Neuromuscular Blocking Agents

With the introduction of neuromuscular blocking agents (NMBAs) the overall goals of a general anesthetic expanded to include amnesia, analgesia, and muscle relaxation. The first documented uses of paralytics were described in the 1500s by Spanish explorers (Conquistadors) who spoke of South American Natives using darts and arrows termed “flying death”. These arrows were coated with curare and caused muscle paralysis and ultimately death when penetrating human flesh. In the 1800s, French physiologic Claude Bernard experimented with curare by injecting it directly into frog legs and observing that the the muscle will not contract with nerve stimulation but will contract with direct muscle stimulation. This lead to the discovery that curare works at the neuromuscular junction.

Thanks to the development of lung ventilation, muscle paralysis became less worrisome as an adjunct to anesthesia. In 1942, Dr. Harold Griffith used curare for a patient undergoing an appendectomy - this is considered the first implementation of muscle paralysis during a general anesthetic. Throughout the 1940s-60s, there was a rapid development of many synergetic NMBAs such as pancuronium, vecuronium, atracurium, and our most commonly used paralytic today - Rocuronium.

NMBAs are reserved for providers who are able to intubate and make airway interventions such as Anesthesiologist, Emergency Medicine, and Intensive Care Physicians. As Anesthesiologists, we primarily use NMBAs for creating optimal intubating conditions for laryngoscopy and airway management. We also use it for certain surgeries when it is extremely important that the patient does not move - for example, during robotic surgery when the arms of the robot are inserted into various laparoscopic port sites. Other uses for NMBAs can include:

• therapeutic hypothermia after cardiac arrest

• Acute respiratory distress syndrome (ARDS)

• Increased intraabdominal pressure (laparoscopic surgeries, abdominal HTN)

• Increased ICP

• Status asthmatics

• Prevention of ventilator dyssynchrony in the OR or ICU

Paralytics work at the neuromuscular junction (NMJ). The NMJ has three components:

1. Presynaptic neuromotor axon

2. Synaptic cleft

3. Postsynaptic neuromuscular endplate

The postsynpatic endplate contains nicotinic receptors that bind to acetylcholine (ACh) molecules that are released from the presynaptic axon after receiving an upstream electrical impulse (originates from the ventral horn of the spinal cord). The binding of ACh molecule to their receptors creates a muscle contraction. There is a second form a ACh receptors called immature extra-junctional receptors that proliferate in disease states such as sepsis, burns, and upper/lower motor neuron diseases. Depolarizing NMBAs, such as Succinylcholine, has an effect on these receptors and can lead to potentially lethal levels of hyperkalemia.

As I eluded to above, there are two broad classes of NMBAs: (1) depolarizing and (2) non-depolarizing agents.

The only depolarizing NMBA that we use in todays practice is Succinylcholine. As the name describes, it causes depolarization at the post-synaptic motor endplate and causes muscle contraction. This manifests as fasciculations and twitches after administration. The depolarization of the endplate makes it refractory to the action of any additional ACh bound to their receptors. The benefit of Succinylcholine is its rapid onset of action (30 to 60 seconds) making it very useful for a rapid sequence induction. It also has a very short duration of action (~6 minutes), owing to the fact that it is quickly redistributed from the NMJ and it is metabolized by plasma enzymes known as butyrylcholinesterases (pseudocholinesterase).

Non-depolarizing NMBAs work with a different mechanism of action. They block ACh molecules from binding to the receptors (competitive antagonist). There are two classes of non-depolarizing paralytics based on their structure:

1. Aminosteroids

   1. Rocuronium

   2. Vecuronium

   3. Pancuronium

2. Benzylisoquinolinium

   1. Mivacurium

   2. Atracurium

   3. Cisatracurium

NMBAs are administered intravenously and can be given either as a bolus or a continuous infusion. Most anesthesiologists will give boluses of Rocuronium throughout a surgical case to keep their patient paralyzed. The dose and frequency of boluses is determined by our monitoring of their paralysis with a twitch monitor. Using a twitch monitor, we can deliver 4 electrical impulses along a neuromuscular group (ie. ulnar, facial, or posterior tibial nerve sites) and see how many times the muscle contracts. This test is called a “Train of 4”. Our goal is to keep the patient between 1 to 2 twitches. This ensures about a 85-90% blockage of ACh receptors.

NMBAs carry several side effects with them. Succinylcholine is probably most recognized as having the most down sides. These can include:

• Hyperkalemia (about 0.5-1 mEq/L increase, extrajunctional receptors increase this number)

  • Use extreme caution in patients with crush injuries, burns, bed bound patients, and patients with neuromuscular disease processes

• Bradycardia (especially in pediatrics, activates muscarinic receptors on myocardium)

• Malignant hyperthermia trigger

• Increased intracranial, intraocular, and intragastric pressures

• Postoperative myalgias (potentially rhabdomyolysis)

Nondepolarizing NMBAs carry less side effects. However, one of the biggest concerns is anaphylaxis. Rocuronium is the leading cause of perioperative anaphylaxis, followed by antibiotics.

When a surgery is finished and we need to reverse our muscle paralytic, we have two options for medications classes. Historically, acetylcholinesterase inhibitors, such as neostigmine, were used to allow for more ACh molecules in the NMJ to out-compete the NMBAs. In recent years, we have moved to using Sugammadex, a cyclodextrin molecule that binds and envelopes aminosteroid NMBAs, making them ineffective in the NMJ and carrying them back into circulation to be metabolized. The major benefits of Sugammadex are its rapid onset of action and its ability to reverse deep paralysis. The one downside to be aware of is Sugammadex wil make oral conceptive pills (OCPs) ineffective for about 2 weeks - this should be communicated to any patient that this applies to.