Atracurium

Mechanism of Action

Atracurium is a non-depolarizing 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. The binding of the postsynaptic nicotinic receptor by atracurium prevents depolarization of the motor endplate 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.[4]

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 continuous infusion is a viable option to achieve a steady state of neuromuscular blockade due to its relatively predictable and organ-independent metabolism.

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 to 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.[5]

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 non-depolarizing muscle relaxant with a 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.[6]

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 acts as 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).[7] 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 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 possible 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.[8][9]

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.[10][11][10]

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 non-depolarizing neuromuscular blocking agent is given, there is a reduction in the amplitude of the evoked responses, the final twitch of the train of 4 sequences (T4) is affected first, then the third (T3), followed by the second (T2), then the first (T1). This sequential decrease in twitch height is known as fade. Lack of response in 3 of 4 twitches indicates 90 to 95% blockade.

As the intensity of the neuromuscular blockade increases, the twitches began to disappear in the same sequence as fade occurs. As neuromuscular blockade is reversed, the reverse order is true, with T1 being the first to reappear. The ratio of twitch intensity when comparing T4 to T1 is an important value; a ratio of 0.9 indicates sufficient neuromuscular blockade reversal.[12]

Enhancing Healthcare Team Outcomes

Atracurium is a neuromuscular blocking agent widely used in anesthesia. While the agent is primarily used by anesthesiologists, nurses in the ICU need to know about its mode of action, duration, and adverse effects. The agent is known to cause histamine release, which may be responsible for a variety of side effects.