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Editorial Views  |   August 1995
Intensive Care Unit Neuromuscular Syndrome?
Author Notes
  • Accepted for publication May 1, 1995.
Article Information
Editorial Views
Editorial Views   |   August 1995
Intensive Care Unit Neuromuscular Syndrome?
Anesthesiology 8 1995, Vol.83, 237-240.. doi:
Anesthesiology 8 1995, Vol.83, 237-240.. doi:
Key words: Complications. Neuromuscular blocking drugs. Prolonged infusion.
Causes of motor dysfunction of critically ill patients in the intensive care unit (ICU) include neuropathies, [1] myopathies, neuromuscular diseases (myasthesia gravis, myasthenic syndrome), dysregulation of acetylcholine receptors (AChRs; burn), [2] nutritional and electrolyte imbalance (Li sup +, Mg sup ++, Ca sup ++, PhO4sup --, Na sup +, K sup +), [3] acid-base abnormalities, hypoxia, fatigue, reperfusion injury, [4] steroids, antibiotics, lesions of the central and peripheral nervous systems, and disuse and immobilization atrophies. [5] Any of these conditions may result in ICU patients responding to neuromuscular blocking drugs (NMBDs) less predictably than do healthy surgical subjects.
Despite the unpredictable effect and the great number of conditions complicating their use, NMBDs are used in the ICU frequently, in large doses, and often for a duration much longer than in the operating suite. [5-11] Furthermore, the cardiovascular, hepatic, renal, respiratory, and central nervous systems take priority over the neuromuscular system, which receives little attention except when it is already diseased. Personnel in the ICU receive inadequate training in the pharmacology and management of NMBDs. [8,12] In contrast with the meticulous choice of drug and dosage and the standard of monitoring in the operating suite, personnel in the ICU seem to settle for one favorite drug (pancuronium, vecuronium, atracurium) administered according to one dosing formula and do not monitor the effect or monitor it infrequently. If NMBDs will cause complications, these are the ideal conditions.
The pharmacology of neuromuscular transmission as it pertains to the use of NMBDs in the ICU received little attention until prolonged paralysis after cessation of long-term use of NMBDs was described in numerous reports, national surveys, [9,13,14] and reviews. [5,10,15] Miller was personally aware of 45 cases of prolonged responses to NMBDs in 5 yr.* In a report of 12 cases, one patient received 2,780 mg vecuronium over 25 days, at an average dose of 111 mg per day, during 35 days of mechanical ventilation, resulting in a moderately severe motor weakness that took 3 months to resolve. [6] In another report, [7] a patient received 7,728 mg vecuronium over 30 days after a lung transplant and required 4 months to regain most of her strength. As is usual of iatrogenic complications, awareness alone may change the practice. Reported cases of NMBD-induced protracted paralysis may represent only the tip of the iceberg, but the problem already may be lessening. [5,13,14,16] A recent prospective study demonstrated that, by monitoring the neuromuscular transmission and providing adequate sedation and analgesia, smaller doses of pancuronium and pipecuronium than those previously used sufficed, and no prolonged paralysis occurred in a series of 60 ICU patients. [16] .
Reports describing prolonged paralysis after administration of NMBD to patients in the ICU have varied widely as to the dose and duration of administration of NMBDs, the duration of paralysis, the underlying critical illness, and the neuromuscular pathology. It is possible that the reported cases represent more than one disease entity or none at all. The pathology of NMBD-induced protracted paralysis includes marked atrophy of type I and type II muscle fibers, destructive myopathy, relatively little inflammation, and relatively intact motor and sensory nerves. [6,7] It appears different from the "critical illness polyneuropathy." [1] The disease process is mainly in the muscle. Some of the reported cases have been suspected as simply an exacerbation of one or more existing conditions, e.g., steroid myopathy, altered pharmacokinetics, antibiotic neuromuscular block, or critical illness polyneuropathy. [5,7,11],* If the post-NMBD paralysis can be explained in its entirety as due to pharmacokinetic changes, as has been suggested, [17] the problem represents only a failure to properly modify the use of NMBDs to fit the patient's conditions. However, often this does not seem to be the case. Watling and Dasta divided the reported cases into two categories: pharmacokinetically related and pharmacokinetically unrelated. [15] The pharmacokinetically unrelated cases suggest specific pathology of the neuromuscular structures.
Is there a neuromuscular pathology specifically attributable to prolonged action of NMBDs? Prolonged prejunctional and postjunctional actions of NMBDs cause dysregulation of the AChRs of the skeletal muscle. [2,18,19] Botulinum toxin [20] and d-tubocurarine [21] have been shown to increase extrajunctional muscle sensitivity to acetylcholine. Recently, Dodson et al. demonstrated upregulation of AChRs in necropsy muscle samples of deceased critically ill adults [22] who had received long-term, high-dose infusion of vecuronium. NMBD-induced upregulation of AChRs may be extensive enough to cause tolerance to NMBDs in the rat [19] and humans* and hyperkalemia after succinylcholine in the rat [23] and possibly humans. [5,24] The dysregulation of AChRs after prolonged exposure to NMBDs is therefore similar to that after traumatic denervation, disuse, or immobilization. However, it may be different from burn-induced dysregulation, with dissimilarities in receptor subunits. [25] .
It is tempting to ascribe NMBD-induced dysregulation of AChRs of the muscle, the increased sensitivity to acetylcholine, the resistance to d-tubocurarine, and the hyperkalemic response to succinylcholine simply to a "chemical denervation." However, this NMBD-induced dysregulation occurs even without disuse or immobilization, namely without "chemical denervation." Hogue et al. [19] have demonstrated tolerance and upregulation of AChRs after chronic infusion of d-tubocurarine in rats even at minimally or non-neuromuscular blocking doses. The hyperkalemic reaction to succinylcholine observed by Yanez et al. [23] occurred even after nonimmobilizing doses of d-tubocurarine. NMBD-induced upregulation of AChRs, therefore, differs from traumatic denervation in at least one aspect: Besides secondarily to "chemical denervation," NMBD-induced upregulation of AChRs may be a primary drug action.
Does NMBD-induced upregulation of AChRs, as a primary drug action or secondary to disuse, cause or contribute to the pathogenesis of the post-NMBD myopathy and motor dysfunction? In this issue, Kim et al. [26] report that prolonged infusion of d-tubocurarine accentuates burn-induced upregulation of AChRs in the rat. This study provides a critical link between NMBD-induced upregulation of AChRs and that of at least one disease process of patients in the ICU (burn). Synergism between NMBD-induced dysregulation of AChRs (A) and other underlying dysregulation processes (B) might be a major determinant (C) of whether the dysregulation will become severe enough to actually progress to myopathies and protracted paralysis in the critically ill. In this regard, the report of Kim et al. is an important step toward understanding the post-NMBD protracted paralysis of the critically ill. It allows NMBDs to play a partial role. It allows the assumption that patients with certain underlying pathologies (if severe enough) may be more prone to the complication than those without. Conversely, it allows the assumption that sufficient action of NMBDs or sufficient AChR dysregulation is required to consummate a clinically significant motor impairment. [16,22] Finally, upregulation of AChRs may hypothetically be the common specific pathologic process of all post-NMBD protracted paralysis, regardless of the underlying critical illness.
Controversies are bound to follow, and many unanswered questions need urgent attention. Clinically, NMBD-induced dysregulation of AchRs occurs in ICU patients. [22] Are the receptor changes and the clinical pathology causally related? If they are, how does the dysregulation cause the myopathy and the motor dysfunction? What is the dose-response relationship? Are the various NMBDs different? Cardiac arrest due to hyperkalemia after administration of succinylcholine has been reported to occur in ICU patients who had no previously recognized predisposing factors except a presumed relative disuse due to ICU confinement. [5,24] However, the exact role of NMBD-induced dysregulation of AChRs in hyperkalemia cannot be assessed from these case reports. Tolerance and increasing requirement of NMBDs have been observed clinically but only sporadically. [5],* Given this preliminary evidence, could the clinical disease in question be an "ICU neuromuscular syndrome" of protracted paralysis, altered sensitivity to the curariform NMBDs, and susceptibility to succinylcholine-induced hyperkalemia, all based on the common mechanism of NMBD-induced upregulation of AChRs? Could the dysregulation-mediated ICU neuromuscular syndrome, as herein defined, be just one variety of NMBD-related prolonged paralysis, which in turn accounts for only part of all prolonged paralysis of the critically ill? The term ICU neuromuscular syndrome is intended to stress its primarily neuromuscular, not neural or muscular, origin and mechanism. Without first somehow defining a problem or part of a problem, the incidence, prevalence, and exact dose requirement of the problem will be confusing. Other unanswered questions include the exact nature of these abnormal AChRs. Does dysregulation of AChRs occur also prejunctionally? AChRs are present at the motor nerve terminal, [27] and "very distal denervation" [6] of the motor nerve has been observed in patients.
Finally, I agree with Coursin [28] and Fiamengo and Savarese [29] that each use of an NMBD in the ICU deserves careful thought in terms of indication, selection, dose, and duration. Excessive reliance on NMBDs should be discouraged. Although still unconfirmed, reducing the dose and duration of administration of NMBDs probably will lessen the risk of prolonged paralysis. [16] Monitoring of neuromuscular transmission is essential, especially in critically ill patients who have numerous reasons to respond abnormally and one new reason to be hurt by NMBDs. Many monitoring methods are available, [30] but even the simplest method (e.g., train-of-four count [31]) applied occasionally but regularly may help avoid gross overdose. Most pharmacokinetically related cases [15] probably could have been prevented by careful monitoring. Unfortunately, even subparalytic doses of NMBDs might suffice to dysregulate AChRs and accentuate the process. [19,26] The safe dose may vary from patient to patient and relaxant to relaxant. Some patients, as has been suspected of those with septicemia and steroid neuropathy, may be particularly susceptible. Until further clarified, therefore, it is advisable to go one step further and refrain from using NMBDs whenever they are dispensable or replaceable. If this is not possible, periodic interruption of NMBD administration, pharmacokinetic study and correlation between the neuromuscular transmission and the serum concentration of NMBD, and neurologic and electrophysiologic studies may be useful in the early detection of a potentially devastating complication.
Chingmuh Lee, M.D. Professor and Chairman, Department of Anesthesiology, University of California, Los Angeles School of Medicine, Harbor/University of California, Los Angeles Medical Center Campus, 1000 West Carson Street, Torrance, California 90509
* Miller RD: Use of muscle relaxants in non-operating room locations: International Anesthesia Research Society 1993 review course lectures. 6-9, 1993.
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