Clinical Practice Guidelines for Sustained Neuromuscular Blockade in the Adult Critically Ill Patient

Am J Health Syst Pharm. 2002;59(2) 

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Skeletal muscle weakness in ICU patients is multifactorial, producing a confusing list of names and syndromes, including acute quadriplegic myopathy syndrome (AQMS), floppy man syndrome, critical illness polyneuropathy (CIP), acute myopathy of intensive care, rapidly evolving myopathy, acute myopathy with selective lysis of myosin filaments, acute steroid myopathy, and prolonged neurogenic weakness (Table 6).[57,58]

There are probably two adverse events related to prolonged paralysis following discontinuation of NMBAs. We define the first, "prolonged recovery from NMBAs," as an increase (after cessation of NMBA therapy) in the time to recovery of 50-100% longer than predicted by pharmacologic parameters. This is primarily due to the accumulation of NMBAs or metabolites. By comparison, the second, AQMS, presents with a clinical triad of acute paresis, myonecrosis with increased creatine phosphokinase (CPK) concentration, and abnormal electromyography (EMG). The latter is characterized by severely reduced compound motor action potential (CMAP) amplitudes and evidence of acute denervation. In the beginning, these syndromes are characterized by neuronal dysfunction; later (days or weeks), muscle atrophy and necrosis may develop.[59]

The steroid-based NMBAs are associated with reports of prolonged recovery and myopathy.[57,60] This association may reflect an increased risk inferred by these NMBAs or may reflect past practice patterns in which these drugs may have been more commonly used.[61] Steroid-based NMBAs undergo extensive hepatic metabolism, producing active drug metabolites. For instance, vecuronium produces three metabolites: 3-des-, 17-des-, and 3,17-desacetyl vecuronium.[62] The 3-desacetyl metabolite is estimated to be 80% as potent as the parent compound. The 3-desacetyl vecuronium metabolite is poorly dialyzed, minimally ultrafiltrated, and accumulates in patients with renal failure because hepatic elimination is decreased in patients with uremia. Thus, the accumulation of both 3- desacetyl vecuronium and its parent compound, vecuronium, in patients with renal failure contributes to a prolonged recovery by this ICU subpopulation. Other explanations have been proposed. One suggests that the basement membrane of the neuromuscular junction acts as a reservoir of NMBAs, maintaining NMBAs at the nAChRs long after the drug has disappeared from the plasma.[63]

Drug-drug interactions that potentiate the depth of motor blockade (Table 7) may also prolong recovery. The specific interaction of NMBAs and exogenous corticosteroids is discussed later.[57,62,63,64,65]

Physiologic changes of the nAChRs are enhanced when patients are immobilized or denervated secondary to spinal cord injury, and perhaps during prolonged NMBA drug-induced paralysis. The nAChRs may be triggered to revert to a fetal- variant structure (Figure 3), characterized by an increase in total number, frequent extrajunctional proliferation, and resistance to nondepolarizing NMBAs. The proliferation and distribution of these altered receptors across the myomembrane may account for tachyphylaxis and the neuromuscular blocking effects of these drugs.

AQMS, also referred to as postparalytic quadriparesis, is one of the most devastating complications of NMBA therapy and one of the reasons that indiscriminate use of NMBAs is discouraged (Table 8).[65,66] This entity must be differentiated from other neuromuscular pathologies (Table 6) seen in an ICU and requires extensive testing. Reports of AQMS in patients receiving NMBAs alone are quite limited; no experimental model has been able to produce the histopathology of this syndrome by administering NMBAs. Afflicted patients demonstrate diffuse weakness that persists long after the NMBA is discontinued and the drug and its active metabolites are eliminated. Neurologic examination reveals a global motor deficit affecting muscles in both the upper and lower extremities and decreased motor reflexes. However, extraocular muscle function is usually preserved. This myopathy is characterized by low-amplitude CMAPs, and muscle fibrillations but normal (or nearly normal) sensory nerve conduction studies.[63,67] Muscle biopsy shows prominent vacuolization of muscle fibers without inflammatory infiltrate, patchy type 2 muscle fiber atrophy, and sporadic myofiber necrosis.[64] Modest CPK increases (0 to 15-fold above normal range) are noted in approximately 50% of patients and are probably dependent on the timing of enzyme measurements and the initiation of the myopathic process. Thus, there may be some justification in screening patients with serial CPK determinations during infusion of NMBAs, particularly if the patients are concurrently treated with corticosteroids. Also, since AQMS develops after prolonged exposure to NMBAs, there may be some rationale to daily "drug holidays" (i.e., stopping the drugs for a few to several hours and restarting them only when necessary). However, no one has demonstrated that drug holidays decrease the frequency of AQMS. Other factors that may contribute to the development of the syndrome include nutritional deficiencies, concurrent drug administration with aminoglycosides or cyclosporine, hyperglycemia, renal and hepatic dysfunction, fever, and severe metabolic or electrolyte disorders.

Evidence supports, but occasionally refutes,[14] the association of concurrent administration of NMBAs and corticosteroids with AQMS.[59,63,68,69] The incidence of myopathy may be as high as 30% in patients who receive corticosteroids and NMBAs. While no period of paralysis is risk free, NMBA administration beyond one or two days increases the risk of myopathy in this setting.[63] Similarly, there is an inconsistent correlation with the dose of corticosteroids, but total doses in excess of 1 g of methylprednisolone (or equivalent) probably increase the risk. Afflicted patients manifest an acute, diffuse, flaccid weakness and an inability to wean from mechanical ventilation. Sensory function is generally preserved.[63] Muscle biopsy shows extensive type 2 fiber atrophy, myo- necrosis, disarray of sarcomere architecture, and an extensive, selective loss of myosin. Experimental evidence in animals shows that denervation for >=24 hours induces profound negative nitrogen balance and increases expression of steroid receptors in muscle. Such denervation sensitizes muscle to even normal corticosteroid concentrations, and evidence suggests that the combination of denervation and high-dose corticosteroids precipitates myosinolysis.

Acute myopathy in ICU patients is also reported after administration of the benzylisoquinolinium NMBAs (i.e., atracurium, cisatracurium, doxacurium).[24,34,69] Common to all these reports is the coadministration of benzylisoquinolinium NMBAs and large doses of corticosteroids, aminoglycosides, or other drugs that affect neuromuscular transmission.

Recommendations: For patients receiving NMBAs and corticosteroids, every effort should be made to discontinue NMBAs as soon as possible. (Grade of recommendation = C)

Drug holidays (i.e., stopping NMBAs daily until forced to restart them based on the patient's condition) may decrease the incidence of AQMS. (Grade of recommendation = C)

Other nerve and muscle disorders have been recognized in the last decade in ICU patients (Table 6). For instance, CIP is a sensory and motor polyneuropathy identified in elderly, septic patients or those with MODS.[58,66,70] EMG testing reveals decreased CMAP, fibrillation potentials, and positive sharp waves.[60,63,64] CIP is primarily an axonopathy and may be related to microvascular ischemia of the nerve but is not directly related to the use of NMBAs. Recovery from ICU myopathy requires a protracted (weeks or months) hospitalization. One economic analysis of 10 patients who developed AQMS showed the median additional hospital charge to be $66,000 per patient.[65] As for any critically ill patient, particularly immobilized patients, deep venous thrombosis (DVT) prophylaxis and physical therapy to maintain joint mobility are important.

Patients receiving NMBAs are also at risk of developing keratitis and corneal abrasion. Prophylactic eye care is highly variable and recommendations may include methylcellulose drops, ophthalmic ointment, taping the eyelids shut to ensure complete closure, or eye patches. In a study of 69 paralyzed or heavily sedated patients by Lenart and Garrity,[71] there was strong evidence that the use of an artificial tear ointment prevented corneal exposure. In this randomized study, patients served as their own controls.

Myositis ossificans can develop in patients who are paralyzed for long periods of time, but inflammation is not characteristic of the ailment. The name is misleading because the process involves connective tissue (not muscle). The name originates from the ossification that occurs within the connective tissue of muscle but may also be seen in ligaments, tendons, fascia, aponeuroses, and joint capsules. The acquired form of the disease may occur at any age in either sex, especially around the elbows, thighs, and buttocks. The basic defect is the inappropriate differentiation of fibroblasts into osteoblasts and is usually triggered by trauma and muscle injury, paraplegia or quadriplegia, tetanus, and burns. Treatment consists of promoting an active range of motion around the affected joint and surgery when necessary.

For reasons mentioned earlier, tachyphylaxis to NMBAs can and does develop.

Coursin and colleagues[31] administered doxacurium to four patients who developed tolerance to atracurium infusions (range, 16 to 40 µg/kg/ min). Patients were successfully blocked with infusion rates of doxacurium 0.25-0.75 µg/kg/min.

Tschida et al.[72] described a patient whose atracurium requirement escalated from 5 to 30 µg/kg/min over 10 days. The patient was successfully blocked with a pancuronium infusion of 10-50 µg/kg/min for a period of five days.

Fish and Singletary[33] describe a patient who was inadequately blocked with a 60-µg/kg/min infusion of atracurium but adequately paralyzed for seven days with 2.3- mg/kg/hr infusion of vecuronium. Tachyphylaxis then developed to vecuronium which prompted discontinuation of NMBAs. Two days later, 50-µg/kg/min atracurium infusions were required with high-dose midazolam and fentanyl infusions to achieve adequate oxygenation and acceptable airway pressures.

Recommendations: Patients receiving NMBAs should have prophylactic eye care (Grade of recommendation = B), physical therapy (Grade of recommendation = C), and DVT prophylaxis. (Grade of recommendation = C)

Patients who develop tachyphylaxis to one NMBA should try another drug if neuromuscular blockade is still required. (Grade of recommendation = C)