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Residual Neuromuscular Block:Rediscovering the Obvious

Sorin J. Brull, MD*

Mohamed Naguib, MD

Ronald D. Miller, MD

Anesthesia . . . is not of itself the therapeutic act which makes possible the

correction of deformity, the restoration to health, or the staying of death. It merely

makes possible the acts which can accomplish these things. (Beecher & Todd,

1954)

Beecher and Todd introduced their seminal article with . . . evidencewill be given that where the muscle relaxants are involved, an appreciableincrease in the anesthesia death rate is presented.1 The evidence on whichthis assertion was made was their finding that the mortality rate ascribed

to anesthesia when muscle relaxants were used (1:370 anesthetics) was sixtimes greater than the mortality rate when muscle relaxants were avoided(1:2100 anesthetics). Furthermore, 63% of the curare deaths (deaths thatinvolved the use of a muscle relaxant) were caused by respiratory failure.

Although the safety of general anesthesia has improved markedly overthe past half century, morbidity continues to be reported, even in areas inwhich significant progress has been made, such as the pharmacology ofneuromuscular blockers. In this issue of Anesthesia & Analgesia, Murphy etal.2 report the incidence of critical respiratory events that occurred inpatients after surgery within the first 15 min of admission to the postan-esthesia care unit (PACU). Data were collected over 1 yr for a large numberof patients (n 7459) who received general anesthesia. Of these patients,

42 cases (patients with signs and symptoms of postoperative residualneuromuscular blockade) were matched with 42 controls (patients withoutresidual paralysis) for statistical analysis. The incidence of prospectivelydefined critical respiratory events observed in the Murphy et al. studyduring the first 15 min in the PACU is significant (0.8%), considering thetotal number of general anesthetics performed annually in the UnitedStates. The Joint Commission noted that 21 million patients underwentgeneral anesthetics in 2004.3 If we assume that two-thirds of these patientsreceived nondepolarizing neuromuscular blockers for general anesthesia,then by extrapolation, approximately 112,000 patients annually are at riskof adverse events associated with discharge from the PACU with residualneuromuscular blockade.

The findings reported by Murphy et al. are significant on several levels.Outcome studies that investigate the clinical implications of residualneuromuscular blockade (train-of-four [TOF] ratios of 0.9 or 0.7) arelacking. Several studies have demonstrated that residual neuromuscular

blockade after long-acting neuromuscular blockers is a risk factor forpostoperative pulmonary complications.4,5 Nevertheless, as Kopman6 pointedout in an editorial, There are no outcome data to substantiate the positionthat patients who arrive in the postanesthesia care unit with TOF ratios of0.50 experience more adverse events than did those who have recovered tovalues 0.800.90. Murphy et al.,2 in reporting short-term outcome dataafter the use of neuromuscular blocking drugs, noted that of the 7459

patients who received general anesthetics, 8 required reintubation, 3 ofthem emergently. This finding is important in that these cases of obvious

From the *Mayo Clinic College of Medi-cine, Jacksonville, Florida; Department ofAnesthesiology and Pain Medicine, Univer-sity of Texas, MD Anderson Cancer CenterUnit 409, Houston, Texas; Department ofAnesthesia and Perioperative Care, Univer-sity of California, San Francisco, San Fran-cisco, California.

Accepted for publication March 7, 2008.

Sorin J. Brull, MD: Funded research(Wyeth, Organon Pharmaceuticals). Mo-hamed Naguib, MD: Consultant on an adhoc basis to Organon Pharmaceuticals andAvera Pharmaceuticals; funded researchmulticenter phase IIIa studies of sugamma-dex. Ronald D. Miller, MD: Consultant toOrganon Pharmaceuticals.

Address correspondence and reprint re-quests to Sorin J. Brull, MD, Department ofAnesthesiology, Mayo Clinic College ofMedicine, 4500 San Pablo Rd., Jacksonville,FL 32224. Address e-mail to sjbrull@comcast.net or brull@apsf.org.

Copyright 2008 International Anesthe-sia Research Society

DOI: 10.1213/ane.0b013e3181753266

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residual neuromuscular blockade occurred, despiteintraoperative use of a conventional (simple) periph-eral nerve stimulator and the use of neostigmine forantagonism of residual neuromuscular blockade in100% of the patients. The authors give no insight intohow clinical decisions about reversal were made inthese eight patients. Two of the patients who requiredreintubation in the PACU had chronic renal insuffi-ciency, probably suggesting an increased risk forprolonged neuromuscular block in patients with im-paired renal function.

Conventional nerve stimulator units require theclinician to evaluate the evoked response by subjectivemeans (i.e., visually or tactilely). A 5-s head lift andlack of subjective evidence of fade were documentedin all patients in the Murphy et al. study. Head lift,however, is an insensitive indicator of the adequacy ofneuromuscular recovery.7 Kopman et al.8 noted thatpatients could sustain a 5-s head lift at a TOF ratio of0.60. Similarly, subjective evaluation of the evokedmuscular response to TOF and tetanic stimulation arenotoriously inaccurate as estimates of fade or postop-erative residual neuromuscular blockade.9,10

Despite the aforementioned limitations, we believethat with appropriate knowledge of clinical neuromus-cular pharmacology, nondepolarizing neuromuscular

blockers can be administered safely. Appropriate intra-operative use of a conventional nerve stimulator maydecrease (but not eliminate) the incidence of postopera-tive residual neuromuscular blockade.11 If neostigmineadministration is timed at a TOF count of 4, thenclinically significant postoperative residual neuromus-cular blockade should be a rare event. However, sinceneuromuscular blockers are often given without theconcomitant use of a quantitative neuromuscularfunction monitor, pharmacologic reversal should beroutine.

Patients in Murphy et al.s study2 underwent intra-operative monitoring that included testing of bothulnar and facial nerve sites. In one study, recovery ofthe four twitches of the TOF in the face occurred 17.0min (sd 6.2) before a similar degree of recovery wasnoted at the thumb.12 This means that, during recov-ery, monitoring of evoked responses at peripheralsites (such as the adductor pollicis muscle at thethumb) introduces an extra margin of safety: recov-ery of airway muscles, including the diaphragm, (i.e.,axial musculature) happens before recovery of periph-eral muscles. Conversely, the time course of recoveryat facial muscles (orbicularis oculi and corrugatorsupercilii) occurs at the same time as respiratorymuscles, such that the margin of safety no longerexists. We do not know how the use of intraoperativemonitoring of facial nerve sites influenced the inci-dence of postoperative residual neuromuscular block-ade reported by Murphy et al.

The obvious question then is, Is there any evidencethat the use of a quantitative neuromuscular function

monitor that displays TOF ratios in real time is asso-ciated with a reduction in the incidence of postopera-tive residual neuromuscular blockade? A recentmeta-analysis could not demonstrate that the intraop-erative use of a nerve stimulator (conventional orquantitative) was associated with a reduced incidenceof residual neuromuscular blockade.13 This findingshould not be interpreted as indicating that there is noclinical advantage to using intraoperative neuromus-

cular function monitors, but rather that the widelycited studies are often poorly designed and inad-equate in detecting any advantages that might beconferred by quantitative monitoring. Although quan-titative neuromuscular function monitoring is fre-quently recommended, many anesthetics are givenwithout such monitoring. This places even greateremphasis on using simple monitoring and routinepharmacologic reversal as vehicles for avoiding re-sidual neuromuscular blockade. Do we need addi-tional studies to prove that neuromuscular monitoringimproves clinical outcomes? With regard to monitor-

ing, prospective studies are needed to determinewhether the intraoperative use of objective measure-ments of reversal (mechanomyographic or accelero-myographic TOF or double-burst stimulation) willdecrease the incidence of critical respiratory events inthe PACU.

Murphy et al.2 address several limitations of theirstudy. Although a prospective observational trial mayidentify associations between residual paralysis andcritical respiratory events, causality cannot be proven.Likewise, the investigators measuring the TOF ratioswere not blinded to the patients obvious respiratory

distress. Other limitations include the introduction ofa delay between the patients admission to the PACUand the time of TOF fade measurement. It is thereforelikely that the TOF on initial PACU admission waseven lower than reported. For example, Murphy et al.noted that acceptable neuromuscular recovery (de-fined as a TOF ratio 0.90) was present in 90.5% ofsubjects in the control group, whereas the same au-thors reported a lower incidence (68%) in a similarclinical setting.14 Furthermore, in a study of patientsundergoing orthopedic surgical procedures, Murphyet al.15 reported a 20.5% incidence of severe hypox-

emia (Spo2

90%) in patients in the PACU who hadreceived rocuronium intraoperatively. This incidenceis significantly less (P 0.001, 2 test) than the 52.4%reported in the cases group of their current study.Could these differences be attributed to lack of blind-ing? Could bias have been introduced by the initialidentification of patients with critical respiratoryevents (cases) by nurses in the study group, whileinvestigators identified those in the control group?Furthermore, neither the cases nor the controls wereprospectively matched for acuity of disease, and no a

priori calculation of the number of patients necessary

for statistical significance was considered. In definingcritical respiratory events, some of the criteria were

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subjective (e.g., inability to breathe deeply whenrequested to by the PACU nurse) and may haveinfluenced the diagnosis. The choice of monitoringequipment may also have introduced variability. Ac-celeromyography has been shown to be only mini-mally sensitive to low levels of residual paralysis, anda minimum TOF ratio of 1.0 is needed to excluderesidual weakness.16 Interestingly, Murphy et al.have chosen a higher current in an attempt to

increase the accuracy of TOF measurements. Al-though experts debate the issue of the importance ofsupramaximal current for TOF monitoring,17 thereis no indication of the precision of TOF measure-ments, as information on how often the measure-ments differed by more than 10% is lacking.

Despite these minor criticisms that are, for the mostpart, limitations of any observational design, the study

by Murphy et al. reiterates that postoperative residualneuromuscular blockade continues to occur in thePACU. Critical respiratory events occurred despite: (1)intraoperative monitoring to guide the degree of neu-

romuscular relaxation; (2) intraoperative monitoringto document adequacy of reversal; (3) administrationof neostigmine for reversal of neuromuscular block;and (4) delivery of clinical care by knowledgeableclinicians with significant experience in quantitativeneuromuscular monitoring techniques. In the currentenvironment of evidence-based medicine, productionpressure, diagnosis-based reimbursement, and finan-cial austerity, Murphy et al. have done our patients ahuge service by underscoring the continuing morbid-ity associated with the use of muscle relaxants in theabsence of objective means of assessment of neuro-

muscular recovery.In summary, the data inexorably associate low TOF

ratios (TOF 0.61 0.25) with the occurrence ofsevere hypoxemia (Spo290%). This report is seminalfor several reasons: (1) it demonstrates that postopera-tive residual paralysis is associated with critical respi-ratory events; (2) it confirms that the classicalthreshold for recovery (TOF 0.70) is insufficient toguarantee absence of critical respiratory events post-operatively; (3) it underscores the need for appropri-ate intraoperative assessment; (4) it confirms thatreversal of competitive neuromuscular block by

cholinesterase inhibitors has limitations; and (5) itdispels the myth that subjective intraoperative de-termination of adequacy of recovery (suggested bylack of visually or tactilely determined fade orclinical signs such as tidal volume) is sufficient tomake clinical decisions about tracheal extubationand spontaneous respiration.

Future progress in achieving rapid return of neuro-muscular function will probably result from someform of chemical reversal of residual block.1821

Binding of free drug molecules in plasma such as theencapsulation of rocuronium and vecuronium by su-

gammadex or rapid degradation by amino acids ofnew relaxants still under development (gantacurium)

should have a significant impact on the incidence ofpostoperative residual neuromuscular blockade.20,21

What Beecher and Todd remarked half a centuryago might indeed have been prophetic:

These data suggest strongly that great caution inthe use of the muscle relaxants should be exercised,that the agents available at present be considered as ontrial, and that they be employed only when there areclear advantages to be gained by their use, that theynot be employed for trivial purposes or as a correctivefor generally inadequate anesthesia.1

REFERENCES

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6. Kopman AF. Surrogate endpoints and neuromuscular recovery.Anesthesiology 1997;87:102931

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12. Caffrey RR, Warren ML, Becker KE Jr. Neuromuscular blockademonitoring comparing the orbicularis oculi and adductor polli-cis muscles. Anesthesiology 1986;65:957

13. Naguib M, Kopman AF, Ensor JE. Neuromuscular monitoringand postoperative residual curarisation: a meta-analysis. Br JAnaesth 2007;98:30216

14. Murphy GS, Szokol JW, Marymont JH, Franklin M, Avram MJ,Vender JS. Residual paralysis at the time of tracheal extubation.Anesth Analg 2005;100:18405

15. Murphy GS, Szokol JW, Franklin M, Marymont JH, Avram MJ,Vender JS. Postanesthesia care unit recovery times and neuro-muscular blocking drugs: a prospective study of orthopedicsurgical patients randomized to receive pancuronium or rocu-ronium. Anesth Analg 2004;98:193200

16. Capron F, Alla F, Hottier C, Meistelman C, Fuchs-Buder T. Canacceleromyography detect low levels of residual paralysis? Aprobability approach to detect a mechanomyographic train-of-four ratio of 0.9. Anesthesiology 2004;100:111924

17. Brull SJ, Ehrenwerth J, Silverman DG. Stimulation with sub-

maximal current for train-of-four monitoring. Anesthesiology1990;72:62932

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18. Naguib M, Daoud W, el-Gammal M, Ammar A, Turkistani A,Selim M, Altamimi W, Sohaibani MO. Enzymatic antagonism ofmivacurium-induced neuromuscular blockade by humanplasma cholinesterase. Anesthesiology 1995;83:694701

19. Bom A, Bradley M, Cameron K, Clark JK, Van Egmond J,Feilden H, MacLean EJ, Muir AW, Palin R, Rees DC, Zhang MQ.A novel concept of reversing neuromuscular block: chemicalencapsulation of rocuronium bromide by a cyclodextrin-basedsynthetic host. Angew Chem 2002;41:26670

20. Epemolu O, Bom A, Hope F, Mason R. Reversal of neuromus-cular blockade and simultaneous increase in plasma rocuro-nium concentration after the intravenous infusion of the novelreversal agent Org 25969. Anesthesiology 2003;99:6327

21. Belmont MR, Horochiwsky Z, Eliazo RF, Savarese JJ. Reversal ofAV430A with cysteine in rhesus monkeys. Anesthesiology2004:A-1180

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