Atracurium

Article Author:
Matthew Ritz
Article Editor:
Armen Derian
Updated:
10/27/2018 12:31:24 PM
PubMed Link:
Atracurium

Indications

Atracurium is indicated as an addition to general anesthesia to facilitate endotracheal intubation and provide skeletal muscle relaxation during surgery or mechanical ventilation. While muscle relaxation is typically reserved to facilitate endotracheal intubation, there have been studies that have shown the efficacy of atracurium to facilitate the placement of a laryngeal mask airway. The study in question showed that when compared to laryngeal mask airway (LMA) placement with only propofol, administration of atracurium led to greater jaw relaxation and faster insertion.

Mechanism of Action

Atracurium is a nondepolarizing neuromuscular blocking drug of the benzylisoquinolinium class. It is a competitive antagonist of the alpha subunit of the postsynaptic nicotinic receptor at the neuromuscular junction. It competes with acetylcholine for binding sites. Binding of the postsynaptic nicotinic receptor by atracurium prevents depolarization of the motor end plate and subsequent skeletal muscle contraction. Unlike binding of depolarizing agents, binding of atracurium or other non-depolarizing agents does not induce a receptor conformational change.

Administration

Route of Administration

Intravenous, should not be administered intramuscularly due to excessive tissue irritation. Atracurium can be given via bolus or infusion. Studies have demonstrated that due to its relatively predicable and organ independent metabolism that it continuous infusions are a viable option to achieve a steady state of neuromuscular blockade.

ED95 and Intubating dose

0.23 mg/kg and 0.5 mg/kg for adults and children older than 2 years of age, 0.3-0.4 mg/kg for children less than 2 years of age. In morbidly obese patients, an atracurium dose should be administered based on ideal body weight.

Onset of Action

Atracurium has an onset of action of approximately 2 minutes when an intubating dose is given.

Duration of Action

Classified as an intermediate-acting nondepolarizing muscle relaxant with duration of action of approximately 40 to 45 minutes.  The Elimination half-life is approximately 20 minutes. In elderly patients, the half-life may increase by approximately 15% due primarily to decreased clearance.

Distribution

160 ml/kg

Protein Binding

Metabolism

Nonenzymatic degradation (Hofmann elimination) accounts for 45% of the metabolism of atracurium. Hoffman elimination is a temperature and pH-dependent process and is slowed by acidosis and hypothermia. The remainder is metabolized via ester hydrolysis by non-specific esterases in the plasma that are unrelated to pseudocholinesterase. A drop in pH enhances the rate of ester hydrolysis. Neuromuscular blocking agents of the Benzylisoquinolinium class are preferred in critically ill patients, as their metabolism is not affected by renal or hepatic dysfunction. A primary metabolite of Hofmann elimination of atracurium is laudanosine which does not have any neuromuscular blocking activity, but it is a central nervous system (CNS) stimulant. Studies have shown that long-term infusions of atracurium in critically ill patients can cause an elevation in laudanosine levels.

Excretion

Less than 5% of atracurium is excreted in the urine. Laudanosine is hepatically and renally eliminated and has a significantly longer elimination half-life than atracurium (197 minutes). Therefore it can potentially accumulate with prolonged atracurium infusion. Animal studies have shown that laudanosine crosses the blood-brain barrier and is detectable in the cerebral spinal fluid. In anesthetized dogs, laudanosine concentrations of greater than 6 micro g/ml caused hypotension and bradycardia, plasma concentrations greater than 10 mg/ml induced epileptic EEG spiking, and plasma concentrations greater than 17 mg/ml produced sustained seizure activity. Interestingly in cats, a similar study was performed, and there was no seizure activity at laudanosine concentrations greater than 100 mg/ml. Given this interspecies discrepancy, it is not meaningful to draw any conclusions regarding laudanosine concentrations in humans. No study has been performed that has documented seizure activity due to laudanosine in humans, but given the animal studies that have been performed, it does remain a concern. Several studies have measured laudanosine levels in critically ill patients on prolonged atracurium infusions. Of the listed studies, infusions were running as long as 71 days with documented levels as high as 8.65 mg/ml. There was no documented seizure activity or epileptiform activity on EEG.

Adverse Effects

The majority of adverse reactions associated with atracurium administration are related to histamine release. The most common side effects associated with histamine release related to atracurium administration are flushing and erythema. Less commonly, more severe adverse effects can occur and include bradycardia, bronchospasm, dyspnea, hypotension, laryngospasm, tachycardia, urticaria, and wheezing. Studies have previously demonstrated that a mean arterial pressure fall of 30 mm Hg can be seen within 2 minutes of administration. Histamine receptor type-1 and histamine-receptor, type-2 blocking agents have been used effectively to attenuate this hypotensive response. Slower injection speed, from 30 to 60 seconds, has also been shown to reduce histamine release and the associated adverse effects.

Contraindications

The primary contraindication to administration is hypersensitivity to atracurium besylate or any component of the formulation. Multiple-dose vials contain benzyl alcohol as a preservative; hypersensitivity to benzyl alcohol is a contraindication to administration. Documented cross-reactivity to neuromuscular blockade drugs is limited, but atracurium should be used with extreme caution in patients with previous anaphylactic reactions to other neuromuscular blocking agents.

Monitoring

There are a number of methods to monitor neuromuscular blockade following administration of atracurium. Clinical signs are often used to attempt to determine the depth of neuromuscular blockade, as well as a reversal. These could include eye-opening, sustained handgrip, leg lift, or sustained head lift for greater than 5 seconds. Unfortunately, these are not accurate determinants of the presence or absence of residual neuromuscular blockade.  Nerve stimulation is a method frequently used for monitoring neuromuscular blockade intraoperatively.  ECG electrodes are applied at either the ulnar, facial, or tibial nerve. Then a train of four stimulation is applied. Four stimuli are applied at the chosen nerve at a frequency of 2 Hz provoking a twitch response.  When atracurium or another nondepolarizing neuromuscular blocking agent is given, there is a reduction in the amplitude of the evoked responses, T (the final twitch of the train of 4 sequences) is affected first, then T, followed T, then T. This sequential decrease is twitch height is known as fade. As the intensity of the neuromuscular blockade increases, the twitches began to disappear in the same sequence as fade occurs, with T disappearing first. As neuromuscular blockade is reversed, the reverse order is true, with T being the first to reappear. The ratio of twitch intensity when comparing T to T is an important value, a ratio of 0.9 is indicative of sufficient neuromuscular blockade reversal.