Muscle Paralysing Agents – Depolarization Agents

Muscle Relaxants – General Principles

Muscle relaxant drugs give a neuromuscular blockade through activity in the neuromuscular junction of the transverse muscles that control the power of muscles and breathing. Muscle relaxants are used to facilitate surgery in connection with general surgery, especially laparoscopic surgery, abdominal surgery, orthopedic surgery, neurosurgery, thoracic surgery or other surgery where it is necessary for the patient to lay still or to be paralyzed. Neuromuscular blockade is also used to control airways with good intubation conditions and to better ventilate pulmonary disease patients.

Axon from nerve endings is normally coupled to muscle fibers via “neuromuscular junctions” in the motor end plate where neurotransmitters are released from presynaptic vesicles and convey the neuromuscular innervation. From these synapses acetylcholine is released which rushes over the synapse and binds to postsynaptic acetylcholine receptors for activity. The acetylcholine receptors are cholinergic receptors but they can also be activated by nicotine and are therefore called nicotinic receptors – nAchR (nicotinergic acetylcholine receptor). Nicotinic receptors are a form of ligand-controlled ion channels that open an ion channel when activated. This affects the rest potential so that the next nerve cell becomes prone to depolarize and generate muscle contractions.

Muscle relaxants are usually quaternary ammonium compounds that are structurally similar to acetylcholine. These bind to the alpha subunit of the nicotinic receptor and block them.

There are two types of muscle relaxants, depolarizing and non-depolarizing agents. Depolarizing muscle relaxants (succinylcholine – suxamethonium) provide initial stimulation which causes depolarization with muscle fasciculations, one can say that the muscles are activated and discharged. Thereafter, the receptor is closed for continued nerve transmission until the muscle relaxant is broken down by the enzyme pseudo cholinesterase. Non-depolarizing muscle relaxants bind to the nicotinergic receptor and block the nerve transmission. Muscle activity is usually blocked for at least 30 minutes after induction.

Succinylcholine chemically looks like a double acetylcholine molecule. In administration, initial fasciculations appear, usually first visible around the eyes immediately followed by the face and the rest of the body. Succinylcholine is short-acting with a fast onset, its effect usually last for 5-10 minutes. Succinylcholine is the muscle relaxant that provides the best intubation conditions and best airway control. It is used not only for intubation but also for solving laryngospasm and severe chest rigidity, for example after overdose of remifentanil. The short duration is due to redistribution from neuromuscular junctions, the substance is broken down by pseudo-cholinesterase, which is the same as butyl cholinesterase and plasma cholinesterase. There is a family deficiency of pseudo-cholinesterase, which may cause some patients to have a prolonged muscle relaxation of succinylcholine. However, usually the effect also releases in these patients after a couple of hours, the condition is unusual. In these cases, administration of succinylcholine should of course be avoided. Prolonged effects of succinylcholine may occur in liver disease, cancer and impaired general condition and the use of other drugs metabolized by cholinesterase.

Succinylcholine has certain side effects such as potassium release (cave burn injuries), arrhythmias, bradycardia (small children), postoperative muscle pain, malignant hyperthermia and histamine release. It should not be given to patients after prolonged immobilization (ICU!), Muscle disease, burns (after 24 hours), spinal cord injury, plasma cholinesterase deficiency, malignant hyperthermia, intracranial pressure increase or uremia. In each case, however, we must weigh the risks to the benefits. The establishment of free airways always has the highest priority in unconscious or worsening patients, and succinylcholine is the fastest and most effective for good airway control.

Non-depolarizing muscle relaxants are chemically structurally either steroid-based or benzylisoquinoline-based esters. Steroid-based non depolarizing muscle relaxants are e.g. vecuronium and rocuronium which are relatively similar. The steroid-based agents have low-frequency allergic reactions, do not pass placenta and are metabolized by hepatic hydroxylation. Rocuronium is an intermediate drug with active metabolites, which implies some risk of prolonged effect in liver failure. It is metabolized in the liver and excreted via the bile. Rocuronium is an alternative to succinylcholine at rapid sequence induction (RSI) in higher doses than normal, 0.9-1.0 mg/kg. If necessary, the effect can be reversed with a specific antidote named sugamadex (Bridion).

Pancuronium is an elderly long acting drug with relatively high muscarinergic activity, which is rarely used today. Pancuronium was the standard remedy for anesthesiological muscle relaxation until the 90’s. It is still used mostly in pediatric anesthesia. There are a variety of other non-depolarizing agents that are pharmacologically categorized as benzylisoquinolines. The agents have relatively low muscarinergic affinity. Among these agents are atracurium, cisatracurium and mivacurium. These agents have a relatively high histamine release effect, which clinically risks skin redness and bronchoconstriction. Atracurium and cisatracurium are broken down by unspecific plasma esterases and have spontaneous chemical degradation via the so-called Hoffman elimination. Mivacurium is broken down by pseudo-cholinesterase. Elimination is independent of liver and renal function.

Atracurium is a medium-acting non-depolarizing agent with a heterogeneous composition of isomers. Atracurium is histamine release and eliminated via Hoffman elimination. Mivacurium is a cardiac non-depolarizing muscle relaxant. Provides some histamine release and is broken down by pseudo-cholinesterase.

Reversal

The effect of non-depolarizing muscle relaxants is usually reversed with neostigmine which is a cholinesterase inhibitor restoring muscular innervation. Neostigmine may cause bradycardia and bronchoconstriction, because at the same time you usually give atropine as anticholinergic. A typical reversal dose for adults is 2.5 mg neostigmine (1 ml) and 0.5 mg atropine (1 ml), totaling 2 ml. Neostigmine may increase the amount of acetylcholine in the synapse and can compete against non-depolarizing muscle relaxants. In case of incomplete reversal, a half reversal dose may be repeated (1/2 ml neostigmine + 1/2 ml atropine). The dosage of neostigmine is 30-70 μg/kg, but the dosage is usually standardized to 1 ml (2.5 mg) to adult and by weight to children. The effect of muscle relaxants and reversal should be monitored continuously with specific monitoring systems (NMT).

Dosage of Muscle Relaxing Agents

SubstanceBrand nameIntubation dose (mg/kg)Maintenance dose = ED95 (mg/kg)
SuccinylcholineCelocurin1-1,5 
MivacuriumMivacron0,2-0,250,04-0,08
AtracuriumAtracurium0,5-0,60,2-0,3
VecuroniumNorcuron0,08-0,10,03
RocuroniumEsmeron0,6-0,90,2-0,3
CisatracuriumNimbex0,15-0,20,06-0,08
PancuroniumPavulon0,08-0,10,03

Effect Duration av Muscle Relaxing Agents

SubstanceBrand nameTime to Intubation (min)Clinical effect (min)
SuccinylcholineCelocurin< 15-10
MivacuriumMivacron3-415-30
AtracuriumAtracurium2-330-60
VecuroniumNorcuron2-330-60
RocuroniumEsmeron1-230-60
CisatracuriumNimbex3-445-75
PancuroniumPavulon2-345-180


NMT – Monitoring of Muscle Paralysis

The effect of muscle relaxants on the neuromuscular transmission (NMT) should always be monitored continuously with specific monitoring systems. Best practice for a reliable monitoring of NMT is to stimulate musculus adductor pollicis that controls the thumb in the hand through nerve stimulation of the ulnar nerve (n. ulnaris). This is done by sending a low voltage current via two flat skin electrodes immediately proximally of the wrist, measuring the impact in the form of twitching in the thumb measured by a small sensor. Muscular contractions give rise to graphical bars T1-T4, a maximum of four. The skin electrodes are placed at 2.5-4 cm intervals. The sensor on the thumb is taped or mounted as a small rail. It is important to place the meter correctly (TOF meter), to place the transducer correctly, have free movement of the thumb, sufficient distance between the thumb and the hand as well as skin temperature above 32 degrees. It becomes difficult to measure if the thumb is adduced to the hand. The neuromuscular activity is generally reduced in hypothermia. The stimulation and control of muscle strength are made through a varied pattern of electrical stimulation; Train-Of-Four (TOF), Single Twitch (Twitch), Post Tetanic Count (PTC), Double-Burst Stimulation (DBS) or Tetanus Stimulation.

Train-Of-Four (TOF)

The neuromuscular transmission is measured by innervation with four short currents against a peripheral nerve. The answer is measured as four bars, “Train of Four” (TOF). The answers are displayed in their own separate monitor (TOF-Watch) or integrated into the existing anesthesia monitoring equipment. In the registration, the amplitude of T1 (T4/T1) is interpreted as the amplitude of T1 (T4), the amplitude of the four-stroke TOF-rat (TOF ratio) is interpreted as the amplitude of T4. If less than four bars are detected, the monitor displays a TOF count value (TOF-cnt) instead of percent (1-4). In case of complete neuromuscular blockade, you will not get any bars at all in the TOF registration. In case of moderate block that permits surgery, one gets one to four bars. During reversal, you get four bars first. After that, you get the original amplitude of the monitor’s bars in percent, TOF% (TOF-rat). As a rule, you can usually extubate at more than TOF 90%. For light surgery usually 2-4 bars, for invasive surgery 1-2 bars. For complete muscle blocking no bars – no TOF response. How often you stimulate varies with the type of surgery and the length of surgery. The stimulation is used to prevent the patient suddenly tensioning, perhaps coughing and obstructing surgery for the surgeon. TOF measurement can prevent hearing from the surgeon’s classic comment: “The patient is tense!”

Post-Tetanic Count (PTC)

At PTC, stimulation with four electric pulses starts every 500th millisecond (2 HZ). If the muscle response is detected, the answer is recorded as a TOF value. If no muscle response is detected, five seconds of tetanic stimulation with pulses at 50 Hz, followed by a 3-second pause followed by 20 single pulses every second (1 Hz), is given. The muscle response detection is only active during the first 4 simple pulses and the last 20. During the last 20 power pulses, the value of the PTC increases in each detected muscle tone. PTC can be used in the absence of muscle responses of TOF-ratio and before their return when the effect of muscle relaxants decreases. Mainly, TOF-ratio is used to evaluate NMT.

Single Twitch (Twitch)

Measures response to simple electric stimulation. The module sends a simple pulse, measures the strength of the resulting contraction and then calculates a contract value such as Twitch%. The answer is given as a percentage of the reference contraction force.

Double-Burst Stimulation (DBS)

The Double-Burst stimulation pattern consists of a sequence of 3 electric pulses delivered every 20 msec (50 HZ) followed by a 750 msec pause, followed by a sequence of 3 power pulses every 20 msec (50 Hz). In each detected muscle response, the DBS count value (DBS-cnt) increases.

TOF measurement allows dosage of muscle relaxants correctly and avoids overdose or subdosage. Assessing the rate of muscle relaxation without monitoring is very difficult. During awakening it is important that the patient not only hugs a hand but also holds his hand closed by force, or alternatively holding his head against the chest without falling back immediately. Usually, the force of the respiratory muscles is maintained significantly longer than the skeletal muscle. The diaphragm muscle is paralyzed before the muscles of the tumb but the diaphragm regains its contraction force before the thumb. Larynx is denervated as fast as the diaphragm but regains power faster.

The best way to estimate muscle contractile force is with a neuromuscular monitoring system and TOF measurement. If the patient is significantly muscle relaxed during wake up, the patient must be anesthetized immediately to avoid the discomfort of being muscle paralyzed. If you have given higher doses of muscle relaxants than is reasonable to reverse, it is better to allow the patient to sleep in the recovery area, the ICU and wait for the wake up. Incomplete reversal is referred to as residual denervation or residual block (RNMB) which is a serious condition that can quickly become life-threatening, deaths have occurred. Rest-curarization is common, unpleasant and potentially dangerous. It increases the risk of postoperative respiratory and cardiac events, the risk of early postoperative lung complications and increases the risk of mortality and morbidity. The aim of wake up is that the patient should recover TOF > 90% before extubation, but sometimes the patient wakes up faster and exhibits clinically good power already at TOF 70%. It is then possible to reverse, but the muscle strength must be carefully checked after extubation. Rest-curarization results in reduced hypoxic respiratory response, i.e. it gives an increased risk of hypoxia. It also provides a pharyngeal dysfunction and can give an upper respiratory obstruction with stridor. At TOF 80-90% you can get double-vision, inability to bite together, lowered face mask control, subjective swallowing difficulties and a feeling of drowning or stiffening.

Reversal

Acetylcholinesterase is an enzyme that quickly cleaves acetylcholine into carbon and acetate. If you inhibit this enzyme with cholinesterase inhibitors you quickly get elevated levels of acetylcholine in synapse, thereby restoring neuromuscular transmission and muscle strength. The acetylcholine competes away non-depolarizing muscle relaxants. The most common cholinesterase inhibitor used is neostigmine. Neostigmine is usually given together with an anticholinergic drug such as glycopyrron (Robinul) or atropine. Dosage of neostigmine is usually 30-70 µg/kg. Higher doses of neostigmine than give maximum effect usually do not provide any further improvement. The reversal usually takes some time, because full recovery of the diaphragm muscle takes about 10 minutes. Neostigmine can also cause significant side effects such as increased salivation, bronchoconstriction, increased intestinal motility, bradycardia, blood pressure drop and nausea. Neostigmine has an effect on both muscarinic receptors and nicotinergic receptors. The muscarinergic effects are counteracted by simultaneously providing an anticholinergic.

An alternative, but significantly more expensive option, is to give sugammadex (Bridion) as antidote to some non-depolarizing drugs. This antidote inactivates rocuronium or vecuronium through a complex formation where the molecule is simply bound into sugammadex and excreted via the kidneys. The antidote may be administered at any given dose of rocuronium or vecuronium. Sugammadex is inert and eliminated via the kidneys. Contraindication is severe kidney failure. Rocuronium or vecuronium should not be re-administered within 24 hours following sugammadex. The dosage of sugammadex is 2 mg/kg if you see a spontaneous return of T2. The dose has effect within 2 minutes. If you stimulate Post Tetanic Count (PTC) and see 1-2 bars given a higher dose, 4 mg/kg and if you want to reverse immediately after full dose you can give 16 mg/kg, then you get muscle activity within one and a half minutes . Sugammadex can be given as a fast bolus injection for 10 seconds.

NMT measurements can interfere with implanted pacemakers and should be used with caution in patients with pacemaker.


Atracurium (Atrakurium-hameln®)

Non-depolarizing muscle relaxant drug. Adjuvant to general anesthesia to facilitate endotracheal intubation and to provide relaxation of skeletal muscles during medium to long duration surgical procedures. Usually, patients are paralyzed under the abdominal surgery (open or laparoscopic), orthopedic surgery and in other surgery where the patient must be absolutely still. To facilitate manual or mechanical ventilation of the injured patient.

Intubation dose: 0.6 mg/kg i v (1.0 mg/kg at RSI); 40-60 mg to normal adult = 4-6 ml, 10 mg/ml solution (formerly Tracrium).

Standard dose: 50 mg i.v. Maintenance dose is 0.15 mg/kg, 10-20 mg per occasion. Repeated dose every 20 to 60 minutes during anesthesia. Spontaneous recovery after about 35 minutes.

Caution: Allergic reactions. Previous reaction to muscle relaxants, myasthenia or similar neuromuscular disease. Cannot be given i.m.

Reversal: Cholinesterase inhibitor Robinul-Neostigmine 1-2 ml intravenously (neostigmine 2.5-5 mg + glycopyrronium 0.5-1 mg).


Mivacurium (Mivacron®)

Non-depolarizing muscle relaxant drug. Adjuvant to general anesthesia to facilitate tracheal intubation and to provide relaxation of skeletal muscles during medium to long duration surgical procedures. Usually, patients are paralyzed under abdominal surgery (open or laparoscopic), orthopedic surgery and in other surgery where the patient must lay absolutely still.

Intubation dose: 0.07-0.25 mg/kg iv, 5-20 mg to normal adult, 2 mg/ml solution.

Standard dose: 15 mg i v. Maintenance 0.1 mg/kg (7.5 mg) per occasion. Giving every 20 to 60 minutes under general anesthesia.

Caution: Previous reaction to muscle relaxants, myasthenia or similar neuromuscular disease.

Reversal: Robinul-Neostigmin 1-2 ml intravenously (neostigmine 2.5-5 mg + glycopyrronium 0.5-1 mg) alt. Atropin 1 mg + Neostigmine 2.5 mg i


Pancuronium (Pavulon) – deregistered in most countries

Non-depolarizing muscle relaxant drug. Be previous standard but no longer available. Adjuvant to general anesthesia to facilitate tracheal intubation and to provide relaxation of skeletal muscles during medium to long duration surgical procedures. Usually, patients are paralyzed under abdominal surgery (open or laparoscopic), orthopedic surgery and in other surgery where the patient must lay absolutely still.

Intubation dose: 0.08-0.1 mg/kg i v, 8-12 mg to normal adult. 2 mg/ml solution = 4-6 ml.

Standard dose: 10 mg i v. Maintenance 0.02 to 0.03 mg/kg, 1-3 mg per occasion. Giving every 20 minutes to 60 minutes during anesthesia.

Caution: Previous reaction to muscle relaxants, myasthenia gravis or similar neuromuscular disease.

Reversal: Robinul-Neostigmin 1-2 ml intravenously (neostigmine 2.5-5 mg + glycopyrronium 0.5-1 mg) alt. Atropine 1 mg + Neostigmine 2.5 mg i v.


Rocuronium (Esmeron®)

Non-depolarizing muscle relaxant drug. Adjuvant to general anesthesia to facilitate endotracheal intubation and to provide relaxation of skeletal muscles during medium to long duration surgical procedures. Usually, patients are paralyzed under abdominal surgery (open or laparoscopic), orthopedic surgery and in other surgery where the patient must lay absolutely still. To facilitate manual or mechanical ventilation of the injured patient.

Intubation dose: 0.6 mg/kg iv (1.0 mg/kg at RSI); 40-60 mg to normal adult adult = 4-6 ml, 10 mg/ml solution (formerly Tracrium).

Standard dose: 50 mg i.v. Maintenance 0.15 mg/kg 10-20 mg per occasion. Giving every 20 minutes to 60 minutes during anesthesia. Spontaneous recovery after about 35 minutes.

Caution: Allergic reactions. Previous reaction to muscle relaxants, myasthenia or similar neuromuscular disease. Can not be given i.m.

Reversal: Cholinesterase inhibitors Robinul-Neostigmine 1-2 ml intravenously (neostigmine 2.5-5 mg + glycopyrron 0.5-1 mg).


Sugammadex (Bridion®)

Antidote to non-depolarizing muscle relaxants, for intravenous use. Sugammadex is a derivative of gamma cyclodextrine. Sugammadex forms complexes with the neuromuscular blocking agents rocuronium and vecuronium in plasma, thereby reducing the amount of muscle relaxants that can bind to the nicotinic receptor in the neuromuscular synapse.

Indication: Reversal of the rocuronium (Esmeron) and vecuronium (Norcuron) muscle relaxants. Effect usually occurs within 2 minutes with almost complete recovery of muscle strength. 

Dosage: For normal reversal 4 mg/kg, giving 280 mg (2.8 ml) to a 70 kg patient. For children and adolescents, only 2 mg/kg, which gives 80 mg (0.8 ml) to a 40 kg child.

Stock strength: Solution at 100 mg/ml (2 or 5 ml vials). 

Side effects: Hypersensitivity, anesthetic complications such as rapid recovery of muscle tone during surgery.

Warning: Risk of rapidly restoring muscle tone during surgery may complicate surgical work. Anaphylactic reactions may occur.


Suxametonium (Succinylcholine – Celocurin®)

Depolarizing muscle relaxant. Ultra-short acting means with very fast elimination. For intravenous use only. Adjuvant to general anesthesia to facilitate endotracheal intubation and to provide relaxation of skeletal muscle during surgical interventions of short duration. To facilitate manual ventilation of an injured patient.

Intubation dose: 1-1.5 mg/kg intravenously = 25-100 mg i v (pretreatment with atropine), 50 mg/ml solution.

Standard dose: 75 mg i v, 50-100 mg, 1-2 ml i v.

Caution: Hyperkalaemia, recent burn, malignant hyperthermia, muscular disease, major tissue damage, bradycardia.


Vecuronium (Norcuron®) – deregistered

Non-depolarizing muscle relaxant drug. Adjuvant to general anesthesia to facilitate endotracheal intubation and to provide relaxation of skeletal muscles during medium to long duration surgical procedures. Usually, patients are paralyzed during abdominal surgery (open or laparoscopic), orthopedic surgery and in other surgery where the patient must lay absolutely still. To facilitate manual or mechanical ventilation of the injured patient.

Intubation dose: 0.08-0.1 mg/kg i v, 8-12 mg to normal adult. 2 mg/ml solution = 4-6 ml.

Standard dose: 10 mg i v. Maintenance 0.02 to 0.03 mg/kg, 1-3 mg per occasion. Giving every 20 minutes to 60 minutes during anesthesia.

Caution: Previous reaction to muscle relaxants, myasthenia gravis or similar neuromuscular disease.

Reversal: Robinul-Neostigmin 1-2 ml intravenously (neostigmine 2.5-5 mg + glycopyrron 0.5-1 mg) alt. Atropine 1 mg + Neostigmine 2.5 mg i v.