Use of neuromuscular blocking medications in critically ill patients

Feb 28, 2000

Neuromuscular blocking agents (NMBAs) paralyze skeletal muscles by blocking the transmission of nerve impulses at the myoneural junction. NMBAs have no sedative, amnestic, or analgesic properties and do not prevent muscles from contracting if directly stimulated. These drugs are useful in the intensive care unit (ICU) to improve patient-ventilator synchrony in order to enhance gas exchange and to diminish the risk of barotrauma. They can also be employed to reduce muscle oxygen consumption, facilitate short procedures, prevent unwanted movements in patients with increased intracranial pressure, and facilitate treatment of acute neurologic conditions such as tetanus (show table 1) [1,2,3,4].

This card will discuss the mechanism of action, clinical use, and potential adverse effects of NMBAs. Adequate sedation and analgesia are essential prior to initiating therapy with NMBAs, and are discussed separately. (See "Use of sedative medications in critically ill patients" and see "Pain control in the intensive care unit").

PHYSIOLOGY OF NEUROMUSCULAR TRANSMISSION AND BLOCKADE — The neuromuscular junction consists of the nerve terminal, the synaptic cleft, and the motor endplate. Acetylcholine (ACh), which is released into the synaptic cleft when nerve impulses reach the nerve terminal, diffuses across the synaptic cleft to the motor endplate. Attachment of ACh to the nicotinic (not muscarinic) receptors on skeletal muscle causes a conformational change in the receptor which increases myocyte cell membrane permeability to sodium, potassium, chloride, and calcium ions and releases calcium from the sarcoplasmic reticulum, leading to transmission of an action potential [5,6]. Depolarization terminates when ACh unbinds from the receptor. ACh either diffuses back into the nerve terminal or is broken down by acetylcholinesterase.

NMBAs are structurally related to ACh and act by interfering with the binding of ACh to the motor endplate. They are divided into depolarizing or nondepolarizing agents based upon their mechanism of action [2,6,7,8,9].

  •  Depolarizing NMBAs bind to cholinergic receptors on the motor endplate, causing initial depolarization on the endplate membrane followed by blockade of neuromuscular transmission. Because calcium is not resequestered in the sarcoplasmic reticulum, muscles are refractory to repeat depolarization until depolarizing NMBAs diffuse from the receptor to the circulation and are hydrolyzed by plasma pseudocholinesterase [5].

  •  Nondepolarizing NMBAs competitively inhibit the ACh receptor on the motor endplate. Drug binding to the ACh receptor either prevents the conformational change in the receptor or physically obstructs the ion channels so that an endplate potential is not generated [5].

The ideal NMBA for use in intensive care produces an early, titratable paralysis, has a moderately rapid offset of action (less than 15 minutes) to allow for repeated neurologic assessment, no adverse hemodynamic or other adverse physiologic effects, elimination independent of hepatic or renal function, inactive metabolites, no propensity to accumulate, stability over 24 hours to allow for continuous infusion, and modest cost [1,10].

DEPOLARIZING NEUROMUSCULAR BLOCKING AGENTS — Succinylcholine is the only depolarizing agent in clinical use in the United States and is utilized almost exclusively to facilitate intubation or treat laryngospasm [1,7]. Although succinylcholine has a rapid onset (less than 1 minute) and brief duration of action (7 to 8 minutes), its use is limited because its actions cannot be reversed by the administration of other medications [11]. Approximately 1 in 3200 patients is homozygous for a defective pseudocholinesterase and may remain paralyzed for 3 to 8 hours after a single dose [12].

Significant adverse effects include hypertension, tachycardia, bradycardia, ventricular arrhythmias, hyperkalemia, and, less commonly, increased intracranial pressure or malignant hyperthermia. Malignant hyperthermia is a rare complication, occurring in patients with mutations in the ryanodine receptor; the onset of hyperthermia is usually within the first hour after administration but may be delayed. (See "Severe hyperthermia: Heat stroke; neuroleptic malignant syndrome; and malignant hyperthermia"). Serum potassium concentrations increase by 0.5 to 1.0 meq/L due to an efflux of potassium from muscle cells, so the drug must be used cautiously in patients with preexisting hyperkalemia [13]. (See "Causes of hyperkalemia").

NONDEPOLARIZING NEUROMUSCULAR BLOCKING AGENTS — A number of nondepolarizing neuromuscular blocking agents are available; onset of action, half-life, and route of elimination are variable and drug-specific (show table 2). The onset of action of these drugs ranges from 1 to 5 minutes, but all are slower than succinylcholine. The half-life ranges from 5 minutes for mivacurium to 300 minutes for metocurine. Older agents such as tubocurarine are more commonly associated with cardiovascular side effects and hypotension due to histamine release than newer nondepolarizing NMBAs such as cisatracurium, doxacurium, pipecuronium, rocuronium, and vecuronium (show table 3) [6,7,8,11,14].

Although nondepolarizing NMBAs are structurally divided into the aminosteroid compounds (pancuronium, pipecuronium, rocuronium, vecuronium) and the benzylisoquinolines (atracurium, cisatracurium, doxacurium, metocurine, mivacurium, tubocurarine), this classification has little clinical significance. The major nondepolarizing NMBAs are listed below:

Atracurium — Atracurium, a mixture of ten stereoisomers, is a benzylisoquinoline with an intermediate duration of action. Atracurium is degraded by both pH- and temperature-dependent Hofmann elimination (autolysis) and by ester hydrolysis; it therefore does not require a dosage adjustment in patients with renal or hepatic failure [11,15]. However, acidosis and severe hypothermia decrease the rate of drug metabolism and should prompt dose reduction. Specific dosing recommendations are not available, and the dose should be titrated according to neurologic response.

The major side effect associated with atracurium is hypotension caused by histamine release and sympathetic ganglionic blockade. In addition, laudanosine, an inactive Hofmann elimination metabolite, causes seizures in dogs at very high doses but is unlikely to be of clinical significance in humans [5,16]. As an example, after an infusion of atracurium at a rate of 0.3 to 0.96 mg/kg per hour for 38 days in a 23 year-old woman with multiple medical problems, no EEG abnormalities were apparent, and the plasma laudanosine level was only 37 percent of concentrations associated with epileptic EEG spiking in dogs [17].

Cisatracurium — Cisatracurium is an isomer of atracurium with three times its potency. Like atracurium, cisatracurium is degraded by pH- and temperature-dependent Hoffmann elimination to laudanosine, and acidosis and severe hypothermia delay its metabolism. However, the greater potency of cisatracurium allows the administration of smaller doses, which results in less laudanosine production, less histamine release, and fewer adverse cardiovascular side effects [9]. Its usefulness in the intensive care unit (ICU) is limited somewhat by its relatively slow onset of action (3 to 6 minutes).

Doxacurium — Doxacurium is a long-acting benzylisoquinoline and is the most potent NMBA available. It is eliminated by the kidney and is associated with few adverse cardiovascular side effects. However, clinical experience with this agent is limited [9,18,19].

Metocurine — Metocurine is another long-acting benzylisoquinoline which is an analog of tubocurarine and is eliminated primarily by the kidney. Metocurine is not commonly used in the ICU because of its propensity to cause hypotension (due to histamine release and sympathetic ganglionic blockade) and because of its near complete dependence upon adequate renal function for elimination.

Mivacurium — Mivacurium is a short-acting benzylisoquinoline with an onset of action comparable to atracurium but with one-third its duration of action because of rapid hydrolysis by plasma pseudocholinesterase. However, patients with renal or hepatic insufficiency may have depressed pseudocholinesterase activity leading to delayed elimination [20,21].

Mivacurium is associated with few adverse cardiovascular side effects following small (0.15 mg/kg) doses, but hypotension, caused by histamine release, may occur following larger bolus injections [22]. Although little information is available about the use of mivacurium in the ICU, it is unlikely to have any advantage over atracurium.

Pancuronium — Pancuronium is a long-acting aminosteroid which is metabolized to the active compound 3-hydroxypancuronium in the liver and then eliminated equally in the urine and bile [5,23]. Adverse cardiovascular effects associated with pancuronium include tachycardia, hypertension, and increased cardiac output due to vagal blockade.

Pipecuronium — Pipecuronium is an aminosteroid with a longer duration of action than pancuronium, and is primarily eliminated unchanged by the kidney. It does not cause histamine release and is associated with minimal adverse cardiovascular side effects [9,24].

Rocuronium — Rocuronium, the newest aminosteroid, is similar to but less potent than vecuronium. It has a rapid onset and short-to-intermediate duration of action [8]. The drug is eliminated primarily by the liver and is associated with few adverse cardiovascular side effects.

Tubocurarine — Tubocurarine is a long-acting benzylisoquinoline which is eliminated by both renal excretion and hepatic metabolism. It causes dose- and rate-dependent histamine release and is associated with profound drops in blood pressure following rapid infusions of large doses [7,25]. Histamine-associated hypotension can be minimized by slow injection, incremental dose increases, and coadministration of histamine-1 and histamine-2 receptor blockers [25,26].

Vecuronium — Vecuronium is an aminosteroid compound with an intermediate duration of action. It is hepatically metabolized to three active metabolites, all of which are eliminated by the kidney [5,27,28]. Minimal adverse cardiovascular side effects have been reported [6].

CLINICAL USE OF NEUROMUSCULAR BLOCKING AGENTS — The ICU staff must be trained in the administration and monitoring of NMBAs. Appropriate airway control, mechanical ventilatory support, and adequate sedation and analgesia are essential prior to the initiation of NMBA therapy. Appropriate equipment for monitoring cardiorespiratory function and the capability of assessing the degree of paralysis must be available [1,3,29].

The selection of an appropriate NMBA agent is based upon the individual characteristics of each patient. We recommend the following agents for given clinical situations:

  •  Normal hepatic and renal function — Pancuronium is the drug of choice for patients with normal hepatic and renal function who require paralysis for more than one hour [1,14].

  •  Hepatic and/or renal insufficiency — Atracurium is preferred in patients with hepatic and/or renal insufficiency because the drug is least dependent upon hepatic and renal elimination [1,11].

  •  Cardiovascular disease — Vecuronium has the least adverse cardiovascular effects and is the drug of choice for patients with cardiovascular disease or hemodynamic instability [11,14]. Doxacurium, pipecuronium, and rocuronium are acceptable alternatives [11].

  •  Elderly patients — Drug selection is dictated by age-associated decreases in renal and hepatic function. Decreased cardiac output prolongs drug delivery and slows the onset of action of NMBAs [11].

The degree of NMBA activity can be affected by a number of drugs or medical conditions, and dosing adjustments may be necessary (show table 4 and show table 5) [6,8,14,30]. Drugs or conditions that inhibit presynaptic ACh release or depress postjunctional sensitivity enhance the degree and duration of neuromuscular blockade [5,7]. On the other hand, phenytoin and carbamazepine significantly increase the requirement for nondepolarizing NMBAs by an unknown mechanism.

Initiation — NMBAs are administered by continuous infusion or intermittent intravenous injection (show table 6) [4,8,9,30]. Due to erratic absorption and the necessity for repeat injections, intramuscular administration is not recommended [30]. Regularly scheduled doses maintain paralysis most effectively; long-acting NMBAs are best administered by intermittent injection, while shorter-acting NMBAs should be given as a continuous intravenous infusion [30].

Maintenance — Complete (100 percent) neuromuscular blockade is not necessary for all patients [8]. As an example, patients with respiratory failure require only a 50 to 70 percent neuromuscular blockade [31]. The intended level of paralysis depends on the clinical situation. When NMBAs are administered, it is more appropriate to think in terms of controlling rather than paralyzing the patient. Some patients can be maintained light enough (eg, 50 percent blockade) that the patient is cognizant of the environment, whereas other patients require nearly complete (eg, 80 to 90 percent) blockade [31].

Sensitivity to NMBAs varies and the metabolism of NMBAs cannot always be predicted in the critically ill. Therefore, we recommend monitoring the degree of neuromuscular blockade with peripheral nerve stimulation (PNS) using train-of-four or tetanic stimulation [4]. Train-of-four is the more commonly used method and involves electrical stimulation of a peripheral motor nerve with four sequential stimuli over a two second period and observation of the responses of a muscle innervated by the stimulated nerve. Patients treated with NMBAs have progressive reduction in the magnitude of response to the four stimuli. Although the train-of-four goal depends on the intended degree of paralysis, the NMBA dose is generally titrated such that only two visible muscle twitches occur in response to each train-of-four. Because electrical stimulation can directly trigger myocyte contraction even in the presence of profound ACh receptor blockade, nerve stimulation should be performed several centimeters from the indicator muscle. The ulnar nerve is commonly stimulated at the wrist, and response of the adductor pollicis is observed (show figure).

The depth of blockade should be assessed with PNS every 2 to 3 hours until the NMBA dose is stable, then every 8 to 12 hours [32]. If no or one twitch is present, the dose should be reduced by 10 percent; if three or four twitches are present, the dose should be increased by 10 percent.

The use of PNS monitoring in this setting is widely accepted, but data supporting its use are limited [33,34]. Few prospective, controlled, randomized studies assessing the utility of PNS have been published, and conflicting results have been reported. One study randomized 77 patients in a medical ICU to treatment with vecuronium guided either by clinical assessment or PNS [35]. The PNS group used significantly less drug and recovered neuromuscular function and spontaneous ventilation approximately 55 percent faster than the control group; patients with renal insufficiency appeared to derive the most benefit for PNS-guided therapy. However, a second trial of 36 patients receiving atracurium found no difference in the total drug administered and time to clinical recovery whether train-of-four or clinical assessment was used to guide therapy [36].

Patients receiving NMBAs require meticulous care because the potential for complications is great [10]. All paralyzed patients require the following precautions:

  •  They cannot be left unsupervised because interruption of the ventilator circuit can be fatal
  •  Since all NMBAs inhibit the cough reflex, suctioning of the endotracheal tube to remove accumulated secretions should be performed as needed based on the amount of secretions present
  •  Artificial tears should be instilled every two to four hours and eyelids should be taped shut to prevent corneal drying and ulceration
  •  Patients require frequent turning and dry, wrinkle-free bedding in order to prevent skin breakdown and decubitus ulcers
  •  Prophylactic deep venous thrombosis therapy with either low dose subcutaneous heparin or mechanical compression devices is required
  • The head of the bed should be elevated to reduce the risk of aspiration, particularly during enteral feeding
  •  Pupillary reflexes should be closely monitored to assess neurologic status (but are unreliable if pancuronium is used because of its antimuscarinic effects)

Discontinuation — Tapering the dose in not necessary when neuromuscular blockade is discontinued. Sedation and analgesia adequate for patient comfort must be maintained as the NMBA is discontinued.

The action of nondepolarizing NMBAs can be reversed by administration of an anticholinesterase drug such as neostigmine, 0.035-0.07 mg/kg [7]. Acetylcholine-related side effects such as salivation, bradycardia, and cardiac standstill are prevented by coadministration of atropine (15 µg/kg) or glycopyrrolate (7 µg/kg) [4].

ADVERSE EFFECTS — Anaphylaxis to NMBAs is extremely rare, and the drugs have no known effects outside of muscles and autonomic ganglia. Nevertheless, NMBAs have the potential for severe adverse effects such as hypotension and prolonged paralysis.

Cardiovascular effects — Adverse cardiovascular side effects associated with NMBAs are related to stimulation or blockade of the autonomic nervous system and vasodilatation due to histamine release. The drugs with the lowest risk of cardiovascular complications are cisatracurium, doxacurium, pipecuronium, rocuronium, and vecuronium (show table 3).

Prolonged paralysis — Prolonged paralysis following drug discontinuation results from accumulation of drug and/or active metabolites, or an acute myopathy [37].

  •  NMBAs that are dependent upon renal clearance (eg, doxacurium, metocurine, pancuronium, pipecuronium, and tubocurarine) accumulate in patients with renal failure if not properly dose adjusted to PNS response [38]. As a result, neuromuscular blockade may continue for as long as one week after drug administration is stopped [27].

  •  NMBAs with active metabolites include pancuronium, vecuronium, and atracurium.

  •  Prolonged paralysis following drug discontinuation may result from an NMBA-associated syndrome of acute myopathy with selective loss of myosin filaments [39]. Most reported cases have occurred after combined treatment with corticosteroids and NMBAs, suggesting that myopathy is the result of an interaction between the two drugs [40,41,42,43,44]. However, acute myopathy also has been described after prolonged treatment with an NMBA or a corticosteroid alone [45,46,47,48,49]. (See "Neuromuscular disorders of critical illness").

The mechanism of muscle injury following combined use of neuromuscular blocking drugs and corticosteroids is uncertain. Experiments in rats suggest that denervation of skeletal muscle unleashes or greatly amplifies a previously unappreciated acute form of corticosteroid-induced myopathy. (See "Drug-induced myopathies", section on Corticosteroids). In these experiments, one soleus muscle is surgically denervated while the rat is treated with high-dose dexamethasone for seven days. The denervated soleus muscle develops marked muscle fiber atrophy with selective loss of myosin filaments. This injury is not observed in the control leg of the dexamethasone-treated rats or in the denervated muscle of control rats not treated with dexamethasone [50].

Additional rat experiments have demonstrated that denervation rapidly increases the number of corticosteroid receptors in the affected muscle, suggesting one mechanism for the apparent steroid-induced muscle injury [51]. A similar mechanism may cause muscle injury in humans who are pharmacologically denervated by a neuromuscular blocking drug while receiving high therapeutic doses of a corticosteroid. A common setting in which this occurs is mechanical ventilation for status asthmaticus.

The risk of this complication, which is the same for the aminosteroids and the benzylisoquinolines, is minimized by limiting the administration of NMBAs to 48 hours or less [14,38,44]. In addition, corticosteroids should not be administered for uncertain or unproven indications during administration of a NMBA [38]. There is no known method of prevention or direct treatment.