“The hazards of postoperative residual neuromuscular block are well-documented; reversal of neuromuscular blocking agents should be routine.”

Image: ImagePower Productions, John Ursino.

Image: ImagePower Productions, John Ursino.

BY the late 1980s, it was well recognized that undetected postoperative residual neuromuscular block (PRNB) was a common occurrence in most postanesthesia care units (PACUs).1–4  However, an editorial in 1989 noted that there was little, if any, objective evidence to validate the hypothesis that PRNB was associated with long-term or even transient adverse respiratory outcomes.5  In the two and a half decades since the editorial by Miller5  was published, outcome data regarding this important patient safety issue have slowly accumulated, but the relevant database remains quite sparse. In this issue of Anesthesiology, Bulka et al.6  provide an important addition to the small list of studies that attempt to examine the long-term consequences of PRNB. They report two main findings: (1) the use of neuromuscular blocking agents (NMBAs) was associated with a higher absolute rate of postoperative pneumonia (POP) when compared to matched cases where patients did not receive relaxants and (2) failure to reverse NMBAs at the end of surgery was associated with a 2.25-fold increase in the incidence of POP. Why should these findings be less than surprising?

Bulka et al.6  noted that the incidence rate ratio (1.79) for POP was significantly higher in patients who received NMBAs. This observation is consistent with the findings from several large database investigations, which have described an association between intraoperative NMBA use and major morbidity and mortality. More than 60 yr ago, Beecher and Todd7  reported that the risk of death related to anesthesia was six times higher in patients receiving NMBAs compared to those administered no muscle relaxants. An analysis of data collected over a 10-yr period (1967 to 1976) involving 240,483 anesthetics revealed that “respiratory inadequacy after myoneural blockade” was the second most common cause of death after surgery.8  Similarly, a study from Great Britain reported that postoperative respiratory failure secondary to dosing of NMBAs was a primary cause of mortality.9  In a large prospective study, the use of the long-acting NMBA pancuronium entailed a higher risk of postoperative pulmonary complications.10  More recent studies reported that patients administered NMBAs had a higher risk of postoperative desaturations and need for reintubation11  and that those given high doses of NMBAs had an increased risk of postoperative respiratory complications.12  The increased incidence of morbidity and mortality reported in patients administered NMBAs is likely secondary to PRNB. Incomplete neuromuscular recovery during a vulnerable postoperative period (between tracheal extubation and achieving a train-of-four [TOF] ratio of less than 0.9 in the PACU) may impair upper airway patency, protective airway reflexes, breathing, swallowing, and coughing, resulting in an increased risk of significant respiratory events (like POP) and death.

Data demonstrating an association between failure to reverse neuromuscular blockade and adverse postoperative outcomes are less certain. A large case–control database investigation revealed that the primary anesthetic management characteristic associated with a reduction in mortality and coma was reversal of the effects of NMBAs.13  In a retrospective data analysis, pulmonary complication outcome scores were significantly improved in older patients with comorbidities reversed with sugammadex, compared to those reversed with neostigmine or not given reversal agents.14  In contrast to these investigations, large-scale studies from the Massachusetts General Hospital suggested an association between neostigmine use and an increased risk of hypoxemia, atelectasis, and postoperative reintubation.11,15  An important limitation of all of these investigations (as well as the study by Bulka et al.6 ) is that the presence or absence of PRNB was not measured in the PACU with quantitative monitoring; therefore, it is uncertain whether postoperative muscle weakness was the cause of the reported adverse events.

There is ample evidence that failure to antagonize nondepolarizing block may result in a very high incidence of PRNB. Baillard et al.16  reported that 42% of patients who received vecuronium but no anticholinesterase had TOF ratios less than 0.7 on arrival to the PACU. A multicenter trial revealed that 95 of 175 patients (57%) administered cisatracuriums with no reversal agent had TOF ratios less than 0.9 in the PACU.17  A recent observational study examined the incidence of PRNB when muscle relaxation was not antagonized and intraoperative monitoring of neuromuscular function was not performed.18  On admission to the PACU, only 11% of elderly patients and 23% of younger patients had achieved an acceptable level of neuromuscular recovery ratio (TOF ratio less than 0.9)!

The authors of this editorial believe that appropriate doses of reversal agents (either neostigmine or sugammadex) should always be administered when NMBAs are used, unless full neuromuscular recovery has been documented with quantitative monitoring. In clinical practice, however, less than one third of anesthesiologists routinely administer anticholinesterase agents.19  The reasons why many anesthetists fail to routinely reverse the residual effects of NMBAs are uncertain but, no doubt, multifactorial. Many clinicians still appear to harbor concerns regarding the administration of anticholinesterase/antimuscarinic drugs and associated adverse cardiovascular and respiratory effects, as well as the potential for an increased incidence of postoperative nausea and vomiting.19  In addition, 80 to 90% of respondents to an international survey assert that they had never observed patients in the PACU with residual neuromuscular weakness.19  There also appears to be a lack of appreciation of the duration of effect of an “intubating dose” of an NMBA. Two hours after a single 2 times the ED95 dose of a relaxant of intermediate duration, 37% of individuals will still not have recovered to a TOF ratio of 0.9 and 10% will still have TOF values less than 0.7.20  Furthermore, the use of qualitative neuromuscular monitors (conventional peripheral nerve stimulators) may provide reassuring but misleading information to the clinician. Once the TOF ratio exceeds 0.4, most individuals can no longer detect the presence of fade by tactile or visual observation.21,22 

Another reason for reluctance to administer neostigmine to reverse NMBAs may be related to concerns about the potential of this drug to produce paradoxical muscle weakness when administered at full neuromuscular recovery. In an attempt to understand why the use of NMBAs appears to be associated with an increase in the incidence of POP, Bulka et al.6  suggest that neostigmine may contribute to severe postoperative respiratory complications when used in an unwarranted fashion (anticholinesterase administration when neuromuscular recovery is already almost complete). They cite several recent articles as the basis for this hypothesis.15,23,24  Their thesis is also compatible with the assertions of Gross-Sundrup et al.11  and Sasaki et al.15  that neostigmine reversal increases the risk of postoperative desaturations and atelectasis. We are not convinced that neostigmine-induced block is the most likely explanation for the association between NMBA administration and POP.

A bit of history may be instructive. A study from 1980 demonstrated that in patients who were not given NMBAs, one or two injections of 2.5 mg neostigmine caused a substantial reduction in the peak tetanic contraction and severe tetanic fade, which persisted for about 20 min (although single twitch height was slightly potentiated).25  These results were subsequently confirmed by Goldhill et al.26  However, the decrement in tetanic tension observed was very brief, lasting not more than 10 min. The authors concluded that “even when considerable spontaneous recovery of muscle power has occurred, a single modest dose of reversal agent is unlikely to cause clinically important muscle weakness, and any effects are probably short lived.”26 

The duration of effect (residual paralysis) appears to be of critical importance. This concept was demonstrated in the only large-scale, randomized trial designed to examine the relationship between PRNB in the PACU and longer term outcomes (POP within 6 days of surgery).27  In patients who received atracurium or vecuronium, the incidence of POP was approximately 5% and was unrelated to the TOF ratio upon arrival in the PACU. In patients who received the long-acting NMBA pancuronium with TOF ratios of less than 0.7, the incidence of POP was almost 17%. The conclusion is that prolonged as opposed to a transient postoperative weakness is a risk factor for pneumonia.

Muscle relaxants are often essential components of a balanced anesthetic technique; yet, they may produce life-threatening complications if not dosed and monitored appropriately. The findings of Bulka et al.6  provide further support to the concept raised more than 60 yr ago that NMBA use is associated with increased morbidity. In order to optimize patient outcomes, clinicians should only administer NMBAs when clinically necessary. If NMBAs are needed intraoperatively, the lowest dose required for surgical relaxation should be used, the depth of neuromuscular blockade should be monitored, and NMBA administration should be minimized during the last hour of the procedure.

Ideally, neostigmine should not be administered until at least the fourth response to TOF stimulation appears; however, the time to achieve acceptable neuromuscular recovery may be as much as 15 min in this setting, even after a large dose (0.06 to 0.07 mg/kg) of neostigmine.28,29  Unless there is quantitative evidence that the TOF ratio at the adductor pollicis has returned to a value of more than or equal to 0.9, an appropriate dose of an anticholinesterase agent or sugammadex should be administered at the end of surgery. When no tactile or visual fade is detectable with TOF stimulation, reversal agents should still be administered since the TOF ratio may be as low as 0.4.21,22  We are unaware of any clinical evidence that suggests that doses of neostigmine of 0.03 mg/kg or less may produce adverse respiratory effects, even when neuromuscular recovery is essentially complete.30–33 

The investigation by Bulka et al.6  adds important additional insights into our growing body of knowledge about the long-term risks of failure to reverse neuromuscular blocking agents. On the basis of existing data, we believe that the well-documented hazards of postoperative residual neuromuscular blockade outweigh any theoretical risks of paradoxical muscle weakness and that reversal of neuromuscular blocking agents should be routine.

Competing Interests

Dr. Murphy has served as a consultant for Merck. The other author declares no competing interests.

Research Support

Support was provided solely from institutional and/or departmental sources.

References

References
1.
Viby-Mogensen
J
,
Jørgensen
BC
,
Ording
H
:
Residual curarization in the recovery room.
Anesthesiology
1979
;
50
:
539
41
2.
Beemer
GH
,
Rozental
P
:
Postoperative neuromuscular function.
Anaesth Intensive Care
1986
;
14
:
41
5
3.
Andersen
BN
,
Madsen
JV
,
Schurizek
BA
,
Juhl
B
:
Residual curarisation: A comparative study of atracurium and pancuronium.
Acta Anaesthesiol Scand
1988
;
32
:
79
81
4.
Bevan
DR
,
Smith
CE
,
Donati
F
:
Postoperative neuromuscular blockade: A comparison between atracurium, vecuronium, and pancuronium.
Anesthesiology
1988
;
69
:
272
6
5.
Miller
RD
:
How should residual neuromuscular blockade be detected?
Anesthesiology
1989
;
70
:
379
80
6.
Bulka
CM
,
Terekhov
MA
,
Martin
BJ
,
Dmochowski
RR
,
Hayes
RM
,
Ehrenfeld
JM
:
Nondepolarizing neuromuscular blocking agents, reversal, and risk of postoperative pneumonia.
Anesthesiology
2016
;
125
:
647
55
7.
Beecher
HK
,
Todd
DP
:
A study of the deaths associated with anesthesia and surgery: Based on a study of 599, 548 anesthesias in ten institutions 1948-1952, inclusive.
Ann Surg
1954
;
140
:
2
35
8.
Harrison
GG
:
Death attributable to anaesthesia. A 10-year survey (1967–1976).
Br J Anaesth
1978
;
50
:
1041
6
9.
Cooper
AL
,
Leigh
JM
,
Tring
IC
:
Admissions to the intensive care unit after complications of anaesthetic techniques over 10 years. 1. The first 5 years.
Anaesthesia
1989
;
44
:
953
8
10.
Pedersen
T
,
Viby-Mogensen
J
,
Ringsted
C
:
Anaesthetic practice and postoperative pulmonary complications.
Acta Anaesthesiol Scand
1992
;
36
:
812
8
11.
Grosse-Sundrup
M
,
Henneman
JP
,
Sandberg
WS
,
Bateman
BT
,
Uribe
JV
,
Nguyen
NT
,
Ehrenfeld
JM
,
Martinez
EA
,
Kurth
T
,
Eikermann
M
:
Intermediate acting non-depolarizing neuromuscular blocking agents and risk of postoperative respiratory complications: Prospective propensity score matched cohort study.
BMJ
2012
;
345
:
e6329
12.
McLean
DJ
,
Diaz-Gil
D
,
Farhan
HN
,
Ladha
KS
,
Kurth
T
,
Eikermann
M
:
Dose-dependent association between intermediate-acting neuromuscular-blocking agents and postoperative respiratory complications.
Anesthesiology
2015
;
122
:
1201
13
13.
Arbous
MS
,
Meursing
AE
,
van Kleef
JW
,
de Lange
JJ
,
Spoormans
HH
,
Touw
P
,
Werner
FM
,
Grobbee
DE
:
Impact of anesthesia management characteristics on severe morbidity and mortality.
Anesthesiology
2005
;
102
:
257
68
quiz 491–2
14.
Ledowski
T
,
Falke
L
,
Johnston
F
,
Gillies
E
,
Greenaway
M
,
De Mel
A
,
Tiong
WS
,
Phillips
M
:
Retrospective investigation of postoperative outcome after reversal of residual neuromuscular blockade: Sugammadex, neostigmine or no reversal.
Eur J Anaesthesiol
2014
;
31
:
423
9
15.
Sasaki
N
,
Meyer
MJ
,
Malviya
SA
,
Stanislaus
AB
,
MacDonald
T
,
Doran
ME
,
Igumenshcheva
A
,
Hoang
AH
,
Eikermann
M
:
Effects of neostigmine reversal of nondepolarizing neuromuscular blocking agents on postoperative respiratory outcomes: A prospective study.
Anesthesiology
2014
;
121
:
959
68
16.
Baillard
C
,
Gehan
G
,
Reboul-Marty
J
,
Larmignat
P
,
Samama
CM
,
Cupa
M
:
Residual curarization in the recovery room after vecuronium.
Br J Anaesth
2000
;
84
:
394
5
17.
Maybauer
DM
,
Geldner
G
,
Blobner
M
,
Pühringer
F
,
Hofmockel
R
,
Rex
C
,
Wulf
HF
,
Eberhart
L
,
Arndt
C
,
Eikermann
M
:
Incidence and duration of residual paralysis at the end of surgery after multiple administrations of cisatracurium and rocuronium.
Anaesthesia
2007
;
62
:
12
7
18.
Pietraszewski
P
,
Gaszyński
T
:
Residual neuromuscular block in elderly patients after surgical procedures under general anaesthesia with rocuronium.
Anaesthesiol Intensive Ther
2013
;
45
:
77
81
19.
Naguib
M
,
Kopman
AF
,
Lien
CA
,
Hunter
JM
,
Lopez
A
,
Brull
SJ
:
A survey of current management of neuromuscular block in the United States and Europe.
Anesth Analg
2010
;
111
:
110
9
20.
Debaene
B
,
Plaud
B
,
Dilly
MP
,
Donati
F
:
Residual paralysis in the PACU after a single intubating dose of nondepolarizing muscle relaxant with an intermediate duration of action.
Anesthesiology
2003
;
98
:
1042
8
21.
Viby-Mogensen
J
,
Jensen
NH
,
Engbaek
J
,
Ording
H
,
Skovgaard
LT
,
Chraemmer-Jørgensen
B
:
Tactile and visual evaluation of the response to train-of-four nerve stimulation.
Anesthesiology
1985
;
63
:
440
3
22.
Brull
SJ
,
Silverman
DG
:
Visual and tactile assessment of neuromuscular fade.
Anesth Analg
1993
;
77
:
352
5
23.
Meyer
MJ
,
Bateman
BT
,
Kurth
T
,
Eikermann
M
:
Neostigmine reversal doesn’t improve postoperative respiratory safety.
BMJ
2013
;
346
:
f1460
24.
Herbstreit
F
,
Zigrahn
D
,
Ochterbeck
C
,
Peters
J
,
Eikermann
M
:
Neostigmine/glycopyrrolate administered after recovery from neuromuscular block increases upper airway collapsibility by decreasing genioglossus muscle activity in response to negative pharyngeal pressure.
Anesthesiology
2010
;
113
:
1280
8
25.
Payne
JP
,
Hughes
R
,
Al Azawi
S
:
Neuromuscular blockade by neostigmine in anaesthetized man.
Br J Anaesth
1980
;
52
:
69
76
26.
Goldhill
DR
,
Wainwright
AP
,
Stuart
CS
,
Flynn
PJ
:
Neostigmine after spontaneous recovery from neuromuscular blockade. Effect on depth of blockade monitored with train-of-four and tetanic stimuli.
Anaesthesia
1989
;
44
:
293
9
27.
Berg
H
,
Roed
J
,
Viby-Mogensen
J
,
Mortensen
CR
,
Engbaek
J
,
Skovgaard
LT
,
Krintel
JJ
:
Residual neuromuscular block is a risk factor for postoperative pulmonary complications. A prospective, randomised, and blinded study of postoperative pulmonary complications after atracurium, vecuronium and pancuronium.
Acta Anaesthesiol Scand
1997
;
41
:
1095
103
28.
Kirkegaard
H
,
Heier
T
,
Caldwell
JE
:
Efficacy of tactile-guided reversal from cisatracurium-induced neuromuscular block.
Anesthesiology
2002
;
96
:
45
50
29.
Kim
KS
,
Cheong
MA
,
Lee
HJ
,
Lee
JM
:
Tactile assessment for the reversibility of rocuronium-induced neuromuscular blockade during propofol or sevoflurane anesthesia.
Anesth Analg
2004
;
99
:
1080
5
30.
Fuchs-Buder
T
,
Meistelman
C
,
Alla
F
,
Grandjean
A
,
Wuthrich
Y
,
Donati
F
:
Antagonism of low degrees of atracurium-induced neuromuscular blockade: Dose-effect relationship for neostigmine.
Anesthesiology
2010
;
112
:
34
40
31.
Fuchs-Buder
T
,
Baumann
C
,
De Guis
J
,
Guerci
P
,
Meistelman
C
:
Low-dose neostigmine to antagonise shallow atracurium neuromuscular block during inhalational anaesthesia: A randomised controlled trial.
Eur J Anaesthesiol
2013
;
30
:
594
8
32.
Schaller
SJ
,
Fink
H
,
Ulm
K
,
Blobner
M
:
Sugammadex and neostigmine dose-finding study for reversal of shallow residual neuromuscular block.
Anesthesiology
2010
;
113
:
1054
60
33.
Choi
ES
,
Oh
AY
,
Seo
KS
,
Hwang
JW
,
Ryu
JH
,
Koo
BW
,
Kim
BG
:
Optimum dose of neostigmine to reverse shallow neuromuscular blockade with rocuronium and cisatracurium.
Anaesthesia
2016
;
71
:
443
9