Chapter 183 Neuromuscular Blockers
Neuromuscular blocking agents are used to facilitate intermittent positive-pressure ventilation (IPPV) as part of a balanced anesthetic technique or as part of an anesthetic technique for animals undergoing intensive care mechanical ventilation. Neuromuscular blockade will help to prevent respiratory dyssynchrony, stop spontaneous respiratory efforts and muscle movement, improve gas exchange, and facilitate inverse ratio ventilation. 1 Neuromuscular blocking agents may also be useful in managing increased intracranial pressure and the muscle spasms of tetanus, drug overdose, or seizures.1 Their use in surgery is to enhance skeletal muscle relaxation, to facilitate control of respiratory efforts during intrathoracic surgery, to immobilize the eye for ocular surgery, and to facilitate difficult intubation.2
These agents do not have anesthetic or analgesic properties, so it is imperative that they be given only when the animal is adequately insensible to pain and awareness.3 Positive-pressure ventilation is mandatory with their use. The duration of action of neuromuscular blocking agents can be altered by hypothermia and acid-base and electrolyte disturbances, conditions commonly seen in critically ill patients. Neuromuscular blockers (NMBs) can be given by intermittent intravenous (IV) bolus or a constant rate infusion (CRI). Intermittent bolus administration may offer some advantages, including controlling tachyphylaxis, monitoring for accumulation, analgesia, amnesia, and limiting complications related to prolonged or excessive blockade.1 There must be constant supervision when animals are receiving NMBs, because they are incapable of spontaneous respiration; should a malfunction of the mechanical breathing circuit occur, it would lead to death of the animal.
The neuromuscular junction is made up of the motor nerve terminus, neurotransmitter acetylcholine, and the postsynaptic muscle end plate.1 The impulse of an action potential causes the release of acetylcholine from the synaptic vesicles, which diffuses across the gap to the postsynaptic end plate.1 The motor end plate contains the specialized ligand-gated nicotinic acetylcholine receptors.1 The receptors convert the chemical signal into electrical signals, which leads to depolarization in the postsynaptic membrane of striated muscle.1
The two main classes of neuromuscular blocking agents are depolarizing and nondepolarizing. The depolarizing agent, succinylcholine, physically resembles acetylcholine and thus binds and activates the acetylcholine receptors.1 There is initial muscle fasciculation followed by muscle relaxation.3 Succinylcholine is metabolized by plasma cholinesterase, pseudocholinesterase.3 In patients with azotemia, renal failure, severe liver dysfunction, or chronic debilitating disease, the decrease in plasma cholinesterase may lead to a prolonged blockade.3 Succinylcholine is contraindicated with penetrating eye injuries, because it causes transient periocular muscle fasciculations that may increase intraocular pressure.3 It should also be avoided in patients with myopathy, malignant hyperthermia, or in whom transient increases in abdominal or thoracic pressure are undesirable.3
The muscle fasciculations caused by succinylcholine are painful and can produce actual muscle injury with increased serum creatine kinase levels.2 The drug can also affect heart rate and blood pressure, with the usual response being an increase in both, although in the cat there is an initial decrease in blood pressure followed by a slow rise. This can be prevented by prior administration of atropine.2 Succinylcholine will increase serum potassium by 0.5 to 1 mEq/L because of its depolarizing effects, and this may result in unsafe levels in trauma patients.3 For these reasons succinylcholine is not recommended for use in the critically ill patient.
Vecuronium is intermediate acting and a relatively noncumulative agent. It has minimal cardiovascular effects with a paralysis duration of approximately 25 minutes at a dosage of 0.05 to 0.1 mg/kg IV, with an onset time of 4 to 8 minutes.2-4 Vecuronium can be repeated at 0.005 to 0.033 mg/kg IV or, if needed, can be given as a CRI of 1 to 1.7 μg/kg/min.3,4 It undergoes renal elimination and bile excretion, so a prolonged effect may occur in patients with renal and hepatic compromise.1 In the human literature vecuronium has been associated with prolonged blockade and when used with glucocorticoids may result in an increased risk of prolonged weakness when the vecuronium is discontinued.1 In cats, metronidazole can potentiate the effects of vecuronium.1
Pancuronium has an onset of blockade in 2 to 3 minutes with a duration of 90 to 140 minutes.1,3 It is dosed at 0.06 mg/kg IV and repeated at 0.03 mg/kg IV.4 It does accumulate, and repeat dosing should be done cautiously.3 Pancuronium is vagolytic and should be used with caution in patients that cannot tolerate an increase in heart rate, because it may lead to hypertension and tachycardia.1,3 Pancuronium undergoes hepatic and renal metabolism and excretion, and this may make it less desirable for compromised patients.2
Rocuronium is 5 to 10 times more potent than vecuronium, with the shortest onset time and an intermediate duration.5 A dosage of 0.4 mg/kg IV has been used in dogs anesthetized with halothane, which resulted in an onset of blockade in 98 ± 52 seconds and a duration of 32.3 ± 8.2 minutes.5 Incremental doses of 0.16 mg/kg were used to prolong the blockade, and up to 7 increments were given that were noncumulative. The incremental doses produced a blockade of 20.8 ± 4.9 minutes in duration.5 Rocuronium can be given as a CRI. Rocuronium is metabolized and excreted in a way similar to that of vecuronium, and the metabolite has only 5% to 10% of activity compared with the parent compound.1,5
The benzyl isoquinolinium compounds include atracurium, cis-atracurium, doxacurium, and mivacurium. Atracurium is intermediate acting, with minimal cardiovascular effects.1 Atracurium is unusual in its degradation process in that it is independent of enzymatic function, it is inactivated in the plasma by ester hydrolysis and Hofmann elimination, and spontaneous degradation occurs at body temperature and pH.1,3,6 Atracurium is indicated for use in neonates and patients with significant hepatic or renal impairment.3
Atracurium blockade occurs within 3 to 5 minutes and has a duration of 20 to 30 minutes.3 Atracurium can be readministered at 0.1 mg/kg IV or given as a CRI of 3 to 8 μg/kg/min IV.4 Recovery of normal neuromuscular activity usually occurs within 1 to 2 hours after discontinuing a CRI and is independent of organ function.1 Long-term CRIs have been associated with tolerance, requiring dosage increases or switching to another NMB.1 Atracurium can be used as part of an anesthetic induction technique. It may be considered when it is desirable to avoid increases in intraocular, intracranial, or intraabdominal pressure caused by coughing or a Valsalva maneuver.3 It may also be used to provide faster control of ventilation in an unstable animal.3
There are two induction techniques. In one method, atracurium is given initially in divided doses of one tenth to one sixth of the calculated dose, and then 3 to 6 minutes later the rest of the calculated dose is given along with the induction agent.3 This will accelerate relaxation after induction. The second technique is to give a single bolus of atracurium and 3 minutes later, at the onset of muscle weakness, give the induction agent.3
Side effects that may occur with atracurium include laudanosine formation and histamine release. Laudanosine is a breakdown product of Hofmann elimination that has been associated with CNS excitement.1 This may be a concern in patients that have received extremely high doses or who have hepatic failure, because laudanosine undergoes liver metabolism.1 At clinically useful doses, 0.1 to 0.3 mg/kg IV, the potential for histamine release does not appear to be a problem.7
Long-term use of atracurium and other NMBs has been associated with persistent neuromuscular weakness.1 The potential for increasing the duration of the blockade may depend on what agents are used for sedation and anesthesia. Inhalant agents will increase the duration of the blockade in a dose-dependent manner.7 There are some differences in this effect; isoflurane, desflurane, and enflurane have more potentiation than halothane, which in turn potentiates to a greater extent than nitrous oxide, barbiturates, opioids, or propofol.7 A study in dogs with an NMB produced by atracuronium and anesthetized with either sevoflurane or propofol CRI demonstrated that the neuromuscular blockade was prolonged by approximately 15 minutes when using sevoflurane compared with propofol.7
cis-Atracurium is an isomer of atracurium. It has a similar duration, elimination profile, and production of laudanosine.1 It produces few if any cardiovascular effects, has a lesser tendency to produce histamine release, and is more potent than atracurium.1,6 As with atracurium, prolonged weakness may occur following long-duration use of cis-atracurium.1 The dosage is 0.1 mg/kg, with incremental doses of 0.02 to 0.04 mg/kg IV in the dog, used to maintain the blockade.6 The initial dose had a duration of 27.2 ± 9.3 minutes, the incremental doses appeared to be noncumulative, and no side effects were noted.6 The kidney and liver excrete the metabolites of laudanosine, but the hepatic excretion is less important in the dog.6 Laudanosine could cause hypotension and seizures, but this may be more likely in dogs with kidney or liver disease.6 The higher potency of cis-atracurium means a lower dose is required, which results in lower metabolites levels.6
Mivacurium has been used in dogs. It consists of three isomers, cis-trans, trans-trans, and cis-cis.8 The pharmacologically active isomers are cis-trans and trans-trans.8 Mivacurium is metabolized by plasma cholinesterase and has the potential to cause histamine release.9 In the dog anesthetized with thiopental and halothane, a dosage of 0.05 mg/kg IV had a significantly longer duration of action (180 minutes) than it did in humans, 24 minutes.8 In a second study of dogs anesthetized with thiopental and halothane, comparing varying doses of mivacurium, 0.01, 0.02, and 0.05 IV, the onset of action and duration of effect were dose related.9 Onset was 3.92 ± 1.70, 2.42 ± 0.53, and 1.63 ± 0.25 minutes, respectively, with the higher dose having the quicker onset.9 The duration was also dose related, being 33.72 ± 12.73, 65.38 ± 12.82, and 151 ± 38.50 minutes, respectively, with the higher dose having the longest duration.9 There was good hemodynamic stability in all dogs at all doses tested.9 Mivacurium may be useful when long-term blockade is desirable.
Doxacurium has also been used in dogs. It had an extremely slow onset of action with a long duration of blockade in dogs anesthetized with isoflurane.10 It is the most potent NMB available, with a potency 2 to 3 times that of pancuronium.10 In dogs and cats it is not metabolized and is excreted unchanged in the urine and bile.10 An animal with impaired renal function may have a more prolonged duration of blockade.10 A dosage of 3.5 to 4.5 μg/kg IV had on onset time of 35 to 53 minutes, a duration of 81 to 158 minutes, and a recovery time of 29 to 51 minutes.10 The long duration of action may be of benefit when considering the use of NMB for long-term mechanical ventilator use.