The introduction of muscle relaxants has revolutionized the practice of anesthesia. By the end of the 1950s, non-depolarizing, neuromuscular, blocking drugs (NMBDs), d-tubocurarine and gallamine, were available. Although these 2 relaxants are no longer in use, several newer NMBDs have emerged over the last 20 years with safer side effect profiles.
Non-depolarizing NMBDs work by competing with acetylcholine (Ach) for binding sites on nicotinic alpha subunits. They produce skeletal muscle relaxation for endotracheal intubation, reduce patient movement to optimize operating conditions, and have been shown to improve compliance with mechanical ventilation. Notably, there has yet to be a non-depolarizing NMBD developed that can work faster than the rapid-onset, depolarizing muscle relaxant succinylcholine. However, onset can be hastened by using larger initial dosing of some non-depolarizing NMBDs, for example, rocuronium. Since muscle relaxants lack analgesic or anesthetic properties, they should not be used without anxiolytic or hypnotic agents or in inadequately anesthetized patients due to increased risk of awareness during general anesthesia.
The Ach receptor housed within the post-junctional motor neuron cell membrane is comprised of 5 glycoprotein subunits: 2 alpha subunits, and 1 each of beta, gamma, and epsilon. These subunits are arranged in a cylindrical fashion with the center containing an ion channel. When Ach binds to the 2 alpha-subunits, there is ion flow through the central ion channel with subsequent depolarization of the motor neuron. A non-depolarizing NMBD is a quaternary ammonium compound with positively-charged nitrogen that imparts an affinity to nicotinic Ach receptors. It only needs to bind one of the 2 alpha subunits to block Ach, thus preventing depolarization and producing muscle relaxation.
The 2 major structural classes of non-depolarizing agents include aminosteroid and benzylisoquinolinium. Recently, a third class has been developed, known as asymmetrical mixed-onium chlorofumarate (i.e., gantacurium). Examples of common aminosteroids include rocuronium, vecuronium, and pancuronium. Common benzylisoquinolinium compounds include atracurium, cisatracurium, and mivacurium.
Weight-based dosing scalars are important because administration based on total body weight may result in overdose while dosing based on ideal body weight may be sub-therapeutic. It is recommended that non-depolarizing NMBDs are dosed based on ideal body weight to avoid prolonged paralysis. Intravenous (IV) injection is the most common mode of delivery, although intramuscular (IM) injections may be performed for some non-depolarizing relaxants. The effective dose 95% (ED95) for NMBDs specifies the dose that produces 95% twitch depression in 50% of individuals. One to 2 times the ED95 dose for a particular non-depolarizing NMBD is typically administered for intubation.
A provider’s choice of non-depolarizing NMBD depends on the desired speed of onset, duration of action, route of elimination, and side effects. For instance, muscle relaxants with a rapid onset (i.e., rocuronium) and brief duration may be desired when endotracheal intubation is the reason for paralysis. On the other hand, a longer-acting agent like pancuronium may also produce intubating conditions in 90 seconds, but at the cost of pronounced tachycardia within the patient and a block that may be irreversible by an acetylcholinesterase inhibitor (for over 60 minutes), increasing the risk of postoperative pulmonary complications. The table below displays the characteristics of various non-depolarizing NMBDs.
A non-immunologic histamine release occurs with administration of benzylisoquinolinium compounds, typically mivacurium, atracurium, and doxacurium. This reaction is dose-related and affected by delivery rate, leading to positive chronotropy (H receptors), positive inotropy (H receptors) positive dromotropy (H receptors), skin flushing and hypotension from peripheral vasodilation, and rarely bronchospasm.
Several large-scale studies showed that NMBDs are the most common causative agents of anesthesia-related anaphylaxis. A prior history for anaphylaxis to one non-depolarizing NMBD also places a patient at increased risk of cross-reactivity to another non-depolarizing NMBD.
Other notable side effects are drug-specific. Pancuronium may cause tachycardia and hypertension due to its vagolytic mechanism on nodal cells mediated through muscarinic receptors. Laudanosine, which is a metabolite of atracurium and cis-atracurium, may accumulate and cause central nervous system stimulation with resultant seizures. Finally, in critically ill patients, long-term infusions of non-depolarizing NMBDs, particularly aminosteroids, can lead to profound weakness, termed critical illness polymyoneuropathy (CIP).
Drug interactions may potentiate weakness from non-depolarizing muscle relaxants, including volatile anesthetics, local anesthetics, certain antibiotics (i.e., aminoglycosides), and magnesium. Physiological alterations may also potentiate paralysis, including respiratory acidosis, metabolic alkalosis, hypothermia, hypokalemia, hypercalcemia, and hypermagnesemia.
Prior hypersensitivity reactions and inadequate sedation are contraindications. The provider should also consider the metabolism of certain non-depolarizing NMBDs. Only pancuronium and vecuronium are metabolized to any significant degree by the liver (deacetylation), and thus caution is advised in hepatic failure. Vecuronium and rocuronium undergo biliary excretion and may accumulate to toxic levels in extrahepatic biliary obstruction. Relaxants that are primarily renally excreted (e.g., doxacurium, pancuronium, pipecuronium) are to be avoided in renal failure. Atracurium and cisatracurium are unique NMBDs because they undergo spontaneous degradation via Hofmann elimination. The metabolism of mivacurium is via plasma pseudocholinesterase, similar to succinylcholine.
Patients who have received NMBDs should be placed on continuous pulse oximetry, cardiac monitoring, and end-tidal carbon dioxide monitoring. Peripheral nerve stimulation is used to measure the depth of neuromuscular blockade. Typically, the ulnar and facial nerves are stimulated for monitoring. Neuromuscular blockade generally occurs more rapidly in laryngeal adductors, diaphragm, and masseter than in the adductor pollicis. Utilizing the nerve stimulator, the train of four (TOF) is commonly used to assess blockade. It consists of 4 stimuli delivered at a frequency of 2 Hertz, and the ratio of the amplitude of the fourth to the first twitch response estimates the degree of block. About 75% of Ach receptors are antagonized when the fourth twitch from TOF disappears, 85% receptor occupancy occurs when the third twitch disappears, 90% receptor occupancy occurs when the second twitch disappears, and 95% to 100% receptor occupancy occurs when the first twitch disappears. Adequate relaxation for surgery is present when 1 to 2 twitches of the TOF are present.
Other unique observations noted on the peripheral nerve stimulator when a non-depolarizing NMBD paralyzes a patient include a tetanic fade response, post-tetanic potentiation, potentiation of blockade by other non-depolarizing NMBDs, and antagonism of the block by acetylcholinesterase inhibitors. Since TOF is user-dependent and introduces a considerable margin of error, other modalities are also available including acceleromyography, strain-gauge monitoring, and electromyography.
After reversal of neuromuscular blockade, a thorough evaluation of muscle strength is performed. A TOF ratio of 0.9 is usually recommended, although visual estimation of TOF may not be accurate. A sustained tetanic response, the ability to lift one’s head for 5 to 10 seconds, and good grip strength also suggest an adequate recovery.
Higher than recommended dosing, for example, based on total body weight, may cause prolonged paralysis beyond the time required for surgery. This may manifest with generalized weakness, decreased respiratory reserve, and even apnea. The management of toxicity should focus on airway maintenance and respiratory support to maintain oxygenation until the NMBD is metabolized. As aforementioned, non-immunologic histamine release is dose-dependent and may lead to significant hypotension and possibly bronchospasm if toxic doses are used.