by interacting with cholinesterase, it produces no cardiac side effects and can be safely used at any level of neuromuscular blockade. The dosing is based on the depth of neuromuscular blockade. If there are no twitches and the reversal is necessary after an intubating dose of rocuronium, then it is recommended to use a 16 mg/kg dose. If there are no twitches to TOF, but there are one to two post-tetanic responses, a 4 mg/kg dose should be used. If there are four twitches present to TOF, then a 2 mg/kg dose can be used. The Suggamadex-NMB complex is eliminated through 75% biliary clearance and 25% biliary clearance as well as excreted via the urine at 65 to 97%. Additionally, a female who takes hormonal contraceptives should be counseled on backup method contraceptives within seven days of its administration.

Enhancing Healthcare Team Outcomes

Proper use of neuromuscular blocking agents by the anesthesiologist, emergency department physician, intensivist, anesthesia nurse, and critical care specialists is paramount. Residual neuromuscular weakness is recognized as a common problem in the post-anesthesia care unit (PACU), where at least 20 to 40% of patients can be shown to have objective evidence of residual weakness.[8] Current evidence suggests that routine monitoring of neuromuscular blockades is not performed regularly on each patient, and subjective assessment of muscle strengths like sustained head-lift as well as handgrips are unreliable markers of a complete reversal of neuromuscular blockade. The only objective method to ensure patient safety and a complete reversal is the TOF ratio greater than 0.9. Sugammadex was introduced in 2008 worldwide, and in 2015 in the USA, there is reliable and consistent literature supporting the safety and reliability of complete reversal of neuromuscular blockade.[9][10][11]