Rocuronium


Article Author:
Ankit Jain


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Christopher Maani


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Tehmina Warsi


Updated:
4/8/2019 8:33:40 PM

Indications

Rocuronium is a non-depolarizing neuromuscular blocker which is 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 one that is 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 de-fasciculating 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 where 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 postjunctional 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, effects on the fetus, minimal renal reabsorption as well as 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 as well as 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 min with effects lasting until 20 to 35 min. Higher doses like 1.0 to 1.2 mg/kg can be used to provide intubating conditions similar to succinylcholine in a short onset of time like 1 min. 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 anaphylaxis in the perioperative setting, and one paper cites the incidence around 1 in 2500 patients.[1] Any patient who after rocuronium administration 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]. Inability to completely reverse the effects of neuromuscular blockade can result in increased risks of postoperative respiratory dysfunction, including hypoxia, 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 who are on steroids and or 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 one who is 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 as well as 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 be used in these clinical situations too with caution.

Monitoring

The effects of neuromuscular blockade are assessable by evaluation of a mechanically evoked response to an electrical stimulation using a peripheral nerve stimulator. Routine use of peripheral nerve stimulator is strongly encouraged by the Anesthesia Patient Safety Foundation (APSF) to monitor the depth of neuromuscular blockade during surgery as well as 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 ulnar nerve is stimulated using two electrodes placed on the anatomical path of 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. Most commonly a train of four (TOF) is 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 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 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. 

  • Anticholinesterases - Drugs like neostigmine and rarely edrophonium and pyridostigmine have been the cornerstone of 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 nondepolarizing drugs like rocuronium. The typical dosing depends on the amount of neuromuscular blockade as monitored by the TOF response to the peripheral nerve stimulator. If there are no twitches visible in response to TOF, administration of neostigmine is not recommended. It is advised to wait for the twitch response to occur before administering neostigmine. If there are less than 2 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 there are 3 or 4 twitches present, 0.04 mg/kg of neostigmine is recommended with appropriate anticholinergic drugs.
  • Suggamadex - A novel gamma cyclodextrin molecule which works by encapsulating steroidal neuromuscular blockers like rocuronium and vecuronium have 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. 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 16mg/kg dose. If there are no twitches to TOF, but there are one to two post-tetanic response, a dose of 4mg/kg should be used. If there are four twitches present to TOF, then a dose of 2 mg/kg can be used. 

Enhancing Healthcare Team Outcomes

Proper use of neuromuscular blocking agents by the anesthesiologist, emergency department physician, intensivist, anesthesia nurse and critical care specialists is of paramount importance. Residual neuromuscular weakness is recognized to be 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.[7] Current evidence suggests that routine monitoring of neuromuscular blockades are not performed regularly on each patient and subjective assessment of muscle strengths like sustained head-lift as well as hand grips are unreliable markers of a complete reversal of neuromuscular blockade. The only objective method to ensure patient safety and ensure complete reversal is the TOF ratio greater than 0.9. Suggamadex since introduced in 2008 worldwide and 2015 in the USA, there is reliable and consistent literature supporting the safety and reliability of complete reversal of neuromuscular blockade.[8][9][10]


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Rocuronium - References

References

Takazawa T,Mitsuhata H,Mertes PM, Sugammadex and rocuronium-induced anaphylaxis. Journal of anesthesia. 2016 Apr;     [PubMed]
Pei DQ,Zhou HM,Zhou QH, Grip strength can be used to evaluate postoperative residual neuromuscular block recovery in patients undergoing general anesthesia. Medicine. 2019 Jan;     [PubMed]
Yang T,Li Z,Jiang L,Wang Y,Xi X, Risk factors for intensive care unit-acquired weakness: A systematic review and meta-analysis. Acta neurologica Scandinavica. 2018 Aug;     [PubMed]
Murphy GS,Szokol JW,Marymont JH,Greenberg SB,Avram MJ,Vender JS, Residual neuromuscular blockade and critical respiratory events in the postanesthesia care unit. Anesthesia and analgesia. 2008 Jul;     [PubMed]
McLean DJ,Diaz-Gil D,Farhan HN,Ladha KS,Kurth T,Eikermann M, Dose-dependent Association between Intermediate-acting Neuromuscular-blocking Agents and Postoperative Respiratory Complications. Anesthesiology. 2015 Jun;     [PubMed]
Fortier LP,McKeen D,Turner K,de Médicis É,Warriner B,Jones PM,Chaput A,Pouliot JF,Galarneau A, The RECITE Study: A Canadian Prospective, Multicenter Study of the Incidence and Severity of Residual Neuromuscular Blockade. Anesthesia and analgesia. 2015 Aug;     [PubMed]
Brull SJ,Kopman AF, Current Status of Neuromuscular Reversal and Monitoring: Challenges and Opportunities. Anesthesiology. 2017 Jan;     [PubMed]
Staals LM,Driessen JJ,Van Egmond J,De Boer HD,Klimek M,Flockton EA,Snoeck MM, Train-of-four ratio recovery often precedes twitch recovery when neuromuscular block is reversed by sugammadex. Acta anaesthesiologica Scandinavica. 2011 Jul;     [PubMed]
Simonini A,Brogi E,Calevo MG,Carron M, Sugammadex for reversal of neuromuscular blockade in paediatric patients: a two-year single-centre retrospective study. Anaesthesia, critical care     [PubMed]
Jahr JS,Miller JE,Hiruma J,Emaus K,You M,Meistelman C, Sugammadex: A Scientific Review Including Safety and Efficacy, Update on Regulatory Issues, and Clinical Use in Europe. American journal of therapeutics. 2015 Jul-Aug;     [PubMed]

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