Continuing Education Activity

The widespread use of neuromuscular blocking agents (NMBA) was a significant milestone in the development of anesthesia. Before the introduction of NMBA, anesthesia was induced and maintained with intravenous and inhalational agents. The introduction of NMBA led to a significant conceptual change in the practice of anesthesia. Anesthesia was redefined to include a triad of narcosis, analgesia, and muscle relaxation. This activity outlines the indications, mechanism of action, methods of administration, important adverse effects, contraindications, monitoring, and toxicity of NMBAs, so providers can direct patient therapy to optimal outcomes in anesthesia and other conditions where NMBA have therapeutic benefit.

Objectives:

• Describe the mechanism of action and administration NMBAs.
• Summarize when the use of a NMBA is indicated.
• Review the adverse effect profile and contraindications of NMBA use.
• Review the importance of improving care coordination among the interprofessional team to enhance the delivery of care for patients who can benefit from therapy with NMBAs.

Indications

The widespread use of neuromuscular blocking agents (NMBA) was a significant milestone in the development of anesthesia.  Before the introduction of NMBA, anesthesia was induced and maintained with intravenous and inhalational agents.  The introduction of NMBA led to a significant conceptual change in the practice of anesthesia.  Anesthesia was redefined to include a triad of [1]:

• Narcosis
• Analgesia
• Muscle relaxation

Native peoples in South America used curare for hunting game and killing prey. The evolution of NMBA began when Spanish explorers, known as the Conquistadors, returned home bringing tales of ‘flying death”.  The South American Indians used arrows and darts coated with curare.  In 1562, a writer in the court of King Ferdinand and Queen Isabella was the first person to write about the poisoned arrow in a book titled De Orbe Novo.[2]  Portuguese, Spanish and British explorers had done earlier work on the discovery and use of curare.

Sir Walter Raleigh, a British explorer, and adventurer described the use of poisoned arrows in modern-day Venezuela in his book titled “Discovery of the Large, Rich and Beautiful Empire of Guiana.  The word ‘Ourari’ came into use by one of Sir Walter Raleigh’s lieutenants.[3][4]

Another pioneer in the discovery and use of curare was Edward Bancroft.  He brought samples of crude curare from South America back to the Old World.  Sir Benjamin Brodie showed that when injecting small animals with curare, they stop breathing but can be kept alive by inflating their lungs with bellows.  This observation led to the conclusion that curare causes the cessation of breathing by paralyzing the respiratory muscles.

Charles Waterton was the manager of a large sugar plantation estate in South America.  He became very interested in the effects of wourali (a South American term for curare) used by the native population.  In 1814, Charles Waterton showed the effects of wourali on three donkeys.  The first donkey was injected in the shoulder and died soon afterward.  The second donkey had a tourniquet applied to the foreleg was injected with wourali distal to the tourniquet.  The donkey lived while the tourniquet was in place but soon after removal it died.  The third donkey appeared to be dead after injection with wourali but was resuscitated using bellows. Charles Waterton's experiment confirmed the paralytic effect of wourali.

Another milestone in the development of NMBA relates to the work done by the French physiologist Claude Bernard (1813-1878).  Bernard showed that when injecting curare into frog legs, the muscle in the leg will not contract when the nerve is directly stimulated but will contract with direct stimulation to the muscle itself.  This experiment showed that the curare acts on the neuromuscular junction.

Neurologist Walter Freeman learned of curare and suggested that Richard Gill, a patient suffering from multiple sclerosis, try using it.  Richard Gill brought twenty-five pounds (11 kg) of raw curare from Ecuador.  The raw curare was given to Squibb and Sons in an attempt to derive an effective antidote to curare.  In 1942, two scientists working for Squibb and Sons, Wintersteiner and Dutcher, isolated the alkaloid d-tubocurarine.  Soon thereafter, AH Holladay, also working for Squibb and Sons, developed a standardized commercial preparation of curare that was named Intocostrin.

Neuropsychiatrist E Bennett, a pioneer in the field of convulsive shock therapy, used curare to minimize the risk of spinal fracture during the procedure.  During the 91st Congress of the American Medical Association, Bennet presented a film describing his use of curare in this setting.  Lewis Wright, a participant at the Congress and employee of Squibb and Sons, was intrigued by the film.  He donated some Intocostrin to E.A. Rovenstine of New York University who passed the medication on to E.M. Papper, one of his residents.  The administration of Intocostrin caused a cessation of breathing in two patients who received it. Papper and colleagues manually ventilated both patients overnight. 

In 1942, Harold Randall Griffith and his resident Enid Johnson at the Homeopathic Hospital in Montreal administered curare to a young patient undergoing an appendectomy.[5][6][7]  This was considered the first major step in the use of NMBA for muscle relaxation in anesthesia.

The 1940s, 1950s, and 1960s saw the rapid development of several synthetic NMBA.  Gallamine was the first synthetic NMBA used clinically. Scientists later developed suxamethonium, pancuronium, vecuronium, atracurium, and rocuronium.

NMBA divide into two groups:

• Depolarizing NMBA
• Non-depolarizing NMBA

In modern medicine, uses for NMBA are:

• Muscular relaxation before the initiation of airway management
• Therapeutic hypothermia after cardiac arrest

Management of patients with [8]:

• Acute respiratory distress syndrome
• Increased intraabdominal pressure
• Increased intracranial pressure
• Status asthmatics
• For patients on mechanical ventilation who require muscular relaxation to prevent patient-ventilator asynchrony, also known as “bucking” the ventilator
• Muscular relaxation for a surgical procedure
• Adjunct therapy for patients undergoing electroconvulsive therapy

Mechanism of Action

NMBA act at the neuromuscular junction (NMJ). The NMJ consists of three parts

• Presynaptic nerve terminal
• Synaptic cleft
• Postsynaptic nicotinic receptors

When an electric impulse transmits along the motor neuron, it causes the release of acetylcholine (ACh) from the presynaptic membrane which travels across the synaptic cleft and acts on the nicotinic receptors on the postsynaptic membrane, causing muscle contraction.

Presynaptic Nerve Terminal

The presynaptic nerve terminal consists of motor neurons originating from the ventral horn of the spinal cord. The motor neuron loses its myelin sheath as it embeds in the muscle tissue. Motor neuron secretes trophic and growth factors.

The presynaptic nerve terminal contains acetylcholine receptors (AChRs) which are on the surface of the nerve membrane. These are nicotinic receptors identified as neuronal AChR (nAChR).[9]

Storage of ACh is in two primary forms:

• Vesicle in a reserve pool
• Readily releasable vesicles

ACh released from readily releasable vesicles triggers the activation of sodium channels at the pre-junctional nerve membrane. These actions trigger the activation of voltage-dependent calcium channel (P-type fast) with causes an inward movement of calcium into the cytoplasm of the motor neuron.[9]

The Synaptic Cleft

The synaptic cleft is the space between the presynaptic and postsynaptic membrane which measures about 50 nm. Several biologically active substances interact in the synaptic cleft to promote and enhance the transmission of nerve impulses. These substances include acetylcholine esterase (AChE), lipoprotein receptor protein 4, (Lrp4), and agrin.

 The post-synaptic membrane basal lamina also contains proteins that help cell adhesion and aid neuromuscular signaling.

In the synaptic cleft agrin, a glycoprotein binds lipoprotein receptor protein 4 which activates muscle-specific tyrosine kinase (MuSK) that helps in the differentiation of acetylcholine receptors.

The postsynaptic membrane

This membrane is made up of multiple shoulders with a high concentration of ACh receptors (AChR). The clefts in this membrane contain voltage-gated sodium channels. Because the post-synaptic membrane contains a high concentration of receptors for ACh, this enables the neurotransmitter to elicit enough depolarization to stimulate the contraction of the muscle. The high density is of AChR is possible because of anchoring to rapsyn and other vital muscular proteins.[10]

AChR receptors exist in two forms

Adult/mature Junctional Receptors are pentametric proteins with five subunits. They have high conductivity and remain open for a short period and have a half-life of approximately 14 days.

Immature/fetal Junctional Receptors are found mainly in fetuses but can proliferate in certain conditions like sepsis, burn, and upper and lower motor neuron diseases. The protein structure is pentameric, and they appear within 18 –24 hours of injury. The half-life of these receptors is short 24 hours. The receptors are resistant to the action of non-depolarizing neuromuscular blocking agents but are sensitive to succinylcholine. Stimulation of these receptors can cause efflux of potassium leading to hyperkalemia.

There are two types of NMBA:

• Depolarizing
• Non-Depolarizing

Depolarizing NMBA

The depolarizing NMBA acts on the receptors at the motor endplate of the neuromuscular junction (NMJ), causing depolarizing of the membrane. This action makes the motor endplate refractory to the action of ACh. An example of depolarizing NMBA is succinylcholine. Succinylcholine or suxamethonium has a quick onset of action and rapidly metabolizes via the enzymatic action of plasma butyrylcholinesterase. The continued disruption of the effect of ACh causes muscular fasciculation and twitching. The onset of action is about 1 minute, and the duration is about 6 minutes.[11] It is the only depolarizing NMBA in clinical use.

Non-Depolarizing NMBA

The non-depolarizing NMDA works by a different mechanism. When administered, instead of causing depolarization of the motor plate at the NMJ, they block acetylcholine from binding to the motor plate at the NMJ, an action achieved by competing for the binding site on the alpha subunit of the nicotinic receptors. As the concentration of non-depolarizing NMBA builds up at the junction, relative to ACh, it establishes a neuromuscular blockade.[12]

There are two major structural classes of non-depolarizing NMBA.

Amino Steroids 

• Vecuronium
• Pancuronium
• Rocuronium
• Benzylisoquinolinium
• Mivacurium
• Atracurium
• Cis–atracurium[12] 

A third class is more recent:

Mixed-onium chlorofumarate (i.e., gantacurium)[13]

Based on the duration of action NMBD are classified as

• Short-acting
• Intermediate-acting
• Long-acting

Short-acting NMDA includes mivacurium and succinylcholine

Intermediate-acting NMDA include vecuronium, rocuronium, and atracurium

Long-acting NMDA–pancuronium, gallamine, and tubocurarine[14] 

Administration

The administration of neuromuscular blocking agents is most effective via an intravenous or intramuscular route. NMBAs are poorly absorbed if administered orally.[15] The route of administration is dependent on the patient’s clinical condition, desired speed of action, and duration of clinical effect. In most instances, NMBA administration is intravenous. Dose administration can be as boluses or continuous infusion. Continuous infusion is usually administered in the intensive care unit setting where prolonged paralysis might be necessary or in instances where the surgical procedures will dictate a significant amount of time.

The dosing scalar for NMBA is based on ideal body weight to prevent overdosing, prolonged and undesired paralysis.[16]

Underdosing NMBA can lead to inadequate paralysis. The recommendation is that adequate sedation and analgesia be provided before the administration of NMBA.

Adverse Effects

NMBA has several adverse effects associated with its use.

Depolarizing NMBA

Succinylcholine administration correlates to a significant rise in serum potassium. Therefore, it is recommended to avoid the use of succinylcholine in patients with chronic renal disease, burn patients, patients with crush injuries, and rhabdomyolysis. Elevated potassium levels can lead to fatal arrhythmias.

Succinylcholine is also associated with bradycardia especially in the pediatric population. The stimulation of the nicotinic receptor activates a muscarinic receptor that produces bradycardia. The effect can be blunted by administering atropine or glycopyrrolate.

The use of succinylcholine carries associations with increased intracranial pressure and intraocular pressure. The administration of adequate age-appropriate sedation can minimize this unwanted side effect.[11]

Another side effect of succinylcholine is malignant hyperthermia; this is a pharmacogenetic disorder that occurs with the use of volatile inhalation anesthetic agents and succinylcholine. Clinically it can manifest with hypercarbia, hyperventilation hyperthermia, rhabdomyolysis, and metabolic acidosis. The condition has correlated with the mutation in the RYR1 and CACNA1S genes.[17]

Other side effects of succinylcholine include jaw rigidity, hypersalivation, and hypersensitive reaction

Non-depolarizing NMBA

Benzylisoquinolinium, mivacurium, atracurium, cisatracurium, and doxacurium can cause histamine release when administered, which can cause bronchospasm, hypotension, and tachycardia from peripheral vasodilation.

Laudanosine which is a metabolite of atracurium and is -atracurium can accumulate in the central nervous system (CNS) causing a seizure.[18]

Amino Steroids

Vecuronium, and rocuronium. Prolonged infusion of amino steroids with concurrent administration of steroids can lead to profound muscular weakness which is otherwise known as critical illness polyneuropathy.[19]

Certain conditions can prolong the effects of neuromuscular blocking agents [20]:

• Hypothermia
• Metabolic derangements
• Hypercalcemia
• Hypermagnesemia
• Hypokalemia
• Hypothermia
• Respiratory acidosis
• Metabolic alkalosis

Contraindications

Any history of a severe allergic reaction to an NMBA or anaphylaxis is a contraindication to the administration of NMBA. In most cases, the use of these drugs is in critical care settings. The clinician should be familiar with the pharmacokinetics of NMBA. Pancuronium and vecuronium undergo liver metabolism by deacetylation. Hence in patients with liver failure, caution should be exercised in using these drugs.

Rocuronium and vecuronium get excreted via the hepatobiliary system and should be avoided in cases of liver failure if there is an alternative agent available.

Pancuronium, doxacurium, pipecuronium should be avoided in kidney failure because they undergo renal excretion.

Atracurium and cisatracurium are options in case of kidney or liver failure. These NMDAs get eliminated by a unique process called Hoffman elimination which is a spontaneous degradation process.[21]

Monitoring

Patients on NMDA are usually in the intensive care unit.  Monitoring of patients on NMDA includes pulse oximetry for oxygen saturation, continuous end-tidal C02. The rise in the level of carbon dioxide might show the development of malignant hyperthermia.

The assessment of the depth of neuromuscular blockage utilizes the train of four. Typically, the ulnar, median, or facial nerves are stimulated to monitor the effect of neuromuscular blockade. Four electric impulses are delivered at a frequency of around 2 Hertz. The ratio of the fourth to first twitch is used to access the depth of neuromuscular blockade. The disappearance of the fourth twitch signifies about 75% blockage; 85% blockage occurs with the disappearance of the third twitch. If there is 90% blockage, the second twitch disappears, and if there is only the first twitch, this shows close to 100% neuromuscular blockade.[22][23][24]

The bispectral index monitor (BIS) is quantitative electroencephalography (EEG) that is used to access the depth of sedation for patients on continuous infusion of NMBA using bi-spectrality and time domain.[25] In patients who are deeply sedated or under general anesthesia, the BIS is sensitive to changes in the electromyogram (EMG).[26][27][28]

Toxicity

Clinicians should know about toxicity associated with the use of NMBAs. Dosing should be based on ideal body weight. An overdose of NMBA manifests with prolonged paralysis longer than the required time frame required. Prolonged muscular weakness, decreased respiratory drive and apnea are the clinical symptoms of NMBA overdose or toxicity. Certain conditions mentioned above can prolong the effect of NMBA.

Enhancing Healthcare Team Outcomes

After the completion of a surgical procedure or when a patient is weaning towards extubation,  NMBA might be reversed pharmacologically to prevent unwanted side effects and facilitate quick extubation. Traditionally neostigmine reverses NMBAs. The mechanism of action of neostigmine is inhibition of acetylcholine esterase (AChE), the enzyme responsible for the breakdown of acetylcholine (ACh). The increased level of ACh will compete with NMBA and stimulate the nicotinic receptors at the neuromuscular junction enhancing signal transmission.

Recent advances in anesthesia have seen the introduction of a new drug sugammadex, which is the cyclodextrin that selectively binds to plasma NMBA. By the process of encapsulation, it rapidly nullifies the effect of the NMBA as it is unavailable to act at the neuromuscular junction.[29]

Sugammadex produces a safe and quick reversal of commonly used NMBA like rocuronium, vecuronium, and pancuronium. Sugammadex can quickly reverse both moderate and deep neuromuscular blockage (NMB).[30][31][32]

With the introduction of Sugammadex, deep NMB can be administered for a long period for surgical procedures with no fear of a prolonged recovery period. Deep NMB creates improve working conditions for a surgeon with the need for less insufflation pressure for laparoscopic surgery.[33][34][35][36]