The Kalaemic and Neuromuscular Effects of.2

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Eur J Anaesthesiol 2015; 32:666–671

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ORIGINAL ARTICLE

The kalaemic and neuromus
cular effects ofsuccinylcholine in centronuclear myopathy
A pilot investigation in a canine model

Manuel Martin-Flores, Monique D. Pare, Luis Campoy, Marta Romano, Emily A. Tomak and

Robin D. Gleed

BACKGROUND Myopathies are generally considered toincrease the risk for succinylcholine-induced hyperkalaemiaand may affect the duration of action of neuromuscular block-ers. Centronuclear (myotubular) myopathy (CNM) is conge-nital and produces various degrees of muscular weakness andassociated complications such as respiratory failure. Theeffects of succinylcholine and the potentially lethal con-sequences of hyperkalaemia on patients with CNM areunknown due to its rarity. One source of information is thedog, as CNM occurs naturally in dogs. Because of its remark-able similarity with the disease in man, canine CNM can serveas a model to further our knowledge of the effects of succi-nylcholine.

OBJECTIVES We examined the kalaemic and neuromuscu-lar effects of succinylcholine in dogs with and without auto-somal-recessive CNM.

DESIGN A prospective, experimental study.

SETTING Anaesthesiology laboratory, College of VeterinaryMedicine, Cornell University, New York, USA.

PATIENTS Six dogs with autosomal-recessive CNM and sixcontrol dogs.

INTERVENTIONS Dogs received succinylcholine 0.3 mgkg�1 during isoflurane anaesthesia.

ht © European Society of Anaesthesiology. Un

m the Department of Clinical Sciences, College of Veterinary Medicine (MM-F, MDdicine, Cornell University, Ithaca, New York, USA (MR, EAT)

rrespondence to Manuel Martin-Flores, DVM, DACVAA, College of Veterinary Medmail: [email protected]

65-0215 Copyright � 2015 European Society of Anaesthesiology. All rights reser

MAIN OUTCOME MEASURES Whole blood potassiumconcentration was measured 5 min before and after succi-nylcholine administration. Neuromuscular function wasmeasured with acceleromyography and single twitch stimu-lation.

RESULTS All dogs recovered uneventfully from anaesthesia.The increase in potassium concentration [mean (SD)] follow-ing succinylcholine was similar between groups: CNM 0.5(0.4) mmol l�1 and control 0.7 (0.4) mmol l�1 (P¼0.47).Recovery of the single twitch to 25, 75 and 90% was longerin the CNM group (all P<0.001); 90% recovery took 35.5(1.18) min for the CNM group and 23.3 (1.68) min for thecontrol group.

CONCLUSION CNM did not exacerbate the increase inblood potassium that is ordinarily seen with succinylcholine.Recovery from succinylcholine was nearly 50% longer indogs with CNM. Although our sample size is too small toevaluate the incidence of succinylcholine-induced hyperka-laemia, extrapolation of these findings suggests thatincreased duration of action should be expected if succi-nylcholine is given to a patient with autosomal-recessiveCNM.

Published online 21 January 2015

Introduction
Centronuclear myopathy (CNM), also called myotubular
myopathy, is a congenital disease characterised by

centrally placed nuclei and generalised muscle weak-

ness.1 CNM exists in X-linked recessive, autosomal-

recessive and autosomal-dominant forms. The severity

of muscular weakness and associated complications such

as respiratory failure is greatest for the X-linked form and

mildest for the autosomal-dominant form.1 From obser-

vations in France, the incidence of confirmed X-linked

CNM is reported to be approximately 2/100 000 male

authorized reproduction of this article is prohibited.

P, LC, RDG), and Cornell University Hospital for Animals, College of Veterinary

icine, Cornell University, Ithaca, NY, 14853 USA

ved. DOI:10.1097/EJA.0000000000000222

mailto:[email protected]

http://dx.doi.org/10.1097/EJA.0000000000000222

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Succinylcholine and centronuclear myopathy 667

births per year; however, the overall incidences of other

forms of CNM are unknown.1

Hyperkalaemia and even fatal rhabdomyolysis have

been associated with the use of neuromuscular blocking

agents such as succinylcholine (SCh) in patients with

other myopathies and some diseases that affect muscle

development, such as Duchenne muscular dystrophy.2–8

Little is known about CNM because its rarity means that

there is very little objective information available

regarding the use of neuromuscular blocking agents

in these individuals. From the available reports, it is

apparent that neuromuscular blocking agents are

usually avoided.9–11 Some anaesthesiologists have even

opted to remove SCh from the operating room when

anaesthetising patients with X-linked CNM, presum-

ably to avoid accidental use.12 Administration of SCh to

patients with unrecognised myopathies has been

reported, in some cases with fatal results.6,13 To our

knowledge, there are no reports on the effects of SCh in

patients with CNM.

Autosomal-recessive CNM has been described in Lab-

rador retriever dogs.14 Clinical signs and histological

characteristics of CNM in these animals are identical

to those encountered in man.15 To our knowledge, the

canine model is the only naturally occurring model avail-

able and it reflects very closely the changes that occur

with autosomal-recessive CNM in humans.15 The rarity

of CNM and the potentially lethal consequences of

hyperkalaemia exclude prospective investigations into

the use of SCh in patients, and accordingly, we have

chosen to use canine CNM as a model for a prospective

investigation into the effects of agents used during gen-

eral anaesthesia in man.

In this pilot investigation, we compared the kalaemic and

neuromuscular effects of SCh in dogs with CNM against

those in control animals. We hypothesised that the

increase in blood potassium (Kþ) after SCh adminis-

tration would be greater in CNM dogs than in normal

control animals and that the duration of neuromuscular

block would be longer in the affected animals.

Materials and methodsAnimalsSix purpose-bred adult Labrador retriever dogs with

diagnosed autosomal-recessive CNM, weighing 20.4 to

33.3 kg, and a group of six healthy adult purpose bred

beagles, weighing 7.1 to 11.3 kg were used. Sample size

was limited by the availability of animals with CNM.

Autosomal-recessive canine CNM was diagnosed

through DNA testing by an independent laboratory

(DDC Veterinary, Fairfield, Ohio, USA). None of the

dogs were receiving any type of medication before this

study. All procedures were approved by the Cornell

Institutional Animal Care and Use Committee (Protocol

number 2012-0088; 19 July 2012).

yright © European Society of Anaesthesiology. U

General anaesthesia and neuromuscular monitoringFood but not water was withheld overnight prior to

anaesthesia. A catheter was placed in a cephalic vein

and dexmedetomidine (Dexdomitor; Orion Corporation,

Espoo, Finland) 2 mg kg�1 was administered intra-

venously (i.v.). General anaesthesia was induced with

i.v. propofol (Propoflo; Abbott Laboratories, North Chi-

cago, Illinois, USA) 2 mg kg�1. The trachea was intubated

and the lungs were ventilated to normocapnia with iso-

flurane (Isothesia; Butle Schein Animal Health, Dublin,

Ohio, USA) (end-tidal concentration 1.3 to 1.5%) in

oxygen. Dexmedetomidine 2 mg kg�1 h�1 and lactated

Ringer’s solution (5 ml kg�1 h�1) were infused through-

out the procedure. The electrocardiogram, SpO2, capno-

graphy, end-tidal isoflurane concentration, systemic

arterial blood pressure waveform and oesophageal

temperature were monitored continuously. Oesophageal

temperature was maintained between 378C and 388C by

the use of a forced warm air device.

Neuromuscular function was assessed on a thoracic limb

with acceleromyography (AMG; TOF Watch SX, Orga-

non, Ireland) as described previously.16 Briefly, with the

dog in left lateral recumbency, the dependent limb was

held extended and slightly elevated so that the carpus

and manus (paw) could flex freely during nerve stimu-

lation. A 150 g elastic preload was applied to the paw to

facilitate return of the carpus to an extended position

during neuromuscular monitoring. Stimulating needles

were placed subcutaneously over the ulnar nerve and the

acceleration transducer was taped to the palmar aspect of

the paw. After at least 30 min of general anaesthesia and

15 min of single twitch stimulation (0.1 Hz, pulse

duration 0.2 ms, 50 mA), the AMG monitor was calibrated

(CAL 2). Single twitch stimulation was then resumed.

After the single twitch signal had been stable for at least

3 min, SCh 0.3 mg kg�1 was administered i.v. as a fast

bolus through a free-flowing infusion of the isotonic

crystalloid solution. This dose produces complete neu-

romuscular block in normal dogs.17,18 During recovery

from SCh, the changes in the height of the single twitch

were recorded until no further increases were observed

for at least 5 min. The average of the first six values for

single twitch amplitude after the recovery plateau was

established was used as the final single twitch amplitude.

All values for single twitch after administration of SCh

were normalised to this final single twitch value.19

Arterial blood was sampled 5 min before and 5 min after

injection of SCh for analysis of electrolytes, glucose and

acid–base status with a point-of-care device (i-STAT

system; Abbott Point of Care Inc, Princeton, New Jersey,

USA). Blood samples were obtained from the arterial

catheter and analysed immediately.

Statistical analysisThe distribution of all variables was tested for normality

(Shapiro–Wilk test, Minitab 16.2.4). Whole blood

nauthorized reproduction of this article is prohibited.Eur J Anaesthesiol 2015; 32:666–671

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668 Martin-Flores et al.

potassium concentration before and after SCh adminis-

tration were compared within groups with the paired

t-test. The increase in Kþ concentration relative to base-

line was compared between groups with the two-sample

t-test. The sensitivity (gain) of the AMG monitor and all

recovery variables [return of single twitch to 25, 75 and

90% of the final single twitch height and recovery index

(interval between ST 25 and 75%)] were compared

between groups with two-sample t-tests. Differences

were considered significant when P value was less than

0.05. All parametric data are summarised as mean (SD).

Descriptive statistics [nonparametric distribution;

median (IQR)] for electrolytes other than Kþ, acid–base

variables and glucose before and after SCh administration

are also presented.

ResultsAll dogs recovered uneventfully from general anaesthe-

sia. A transient decrease in arterial blood pressure of at

least 20% was observed in two CNM dogs following SCh.

These changes were self-limiting and required no inter-

vention.

Kalaemic, other electrolytic, acid–base and glucoseeffects of succinylcholineIn two animals from the control group, venous blood

samples were used in lieu of arterial samples because of

failure of the arterial catheter. Following SCh adminis-

tration, Kþ increased by 0.5 (0.4) mmol l�1 [16% (1.15)] in

the CNM group and by 0.7 (0.4) mmol l�1 [18% (1.2)] in

control dogs; each was a significant increase from base-

line; P¼ 0.03 and 0.01, respectively (Fig. 1). However,

the percentage increase from baseline was not different

between groups (P¼ 0.47). Other electrolyte, acid–base

and glucose values obtained before and after Sch admin-

istration are summarised in Table 1. There was a little

change after SCh was given.

ight © European Society of Anaesthesiology. Un

Fig. 1

5.0

4.5

4.0

3.5

3.0

2.5Pre Post

Control

K+

(m

mol

L–1

)

Blood potassium concentration before and after succinylcholine 0.3 mg kg�1

�Significant increase from baseline after succinylcholine; P<0.05. Howeve

Eur J Anaesthesiol 2015; 32:666–671

Neuromuscular effects of succinylcholineOnset time was 1.4 (0.4) min for CNM and 1.7 (0.6) min

for control dogs (P¼ 0.47). Times to 25, 75 and 90%

recovery were significantly longer (P� 0.001) for CNM

dogs than for controls (Fig. 2). The recovery index

was not significantly different between the treatment

groups [CNM 8.3 (3.5) vs. control 3.9 (2.1) min; P¼ 0.15].

Performance of acceleromyographyCalibration of the AMG required several attempts in dogs

affected with CNM, in which the evoked excursion of the

paw was minimal. After calibration, the AMG reports the

value of sensitivity (gain) required to set the control

response to 100%. The sensitivity after calibration was

significantly greater for CNM dogs [CNM 481 (30) vs.

control 308 (80); P¼ 0.003], suggesting that signal ampli-

fication by the AMG monitor was larger in those animals.

In one dog with CNM, the gain had to be increased

manually to its maximum (512) because calibration failed

after several attempts. We did not encounter any pro-

blems during AMG calibration in control animals.

In three out of six dogs with CNM, the AMG monitor

reported single twitch values between 10 and 20% at a

time when neuromuscular block was expected to be

maximal and when evoked motor response could neither

be seen nor palpated (Fig. 3). Such erroneous measure-

ments were not observed in the control dogs (Fig. 3).

DiscussionOur results show that the increase in Kþ after SCh was

similar for the two groups of dogs. No electrocardio-

graphic signs consistent with hyperkalaemia, such as tall

T waves, absence of P waves or wide QRS complexes,

were observed at any time.20 In two CNM dogs, we

observed a transient decrease in arterial blood pressure

after SCh, which resolved spontaneously. This might

have been due to histamine release, but no other signs


5.0

4.5

4.0

3.5

3.0

2.5Pre Post

CNM

in dogs with autosomal-recessive centronuclear myopathy and controls.r, the increase was similar between groups.

Cop


Table 1 Median (interquartile range) concentration of electrolytes, acid–base status and glucose concentration measured 5 min before (Pre)and 5 min after (Post) succinylcholine was given to centronuclear myopathy and control dogs

CNM Control

NormalPre Post Pre Post

pH 7.39 (0.03) 7.39 (0.04) 7.3 (0.04) 7.3 (0.02) 7.35 to 7.45SBE (mmol l�1) �1 (1.5) 0 (3.25) �2.5 (2) �3 (2) �5 to 0Naþ (mmol l�1) 142.5 (1.75) 142.5 (4.75) 143.5 (3.5) 141.5 (5.25) 139 to 150iCa2þ (mmol l�1) 1.29 (0.11) 1.3 (0.09) 1.38 (0.07) 1.36 (0.03) 1.12 to 1.4Glucose (mg dl�1) 122 (26) 118.5 (36) 96 (18.5) 106.5 (11.5) 60–115

iCa2þ, ionized calcium; CNM, centronuclear myopathy; SBE, standard base excess.

such as flushing of the mucous membranes, urticaria or

signs of bronchospasm were observed. As the highest Kþ

concentrations recorded did not exceed the normal limit

for dogs (5.5 mmol l�1), it appears unlikely that an

increase in Kþ was responsible for these haemodynamic

changes.20 Moreover, the increment in Kþ observed in

both groups after SCh is in agreement with previous

reports in man (0.5 to 1 mmol l�1).21 In our study, Kþ

was measured 5 min after SCh administration; we chose

5 min because in humans, the increase in Kþ induced by

SCh peaks at 3 to 4 min.2,22,23

Succinylcholine-induced hyperkalaemia has been

reported in a variety of pathological states including

muscle trauma (inflammatory or thermal), upper and

lower motor neurone defects and severe infection,2–5

when SCh may be contraindicated. In patients with

disease of this nature, upregulation of extrajunctional

(fetal or immature) acetylcholine receptors and also an

isoform of the acetylcholine receptor, known as a7AChR,

is observed. Upon interaction with SCh, depolarisation of

extrajunctional and a7AChR occurs resulting in an exag-

gerated efflux of Kþ.23 As we did not observe hyperka-

laemia in dogs with CNM, it is unlikely that significant

upregulation of these receptors occurred. Recent obser-

vations of endplates of an individual affected with CNM

found a reduced number of acetylcholine receptors per


Fig. 2

100

80

60

40

20

00 10 20 30 40 50

ST

(%

)

Time (minutes)

*

*

*

CNM

Control

Spontaneous recovery of the single twitch (ST) to 25, 75 and 90%(normalised to final single twitch value) after succinylcholine0.3 mg kg�1 in dogs with autosomal-recessive centronuclear myopathy(CNM) and controls. �Significant difference between groups; P<0.05.

endplate and a reduction in the acetylcholine receptor

index. The authors also observed formation of immature

endplate regions that could potentially express immature

acetylcholine receptors.24

Succinylcholine is usually avoided in patients with malig-

nant hyperthermia, as it is known to trigger the condition.

The skeletal muscle ryanodine receptor (RYR1) gene has

been implicated in the development of MH and recent

evidence has shown that RYR1 mutations can also be

involved in the development of some forms of myopa-

thies with central nuclei or in patients presenting with

mixed diseases that include both core and central

nuclei.25,26 In at least one instance, malignant hyperther-

mia has developed in an anaesthetised patient with

CNM.27 Although many cases of CNM remain geneti-

cally unresolved,28 it has been suggested that RYR1

mutations might be common in individuals with CNM

and that they should be considered at risk for developing

malignant hyperthermia.26 Our experience with dogs

with autosomal-recessive CNM provided no evidence

of any signs of malignant hyperthermia being triggered

by SCh or isoflurane. Of note, this group of dogs has been

anaesthetised at least four times with isoflurane or

sevoflurane for different unrelated investigations; no

complications indicative of malignant hyperthermia were

observed.

Although there were no differences between groups in

onset time, our results show moderately longer duration

of neuromuscular blockade in dogs with CNM; the

recovery of the single twitch to 90% was delayed in

the CNM dogs by nearly 10 min. The difference in the

recovery index between groups did not quite reach

significance, but it is possible that our sample size is

too small to detect such a difference. We chose a dose of

SCh of 0.3 mg kg�1 in our investigation. Although this

dose might appear lower than that typically used in

humans, in dogs, it is commonly used to produce com-

plete block;17,18 the return of the first twitch of the TOF

to 80% of baseline after 0.3 mg kg�1 SCh takes 20 to

30 min.17,18 It is possible that the longer duration of

neuromuscular block observed in the CNM dogs could

be attributed to breed differences (Labrador retriever vs.

beagle), but no breed-specific alterations in the time-

course of neuromuscular blockers have been reported for

dogs. Furthermore, when duration of SCh was compared


Copyr

670 Martin-Flores et al.

Fig. 3

100

50

00 10 20 30 40

Time (minutes)

ST

(%

)

100

50

00 10 20 30 40

Time (minutes)

ST

(%

)

Control CNM

No visible twitch

Examples of the single twitch (ST) height after succinylcholine 0.3 mg kg�1 (time zero) in a control dog and one with centronuclear myopathy (CNM).In the CNM dog, twitch heights of �20% continued to be displayed by the monitor despite the absence of any observable evoked twitch.

between greyhounds and mixed breed dogs, no differ-

ences were observed.29 It appears that the differences in

recovery times that we observed between control and

CNM dogs are relatively benign, especially if the extent

of neuromuscular blockade is being measured objec-

tively.

Acceleromyographic monitoring in dogs with CNM

proved challenging. Several attempts were required

before calibration could be performed. This was not

the case in the control animals, nor has it been our

experience when using similar protocols in earlier work.

In one dog, calibration was not possible and the gain was

manually increased to its maximum. During calibration of

the AMG, the signal (gain) is amplified so that the

response can be set to 100%. It follows that small evoked

responses might require higher signal amplification.

When signal amplification is high, the potential for erro-

neous measurements arising from background noise, such

as movement from surgical table, increases. In dogs with

CNM, the sensitivity used by the AMG was significantly

higher than in the control group, indicating higher signal

amplification. In these dogs, erroneous results were

observed at the time of complete block; the AMG dis-

played twitch heights of up to 20% when no visible or

palpable twitch could be detected (Fig. 3). This obser-

vation suggests that AMG monitoring might be prone to

erroneous measurements whenever the evoked response is

very small (and signal amplification high), as is the case in

many patients with neuromuscular disease. Similar diffi-

culties have been reported when calibrating an AMG

monitor on neonates and small infants and whether the

sensitivity of the AMG monitor is adequate for patients

producing small responses is in question.30 Presumably,

our experience of myopathic dogs represented an exag-

geration of that observation.

ight © European Society of Anaesthesiology. UnEur J Anaesthesiol 2015; 32:666–671

Our study has limitations. The sample size is small

reflecting the availability of animals with CNM and

because this is an animal model with small numbers,

our findings cannot be extrapolated directly to humans.

Nevertheless, this study adds information that might be

relevant to anaesthesiologists presented with patients

with this rare condition. The dogs in this study were

autosomal-recessive; we cannot exclude the possibility

that autosomal-dominant individuals might behave

differently. Weakness in individuals with CNM can

worsen mildly with time.1 We cannot speculate on how

progression of the disease might affect the duration and

effects of SCh. We compared groups of dogs of different

breeds and different size and weight; the control group

was composed of beagles, which were smaller than the

Labradors with CNM. Beagles are commonly used for

research purposes, and to our knowledge, no breed-

related differences in the response to neuromuscular

blockers have been reported in dogs. We did not measure

cholinesterase activity in either group, and hence, we

cannot comment on whether that could have influenced

the duration of action of SCh. However, it is noteworthy

that duration of SCh in the beagles is in accord with

previous reports.16,17 Whole blood Kþ concentrations

were only measured at baseline and 5 min after SCh

administration and it is possible that higher values of

Kþ could have gone unnoticed. However, no electrocar-

diographic changes indicative of hyperkalaemia were

observed at any point in any of the dogs. Rhabdomyolisis

has been reported after SCh was given to patients with

other myopathies.6 Although specific biomarkers for

muscle injury were not measured in these experi-

ments, all of the animals returned quickly to their pre-

experimental condition and none had signs of muscle

pain, suggesting that any muscle injury was minimal in

these animals.


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In summary, SCh 0.3 mg kg�1 resulted in similar onset

but longer duration of action in dogs with autosomal-

recessive CNM than in control ones. Autosomal-recessive

CNM did not exacerbate the increase in Kþ ordinarily

seen after succinylcholine in these animals. Although our

sample size is too limited to evaluate the incidence of

succinylcholine-induced hyperkalaemia, extrapolation of

these findings suggests that increased duration of action

should be expected if succinylcholine is given to a patient

with autosomal-recessive CNM.

Acknowledgements relating to this articleAssistance with the study: none.

Financial support and sponsorship: this work was supported by

the Section of Anesthesiology, College of Veterinary Medicine,

Cornell University.

Conflicts of interest: none.

Presentation: none.

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The Kalaemic and Neuromuscular Effects of.2