Historic Perspective

One of the first documented uses of a neuromuscular blocking agent (NMBA) to aid in surgical closure of the abdomen occurred in 1912 in Germany.¹ In the 1940s, the use of NMBAs during surgery started to become commonplace. Since the 1940s, the safety profile of NMBAs has significantly improved, and their use in the operating room (OR) has become routine. The introduction of mechanical ventilation in the intensive care unit (ICU) was closely followed by the use of NMBAs in the ICU. Most of our clinical experience with the use of NMBAs comes from the care of relatively healthy patients for a finite period of time in the OR. In contrast to patients in the OR, patients in the ICU are typically critically ill with multiple organ systems failing, require prolonged neuromuscular paralysis, and are receiving a large number of concomitant medications. Clinical studies have only recently started to examine indications for and complications of NMBAs in the ICU.

Current Epidemiology

Retrospective surveys reported by intensivists in 1991 and 1992 revealed that 10 patients per ICU per month required prolonged neuromuscular blockade.² However, a study by Murray et al.³ in 1993 showed the probability of receiving a NMBA ranged from 0% in the neurosurgical ICU to 14% in the neonatal ICU. Several different situations have been identified that require short- or long-term neuromuscular paralysis.

Indications

Despite adequate sedation, some patients will not be able to tolerate mechanical ventilation, which can lead to unsafe peak inspiratory airway pressures. In a retrospective survey, Klessing⁴ reported that 89% of the cases requiring the use of NMBAs were related to the facilitation of mechanical ventilation, making it the most common reason for the use of neuromuscular paralysis. Other indications for NMBA use are the facilitation of endotracheal intubation, control of increased intracranial pressure (ICP), decrease of high muscle tone in certain medical conditions, and facilitation of needed medical procedures or diagnostic studies⁵ (Table 1). Short-acting NMBAs such as succinylcholine can be used to quickly secure an unprotected airway. However, many critically ill patients can have an airway secured by endotracheal intubation without the use of NMBAs. In patients with increased ICP, agitation or coughing caused by tracheobronchial suctioning can cause dangerous increases in ICP. Werba et al.⁶ demonstrated that pretreatment with vecuronium attenuated transient increases in ICP during suctioning.

Table 1 Indications for Use of Neuromuscular Blocking Agents in Intensive Care Unit

Mode of Action

In general, NMBAs function by competing with acetylcholine (ACh) at the nicotinic cholinergic receptor (nAChR) at the neuromuscular motor end plate (Figure 1). NMBAs are classified as either depolarizing or nondepolarizing agents. The nondepolarizing agents are further divided into short, intermediate, and long acting, and classified according to their chemical structure as aminosteroidal or benzyl-isoquinoline compounds.⁹ The ideal muscle relaxant would have rapid onset, with predictable and controllable duration of action, and lack adverse effects on hemodynamics or significant toxicity. Its elimination should be independent of liver and renal function without accumulation over time. The ideal paralytic agent would have no interactions with other medications, as well as being cost effective with a long shelf life.

Figure 1 Neuromuscular end plate. Nerve impulse travels down the nerve (A) to the axon terminal (B), which triggers the release of ACh into the synaptic cleft (C). The ACh molecules traverse the synaptic cleft and bind the nicotinic ACh receptors (nAChRs), which result in a muscle contraction. When succinylcholine binds to the nAChRs (D) a muscle contraction results; however, succinylcholine does not readily dissociate from the receptor as ACh does. As a result, the receptors are unable to repolarize, preventing further muscle contractions. In contrast to succinylcholine, the binding of nondepolarizing muscle relaxants such as rocuronium (E) to the receptor does not cause a muscle contraction and blocks the binding of ACh to the receptors, preventing a muscle contraction. ACh, Acetylcholine.

Monitoring of Neuromuscular Blockade

The primary use of NMBAs in the ICU is to facilitate mechanical ventilation.⁴ The degree of neuromuscular blockade required to reach this clinical goal will vary from patient to patient. The first set of guidelines detailing the use of NMBAs in the ICU was published in 1995 and later reevaluated in 2002. The current guidelines state that any patient receiving a NMBA should be assessed both clinically and by train-of-four (TOF) monitoring, with the clinical goal of NMBA titration to one or two twitches.¹¹ Daily clinical assessment involves the observation of skeletal muscle movement and respiratory effort by the patient. Peripheral nerve stimulation by four equal electrical charges delivered at 0.5-second intervals can be evaluated with visual, tactile, or mechanical means (Figure 2). The TOF count is the observed number of twitches out of four. A TOF count of one out of four signifies that 90%–95% of the nAChRs are occupied. A TOF count of three out of four signifies that 75%–80% of the nAChRs are occupied. At 50% occupancy of the nAChRs, the patient can be safely extubated.¹² This translates clinically to a sustained head lift for 10 seconds or to a train of four of four plus sustained tetanus to a 5-second stimulation with 100 Hz. Complete resolution of neuromuscular blockade is important not only to ensure adequate respiratory muscle power to sustain the work of breathing without ventilator support, but even more for the patient to protect the airway by unimpaired activity the bulbar muscles. Ulnar nerve innervation of the adductor pollicis muscle of the thumb is the most frequently used site to monitor TOF. The electrical stimulus should flow through the nerve, reach the neuromuscular junction, and release ACh, leading to a muscle contraction. If the electrodes are too close to the muscle tested, the current may directly cause a false-positive contraction. Hence any nerve/muscle pair that is at a certain distance apart can be used, such as the facialis/orbicularis oculi or the peroneus nerve/tibialis anterior. The monitoring of the degree of neuromuscular blockade may allow for the lowest NMBA dose and may minimize the adverse effects of prolonged NMBA use.¹¹

Figure 2 Patient’s hand with electrodes of nerve stimulator attached on volar side of forearm over the ulnar nerve. After stimulation of the ulnar nerve, the gloved hand of the medical practitioner senses the adduction of the thumb to the index. This is the response of interest to monitor the neuromuscular junction. Caution: the flexors of the hand often contract in response to direct stimulation of the muscles, even in the presence of neuromuscular blockers.