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REVIEW ARTICLE
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Extravascular injection of neuromuscular blocking drugs

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A systematic review of current evidence and management

 Van Herreweghe, Vincent Godschalx and Filiep Soetens
Frederik Nietvelt, Imre

Extravascular injection of neuromuscular blocking drugs neuromuscular block at the end of the surgery. Postoperative
(NMBDs) can cause a neuromuscular block because of monitoring in the recovery room was prolonged (median time
systemic absorption. Currently, there are no guidelines avail- 4 h). Most studies suggest that the delay in NMBD onset and
able on managing extravasation of NMBDs. This article recovery is caused by the formation of a subcutaneous depot,
reviews the available literature on extravasation of NMBDs. from which the NMBD is slowly absorbed into the systemic
Medline and Embase databases were searched for studies circulation. According to the current literature, extravasation of

F
concerning the paravenous or subcutaneous injection of NMBDs results in an unpredictable neuromuscular block.
NMBDs. Nine articles were included consisting of seven case Strategies to prevent potentially harmful side effects, such
reports, one case series and one clinical trial. Rocuronium was as frequent train-of-four (TOF) monitoring, the use of NMBD
used as primary NMBD in nine cases, vecuronium in two cases O reversal agents and prolonged length of stay in the posta-
and pancuronium in one case. Although there exists significant naesthesia care unit (PACU), should be considered. This
heterogeneity between the reported information in the includ- article suggests a clinical pathway that can be used after
ed studies, the majority of the case reports describe a slower extravascular injection of NMBDs.
onset, with a median delay of 20 min and prolonged duration of
O
the neuromuscular block. Nine patients had a residual Published online xx month 2024
PR

Much of the recommendations included in this

KEY POINTS article are not studied but rather based on clinical

Currently there are no guidelines on managing experience with a scientific basis. Further research is
extravasation of NMBDs. required to assess any clinical benefit of the

According to the current literature, extravasation of provided pathway.
NMBDs results in an unpredictable
neuromuscular block.

The formation of a subcutaneous depot with a Introduction
delayed systemic absorption and altered pharma- Neuromuscular blocking drugs (NMBDs) are usually
cokinetics of NMBDs are probably responsible for administered by an intravenous injection, but accidental
the delay in onset and recovery of the extravasation may occur when a peripheral intravenous
neuromuscular block. catheter is not positioned correctly. Risk factors for

Strategies to prevent potentially harmful side extravasation are small or fragile veins, advanced age,
effects, such as frequent TOF monitoring, the use obesity, multiple venipunctures, high injection pressure,
of NMBD reversal agents and prolonged length of poor cannula fixation, the presence of disseminated skin
stay in the PACU, should be considered. diseases and patient movement during cannula place-

The patency of the intravenous line should always ment.1 One study found that up to 39% of the cannulas
be checked before the injection of NMDBs. were dislocated after 72 h.2 Depending on the injected
drug, leakage in the surrounding extravascular tissue may
cause harmful effects such as local irritation or even tissue
From the Department of Anaesthesiology, UZ Leuven, Leuven, Belgium (FN, VG), Department of Anaesthesiology, Ziekenhuis Oost-Limburg, Genk, Belgium (IVH) and
Department of Anaesthesiology, AZ Turnhout, Turnhout, Belgium (FS)
Correspondence to Frederik Nietvelt, Lijsterdreef 7, 2200 Herentals, Belgium.
Tel: +32 478 50 74 04; e-mail: [email protected]
0265-0215 Copyright ß 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Society of Anaesthesiology and Intensive Care.
DOI:10.1097/EJA.0000000000001967
This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is
permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
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2 Nietvelt et al.

necrosis.3 Moreover, the injected drug may be absorbed the NMBDs were injected intramuscularly, only the
into the circulation and cause systemic effects. abstract was available, articles concerning the paediatric
population or animals and studies where agents other
As NMBDs are often used during induction of anaesthe-
than NMBD agents were injected subcutaneously.
sia, it is likely that anaesthetists may encounter accidental
References of the selected articles were also screened
extravasation of NMBDs. However, little is known about
using the above-mentioned exclusion criteria.
the absorption of NMBDs injected into the subcutaneous
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tissue and their effect on the onset and the duration of the The following variables were extracted from the selected
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neuromuscular block. This review aims to summarise the articles: age, sex, weight, type of NMBD, injection site,
current evidence on extravasation of NMBDs and its difficult intravenous insertion, intravenous cannula already
systemic adverse effects. Additionally, a flowchart will in situ, dose of NMBD (subcutaneous, intravenous and
be presented to guide clinical decision-making after the total dose), onset and duration of neuromuscular block,
extravasation of NMBDs. reversal of the neuromuscular block [time, train-of-four
(TOF) count or ratio, agent and dose], type of surgery and
Methods duration of postoperative monitoring after extubation. The
The recommendations and checklist from the PRISMA articles were also screened for risk factors that could
2020 statement (Preferred Reporting Items for System- influence the absorption and metabolism of NMBDs such
atic Reviews and Meta-Analyses) were used to construct as peripheral vascular disease, skin oedema, chronic renal
this narrative review. A literature search was performed failure, hepatic insufficiency, obesity, use of anticonvul-
on 5 February 2023 in the Ovid MEDLINE and Ovid sants, prolonged immobility and burns.
EMBASE database using the search terms ‘rocuronium’,

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‘pancuronium’, ‘vecuronium’, ‘atracurium’, ‘cisatracur-
Results
ium’, ‘mivacurium’ or ‘succinylcholine’ in combination
The initial search revealed 77 articles after removal of
with ‘subcutaneous’, ‘paravenous’, ‘extravasation’ or ‘ex-
O duplicates. From these 77 articles, 71 were excluded based
travascular leakage’.
on the exclusion criteria. Most articles were excluded
All abstracts and titles that contained a combination of because no extravasation of NMBDs occurred. Ultimately,
these search terms, were published before February 2023 our search yielded nine articles: seven case reports,4–10 one
and were written in English, were considered. Three case series describing four cases11 and one article reporting
O
authors assessed the articles independently for their one case report with a consecutive clinical trial.12 The flow
relevance. The exclusion criteria were defined as follows: of the articles can be found in Fig. 1.
Fig. 1 Flow of the articles retrieved on Embase and Medline.
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Records identified through

database searching (n = 110)
- OVID Medline (n = 35)
- OVID Embase (n = 75)

Records removed before screening:

- Removal of duplicate (n = 33)

Records screened by title

and abstract (n = 77)
Records excluded:
- Abstract only (n = 3)
- No subcutneous NMBD
injection (n = 67)
- Animal study (n = 1)
Full-text articles assessed
for eligibility (n = 6)
Records identified through
references (n = 3)

- Case report (n = 7)
Studies included in final
- Case series (n = 1)
analysis (n = 9)
- Clinical trial (n = 1)

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Extravascular injection of neuromuscular blocking drugs 3

Table 1 Demographics, characteristics of intravenous insertion and type of surgery

Case Age (years) Sex Weight (kg) BMI (kg mS2) Difficult i.v. i.v. present Type of surgery Comorbidity
4
1 69 M 86 NA NA NA Lymph node biopsy Chronic renal failure
25 65 F 114 NA NA NA PTA Morbid obesity, PAD
36 51 F 67 25 No Yes Knee debridement Chronic renal insufficiency,
DM, Skin oedema
47 59 F 120 48 Yes No CCE Morbid obesity, AHT, CVA
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58 38 F 82 33 Yes Yes Mastectomy Obesity

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611 18 M 65 21 No NA Abscess debridement Hepatic insufficiency

711 21 F 80 28 NA NA Ovarian cyst resection NMDA receptor encephalitis,
Immobility
811 75 M 30 13 NA NA Intracranial haematoma evacuation AHT, PAD
911 64 M 35 14 NA NA Electroconvulsive therapy Immobility
109 NA F NA NA NA NA Neurosurgery Chronic renal failure
1110 22 M NA NA Yes No Wound care after burn injury 18 Burns (4 days, 45% BSA)
1212 67 M 54 NA No No Brain tumour resection NA

AHT, arterial hypertension; BSA, body surface area; case column, case number with reference in superscript; CCE, cholecystectomy; CVA, cerebrovascular accident; DM,
diabetes mellitus; F, female; i.v., intravenous cannula; M, male; NA, information not available; PAD, peripheral arterial disease; PTA, percutaneous transluminal angioplasty.

The demographics of the patient and characteristics of the injection. The subcutaneous injections occurred at the
intravenous insertion and procedure are listed in Table 1. level of the upper (n ¼ 8),4–7,9,11 the lower (n ¼ 2) extrem-
The median age is 59 years, the male/female distribution is ity8,12 and the neck (n ¼ 1).10 One case did not specify the
6/6 with an average BMI of 25 kg m2. Two cases reported site of injection.11 The median doses of the subcutaneous

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the presence of the intravenous cannula upon arrival in injection of rocuronium and vecuronium were 1.1 and
the operating room.6,8 Three cases reported difficult in- 0.1 mg kg1, respectively. The dose of pancuronium was
sertion of the intravenous cannula.7,8,10 O 0.1 mg kg1. After the suspicion of extravasation, seven
patients received an additional dose of intravenous
Table 2 shows the characteristics of the subcutaneous
NMBD (five patients rocuronium and two patients vecur-
injection of NMBDs. Rocuronium was used in nine
onium) to facilitate intubation and achieve adequate
cases,4–8,11 vecuronium in two cases9,10 and pancuronium
surgical relaxation before the start of the surgery.5,7–
in one case.12 No case reports were retrieved describing
O
9,11
All intravenous top-up doses of NMBDs were admin-
the extravasation of atracurium, cisatracurium, mivacur-
istered through a newly placed intravenous line. In four
ium or succinylcholine. Only three cases mention that the
cases, the additional intravenous top-up dose of NMBD
intravenous line was checked prior to induction.6,8,9
was given prior to measurement of the TOF count.5,9,11
Except for one case, all cases suspected extravasation
PR

because of the observation of local swelling.11 None of Apart from the doses mentioned in Table 2, no additional
the cases reported a high injection pressure during initial doses of NMBDs were given during the procedure.

Table 2 Parameters of the neuromuscular block

Dose (mg kgS1) NMB Reversal

Case NMBD Injection site Total SC i.v.a Onset Onset Duration TOF Agent Dose Duration of
(min) (min) (mg kgS1) monitoring
after
reversal (h)
14 Roc Dorsum hand 1.2 1.2 0 Delayed 35 80b 1/4d Sug 4 5
25 Roc Elbow 0.4 0.4 Vec 5 mg Delayed NA 60b 4/4d Neo 0.04f NA
36 Roc Elbow 1.0 1.0 0 Delayed 20 140b 2/4d Sug 4.5 6 (ICU)
47 Roc Dorsal wrist 0.8 0.4 0.4 Delayed NA 120b 2/4d Sug 2 4
58 Roc Greater saphenous vein 1.2 0.6 0.6 Delayed NA 180b 4/4d Sug 2 4
611 Roc Forearm 1.2 1.1 0.1 NA NA 75b 100%d Sug 2.3g 1
711 Roc NA 1.9 1.3 0.6 Delayed NA 201c 1/4e Nonej None ICU
811 Roc Forearm 2.7 1.7 1.0 Delayed NA 337c 1/4e Nonej None ICU
911 Roc Forearm 0.9 0.9 0 NA NA NA 4/4e Sug 17.1h 5
109 Vec Elbow 0.2 0.1 0.1 Delayed NA 240c 4/4e Nonej None ICU
1110 Vec External jugular vein 0.1 0.1 0 Delayed NA 130b NA Neo 2.5 mgi NA
1212 Pan Ankle 0.1 0.1 0 Delayed 10 330b 46%d Neo 0.05 2

Case column: case number with reference in superscript. ICU, transfer to intensive care unit; i.v., intravenous; NA, information not available; Neo, neostigmine; NMB, neuro
muscular block; NMBD, neuro muscular blocking drug; Pan, pancuronium; Roc, rocuronium; SC, subcutaneous; Sug, sugammadex; Vec, vecuronium. a IV dose of NMBD
via a new intravenous cannula. b Duration is time between injection of the NMBD and the time of reversal. c Time until measured spontaneous recovery of train-of-four (TOF).
d
TOF at time of reversal. e TOF at time of measured spontaneous recovery. f Patient remained ventilated and sedated because she had to lie flat postoperatively for 4 h.
Reversal was given after 4 h because of unknown absorption of the s.c. NMBD. g Reversal was given because of unknown absorption of SC NMBD. h The first dose
(200 mg) of SUG was probably given SC, the second dose (200 mg) completely reversed the NMB, the third dose (200 mg) was because of unknown absorption of the
SC NMBD. i Sedation and mechanical ventilation until complete spontaneous recovery of the NMB. j Weight not mentioned.

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4 Nietvelt et al.

This resulted in an average total (intravenous with sub- pharmacokinetics of the subcutaneous injected NMBDs
cutaneous) injected dose of 1.4, 0.2 and 0.1 mg kg1 for may be altered as this depends on many factors such as
rocuronium, vecuronium and pancuronium, respectively. lipid solubility, protein binding and local tissue perfusion.
One of these patients received an intravenous injection of Therefore, most of the cases report a delayed onset,
vecuronium after an initial extravasation of rocuronium failure of muscle relaxation and a prolonged duration
and was thus not included in our calculation of median of action of the NMBDs. However, seven patients re-
and average doses.5 All cases noticed a delay in onset of
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ceived a supplemental dose of NMBDs through a newly

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neuromuscular blockade, based on TOF measurement placed intravenous cannula and this explains the high
and clinical findings such as persistent spontaneous res- total dose of NMBDs administered. The additional dos-
piration. Three of the cases reported a time of onset of the ing of NMBDs makes interpretation of the pharmacoki-
neuromuscular block with a median delay of 20 min.4,6,12 netic effects after subcutaneous administration of
The depth of neuromuscular block throughout the pro- NMBDs impossible. Moreover, the initial dose of
cedure was measured using TOF count or ratio, except NMBD may be partially injected intravenously consid-
for one case in which the patient had extensive burn ering some cases reported a loss of consciousness despite
injuries and placement of electrodes was impossible.10 extravasation. Only a small portion of the case reports
With exception of cases 2 and 9, which did not specify mention that they had checked the intravenous line prior
electrode placement, all cases using TOF measurement to intravenous injection. It is hard to know whether this
applied electrodes to the ulnar nerve to evaluate thumb was simply not reported in some articles, but we would
adduction.4,6–12 All of the subcutaneous injections of like to highlight that not checking the patency of the
NMBDs were the result of an accidental extravasation intravenous line prior to intravenous injection is unsafe

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during administration of NMBDs through a peripheral practice and that the intravenous line must always be
venous catheter. checked, particularly when NMBDs are used or if there is
a pre-existing intravenous line of uncertain quality.
Nine patients had a measured residual neuromuscular
block at the end of the surgery.5,10,11 The median time of
O
the surgical procedures was 138 min. In nine patients, the
neuromuscular block was reversed at the end of the
surgery: in six patients, sugammadex was administered
Absorption is dependent on the site of the subcutaneous
depot. Iwasaki et al.12 compared the TOF ratio of the same
dose of pancuronium after intravenous injection, subcuta-
neous injection in the hand and subcutaneous injection in
and in three patients, neostigmine was used.4–8,10–12 the ankle. The onset of the neuromuscular block in the
O
Sugammadex was only used in cases where rocuronium subcutaneous ankle group was delayed in comparison to
was administered as sugammadex was not yet available the subcutaneous hand group and the intravenous group.
when the case with extravasation of pancuronium oc- Furthermore, twitch recovery was much slower in the
curred. The median time of the administration of the subcutaneous ankle group in comparison to the subcuta-
PR

reversal agent after induction was 125 min. The median neous hand group and the intravenous group. In the
doses of sugammadex and neostigmine were 3.2 mg kg1 subcutaneous hand group and the intravenous group, a
and 45 mg kg1, respectively. The other three patients complete neuromuscular block was observed in all sub-
were sedated and mechanically ventilated in the inten- jects. In contrast, only one patient in the subcutaneous
sive care unit (ICU) until complete spontaneous recovery ankle group achieved a complete neuromuscular block.
of the neuromuscular block occurred.9,11 The patients not These findings suggest that the site of extravasation influ-
admitted to the ICU spent a median of 4 h in the recovery ences the pharmacokinetic profile. The skin blood flow is
room after extravasation of NMBDs. generally higher in the upper than in the lower body half, as
a result the absorption from a subcutaneous depot is faster
Discussion in the upper body half.13 This skin blood flow is also
In most cases, extravasation of NMBDs resulted in an increased by general anaesthesia.14 NMBDs injected in
unpredictable neuromuscular block with a delayed onset more vascularised regions will likely have a faster onset and
and prolonged duration of the neuromuscular motor recovery than regions that are less vascularised. For the
block, requiring reversal agents for safe extubation of same reason, factors that affect the local circulation such as
the patients. diabetes and atherosclerosis, may decrease the absorption
of the subcutaneous NMBD, making it very difficult to
The plasma concentration of inadvertent extravascular
predict its onset and duration of action. Longer duration of
injection of NMBD is dependent on the balance between
action may occur in patients when elimination is impaired,
the rate of absorption of the NMBD from the subcuta-
such as in chronic renal failure, where rocuronium has a
neous tissue and the elimination of the NMBD from the
37% longer elimination half-time.15
plasma. In contrast to intravenous injection where the
plasma concentration immediately peaks after adminis-
tration, subcutaneous injection results in the formation Limitations
of a subcutaneous depot, from which the NMBD is This article reviewed the literature on extravasation of
slowly absorbed into the systemic circulation. The NMBDs, but there are several limitations.

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Extravascular injection of neuromuscular blocking drugs 5

First, few randomised controlled trials are available, and outcome may be underreported in the literature.
most literature consists of case reports. As a result, there is Clinicians may not have related the bad outcome to
a lot of heterogeneity between the different reports. extravasation of NMBDs. Therefore, it would be ben-
Furthermore, because of the small sample size, no statis- eficial to have qualitative randomised clinical trials that
tical analysis was performed. examined the effects of subcutaneous injection
of NMBDs.
Second, we were not able to retrieve articles that dis-
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cussed the subcutaneous injection of atracurium, cisatra-

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curium, mivacurium or succinylcholine. Extravasation of Guidelines for management of extravasation of

short-acting NMBDs, such as succinylcholine or miva- neuromuscular blocking drugs
curium, might not be of clinical importance because of a A clinical pathway based on current literature is sug-
faster elimination than absorption rate. Also, the presence gested in Fig. 2. Preventive measures include correct
of genetic anomalies such as pseudocholinesterase defi- labelling of medication as well as assessing the quality of
ciency might account for a substantial increase in dura- the intravenous line. If an intravenous cannula is present,
tion of clinical action. the injection site should be checked for oedema, inflam-
mation and pain. We recommend that the administration
Third, we could not extract any data from these case
of NMBDs via an intravenous cannula with absence
reports concerning the delayed extubation time, incidence
of backflow or increased injection pressure should be
of postreversal recurarisation nor the quality of reversal.
handled with caution.
Last, the topic of extravasation of NMBDs remains
After suspicion of extravasation, a new intravenous line
subject to publication bias. Cases with a bad or good

F
should be secured as soon as possible to ensure safe
Fig. 2 Management pathway

O
Suspected extravasation
of NMBDs
O
Secure new i.v. cannula
PR

Monitor TOF count/ratio

Stable or increasing?

Yes No

Yes No
TOF ratio >0.9 ?

Extubation Reversal or maintain sedation until

spontaneous recovery

Monitor in PACU
(4 to 5 h)

IV, Intravenous; NMBDs, Neuromuscular blocking drugs; PACU, Post-anaesthesia care unit; TOF, Train-of-four.

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6 Nietvelt et al.

anaesthesia. After accidental subcutaneous injection, a Conclusion

prolonged and unpredictable duration of neuromuscular Extravasation of NMBDs is a potentially dangerous
block must be presumed, certainly if additional intra- complication that requires adequate anaesthetic manage-
venous doses of NMBDs were administered. Quantita- ment. Current literature consists of articles with hetero-
tive monitoring of the neuromuscular block should geneous data. The available literature suggests that
always be applied as there is a risk for ongoing neuro- extravasation of NMBDs can result in a neuromuscular
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muscular block. Ideally the application of the TOF block with delayed onset and prolonged and unpredict-
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monitoring should take place at the start of induction able duration. Currently, no guidelines exist on how to
of anaesthesia to assess the onset of the neuromuscular approach an accidental subcutaneous administration of
block. After suspected extravasation of NMBDs, we NMBDs. Therefore, we suggest a clinical pathway that
advise TOF measurement before an additional intrave- can be used after extravasation of NMBDs. This pathway
nous dose of NMBD is administered to accommodate includes observation with thorough monitoring, the po-
anaesthesia best practices. NMBDs might have a tential need for prolonged sedation and ventilation and a
delayed absorption from subcutaneous tissue, therefore, suggested method to reverse the neuromuscular block.
spontaneous recovery or stabilisation of the neuromus-
cular block must be observed before reversal. Prolonged Acknowledgements relating to this article
ventilation and sedation may be required at the end of Assistance with the study: none.
the surgery. Financial support and sponsorship: none.
Once the TOF count or ratio is increasing, reversal of Conflicts of interest: none.
NMBDs can be obtained with sugammadex and neo-

F
Presentation: none.
stigmine. Though, because of its pharmacological profile
and the possibility of a prolonged neuromuscular block, This manuscript was handled by Dan Longrois.
sugammadex is the product of choice after aminosteroid
NMBDs.16,17 Not only can any further absorbed
O References
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