Clinical practice guidelines for sustained neuromuscular blockade in the adult critically ill patient

The decision to treat a patient in the intensive care unit (ICU) with neuromuscular blocking agents (NMBAs) (for reasons other than the placement of an endotracheal tube) is a difficult one that is guided more commonly by individual practitioner preference than by standards based on evidence-based medicine. Commonly cited reasons for the use of NMBAs in the ICU are to facilitate mechanical ventilation or different modes of mechanical ventilation and to manage patients with head trauma or tetanus. Independent of the reasons for using NMBAs, we emphasize that all other modalities to improve the clinical situation must be tried, using NMBAs only as a last resort. In 1995, the American College of Critical Care Medicine (ACCM) of the Society of Critical Care Medicine (SCCM) published guidelines for the use of NMBAs in the ICU. The present document is the result of an attempt to reevaluate the literature that has appeared since the last guidelines were published and, based on that review, to update the recommendations for the use of NMBAs in the ICU. Appendix A summarizes our recommendations. Using methods previously described to evaluate the literature and grade the evidence (1), the task force reviewed the physiology of the neuromuscular receptor, the pharmacology of the NMBAs currently used in the ICU, the means to monitor the degree of blockade, the complications associated with NMBAs, and the economic factors to consider when choosing a drug. NEUROMUSCULAR JUNCTION IN HEALTH AND DISEASE The neuromuscular junction consists of a motor nerve terminus, the neurotransmitter acetylcholine, and the postsynaptic muscle endplate (Fig. 1). The impulse of an action potential causes the release of acetylcholine from synaptic vesicles (each containing about 10,000 molecules of acetylcholine) diffusing across the 20-nm gap to the postsynaptic endplate. The motor endplate contains specialized ligand-gated, nicotinic acetylcholine receptors (nAChRs), which convert the chemical signal (i.e., binding of two acetylcholine molecules) into electrical signals (i.e., a transient permeability change and depolarization in the postsynaptic membrane of striated muscle).Figure 1: Neuromuscular Junction. Schematic model of the organization and structure of the neuromuscular junction, with focus and enlargement on the postsynaptic membrane. Agrin is the nerve-derived protein that triggers receptor clustering during synapse formation. Receptor aggregation appears to occur in distinct steps, however, initiated with acetylcholine receptors (AChR) localized together by rapsyn. Meanwhile, D-dystroglycan, the extracellular component of dystrophin-associated glycoprotein complex (DGC), is the agrin receptor which transduces final AChR clustering. This process utilizes the structural organization of additional proteins like utrophin, which stabilize the mature, immobile domains by interaction with the underlying cytoskeleton (actin). When completed, this process concentrates AChR density 1000-fold compared to typical muscle membrane. ACh = acetylcholine, MuSK = muscle-specific-receptor kirase, MASC = MuSK-accessory specificity component. (Reprinted with permission, from Wall MH, Prielipp RC. Monitoring the neuromuscular junction. In: Lake C, Blitt CD, Hines RL, eds. Clinical Monitoring: Practical Applications for Anesthesia and Critical Care. Philadelphia: W.B. Saunders, 2000, Figure 10-3.)There are depolarizing and nondepolarizing NMBAs. Depolarizing NMBAs physically resemble acetylcholine and, therefore, bind and activate acetylcholine receptors. Succinylcholine is currently the only available depolarizing NMBA and is not used for long-term use in ICUs. Nondepolarizing NMBAs also bind acetylcholine receptors but do not activate them—they are competitive antagonists. The difference in the mechanism of action also accounts for different effects in certain diseases. If there is a long-term decrease in acetylcholine release, the number of acetylcholine receptors within the muscle increases. This upregulation causes an increased response to depolarizing NMBAs but a resistance to nondepolarizing NMBAs (i.e., more receptors must be blocked). Conditions in which there are fewer acetylcholine receptors (e.g., myasthenia gravis) lead to an increase in sensitivity to nondepolarizing NMBAs. Adult skeletal muscle retains an ability to synthesize both the mature adult nAChR as well as an immature nAChR variant in which a gamma subunit is substituted for the normal epsilon subunit. Synthesis of immature (fetal) receptors may be triggered in the presence of certain diseases (e.g., Guillain-Barré syndrome, stroke) and other conditions producing loss of nerve function. These immature nAChRs are distinguished by three features. First, immature receptors are not localized to the muscle endplate but migrate across the entire membrane surface (2). Second, the immature receptors are metabolically short-lived (<24 hours) and more ionically active, having a 2- to 10-fold longer channel "open time." Lastly, these immature receptors are more sensitive to the depolarizing effects of such drugs as succinylcholine and more resistant to the effects of competitive antagonists, such as pancuronium. This increase in the number of immature acetylcholine receptors may account for the tachyphylaxis seen with NMBAs and some of the complications associated with their use. For the remainder of this document, only nondepolarizing NMBAs will be discussed. PHARMACOLOGY OF NEUROMUSCULAR-RECEPTOR BLOCKERS Aminosteroidal Compounds The aminosteroidal compounds include pancuronium, pipecuronium, vecuronium, and rocuronium (Tables 1 and 2)(3–11).Table 1: Selected neuromuscular blocking agentsa for ICU useTable 1A: (Continued)Table 2: ICU studies of aminosteroidal drugsaPancuronium. Pancuronium, one of the original NMBAs used in ICUs, is a long-acting, nondepolarizing compound that is effective after an intravenous bolus dose of 0.06–0.1 mg/kg for up to 90 minutes. Though it is commonly given as an i.v. bolus, it can be used as a continuous infusion (12) by adjusting the dose to the degree of neuromuscular blockade that is desired (Table 1). Pancuronium is vagolytic (more than 90% of ICU patients will have an increase in heart rate of ≥10 beats/min), which limits its use in patients who cannot tolerate an increase in heart rate (12). In patients with renal failure or cirrhosis, pancuronium's neuromuscular blocking effects are prolonged because of its increased elimination half-life and the decreased clearance of its 3-hydroxypancuronium metabolite that has one-third to one-half the activity of pancuronium. Pipecuronium. Pipecuronium is another long-acting NMBA with an elimination half-life of about two hours, similar to pancuronium's. Khuenl-Brady and colleagues (13) conducted an open-label evaluation of pipecuronium compared with pancuronium in 60 critically ill patients to determine the minimum doses required for ventilatory management. The administration of 8 mg of either drug followed by intermittent boluses of 4–6 mg when needed resulted in optimal paralysis. Patients were paralyzed for a mean duration of 62.6 hours (45–240 hours) and 61.5 hours (46–136 hours) with pancuronium and pipecuronium, respectively. No adverse effects were attributed to either drug. Perhaps because of this lack of difference and because there are no recent studies examining pipecuronium's use in the ICU, most clinicians continue to use the more familiar drug, pancuronium. Vecuronium. Vecuronium is an intermediate-acting NMBA that is a structural analogue of pancuronium and is not vagolytic. An i.v. bolus dose of vecuronium 0.08–0.1 mg/kg, produces blockade within 60–90 seconds that typically lasts 25–30 minutes. After an i.v. bolus dose, vecuronium is given as a 0.8–1.2-μg/kg/min continuous infusion, adjusting the rate to the degree of blockade desired. Because up to 35% of a dose is renally excreted, patients with renal failure will have decreased drug requirements. Similarly, because up to 50% of an injected dose is excreted in bile, patients with hepatic insufficiency will also have decreased drug requirements to maintain adequate blockade. The 3-desacetylvecuronium metabolite has 50% of the pharmacologic activity of the parent compound, so patients with organ dysfunction may have increased plasma concentrations of both the parent compound and the active metabolite, which contributes to the prolongation of blockade if the dose is not adjusted. Vecuronium has been reported to be more commonly associated with prolonged blockade once discontinued, compared with other NMBAs. a Members of the task force believe that vecuronium is being used with decreased frequency in the ICU. Vecuronium has been studied in open-label prospective trials (14, 15). In one of these studies, the mean infusion rate for vecuronium was 0.9 ± 0.1 μg/kg/min for a mean duration of 80 ± 7 hours. Recovery of a train-of-four (TOF) ratio of ≥0.7 was significantly longer than with cisatracurium (14, 15). Recovery time averaged 1–2 hours but ranged from ≤30 minutes to more than 48 hours. Although Rudis et al. (14) observed no difference in the incidence of prolonged blockade between patients receiving vecuronium with and without concomitant administration of corticosteroids, the opinion of the task force was that patients receiving vecuronium and corticosteroids were at increased risk of prolonged weakness once the drug was discontinued. Rocuronium. Rocuronium is a newer nondepolarizing NMBA with a monoquaternary steroidal chemistry that has an intermediate duration of action and a very rapid onset. When given as a bolus dose of 0.6–1.0 mg/kg, blockade is almost always achieved within two minutes, with maximum blockade occurring within three minutes. Continuous infusions are begun at 10 μg/kg/min (8). Rocuronium's metabolite, 17-desacetylrocuronium, has only 5–10% activity compared with the parent compound. Sparr, Khuenl-Brady, and colleagues (8, 9) studied the dose requirements, recovery times, and pharmacokinetics of rocuronium in 32 critically ill patients, 27 of whom were given intermittent bolus doses, and 5 received a continuous infusion. The median duration of drug administration was 29 hours and 63.4 hours in the bolus dose and infusion groups, respectively. The mean dose of rocuronium required to maintain 80% blockade was 0.34 mg/kg, and the median infusion rate required to maintain one twitch of the TOF was 0.54 mg/kg/hr. The median time from the last bolus dose to the appearance of TOF response was 100 minutes; in the infusion group, the TOF response returned 60 minutes after the infusion was stopped. Rapacuronium. Rapacuronium, a propionate analogue of vecuronium, was marketed as a nondepolarizing NMBA as an alternative to succinylcholine. It was withdrawn from the market on March 27, 2001, because of reports of morbidity (bronchospasm) and mortality associated with its use. Benzylisoquinolinium Compounds The benzylisoquinolinium compounds include D-tubocuranine, atracurium, cisatracurium, doxacurium, and mivacurium (Tables 1 and 3)(12, 15, 16, 31).Table 3: ICU Studies of Benzylisoquinolinium Drugsad-Tubocurarine. Tubocurarine was the first nondepolarizing NMBA to gain acceptance and usage in the ICU. This long-acting benzylisoquinolinium agent is rarely used in ICUs because it induces histamine release and autonomic ganglionic blockade. Hypotension is rare, however, when the agent is administered slowly in appropriate dosages (e.g., 0.1–0.2 mg/kg). Metabolism and elimination are affected by both renal and hepatic dysfunction. Atracurium. Atracurium is an intermediate-acting NMBA with minimal cardiovascular adverse effects and is associated with histamine release at higher doses. It is inactivated in plasma by ester hydrolysis and Hofmann elimination so that renal or hepatic dysfunction does not affect the duration of blockade. Laudanosine is a breakdown product of Hofmann elimination of atracurium and has been associated with central nervous system excitation. This has led to concern about the possibility of precipitating seizures in patients who have received extremely high doses of atracurium or who are in hepatic failure (laudanosine is metabolized by the liver). There has been only one report of a surgical patient who had a seizure while receiving atracurium (32). Atracurium has been administered to various critically ill patient populations, including those with liver failure (17), brain injury (21), or multiple organ dysfunction syndrome (MODS), to facilitate mechanical ventilation. In these reports, atracurium infusion rates varied widely, but they typically ranged from 10 to 20 μg/kg/min with doses adjusted to clinical endpoints or by TOF monitoring. Infusion durations ranged from ≤24 hours to >200 hours. Recovery of normal neuromuscular activity usually occurred within one to two hours after stopping the infusions and was independent of organ function. Long-term infusions have been associated with the development of tolerance, necessitating significant dose increases or conversion to other NMBAs (31, 33). Atracurium has been associated with persistent neuromuscular weakness as have other NMBAs (34–38). Cisatracurium. Cisatracurium, an isomer of atracurium, is an intermediate-acting benzylisoquinolinium NMBA that is increasingly used in lieu of atracurium. It produces few, if any, cardiovascular effects and has a lesser tendency to produce mast cell degranulation than atracurium. Bolus doses of 0.1–0.2 mg/kg result in paralysis in an average of 2.5 minutes, and recovery begins at approximately 25 minutes; maintenance infusions should be started at 2.5–3 μg/kg/min. Cisatracurium is also metabolized by ester hydrolysis and Hofmann elimination, so the duration of blockade should not be affected by renal or hepatic dysfunction. Prolonged weakness has been reported following the use of cisatracurium (38). Cisatracurium has been compared with atracurium and vecuronium for facilitating mechanical ventilation in several open-label prospective trials (15, 18–21). Cisatracurium infusion rates ranged from 2 to 8 μg/kg/min and were adjusted to clinical endpoints or to TOF count. Infusion durations varied from 4 to 145 hours. Recovery of a TOF ratio >0.7 occurred within 34–85 minutes after drug discontinuation and was independent of organ function. These recovery times are similar to those seen with atracurium (18, 21) and less than those observed with vecuronium (15). Doxacurium. Doxacurium, a long-acting benzylisoquinolinium agent, is the most potent NMBA currently available. Doxacurium is essentially free of hemodynamic adverse effects. Initial doses of doxacurium 0.05–0.1 mg/kg may be given with maintenance infusions of 0.3–0.5 μg/kg/min and adjusted to the degree of blockade desired. An initial bolus dose lasts an average of 60–80 minutes. Doxacurium is primarily eliminated by renal excretion. In elderly patients and patients with renal dysfunction, a significant prolongation of effect may occur. Murray and colleagues (12) conducted a prospective, randomized, controlled, multicenter comparison of intermittent doses of doxacurium and pancuronium in 40 critically ill patients requiring neuromuscular blockade to optimize mechanical ventilation or to lower intracranial pressure (ICP). Patients were given another bolus dose based on TOF monitoring and were paralyzed for a mean duration of 2.6 days with doxacurium or 2.2 days with pancuronium. There was a clinically significant increase in heart rate after the initial bolus dose of pancuronium compared with baseline (120 ± 23 versus 109 ± 22 beats/min, respectively) without any differences after the initial dose of doxacurium (107 ± 21 versus 109 ± 21 beats/min, respectively). Once the drugs were discontinued, the pancuronium group had a more prolonged and variable recovery time (279 ± 229 min) than the doxacurium group (135 ± 46 min). Mivacurium. Mivacurium is one of the shortest-acting NMBAs currently available. It consists of multiple stereoisomers and has a half-life of approximately two minutes, allowing for rapid reversal of the blockade. There are little data to support its use as a continuous infusion in the ICU. INDICATIONS NMBAs are indicated in a variety of situations (Table 4)(8, 9, 12–15, 17–21, 30, 39, 42). There have been no studies randomizing patients who are considered candidates for NMBAs to a placebo versus an NMBA. We therefore reviewed many studies comparing one NMBA to another to assess the clinical indications for enrolling patients in these studies. The most common indications for long-term administration of NMBAs included facilitation of mechanical ventilation, control of ICP, ablation of muscle spasms associated with tetanus, and decreasing oxygen consumption (Figure 2).NMBAs are often used to facilitate ventilation and ablate muscular activity in patients with elevated ICP or seizures but have no direct effect on either condition. Patients who are being treated for seizures who also take NMBAs should have electroencephalographic monitoring to ensure that they are not actively seizing while paralyzed.Figure 2: Use of NMBAs in the ICU. a Monitor train-of-four ratio, protect eyes, position patient to protect pressure points, and address deep venous thrombosis prophylaxis. Reassess every 12–24 hrs for continued NMBA indication.Table 4: Indications for the long-term use of neuromuscular blocking agents (NMBA) in critically ill patientsaWith the exception of atracurium and cisatracurium, which need to be given continuously because of their short half-lives, bolus administration of NMBAs offers potential advantages for controlling tachyphylaxis; monitoring for accumulation, analgesia, and amnesia; and limiting complications related to prolonged or excessive blockade; and improving economics. However, in many ICUs, NMBAs are administered continuously, achieving adequate paralysis and faster recovery with TOF monitoring. Facilitate Mechanical Ventilation Numerous reports have described the use of NMBAs to facilitate mechanical ventilation. Most of the reports are limited to case studies, small prospective open-label trials, and small randomized open-label and double-blind trials enrolling a wide variety of critically ill patients to whom NMBAs were given to prevent respiratory dysynchrony, stop spontaneous respiratory efforts and muscle movement, improve gas exchange, and facilitate inverse ratio ventilation. However, none of these reports compared NMBAs to placebos. Manage Increased ICP The data supporting the use of NMBAs to control ICP are limited to a case report and an open-label trial. Prielipp (30) evaluated doxacurium use in eight patients with severe head injury in an open-label prospective study. NMBAs were given to facilitate ventilation or to manage brain injuries. Patients received an initial bolus injection of doxacurium 0.05 mg/kg followed by a continuous infusion of 0.25 μg/kg/min adjusted to maintain one twitch of the TOF. Doxacurium had no effect on ICP, heart rate, or blood pressure. Infusion rates were similar at the beginning (1 ± 0.1 mg/hr) and at the end (1.3 ± 0.2 mg/hr) of the study. TOF responses returned at 118 minutes; a TOF ratio of 0.7 was measured at 259 ± 24 minutes. No adverse events were reported. McClelland et al. (40) treated three patients with atracurium for four to six days to manage increased ICP. Patients could undergo a neurologic examination within minutes after discontinuing atracurium. No adverse events were reported. There have been no studies the of NMBAs in the of increased ICP. studies the use of NMBAs in the of muscle associated with tetanus, drug and many were published and administered a continuous rocuronium infusion to control muscle in patients with tetanus. spasms at an infusion rate of 8 and a bolus dose of 0.9 mg/kg the infusion rate to 10 μg/kg/min the muscle but increase heart to a different NMBA could control the et al. evaluated the effects of vecuronium on oxygen oxygen oxygen and in a randomized, in critically ill patients with severe Although the infusion of vecuronium achieved an adequate of paralysis and respiratory it not oxygen oxygen or oxygen INDICATIONS There are no prospective, randomized, trials patients to an NMBA versus a placebo with a of if such patients could be by means other than NMBA NMBAs should be used for an adult patient in an ICU to manage ventilation, manage increased ICP, treat muscle and decrease oxygen consumption only when all other means have been without of = There in been no since the last guidelines were published that the use of pancuronium for the of patients in an ICU. prospective, randomized, trials that have been conducted do not the of using newer agents or any other agents of pancuronium. There are no studies with to this a A but there is evidence in the literature that patients on pancuronium as well as or than patients receiving any other NMBA. The two adverse effects of pancuronium that are on are and an increase in heart patients who not tolerate an increase in heart rate, those with cardiovascular should an NMBA other than pancuronium. The indications for the use of an NMBA must the risk of and that is based on of the of the underlying cardiovascular For a patient with a of in and tolerate pancuronium than a patient who is with and with mechanical ventilation. The should an NMBA on the of other patient benzylisoquinolinium compound or aminosteroidal compound could be substituted for pancuronium in these There are no that support this but there are data that patients more following administration of cisatracurium or atracurium compared with patients receiving other NMBAs if they have evidence of hepatic or renal The of patients in an ICU who are an NMBA can be with pancuronium. of = For patients for whom is (e.g., those with cardiovascular NMBAs other than pancuronium may be of = Because of their cisatracurium or atracurium is for patients with significant hepatic or renal of = Monitoring neuromuscular blockade is (Table Monitoring the of neuromuscular blockade may use of the NMBA dose and may adverse No has reported that the dose of an NMBA can prevent persistent this lack of evidence and the lack of a of of the of neuromuscular blockade in ICU patients is Monitoring the degree of neuromuscular or of the muscle or some of these three is commonly used to monitor the of neuromuscular blockade. of skeletal muscle and respiratory the of clinical methods include the use of allowing of to spontaneous ventilatory efforts and the of the muscular response by or means to a of to nerve the last guidelines were only two studies have the of monitoring the of neuromuscular blockade, and none have compared the or of The first was a prospective, randomized, of patients in a ICU who were administered vecuronium based on either clinical the ventilatory or TOF with a of one of four resulted in a significantly lower dose and lower mean infusion rate of NMBA as well as a faster time to recovery of neuromuscular and spontaneous ventilation. A to the of blockade by atracurium either by clinical (i.e., maintenance of and of patient or TOF monitoring a of three of four of the ICU patients in this prospective, no difference in the dose, mean dose, or the mean time to clinical recovery This may have been to or An additional examining the of the of a using to monitor the of blockade in patients receiving a variety of NMBAs a in the incidence of persistent neuromuscular weakness methods of monitoring of the of blockade are with TOF monitoring of the and most available its and there is no for twitch monitoring. The of the number of for blockade is by the and of The of the nerve for monitoring may be by risk of for the effect of on patient and should be included in the of blockade these in evidence-based appears to be the frequency with which is The of blockade measured compared with that of the nerve and the of three more than one of monitoring should be in using any will produce and more clinical studies are to determine the OF the patient may and clinicians the indications and limits of NMBAs. multiple that NMBAs have no or it is not to a degree of or significantly or It is difficult to assess and in the patient receiving NMBAs, but patients must be for and the lack of or In common and drugs are adjusted the patient does not to be and NMBAs are There have been no studies of the use of monitoring in of or In a of critically ill adult trauma patients who required patients compared their of to patients or the for the use of the drugs and being to and with The use of effective and and a may have affected the Patients receiving NMBAs should be both clinically and by TOF monitoring of = with a of adjusting the degree of neuromuscular blockade to one or two of = neuromuscular blockade, patients should be with and drugs to adequate and in with the clinical to optimize of = muscle weakness in ICU patients is producing a of and including syndrome syndrome, of intensive with of and prolonged weakness (Table in ICU and are two adverse events related to prolonged paralysis following discontinuation of NMBAs. We the recovery from as an increase of NMBA in the time to recovery of longer than by pharmacologic This is primarily to the of NMBAs or