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. no difference in the of prolonged blockade patients vecuronium with and administration of the of the task force was that patients vecuronium and were increased of prolonged once the drug was is a nondepolarizing NMBA with a that has an duration of action and a When given as a bolus dose of mg/kg, blockade is within two with blockade within three minutes. are μg/kg/min metabolite, has only activity compared with the parent and colleagues studied the dose and of rocuronium in critically ill of were given intermittent bolus and a continuous The duration of drug administration was hours and hours in the bolus dose and infusion respectively. The mean dose of rocuronium required to maintain blockade was mg/kg, and the infusion rate required to maintain one of the was The time from the last bolus dose to the of response was in the infusion the response 60 minutes after the infusion was a analogue of vecuronium, was as a nondepolarizing NMBA as an to was from the on because of of and associated with its use. Compounds The compounds include and (Tables 1 and ICU of was the nondepolarizing NMBA to and in the ICU. This long-acting is used in because it release and blockade. is however, when the is in (e.g., and elimination are by both renal and hepatic is an intermediate-acting NMBA with adverse effects and is associated with release is in plasma by and elimination so that renal or hepatic dysfunction not the duration of blockade. is a of elimination of and has been associated with This has to about the of in patients who have doses of or who are in hepatic failure is by the has been only one of a patient who a has been to critically ill patient with failure or organ dysfunction to facilitate mechanical In these infusion but typically ranged from to μg/kg/min with doses to clinical or by ranged from hours to hours. Recovery of normal neuromuscular activity within one to two hours after the and was of organ function. have been associated with the of dose or to other NMBAs has been associated with neuromuscular as have other NMBAs an of is an intermediate-acting NMBA that is used in of produces if effects and has a to than doses of mg/kg result in in an of and be is also by and so the duration of blockade not be by renal or hepatic has been reported the use of cisatracurium has been compared with and vecuronium for mechanical ventilation in open-label prospective trials infusion ranged from to 8 μg/kg/min and were to clinical or to from to hours. Recovery of a ratio within minutes after drug and was of organ function. These are similar to seen with and than with vecuronium a long-acting is the most NMBA currently is of adverse doses of mg/kg may be given with of μg/kg/min and to the degree of blockade desired. An bolus dose lasts an of minutes. is by renal In patients and patients with renal a prolongation of may and colleagues (12) conducted a of intermittent doses of and pancuronium in critically ill patients neuromuscular blockade to mechanical ventilation or to Patients were given another bolus dose based on and were paralyzed for a mean duration of with or with pancuronium. was a increase in heart rate after the bolus dose of pancuronium compared with ± ± after the dose of ± ± the drugs were discontinued, the pancuronium a more prolonged and time ± than the ± is one of the NMBAs currently consists of and has a half-life of two for of the blockade. are to its use as a continuous infusion in the ICU. NMBAs are in a of (Table have been no studies patients who are for NMBAs to a an reviewed studies one NMBA to another to the clinical for patients in these The most for long-term administration of NMBAs of mechanical of of muscle associated with and are used to facilitate ventilation and activity in patients with or but have no on either Patients who are being for who also NMBAs have to that are not 2: of NMBAs in the ICU. a train-of-four patient to and for NMBA for the long-term use of neuromuscular blocking agents in critically ill the of and which to be given because of their bolus administration of NMBAs potential for for and and complications to prolonged or and in ICUs, NMBAs are adequate and with have described the use of NMBAs to facilitate mechanical of the are to studies, prospective open-label and open-label and trials a of critically ill patients to NMBAs were given to and muscle improve and facilitate ratio of these compared NMBAs to The the use of NMBAs to are to a and an open-label Prielipp use in patients with head in an open-label prospective NMBAs were given to facilitate ventilation or to manage Patients an bolus of mg/kg followed by a continuous infusion of μg/kg/min to maintain one of the no on heart or were similar the ± 0.1 and the ± of the a ratio of was ± minutes. No adverse were et al. three patients with for to to manage increased Patients a within minutes after No adverse were have been no studies the of NMBAs in the of increased studies the use of NMBAs in the of muscle associated with drug and were published and a continuous rocuronium infusion to muscle in patients with tetanus. an infusion rate of 8 and a bolus dose of 0.9 mg/kg the infusion rate to μg/kg/min the muscle but increase heart to a different NMBA the et al. the effects of vecuronium on and in a in critically ill patients with Although the infusion of vecuronium an adequate of and it not or are no trials patients to an NMBA a with a of if such patients be by means other than NMBA NMBAs be used for an adult patient in an ICU to manage manage increased treat muscle and decrease only when all other means have been of = in been no since the last guidelines were published that the use of pancuronium for the of patients in an ICU. trials that have been conducted do not the of using agents or other agents of pancuronium. 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 other The two adverse effects of pancuronium that are on are and an increase in heart patients who not tolerate an increase in heart with an NMBA other than pancuronium. The for the use of an NMBA must the of and that is based on of the of the underlying For a patient with a of in and tolerate pancuronium than a patient who is with and with mechanical The an NMBA on the of other patient compound or aminosteroidal compound be substituted for pancuronium in these are no that this but there are that patients more administration of cisatracurium or compared with patients other NMBAs if have evidence of hepatic or renal The of patients in an ICU who are an NMBA can be with pancuronium. of = For patients for is (e.g., with NMBAs other than pancuronium may be of = Because of their cisatracurium or is for patients with 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 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 the of clinical methods include the use of of to ventilatory and the of the response by or means to a of to nerve the last guidelines were only two studies have the of the of neuromuscular blockade, and have compared the or of The was a of patients in a ICU who were vecuronium based on either clinical the ventilatory or with a of one of resulted in a significantly dose and mean infusion rate of NMBA as well as a time to of neuromuscular and A to the of blockade by either by clinical (i.e., of and of patient or a of three of of the ICU patients in this no difference in the dose, mean dose, or the mean time to clinical This may have been to or An additional examining the of the of a using to monitor the of blockade in patients a of NMBAs a in the of neuromuscular methods of of the of blockade are with of the and most available its and there is no for The of the number of for blockade is by the and of The of the nerve for may be by of for the of on patient and be in the of blockade these in evidence-based appears to be the frequency with which is The of blockade compared with that of the nerve and the of three more than one of be in using will and more clinical studies are to determine the OF the patient may and clinicians the and limits of NMBAs. that NMBAs have no or it is not to a degree of or significantly or is difficult to and in the patient NMBAs, but patients must be for and the lack of or In and drugs are the patient not to be and NMBAs are have been no studies of the use of 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 the Patients NMBAs be both and by of = with a of adjusting the degree of neuromuscular blockade to one or two of = neuromuscular blockade, patients be with and drugs to adequate and in with the clinical to of = muscle in ICU patients is producing a of and syndrome, of intensive with of and prolonged (Table in ICU and are two adverse to prolonged of NMBAs. the from as an increase of NMBA in the time to of longer than by pharmacologic This is to the of NMBAs or the with a clinical of with increased and The is by compound motor action potential and evidence of In the these are by or muscle and may Recovery NMBAs The NMBAs are associated with of prolonged and This may an increased by these NMBAs or may in which these drugs may have been more commonly used NMBAs hepatic producing active drug For vecuronium produces three and vecuronium The metabolite is to be as as the parent The vecuronium metabolite is and in patients with renal failure because hepatic elimination is decreased in patients with the of both vecuronium and its parent compound, vecuronium, in patients with renal failure contributes to a prolonged by this ICU have been that the membrane of the neuromuscular junction as a of NMBAs, NMBAs the nAChRs after the drug has from the plasma that the of motor blockade (Table also The interaction of NMBAs and is of neuromuscular blocking agents of the nAChRs are when patients are or to and during prolonged NMBA paralysis. The nAChRs may be triggered to to a structure by an increase in and resistance to nondepolarizing NMBAs. The and of these receptors across the may account for tachyphylaxis and the neuromuscular blocking effects of these The mature nicotinic acetylcholine receptor (AChR) with its glycoprotein the molecules of acetylcholine bind to the two to convert the channel to an The or receptor is on the with a subunit which such as or These immature receptors are by 10-fold and with permission, from et al. of skeletal muscle acetylcholine receptors. also to as is one of the most complications of NMBA and one of the reasons that use of NMBAs is (Table This must be from other neuromuscular (Table seen in an ICU and of in patients NMBAs are no model has been to the of this by NMBAs. patients that after the NMBA is and the drug and its active are a motor in both the and and decreased motor muscle is This is by and muscle but normal nerve studies of muscle muscle and to normal are in 50% of patients and are on the of and the of the there may be some in patients with during infusion of NMBAs, if the patients are with since after prolonged to NMBAs, there may be some to (i.e., the drugs for a to hours and only when no one has that drug decrease the frequency of factors that may to the of the include drug administration with or renal and hepatic and or complications of neuromuscular blockade use in the but the of administration of NMBAs and with The of may be as as in patients who and NMBAs. no of is NMBA administration one or two the of in this Similarly, there is an with the dose of but doses in of 1 of increase the patients an and an to from mechanical is of and an loss of evidence in that for hours and of receptors in muscle to normal and evidence that the of and in ICU patients is also reported after administration of the NMBAs (i.e., to all these is the of NMBAs and doses of or other drugs that neuromuscular For patients NMBAs and be to NMBAs as as of = (i.e., NMBAs to based on the may decrease the of of = nerve and muscle have been in the last in ICU patients (Table For is a and motor in patients or with decreased and is an and may be to of the nerve but is not to the use of NMBAs. Recovery from ICU a or economic of patients who the additional to be patient for critically ill and to maintain are Patients NMBAs are also of and care is and recommendations may include the to or In a of paralyzed or patients by and there was evidence that the use of an In this patients as their can in patients who are paralyzed for of but is not of the The is because the process The from the that within the of muscle but may also be seen in and The of the may occur in either the and The is the of into and is triggered by trauma and muscle or and consists of an active of the and when For reasons tachyphylaxis to NMBAs can and and colleagues to patients who to to Patients were with infusion of et al. described a patient from to μg/kg/min The patient was with a pancuronium infusion of μg/kg/min for a of and a patient who was with a infusion of but paralyzed for with infusion of to vecuronium which of NMBAs. were required with and to adequate and Patients NMBAs have care of = of = and of = Patients who tachyphylaxis to one NMBA another drug if neuromuscular blockade is of = have been of NMBAs. In one of these economic were when guidelines for NMBAs were initiated in the of a In another that to one of three NMBAs, there were no vecuronium, and rocuronium for two hours or but vecuronium and rocuronium were if the duration of was two to hours In a long-acting NMBAs (e.g., and were associated with prolonged compared with agents (e.g., and The in the of the that based on in seen with the agents the in drug For patients to the ICU, this may not be a NMBAs in the ICU the associated with prolonged of nondepolarizing NMBAs. In one were when was In another patients who prolonged motor after NMBAs were compared with a ICU and were in the patients with prolonged A with patients no in duration of or duration of ICU or patients who pancuronium = vecuronium = or both = agents is if these to of such as with renal or hepatic If the of this are the of be based on using and A to clinical decreased NMBA and of ventilation with has the potential to decrease associated with NMBA use in ICUs. Appendix the in a of the NMBAs. and can be used to the with in the an economic using their when choosing NMBAs for use in an ICU. of = The and reviewed this the American College of the American of the American of Critical Care the American the American the American College of Clinical and