818 | Editorials
21. Joffe AM, Hetzel S, Liew EC. A two-handed jaw-thrust tech-
nique is superior to the one-handed ‘EC-clamp’ technique
for mask ventilation in the apneic unconscious person.
Anesthesiology 2010; 113: 873–9
22. UK Health Departments. Report on Confidential Enquiries Into
Maternal Deaths in the United Kingdom 1985–87. London: HMSO,
1991
23. Cook TM, Kelly FE. Time to abandon the ‘vintage’ laryngeal
mask airway and adopt second-generation supraglottic
airway devices as first choice. Br J Anaesth 2015; 115: 497–9
24. Pandit JJ, Andrade J, Bogod DG, et al. 5th National Audit Project
(NAP5) on accidental awareness during general anaesthesia:
summary of main findings and risk factors. Br J Anaesth 2014;
113: 549–59
British Journal of Anaesthesia 115 (6): 818–21 (2015)
Advance Access publication 16 July 2015 . doi:10.1093/bja/aev228
Succinylcholine resistance
H. B. Ammundsen*, M. K. Sørensen and M. R. Gätke
Department of Anaesthesiology, University of Copenhagen, Herlev Hospital, Herlev Ringvej 75, 2730 Herlev, Denmark
*Corresponding author. E-mail: henriette_ammundsen@dadlnet.dk
Succinylcholine has a rapid onset and a short duration of action
in most patients. It is therefore considered the drug of choice for
rapid sequence tracheal intubation.1 On rare occasions succinyl-
choline does not have the expected clinical effect. The patient
seems resistant to the drug resulting in an unanticipated difficult
airway management situation with potential morbidity or mor-
tality. The primary aim of this paper is to discuss the possible
aetiologies for succinylcholine resistance (Table 1), but also to
discuss the diagnosis, the potential clinical consequences and
postoperative measurements.
Increased butyrylcholinesterase (BChE,
plasma cholinesterase) activity
Succinylcholine is normally rapidly hydrolysed by butyrylcholi-
nesterase in plasma.17 The homozygous wild type butyrylcholi-
nesterase gene (BCHE) is the normal variant, and the consequent
BChE enzyme has a large capacity to hydrolyze succinylcholine.
Only about 10% of the i.v. injected drug reaches the effect site at
the neuromuscular junction.18 In some patients the BChE activity
is increased, potentially decreasing the amount of succinylcholine
reaching the neuromuscular endplate. Some apparent genotypi-
cally normal patients have a mild to moderate increase in enzyme
activity. Thus, increased BChE activity has been described in pa-
tients with hyperlipidaemia, nodular goiter, obesity, diabetes mel-
litus, psoriasis, essential hypertension, thyrotoxicosis, nephrosis,
bronchial asthma, alcoholism, anxiety states and schizophrenia.19
The reasons for this increased enzyme activity remains unknown
or at best speculative. The presence of the C5+ gene may, at least in
some patients, be responsible for the increased enzyme activity. In
many of the published cases, the patients were not checked for the
presence of this gene variant, which causes an increased enzyme
activity of about 30% (see below).20
25. Kristensen MS, Teoh WH, Baker PA. Percutaneous emergency
airway access; prevention, preparation, technique and train-
ing. Br J Anaesth 2015; 114: 357–61
26. Royal College of Obstetricians and Gynaecologists. Maternal
Collapse in Pregnancy and the Puerperium. Green-top Guideline
No. 56. London: RCOG, 2011
27. Difficult Airway Society. Airway Alert Form 2015. Available
from http://www.das.uk.com/guidelines/downloads.html
(accessed 10 June 2015)
28. Wilkes M, Beattie C, Gardner C, McNarry AF. Difficult airway
communication between anaesthetists and general practi-
tioners. Scot Med J 2013; 58: 2–6
In patients with mutations in the BCHE the quality and the
quantity of active enzyme are often changed. Most common
and best known among anaesthetists, are probably the BCHE var-
iants associated with decreased or impaired activity of the active
enzyme, causing prolonged duration of action of succinylcholine
and mivacurium.21–23 However, some mutations in BCHE may
result in an increased enzyme activity, potentially decreasing
the effect of injected succinylcholine, clinically showing as
resistance to the drug.
Determination of butyrylcholinesterase activity
In a laboratory assay, BChE catalyses the breakdown of an appropri-
ate substrate and the BChE activity is measured using spectropho-
tometry. As the rapid enzymatic hydrolysis of succinylcholine by
BChE is difficult to measure with sufficient accuracy, several other
substrates have been – and are – used for measuring BChE activity.
It should be acknowledged that the measured enzyme activity var-
ies with the substrate used and that there is not necessarily a cor-
relation between the measured enzyme activity and the clinical
response to succinylcholine. Thus, a BChE activity found when
using, for example, the traditionally most often used substrate,
benzoylcholine, does not always correlate with the activity found
when using succinylcholine. Another consequence of the above is
that the reference values for normal, decreased or increased BChE
activity varies among different laboratories, simply because they
use different substrates for measuring the enzyme activity.
Significance of increased
butyrylcholinesterase activity
In patients with genetically normal BChE activity a neuromuscu-
lar block induced by succinylcholine 1 mg kg−1 recovers within
4–8 min, measured as the time from injection of succinylcholine
 Editorials | 819

succinylcholine 1 mg kg−1 may not effectively depolarize the

Table 1 Reasons for no or inadequate effect of succinylcholine endplate, resulting in a decreased effect and consequently in re-
sistance to succinylcholine. The ED95 of succinylcholine in
Problem Result References
myasthenic patients seems to be 2.6 times the normal.8 Accord-
2–7
Increased BChE Rapid hydrolysis of ingly, it appears that rapid sequence induction and intubation
activity succinylcholine in can be performed with succinylcholine 1.5–2.0 mg kg−1.8 How-
plasma ever, myasthenia gravis patients are often in preoperative treatment
8–11
Modified effector Variable response to with a cholinesterase inhibitor, such as pyridostigmine. Besides the
site (e.g. succinylcholine wanted effect of the cholinesterase inhibitor (inhibition of acetylcho-
Myasthenia linesterase at the neuromuscular junction) the cholinesterase in-
Gravis) hibitor also inhibits BChE in plasma, thereby increasing the
12 13
Inadequate dose Inadequate
amount of succinylcholine reaching the neuromuscular junction.
neuromuscular block
14 15
Some myasthenic patients treated with a cholinesterase inhibitor
Ineffective storage Decreased effect of
may therefore react with no signs of resistance when given 1 mg
succinylcholine
16 kg−1 succinylcholine, but they will demonstrate a prolonged neuro-
Impatient Inadequate block at the
muscular block sometimes showing as a phase II block.9
anaesthetist time of attempted
In Charcot-Marie-Tooth disease the number of acetylcholine re-
tracheal intubation
ceptors are also decreased and the response to succinylcholine
will be reduced, but data from these patients are limited.10
Patients with Juvenile Hyaline Fibromatosis show a normal reac-
tion to neuromuscular blocking agents. However, Baraka11 has
to the first response, to train-of-four (TOF) nerve stimulation.2 17
convincingly documented resistance to succinylcholine in
In genetically normal patients with increased BChE activity the
one such patient. The reason for the resistance remains specula-
first response to TOF stimulation may appear as early as 2.5
tive, as does the documented absence of fasciculations after the
min after the injection of succinylcholine 1 mg kg−1.17
injection of succinylcholine.
Patients with genetically abnormal BCHE and increased BChE
activity in plasma may be resistant to succinylcholine, showing
clinically as no or a decreased effect of the injected succinylcho- Inadequate dose
line. It is a rare condition and only reported in few patients.3–5 20
During rapid sequence intubation the goal is to achieve excellent
Using two-dimensional electrophoresis of plasma Harris and col-
tracheal intubation conditions in approximately 60 seconds
leagues20 discovered a variant in 1963 (named the C5+ variant)
after i.v. injection of succinylcholine. Succinylcholine 1 mg kg−1
that caused a 30% increase in BChE activity. Approximately 10%
provides acceptable intubating conditions in 95% of patients.12
of Caucasians are reported to have this gene.20 In 1966, Neitlich
However, in one study the incidence of ‘excellent’ intubating
reported the first patients with very high BChE activity.3 The
conditions was significantly more frequent, in patients receiving
BChE activity of the proband was 2–3 times of that normally
succinylcholine 1.5 mg kg−1 than lower dosage of succinylcho-
found, causing succinylcholine to be hydrolysed in plasma before
line.13 Furthermore, succinylcholine 1 mg kg−1 may be insuffi-
reaching the effect site at the neuromuscular junction. The pro-
cient to achieve excellent intubation conditions for a period
band received a small dose succinylcholine 0.1 mg kg−1 without
long enough for subsequent intubation attempts, in case of an
any resulting reduction in muscle strength. Five controls were
unanticipated difficult airway situation.
given the same dose, which resulted in a 90% decrease in grip
strength. The genetic variant responsible for the resistance to suc-
cinylcholine was also present in family members. In 1979, Delbruck Ineffective storage
and Henkel found a further two families with extremely high BChE
Unsuccessful storage of succinylcholine is another reason for a
activity. This variant of BCHE is now called E-Cynthiana.4
decreased effect of the drug. Cool storage is required for a stable
Other variants with high BChE activity also exist.5 24 Two case and long lasting drug effect. Succinylcholine has a linear decline
reports have described the relationship between high BChE activity in the concentration of the drug over time. It can be stored at
and the clinical effect of succinylcholine (i.e. an unexpected diffi-
room temperature for 5–6 months with a 10% loss of potency
cult tracheal intubation).6 7 Measurements of BChE activity in
approximately.14 15 In the tropics, succinylcholine is normally
one family indicated an inherited condition.6 The variant was de- stored as a stable powder.
tected as an extra band on a polyacrylamide electrophoretic gel.
These studies were conducted before sequencing of the BCHE
was available. However, pedigree analysis showed strong heredi- The impatient anaesthetist
tary relationship, with high BChE activity in three generations. Impatience on the side of the anaesthetist may result in inad-
equate muscle relaxation at the time of intubation. Time from
onset of fasciculations to maximum blockade depth occur within
Modified effector site a range of 21–72 s.16 Thus, it is likely that intubation is more
In the autoimmune disorder myasthenia gravis the response to difficult if attempted at the start of the fasciculations, and less
succinylcholine is variable and often unpredictable. Antibodies difficult at 60 seconds after injection of succinylcholine.
are produced against the post-synaptic acetylcholine receptors
at the neuromuscular junction, resulting in functional blockade
What to do when resistance to succinylcholine
by the antibodies and/or destruction of the receptors. The de-
crease in the number of functional receptors causes a decrease
is suspected
in the response, not only to the normal transmitter acetylcholine, Resistance to succinylcholine may show as difficult tracheal intub-
but also to succinylcholine. Thus, a normal dose of ation in a patient with an anatomically normal airway. However,
820 | Editorials

failure in achieving inactive and fully abducted vocal cords at tra- References
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cular function, documented with a nerve stimulator, should
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the patient will be recovering from a neuromuscular block, with-
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out having a secured airway. Further attempts can prove even
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more difficult with the return of the patient’s airway reflexes.25
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Therefore, the patient should be allowed to return to spontan-
4. Delbrück A, Henkel E. A rare genetically determined variant of
eous ventilation, the priority being adequate oxygenation and
psuedocholinesterase in two German families with high
avoidance of secondary injury.
plasma enzyme activity. Eur J Biochem 1979; 99: 65–9
We advocate for the mandatory use of neuromuscular monitor-
5. Krause A, Lane AB, Jenkins T. A new high activity plasma
ing, whenever succinylcholine is used in order to detect any change
cholinesterase variant. J Med Genet 1988; 25: 677–81
in expected onset or duration of action of succinylcholine, and in
6. Warran P, Theeman M, Bold AM, Jones S. Hypercholinestera-
patients with neuromuscular disorders it is a critical necessity.
saemia and suxamethonium resistance. Anaesthesia 1987; 42:
Postoperatively, the aetiology of the suspected resistance to
855–7
the action of succinylcholine should be systematically analysed.
7. Yao FF, Savarese JJ. Pseudocholinesterase hyperactivity with
The analysis should include blood samples for measurement of
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BChE activity ( plasma) and BCHE genotype (whole blood or gen-
tubation. J Clin Anesth 1997; 9: 328–30
omic DNA extracted from leucocytes). These analyses may prove
8. Eisenkraft JB, Book WJ, Mann SM, Papatestas AE, Hubbard M.
important in connection with potential future acute surgical pro-
Resistance to succinylcholine in myasthenia gravis: a dose-
cedures. If the patient has received transfusion of blood or plas-
response study. Anesthesiology 1988; 69: 760–3
ma, it should be kept in mind that the half-life of BChE in plasma
9. Baraka A. Suxamethonium block in the myasthenic patient. Cor-
is approximately 12 days.26 Ideally, the blood used for measure-
relation with Plasma Cholinesterase. Anaesthesia 1992; 47: 217–9
ment of BChE activity should not be drawn within approximately
10. Baur CP, Schara U, Schlecht R, Georgieft M, Lehmann-Horn F. An-
60 days of transfusion (i.e. 5 times the half-life).
esthesia in neuromuscular disorders. Part 2: specific disorders.
If the patient has received a cholinesterase inhibitor, such as
Anasthesiol Intensivmed Notfallmed Schmerzther 2002; 37: 125–37
pyridostigmine or neostigmine, the BChE activity will be de-
11. Baraka AS. Resistance in a Patient with Juvenile Hyaline
creased for some time. The half-life of neostigmine is 77 min27
Fibromatosis. Anesthesiology 1997; 87: 1250–2
and for pyridostigmine it is 113 min.28 A blood sample for BChE
12. Naguib M, Samarkandi A, Riad W, Alharby SW. Optimal dose
activity should therefore be drawn the next day.
of succinylcholine revisited. Anesthesiology 2003; 99: 1045–9
If the suspicion of resistance to succinylcholine is verified, the
13. Naguib M, Samarkandi AH, El-Din ME, Abdullah K, Khaled M,
use of an alternative strategy for rapid sequence tracheal intub-
Alharby SW. The dose of succinylcholine required for excel-
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lent endotracheal intubating conditions. Anesth Analg 2006;
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102: 151–5
sugammadex.29
14. Roy JJ, Boismenu D, Mamer OA, Nguyen BT, Forest J-M,
In conclusion, resistance to succinylcholine is a rare event,
Hildgen P. Room Temperature Stability of Injectable Succinyl-
but when it does occur, for instance in connection with a rapid
choline Dichloride. Int J Pharm Compd 2008; 12: 83–5
sequence tracheal intubation, it is potentially life threatening.
15. Adnet F, Le Moyec L, Smith CE, Galinski M, Jabre P,
Most often it is because of an increased BChE activity (in-
Lapostolle F. Stability of succinylcholine solutions stored at
herited or acquired), but other possible reasons are a diseased
room temperature studied by nuclear magnetic resonance
neuromuscular junction, an inadequate dose of succinylcholine,
spectroscopy. Emerg Med J 2007; 24: 168–9
ineffective succinylcholine caused by unsuccessful storage and
16. Chestnut RJ. Resistance to suxamethonium. Anaesthesia 1988;
impatience on the side of the anaesthetist. Whatever the sus-
43: 255
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17. Viby-Mogensen J. Correlation of succinylcholine duration of ac-
cinylcholine should be systematically analysed postoperatively.
tion with plasma cholinesterase activity in subjects with the
The analysis should include determination of BChE activity and
genotypically normal enzyme. Anesthesiology 1980; 53: 517–20
BCHE genotype.
18. Gissen AJ, Katz RL, Karis JH, Papper EM. Neuromuscular block
in man during prolonged arterial infusion with succinylcho-
line. Anesthesiology 1966; 27: 242–9
Acknowledgements 19. Whittaker M. Plasma cholinesterase variants and the anaes-
We thank Professor Emeritus Jørgen Viby-Mogensen for his kind thetist. Anaesthesia 1980; 35: 174–97
help in revising this editorial. 20. Harris H, Hopkinson DA, Robson EB, Whittaker M. Genetical
studies in a new variant of serum cholinesterase detected
by electrophoresis. Ann Hum Genet 1963; 26: 359–82
21. Viby-Mogensen J. Succinylcholine neuromuscular blockade
Declaration of interest in subjects heterozygous for abnormal plasma cholinester-
H.B.A. and M.K.S.- none declared. M.R.G. has received GBP 73.969 ase. Anesthesiology 1981; 55: 231–35
from the Investigator Initiated Studies Program, from the pharma- 22. Viby-Mogensen J. Succinylcholine neuromuscular blockade
ceutical company MSD to perform clinical studies. MRG has received in subjects homozyogous for atypical plasma cholinesterase.
payment and travel funding for lectures from MSD. Total GBP 12,130. Anesthesiology 1981; 55: 429–34

23. Pantuck EJ. Plasma cholinesterase: gene and variations.
Anesth Analg 1993; 77: 380–6
24. Pedersen NA, Jensen FS. Clinical importance of plasma
cholinesterase for the anaesthetist. Ann Acad Med Singapore
1994; 23: 120–4
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saturation after succinylcholine-induced apnea: a study of
the recovery of spontaneous ventilation in healthy volun-
teers. Anesthesiology 2001; 94: 754–9
26. Ostergaard D, Viby-Mogensen J, Hanel HK, Skovgaard LT.
Half-life of plasma cholinesterase. Acta Anaesthesiol Scand
1988; 32: 266–9
British Journal of Anaesthesia 115 (6): 821–4 (2015)
Advance Access publication 3 November 2015 . doi:10.1093/bja/aev357
Opioids and neovascularization; pro or anti?
W. Mahbuba1,2 and D. G. Lambert1
1
Department of Cardiovascular Sciences, (Division of Anaesthesia, Critical Care and Pain Management), University of
Leicester, Leicester Royal Infirmary, Leicester LE2 7LX, UK, and
2
Department of Surgery, College of Medicine, University of Kufa, Kufa, Iraq
*Corresponding author. E-mail: dgl3@leicester.ac.uk
Opioid receptors
Because of their potent and efficacious analgesic effects, opioids
are the most commonly used medication for perioperative pain
and pain as a result of cancer; however, their uses are extended
to other conditions including cough1 and diarrhoea.2 Despite
this, they are associated with a wide range of adverse effects
such as tolerance, nausea and vomiting and respiratory depres-
sion.3 In addition, long-term use of opioids may cause hormonal
disturbances secondary to hypothalamic-pituitary malfunction.4
Moreover, the presence of opioid receptors in non-CNS tissues
results in various systemic impacts.5 In addition opioids can
modulate immune function at non-leucocyte targets.6
Opioid receptors are members of the G protein coupled recep-
tor (GPCR) superfamily.7 Classical naloxone sensitive opioid
receptors are classified as MOP (μ; mu), DOP (δ: delta) and KOP
(κ: kappa). In addition the non-classical receptor for Nociceptin/
OrphaninFQ (N/OFQ), NOP, is a member of this family.8 NOP is
naloxone insensitive. Once endogenous ligands or exogenous
drugs stimulate opioid receptors, two activation pathways are
engaged.9 The most well known pathway involves G-protein
(guanine nucleotide binding protein) activation and subsequent
inhibition of adenylyl cyclase (reducing cyclic AMP), activation
of an outward K+ current and closing of voltage gated Ca2+
channels.10 The second, pathway is responsible for receptor
desensitization via internalization.11 Opioid receptors are phos-
phorylated by GPCR kinases, resulting in the recruitment of
β-arrestin and the non-receptor tyrosine kinase C-Src. This com-
plex is internalized in clathrin- lined pits before either recycling
to the cell surface or degradation.10–12 Both pathways may end
with stimulation of mitogen-activated protein kinases (MAPK);
particularly extracellular-signal-regulated kinases(ERK) 1 and 2
pathway10 and both are linked.
Editorials | 821
27. Morris RB, Cronelly R, Miller RD, Stanski DR, Fahey MR.
Pharmacokinetics of edrophonium and neostigmine when
antagonizing D-tubocurarine neuromuscular blockade in
man. Anesthesiology 1981; 54: 399–401
28. Cronelly R, Stanski DR, Miller RD, Sheiner LB. Pyridostigmine
kinetics with and without renal function. Clin Pharmacol and
Ther 1980; 28: 78–81
29. Sørensen MK, Bretlau C, Gätke MR, Sørensen AM, Rasmussen LS.
Rapid sequence induction and intubation with rocuronium-su-
gammadex compared with succinylcholine: a randomized trial.
Br J Anaesth 2012; 108: 682–9
VEGF signalling and angiogenesis
Angiogenesis is defined as a process of new blood vessel forma-
tion.13 Although this generic definition is adopted by many, it is
hard to distinguish between angiogenesis, arteriogenesis, vascu-
logenesis and neovascularization.14 While neovascularization
covers all other terms and may refer to any type of new vessel cre-
ation, angiogenesis is limited to the generation of new capillary
plexuses from already established blood vessels. These capillar-
ies are composed from endothelial cells only without any
supporting vascular wall structure, apart from pericytes and
basement membrane.14
Vascular endothelial growth factor (VEGF)-A and its receptor,
VEGFR-2, play a central role in angiogenesis via various mechan-
isms. One of these pathways works in conjunction with a Rho
(GTP binding protein)/Rho Kinase, whereby VEGF-A leads to an
increase in endothelial (EC) permeability. In this pathway, VEGF
enhances migration capability and promoting cytoskeletal mod-
ulations and stress fibre generation.15 Controlled inhibition of
Rho/Rho Kinase via MAPK (ERK 1, 2) activation will decrease
endothelial cell apoptosis and stimulate cellular sprouting,
resulting in new blood vessel formation.16 According to Gupta
and colleagues,17 in 1999, VEGF-A stimulation can augment
angiogenesis via an additional pathway. Stimulation of VEGF-
VEGFR-2 will promote phosphorylation of PI-3kinase and, sub-
sequently, Akt resulting in inhibition of apoptosis and increased
cell proliferation.18 In the same manner, VEGF can activate MAPK
pathways via stimulating endothelial nitric oxide (eNO-NO) pro-
duction18, where MAPK activation will decrease apoptosis
and increase cell survival, by stimulating ERK1,2 and inhibit
stress-activated protein kinase/c-jun-NH2-kinase(SAPK-JNK).17
The effects of opioids on blood vessel formation are highly
contentious.