International Journal of Surgery Open 26 (2020) 73e80

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International Journal of Surgery Open

journal homepage: www.elsevier.com/locate/ijso

Review Article

Preventive strategies of residual neuromuscular blockade in resource-limited

settings: Systematic review and guideline
Meseret Firde a, *, Tikuneh Yetneberk a, Seid Adem b, Girmay Fitiwi b, Tadesse Belayneh b
a
Debre Tabor University, College of Health Sciences, Department of Anesthesia, Ethiopia
b
University of Gondar, College of Medicine and Health Sciences, Department of Anesthesia, Ethiopia

a r t i c l e i n f o a b s t r a c t

Article history: Background: Following surgery, neuromuscular paralysis is no longer needed, its action could be quickly
Received 31 July 2020 and effectively terminated. However, evidences shown that NMBAs often continues in the PACU, even
Received in revised form after the administration of acetylcholinesterase inhibitor. Hence, stratifying risks of patients and
20 August 2020
developing evidence-based guidelines are required by rationalizing residual neuromuscular block pre-
Accepted 23 August 2020
Available online 29 August 2020
ventive strategies in resource limiting setup.
Methods: Preferred reporting items for systematic reviews and meta-analyses protocol was used to
conduct this review. PubMed, Google Scholar, and Cochrane Library data bases were used to find evi-
Keywords:
Anesthesia
dences that helps to draw recommendations and conclusions.
Muscle relaxant Discussion: The incidence of residual neuromuscular block is high in aged, female, and hypothermic
Post-operative complication patients. Full recovery of neuromuscular block may require 15e30 min after administration of
Residual neuromuscular block anticholinesterase.
Conclusions: Undetected neuromuscular block following the administration of NMBAs is still a common
problem in today's anesthesia care. A residual neuromuscular block is a preventable anesthetic
complication by application of simple measures like the timing of reversal, appropriate assessment of
patient and surgery specific usage of NMBAs.
© 2020 The Author(s). Published by Elsevier Ltd on behalf of Surgical Associates Ltd. This is an open
access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

1. Background
Neuromuscular blocking agents (NMBAs) are drugs that pro-
duce skeletal muscle paralysis primarily by causing a decreased
response to the neurotransmitter (acetylcholine) at the neuro-
muscular junction of skeletal muscle [1]. The use of NMBAs during
surgery facilitates tracheal intubation, protects patients from vocal
cord injury, and improves surgical conditions by suppressing
voluntary or reflex skeletal muscle movements [2,3].
Following surgery, neuromuscular paralysis is no longer
needed, it can be quickly and effectively terminated. However,
several studies have reported that NMBAs often continue their
action in the post-anesthesia care unit (PACU), even after the
administration of acetylcholinesterase inhibitor(4). A residual
neuromuscular block (rNMB) is defined as the presence of signs or
symptoms of muscle weakness in the postoperative period after
the intraoperative administration of NMBAs [5]. Quantitatively,
* Corresponding author. Debre Tabor University, 272, Ethiopia.
E-mail address: mesiwyeabeye@gmail.com (M. Firde).
rNMB also defined as a train of four ratios (TOFr) less than 0.9, in
the PACU secondary to non-depolarizing muscle relaxants
administration [6].
The prevalence of rNMB ranges between 5% and 85% depending
on the diagnostic criteria, type of NMBA, administration of reversal
agent, and application of neuromuscular monitoring [4]. A double-
blinded multicenter cohort study conducted in the united states on
two hundred fifty-five patients revealed that the incidence of rNMB
at the time of endotracheal tube extubation was 64.7% [7]. Another
study done in Ethiopia on three hundred eighty-four patients
showed that the overall incidence of rNMB was 12.9% during the
first 20 min of the postoperative period [8].
Respiratory muscle paralysis related to rNMB including, but
not limited to, Difficulty of swallowing and maintaining a clear
airway, inability to breath comfortably, increased risk of aspira-
tion with the resultant risk of pneumonia, impaired inspiratory
airflow leading to potential hypoxia, hypercapnia, atelectasis,
reduced hypoxic ventilatory drive, slurred speech, and impaired
clinical recovery after surgery [9e12]. Even small degrees of re-
sidual paralysis with a train of four ratios greater than 0.6 may

https://doi.org/10.1016/j.ijso.2020.08.010
2405-8572/© 2020 The Author(s). Published by Elsevier Ltd on behalf of Surgical Associates Ltd. This is an open access article under the CC BY-NC-ND license (http://
creativecommons.org/licenses/by-nc-nd/4.0/).
74 M. Firde et al. / International Journal of Surgery Open 26 (2020) 73e80
lead to clinically relevant consequences, like marked impairment
of upper airway integrity and swallowing [1].
2. Method and materials
This systematic review was carried out per the preferred
reporting items for systematic review and meta-analyses (PRISMA)
guideline [13] (Fig. 1). A computerized systematic search of the
PubMed, Google Scholar, and Cochrane database library were used
to find the appropriate articles. The following Mesh terms were
used for searching “incidence”, “prevalence”, “risk factors”, “pre-
disposing factors”, “prevention”, “emergence”, “surgery”, “extuba-
tion”, “residual blockade”, “postoperative paralysis”,
“complication”, “consequences”, “anticholinesterase”, “reversal
agents”, “monitoring”, “assessment”, “peripheral nerve stimulator”
combined each other with Boolean operators (AND, OR).
For this review, only human studies published in English per-
taining to the preventive strategies of residual neuromuscular
blockade were considered. After comprehensive and in-depth
appraisal of literature, evaluation of quality was conducted by
categorizing them into levels according to good clinical practice,
GCP, WHO, 2011: 1a (Meta-analysis, systematic review of RCTs,
Evidence based guidelines), 1b (Systematic review of one RCT), 1c
(RCTs), 2a (Systematic review of cohort or case control studies) and
Identification
Searching on (PubMed, Google scholar
and Cochrane library) n= 32,000
Records after duplication removed n =1,540
Screening
Records screened
n = 400
Full-text articles assessed for
Eligibility
eligibility
n = 60
Studies included in the review
Including
n = 60
Fig. 1. Prisma 2009 flow diagram.
3a (Non analytical studies like case report and case series, Clinical
audits, commentaries) (Table 1). Finally, conclusions and recom-
mendations has drown based on the level of evidences (see Table
3).
Preventive strategies of residual neuromuscular blockade in
resource-limited settings is a moderate quality review as we eval-
uated using AMSTAR 2 criteria [14]. This study registered at www.
researchregistry.com with Research Registry UIN: research registry
965.
3. Discussion
In the absence of residual paralysis the normal physiology of
neuromuscular transmission has recovered sufficiently, and unas-
sisted patients able to breathe normally, clear secretions, cough
effectively, maintain a patent upper airway(4). A rNMB or paralysis
with a TOF ratio of less than 0.9 often persists in the recovery room
and PACU [3,4,8,15e18]. Even with the routine use of anticholin-
esterase drugs, 39%e64% of patients continue to arrive in the PACU
with the objective evidence of rNMB [15,19].
Small degrees of residual muscle weakness from residual
blockade may potentially impair recovery after surgery and pro-
duce a life-threatening postoperative complication [1]1a. Studies
have found that the complications of rNMB following surgery
Addition records identified through
other sources (Euro PMC) n=2000
Records excluded
n =1,140
results which is not strongly related
with our objective were excluded
n = 340
 M. Firde et al. / International Journal of Surgery Open 26 (2020) 73e80
Table 1
Levels of evidence and degree of recommendation, Good clinical practice, GCP,
WHO, 2011.
Level Type of evidence Degree of recommendation
1a Meta-analyses, systematic Strongly recommended/directly
reviews of RCTs applicable
1b Systematic review Highly recommended/directly
applicable
1c Randomized clinical trials/RCTs Recommended/applicable
2a Systematic reviews of Extrapolated evidence from
case-control or cohort studies other studies
3a Non-analytic studies, e.g. case Extrapolated evidence from
reports, case series other studies
include, increased risk of postoperative hypoxemia [20,21],
increased incidence of upper airway obstruction during transport
to PACU [20], higher risk of critical respiratory events [20,22], de-
lays in fulfilling PACU discharge criteria and attaining actual
discharge [21], lengthy postoperative ventilator weaning times af-
ter cardiac surgery [2], increased risk of postoperative pulmonary
complications [23].
3.2. Preventive strategies to reduce the incidence of rNMB
3.2.1. Evaluate the real need for NMBDs
A NMBAs should not be given when the surgical procedure can
be performed without relaxation and the airway secured using a
supra-glottic device, such as a laryngeal mask airway [24]1a.
However, NMBAs improve the quality and ease of tracheal intu-
bation and lead to less subsequent laryngeal morbidity. Thus, a
neuromuscular block is recommended for tracheal intubation, even
if paralysis is not required for surgery [24]. If the duration of the
procedure is short, succinylcholine can be an alternative to NMBAs
but consider expose of the patient to the drug's adverse effects [4]
1a.
3.2.2. Depth of neuromuscular blockade
The primary purpose of the intraoperative administration of
NMBAs is to provide optimal surgical conditions. The appropriate
depth of intraoperative neuromuscular block is a clinical judgment
and highly variable depends on factors including the type and
phase of the surgical procedure, individual patient and surgeon,
and also on the anesthetic technique [24,25]1b. The block should
not be deeper than what is required [26], and for instance, deep
neuromuscular blockade with no response to train-of-four (TOF)
stimulation may be necessary throughout ophthalmic, neurosur-
gical, thoracic, cardiac, and microsurgical procedures.
A decrease in the tone of abdominal muscles during laparo-
scopic surgery also limits the increase in the insufflation pressure of
carbon dioxide during pneumoperitoneum, thereby decreasing
intra-abdominal pressure while providing optimal surgical condi-
tions [27]. Many procedures like lower abdominal surgery; deep
neuromuscular blockade is usually not needed to facilitate surgical
exposure [28]. In these situations, a TOF count of 1e2 is appropriate
[25,29]1a. Optimal adjustment of the depth of the block requires
effective communication with the surgeon regarding his/her
requirement for intraoperative muscle relaxation [48]1a.
3.2.3. Avoiding long-acting NMBAs as much as possible
Several studies have demonstrated that the use of long-acting
muscle relaxants is associated with an increased incidence of a
residual neuromuscular block as compared to intermediate-acting
muscle relaxants [30e33]. The use of intermediately acting
NMBDs is associated with a lower incidence of residual neuro-
muscular blockade in the PACU and ICU compared with long-acting
75
NMBAs [11,30]1a. These data provide convincing evidence that the
use of long-acting muscle relaxant agent places the surgical patient
at increased risk of complications related to residual paralysis.
3.3. Identify and optimize risk factors for rNMB
3.3.1. Age
Age-related reductions in organ function, muscle mass, and
ability to regulate temperature can significantly prolong the effects
of drugs including NMBAs in patients over the age of 65 years [34].
Also, the efficacy of anticholinesterases in reversing neuromuscular
function may be reduced in these patients [35,36]. A study done by
Murphy et al. shown that the incidences of rNMB in elderly patients
were higher (57.7%) than younger (30.0%) [37]. Careful reversal
dose adjustment and monitoring are required to improve periop-
erative outcomes [34,36,38]1a.
3.3.2. Gender
Evidences showed that females are more likely to develop rNMB
when compared to men [8,39,40]. This might be due to the physi-
ological difference between men and women. Women were more
sensitive to muscle relaxants than men and have much amount of
fat tissue and less muscle mass relative to men and this may
decrease the volume of distribution and lead to an increased
plasma concentration of muscle relaxants(41)2a. A study con-
ducted by Milan et al. found that in females the onset time was
shortened and the clinical duration increased after a single dose of
rocuronium(42). Perioperative monitoring and reduced dose of
muscle relaxants need to be considered [40,41]1c.
3.3.3. Hypothermia (body temperature of <36
C)
Body temperature below 36
C was recognized as a significant
risk factor for rNMB after surgery(41)2a. Hypothermia on muscle
strength has found that a reduction of body temperature by 2
C
may double the duration of the neuromuscular blockade [39,40].
Prevention of hypothermia and use nerve stimulator to adjust the
degree of the block during the procedure and to detect residual
paralysis during emergence is recommended to improve patient
outcome [4]1a.
3.3.4. Type of anesthesia
Inhalational anesthetics strengthen the action of NMBAs when
compared with intravenous anesthetics [42,43]. Neuromuscular
block in patients receiving inhalational agents and propofol showed
that recovery after inhalational agents were slower as compared to
propofol(45). Neuromuscular function monitoring and sufficient
time for recovery should be considered in patients maintained with
volatile anesthetic agents [40,44,45]1a.
Residual neuromuscular block prediction score (REPS) value of 4
and above is considered as high risk and those with REPS value of
below 4 are at low risk for rNMB (Table 2) [46]. A large cohort study
found that the REPS can be used to identify patients at greater risk
of rNMB and the tool may inform anesthetists better than an intra-
operative TOF count and enable perioperative anesthetic practices
to be safe the patient and minimize the undesirable effects of rNMB
[47]2a.
3.3.5. Routine reversal of NMBAs
Using anticholinesterase drugs for reversing neuromuscular
blockade is not without risks. They adversely produce many ef-
fects like bradyarrhythmia, nausea and vomiting, and broncho-
constriction [22]1a. Some clinicians believe that risks related to
the use of reversal agents outweigh its potential benefits, they
recommended using reversal agents when there is obvious
muscle weakness only [30,48]. The practice of avoiding (or
76 M. Firde et al. / International Journal of Surgery Open 26 (2020) 73e80

Table 2 3.3.7. Allow sufficient time after reversal administration to

Residual neuromuscular block Prediction Score (REPS).
Prediction variable
Hepatic failure
Neurological disease possibly leading to immobility
Metastatic solid tumor
Female sex
Elapse time between last NMBA administration
and extubation >120 min
No certified anesthetist on the case
NMBA group e amino steroids
Morbid obesity (BMI > 35 kg m 2
Experienced surgeon
BMI¼ Body mass index, NMBA¼ Neuromuscular blocking agent.
selectively using) reversal agents increases the risk of post-
operative paralysis [22]. It is recommended that due to the un-
predictable nature of spontaneous neuromuscular recovery after
NMBA clinicians should routinely reverse the effects of NMBAs
[17,30]1a.
3.3.6. Allow sufficient time between the last dose of relaxant and
reversal
The time needs to achieve complete neuromuscular recovery is
dependent upon the extent of spontaneous recovery when the
block is reversed with anticholinesterases [22]1a. An interval of
fewer than 30 min between the last administration of relaxant
agents and anticholinesterase has determined as a significant risk
factor for rNMB [40]1a. This finding was supported by a systematic
review of 19 RCT, in which, neostigmine should delay until the
advanced degree of pre-reversal recovery has occurred [45]1a. A
further investigation done by Song et al. demonstrated that the
recovery time for cisatracurium was significantly shorter when the
reversal was delayed [49,50].
extubation
Score value To achieving full recovery of more intense levels of neuromus-
3.62
cular block may require up 15e30 min after administration of anti-
2.15 cholinesterase. The reversal should be administered at least
1.36 15e30min before the anticipated time of tracheal extubation [22]1a.
1.23
1.10
3.3.8. Neuromuscular monitoring
1.01 Neuromuscular monitoring started to be applied since 60 years
1.05 before, but it is not a common practice in most hospitals recently,
1.03
1.00
particularly in low-income countries(41). Furthermore, it is in
dilemma whether the use of objective neuromuscular monitoring
can significantly reduce residual paralysis and has a relevant impact
on patients’ outcomes or not(31). A study done in France showed
that subsequent TOF monitoring led to a decrease in the incidence
of rNMB from 62% to 3% [51]. However, a meta-analysis found that
intraoperative objective neuromuscular function monitoring has
not any significant effect on the incidence of rNMB [30]1a.
3.3.9. Tests to detect residual paralysis
The degree of residual paralysis is stated to be monitored in
three different ways(4). These are clinical (bedside) tests, qualita-
tive monitors in which by using peripheral nerve stimulators
deliver a stimulus to a peripheral nerve and the consequent
muscular response is visually or tactilely observed [27,52]. The third
way of detecting rNMB is quantitative monitors in which the
strength of muscle contraction objectively measure and display the
results on a screen [53]. Monitors should complement clinical ex-
amination in the assessment of the status and adequacy of neuro-
muscular transmission(4)1a.
3.3.9.1. Clinical signs. An ideal clinical test should be applicable and
reliable during emergence from anesthesia before tracheal

Table 3
Summary of some literature reviewed.

S. N. Authors/year Title Design Outcome Recommendation

1. Najat Tajaate et al., 2017 Neostigmine-based reversal of a systematic review of RCT. Reducing the risk of rNMB Strongly recommended
intermediate-acting NMBA to
prevent rNMB
2. M.Naguib1et al., 2007 [27] Neuromuscular monitoring and Meta analysis of RCT rNMB significantly lower after Strongly recommended
postoperative residual the use of intermediate NMBAs.
curarization:
3. Adembesa et al., 2018 RCT comparing TOFr >0.9 to RCT Decrease prevalence with PNS Strongly recommended
clinical assessment of return of
NMF
4. Thilen et al., 2017 Qualitative neuromuscular RCT Reduce rNMB Strongly recommended
monitoring: how to optimize
the use of a PNS to reduce the
risk rNMB
5. HailuYimeret al. 2017[8] Incidence and associated Cross-sectional Study Reducing rNMB applicable
factors of rNMB among patients
underwent general anesthesia
6. Da-Qing Pei et al., 2018 Grip strength can be used to RCT Strongly correlated Strongly recommended
evaluate postoperative rNMB
recovery
7. Maı'ra I. Rudolph et al., 2018 [43] clinical score to estimate the Large cohort study REPS had a higher accuracy applicable
risk of rNMB Prediction score than the last documented intra-
operative TOF count
8. Adekanye et al., 2009 [56] AAGBI guidelines on the use of Guidline Reducing rNMB Strongly recommended
neuromuscular blockade
monitoring
9. Viby-Mogensen et al., 2010 Evidence-based management Systematic review Reducer rNMB and Strongly recommended
of neuromuscular block postoperative pulmonary
complications
10. Kopman et al., 1998 Relationship of the TOF fade RCT TOFr and clinical signs for rNMB applicable
ratio to clinical signs and
symptoms of residual paralysis
 M. Firde et al. / International Journal of Surgery Open 26 (2020) 73e80 77

extubation(22). Unfortunately, these tests require a degree of pa-
tient co-operation and wakefulness to perform them appropriately,
and this exposes patients to the risk of rNMB if applied inappro-
priately [54]. Poor understanding of which clinical signs are reliable
tests may also limit its ability to detect rNMB [1,10,48].
Currently, evidences recommended the use of quantitative
neuromuscular monitoring especially for those risky patients both
during intraoperative period and emergence before extubation
[10,18,36,55]. However, frequently in the clinical practice of anes-
thesia only clinical signs are used to assess neuromuscular recovery
[1,10,48].
The result of a survey conducted to investigate the attitudes and
practice toward the management and monitoring of neuromus-
cular blockade amongst Singaporean anesthetists revealed that
objective neuromuscular monitoring was routinely utilized by only
13.1% of anesthetists despite the widespread availability of objec-
tive monitors in each operating theater [48]. Another study done on
534 anesthetists in the united kingdom found that only 10% of
anesthetists routinely use objective neuromuscular monitoring and
>60% never use such a monitor device for NMF despite of its
availability(10).
Several studies have conducted to examine the correlation be-
tween TOFr and clinical tests. Dam and Goldman proposed that the
head-lift test could be used as a reliable test for assessing neuro-
muscular recovery. At a TOFr of 0.4 or less, no patient can lift the
head from table (4). At a ratio of 0.6, the patient can sustain head-
lift for 3 s [51], but vital capacity and inspiratory force will often be
reduced [56]. At a TOF ratio of 0.75 the patients, also, sustain head-
lift for at least 5 s, open the eyes widely, protrude the tongue, and
exhibit cough-sufficiently.
At a TOF ratio of 0.8 and more, the vital capacity and inspiratory
force are normal [57]. However the clinical practice of this test is
limited by the fact that it is rarely performed for 5 s and can be
affected by other factors like pain [1]1a. The sensitivity of the head-
lift test was approximately 10%, whereas specificity was approxi-
mately 87% [17]. A study conducted on ten volunteers of the
American society of anesthesiologists aged between 23 and 33 to
assess the correlation between TOF ratio and corresponding clinical
tests revealed that head lift and leg lift for 5 s was achieved at a
TOFr of 0.75 in all subjects(59).
The result of a clinical trial to determine the correlation between
TOFr and grip strength on 120 patients, showing that 83% of patients
were achieved pre-operative grip strength at a TOFr of 0.9(60)1a.
Hence, evaluation of grip strength can be used as part of the strategy
to evaluate postoperative residual neuromuscular blockade.
The tongue-depressor test currently considered as the most
sensitive clinical sign for assessing NMF recovery(61). As the result
of the study, a masseter strength is not returned to pre relaxation
ability till TOFr of 0.86 in a majority of study subjects [58]1c. Four
Volunteers given mivacurium were unable to hold the tongue
depressor at a mean TOFr of less than 0.86 [1]. However, the
sensitivity of the tongue-depressor test was 13%, but its specificity
was higher (90%) [1,17]. Several studies and guidelines has recom-
mended the use of additional monitors as a complement, like pe-
ripheral nerve stimulator, acceleromyography and
mechanomyography in order to exclude a certain degree of per-
sisted residual paralysis (20, 51, 62)1b.
the patient should be kept anesthetized or deeply sedated to the
TOF count of 2 or 3. If TOF becomes 2 or 3 administer 0.05 mg/kg of
neostigmine. If 4 TOF count without fade is achieved the dose of
neostigmine should be adjusted to be 0.025 mg/kg when fade is
observed with a qualitative TOF count of 4 reverse with 0.04 mg/kg
of neostigmine monitoring (26, 55, 63, 64) 1a.
The increasing number of TOF twitches before reversal corre-
lates with a decreasing prevalence and severity of residual paral-
ysis, and a decreased incidence of postoperative pulmonary
complications such as atelectasis and pneumonia [24]1a.
4. Conclusion
The undetected neuromuscular block following the adminis-
tration of NMBAs is still a common problem in today's anesthesia
care. A residual neuromuscular block is a preventable anesthetic
complication by application of simple measures like the timing of
reversal, appropriate assessment of patient and surgery specific
usage of NMBAs. The limitation of this review is it does not do
further meta-analysis.
Ethical approval
Not applicable.
Funding
There is no funding for this research.
Author contribution
MF initiated the idea, carried out the study, and involved in
drafting the manuscript. TY contributed to the statistical analysis
and preparation of the manuscript. TB and GF contributed to the
entry, analysis, critically revised the paper and provided the final
version. SA and MF edit starting from the proposal development up
to the final manuscript writing and critically reviewed the manu-
script for intellectual content. All authors have read and approved
the final manuscript.
Declaration of competing interest
There no any conflict of interest.
Guarantor
Meseret Firde.
Registration of research studies
Not applicable.
Consent
Not applicable.
Acronyms and abbreviations

3.3.10. When qualitative neuromuscular monitoring is present and NMBA Non-depolarizing neuromuscular blocking Agent
used NMF Neuromuscular function
Subjective assessment by using peripheral nerve stimulator is PACU Post-anesthesia care unit
not reliably identifying fade when the TOFr exceeds 0.4(57,58). A REPS Residual neuromuscular block Prediction Score
conventional nerve stimulator has been used and visual or tactile rNMB Residual neuromuscular blockade
fade on TOF stimulation can be detected then an antagonist should TOF Train of four
be administered (63). If there is no response for TOF stimulation, TOFr Train of four ratios
78 M. Firde et al. / International Journal of Surgery Open 26 (2020) 73e80
 M. Firde et al. / International Journal of Surgery Open 26 (2020) 73e80
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.ijso.2020.08.010.
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