Diabetes mellitus affects the duration of action of vecuronium in dogs

R E S E A R C H P A P E R

Diabetes mellitus affects the duration of action of

vecuronium in dogs

Louise Clark, Elizabeth A Leece & Jacqueline C Brearley

Animal Health Trust, Lanwades Park, Newmarket, CB8 7UU, UK

Correspondence: Louise Clark, Davies Veterinary Specialists, Manor Farm Business Park, Higham Gobion, Hitchin, Hertfordshire, SGS 3HR,

UK. E-mail: [email protected]

Abstract

Objective To compare the duration of action of

vecuronium in diabetic dogs with a control group.

Study design Prospective clinical study.

Animals Forty client-owned diabetic (n = 20) and

non-diabetic dogs.

Methods Dogs were considered free from other

concurrent disease based on clinical examination

and laboratory data. After pre-anaesthetic medica-

tion with acepromazine and methadone, anaesthe-

sia was induced with intravenous (IV) propofol and

maintained with isoflurane-nitrous oxide in oxygen.

Neuromuscular blockade (NMB) was achieved with

vecuronium, 0.1 mg kg)1 IV and its effects recorded

by palpation (pelvic limb digital extension) and

electromyography (m. tibialis cranialis) of responses

(twitches; T) to repeated train-of-four (TOF) nerve

stimulation. Time to onset of NMB was the period

between vecuronium injection and loss of fourth

twitch (T4) in the TOF pattern recorded by EMG and

palpation. Duration of NMB was defined as the time

from drug administration to return of T1 by

palpation (T1tactile) and EMG (T1EMG). Times to

return of T2-4 were also recorded. Time from

induction of anaesthesia to vecuronium injection

was recorded. Heart rate, non-invasive mean arte-

rial pressure, body temperature, end-tidal isoflurane

and end-tidal CO2 concentrations were recorded at

onset of NMB and when T1EMG returned. Loss and

return of palpable and EMG responses for diabetic

and non-diabetic dogs were compared using t-tests

and Mann Whitney U-tests.

Results There were significant (p < 0.05) differ-

ences between diabetic and non-diabetic dogs for

the return of all four palpable and EMG responses.

Times (mean ± SD) for return of T1tactile were

13.2 ± 3.5 and 16.9 ± 4.2 minutes in diabetic

and non-diabetic dogs respectively. There were no

differences between diabetic and non-diabetic dogs

in the time to onset of vecuronium with EMG or

tactile monitoring.

Conclusions and clinical relevance The duration of

action of vecuronium was shorter in diabetic dogs

as indicated by both tactile and EMG monitoring.

Keywords diabetes mellitus, dog, muscle relaxant,

neuromuscular blockade, vecuronium.

Introduction

Dogs with diabetes mellitus commonly are

anaesthetized for phacoemulsification of cataracts.

Neuromuscular blockade (NMB) produced by non-

depolarising drugs, such as vecuronium, is desirable

as part of the anaesthetic technique because it

predictably produces a central, immobile eye which

facilitates surgery. In human patients with type II

diabetes mellitus and receiving peri-operative insu-

lin, when compared to non-diabetic subjects the

duration of action of vecuronium is prolonged, i.e.,

1

Veterinary Anaesthesia and Analgesia, 2012 doi:10.1111/j.1467-2995.2012.00714.x

an increased time after injection to return of first

(T1) and fourth (T4) response to ‘train of four’ (TOF)

stimulation of a peripheral nerve. An increased

current is also required for supramaximal nerve

stimulation (Saitoh et al. 2003). Furthermore,

antagonism of NMB with neostigmine and atropine

is less effective; a significantly greater number of

diabetic than non-diabetic patients have a TOF ratio

of <0.9 following reversal. That is T4 remains

<90% of T1, despite the administration of reversal

agents. The basis of these effects is not completely

understood but may result from changes in the

neuromuscular junction and motor nerve conduc-

tion (Saitoh et al.2004). These altered responses to

vecuronium are observed in human diabetic

patients during inhalational anaesthesia with

sevoflurane but not total intravenous anaesthesia

(Saitoh et al. 2005).

Although the pharmacokinetics of vecuronium

have been documented in the dog (Marshall et al.

1980a,b; Jones 1985a,b; Thut et al. 1994) there is

no information available regarding the clinical use

of the drug in diabetic dogs. The aim of this study

was to record the duration of action of vecuronium

in dogs with diabetes mellitus and compare it with a

control population undergoing anaesthesia for the

same procedure.

Methods

This prospective clinical study included 40 dogs pre-

sented to the Animal Health Trust for phacoemulsi-

fication of cataracts between January 2005 and

January 2006. All animals underwent pre-operative

physical examination. Routine pre-anaesthetic blood

sampling was undertaken to determine packed cell

volume, plasma total protein, urea, creatinine and

electrolyte concentrations. A more extensive bio-

chemical evaluation and venous blood gas analysis

was performed on the basis of preliminary findings.

Animals with alanine transaminase (ALT) or alkaline

phosphatase (ALKP) concentrations in excess of

500 iu L)1 were not studied in an attempt to exclude

hepatopathy as a confounding factor affecting vecu-

ronium clearance (Feldman & Nelson 2004).

Dogs were regarded as being diabetic on the basis of

a history consistent with diabetes mellitus, persistent

serum hyperglycaemia, glucosuria and an appropri-

ate response to insulin administered at the referring

veterinary surgeon. Non-diabetic animals did not

meet any of these criteria. Additionally, owners

evaluated diabetic stability based on polyuria, poly-

dipsia and polyphagia, and referring veterinary sur-

geons serially evaluated blood glucose and serum

fructosamine prior to referral. No further attempt was

made to evaluate the stability of diabetic cases

following referral. Dogs were excluded from the study

if there was a history and/or clinical signs of, or

biochemical indicators of severe cardiovascular or

other systemic disease, if they were <6 months of age,

or temperament precluded the use of a standard

anaesthetic technique. Current medications were

recorded. Dogs were fasted from midnight on the day

prior to surgery. Water was freely available. All dogs

received topical non-steroidal anti-inflammatory

drugs and appropriate mydriatic drugs before surgery.

Blood glucose was measured prior to pre-anaes-

thetic medication in all diabetic patients and insulin

administered at the discretion of the anaesthetist.

All procedures were undertaken in the morning. In

all cases, pre-anaesthetic medication was metha-

done (0.2 mg kg)1) (Physeptone; Martindale Phar-

maceuticals, UK) and acepromazine (0.01 mg kg)1)

(ACP; Novartis Animal Health, UK) administered

intramuscularly (IM) given approximately 30 min-

utes before aseptic placement of an over-the-needle

catheter in a lateral saphenous vein.

Anaesthesia was induced with propofol (Propoflo;

Abbott Animal Health, UK) administered intrave-

nously (IV) to effect. The trachea was intubated

with an appropriately sized cuffed endotracheal tube

to which a heat and moisture exchange device had

been attached. This was then connected to an

appropriate breathing system and ventilator, and

intermittent positive pressure ventilation imposed.

Anaesthesia was maintained with isoflurane (end-

tidal isoflurane concentration (FE¢ISO) 1.0–1.5%)

vaporized in oxygen and nitrous oxide with an

inspired oxygen concentration >0.3. Non-steroidal

anti-inflammatory drugs (carprofen or meloxicam)

or steroids (dexamethasone), and antibiotics (poten-

tiated amoxycillin) were administered IV at the

discretion of the surgeon.

Routine anaesthetic monitoring, applied to all

dogs, consisted of capnography and inspired/end

tidal agent monitoring, pulse oximetry, electrocardi-

ography, non-invasive blood pressure (oscillometric),

and rectal temperature (Kolormon 7251 plus;

Kontron, UK). End tidal carbon dioxide concen-

tration (PE¢CO2) was maintained at 4.6–6.4 kPa

(35–45 mmHg) and mean arterial pressure (MAP)

>60 mmHg. Persistent hypotension unresponsive to

a decreased inspired isoflurane concentration was

grounds for exclusion from the study. In diabetic

Duration of action of vecuronium in diabetic dogs L Clark et al.

� 2012 The Authors. Veterinary Anaesthesia and Analgesia2 � 2012 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesiologists

dogs, blood glucose was measured at the time of NMB

administration, when T1EMG returned and every

30 minutes thereafter. Hartmann’s solution was

administered at 10 mL kg)1 hour)1 IV. This was

supplemented with 0.18% saline and 4% glucose if

blood glucose concentrations were <3.3 mmol L)1.

Body temperature was maintained using a circulat-

ing warm air blanket (Bairhugger 505; Augustine

Medical, distributed by Actamed Ltd, UK).

Neuromuscular monitoring was established by

placing two stimulating electrodes over the peroneal

nerve at the level of the femoro-tibial joint of the

non-dependent limb. The distal limb was allowed to

move freely and recording electrodes were placed in

m. tibialis cranialis. Train of four stimuli (TOF) (Lee

1975) were applied using an electromyographic

(EMG) monitoring system (Medelec Sapphire 2ME,

Viasys Healthcare, UK). The stimuli consisted of

0.2 ms square waves applied at 2 Hz. The supra-

maximal stimulus was determined for each dog. The

corresponding electromyographic amplitudes were

displayed, measured and recorded.

Vecuronium (0.1 mg kg)1) (Norcuron; Organon,

UK) was administered IV as a bolus and the IV

catheter flushed with heparinized saline (t = 0).

Trains of four (TOF) were applied every 12 seconds

from t = 0 until no response to stimulation was

elicited. The time from induction of anaesthesia to

administration of vecuronium was recorded. The

EMG amplitude of the response to the TOF stimu-

lation was recorded every 12 seconds. Simulta-

neously, the distal limb was palpated to determine

the tactile response to nerve stimulation. One of two

similarly trained observers assessed tactile response

in all cases. Electromyographic and tactile loss of T4

to T1 was recorded. Times to onset of NMB were the

periods between vecuronium injection and loss of

the fourth twitch (T4) in the TOF pattern recorded

by EMG (time to onset of vecuroniumEMG) and by

palpation (time to onset of vecuroniumtactile). Heart

rate (HR), MAP, FE¢ISO, PE¢CO2, blood glucose and

temperature at the onset of NMB were recorded.

Train of four nerve stimulation was applied every

30 seconds starting from 10 minutes after vecuro-

nium was administered, unless the anaesthetist had

reason to suspect that NMB was no longer adequate.

Time to return of T1EMG–T4EMG and T1tactile–T4tactile

were recorded, as was the HR, MAP, FE¢ISO, PE¢CO2,

blood glucose and temperature at the time of return

of T1EMG. Muscle or skin temperatures were not

monitored. The duration of action of vecuronium

(tactile) was determined by time to return of T1tactile

and the duration of action vecuronium(EMG) by the

time to return of T1EMG. Time to loss of, and return

of, T1EMG and T4EMG, and T1tactile and T4tactile were

compared between sexes, within and between

groups.

Descriptive statistics are reported as mean ± stan-

dard deviation for normally distributed variables

and as median (minimum–maximum) for data with

skewed distributions. Loss and return of tactile and

EMG responses, time from induction of anaesthesia

to vecuronium administration, age, body mass,

body temperature as well as HR, MAP, FE¢ISO and

PE¢CO2 at onset of NMB and return of T1EMG for

diabetic and non-diabetic dogs were compared using

t-tests for independent samples or Mann Whitney

U-tests if the assumptions of normality and equal

variances were violated. Correlations between

tactile and EMG responses were determined for both

groups using the Spearman correlation test. Paired

t-tests were used to compare the tactile and EMG

responses overall. Data are displayed as mean ± SD

or median (minimum–maximum). The differences

between each sex, within each group and the times

to onset of NMB and duration of NMB were

examined using ANOVA. The data from each group

were then pooled and any differences between

female (entire and neutered) and male (entire and

female) dogs in onset or duration of NMB were

examined. Significance was set at p < 0.05.

Results

Twenty diabetic and 20 non-diabetic cases were

included in this study. Group characteristics, are

detailed in Tables 1 and 2. Propofol dose was not

significantly different between groups (p = 0.16).

Median dose of propofol was 4.0 (3.2–7.0) mg kg)1

in the diabetic dogs and 5.0 (2.0–9.0) mg kg)1 in

the non-diabetic dogs. No difference in physiological

measurements were seen between groups at the time

of onset or offset of NMB except that HR at onset of

NMB was significantly higher for diabetics (mean

HR = 96 ± 25 beats minute)1) compared with non-

diabetics (mean HR = 78 ± 23 beats minute)1)

(p = 0.03). No dog required additional glucose sup-

plementation.

Tactile response data were available for all dogs and

EMG data for 16 dogs in each group although some

response times were missing. Two dogs in the diabetic

groupfailed tolose tactile responses and were excluded

from the data analysis for tactile responses. One dog

had a TOF count (recorded by EMG) of 3 after


� 2012 The Authors. Veterinary Anaesthesia and Analgesia� 2012 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesiologists 3

6 minutes 52 seconds, and four palpable twitches

remained. One of these dogs also failed to lose both

tactile and EMG responses. This suggests a degree of

resistance to NMB in these cases. The differences in

EMG and palpable twitches may be due to methodo-

logical differences. T1-T4EMG returned before

10 minutes in one dog in the non-diabetic group and

so no data were available for this dog for return of

EMG responses. There were no differences between

diabetic and non-diabetic dogs for the loss of EMG or

tactile responses (p > 0.3). Thus there was no differ-

ence in the onset time of vecuronium in diabetic or

non-diabetic dogs. There were statistically significant

differences between diabetic and non-diabetic dogs for

tactile evaluation and EMG evaluation for the return

for all four responses (Table 2). The duration of action

of vecuronium(tactile), as determined by time to return

of T1tactile for non-diabetics was 16.8 ± 4.2 minutes

and for diabetics was 13.2 ± 3.5 minutes. The dura-

tion of action vecuronium(EMG) as determined by the

time to return of T1EMG for non-diabetics was

16.4 ± 3.6 minutes and for diabetics was

13.6 ± 3.4 minutes.

Paired t-tests did not show any differences

between the tactile and EMG paired responses

(p > 0.2). Both the loss and return of tactile and

EMG responses were correlated highly with one

another in both the diabetic group (rs ‡ 0.9,

p < 0.0001 and rs ‡ 0.6, p < 0.02 respectively)

and the non-diabetic group (rs ‡ 0.81, p = 0.0001

and rs 0.95, p < 0.0001).

The sexes represented in each group were similar

(Fig. 1). There were no differences between the sexes

within each group for time to loss of, and return of

T1EMG and T1tactile (diabetics: p > 0.12 and p > 0.6

respectively; non-diabetics: p > 0.9 and p > 0.3

respectively). When data from both groups were

pooled and all male and male neutered animals were

compared with all female and female neutered

animals, the time to loss of T1EMG in the female group

Table 1 Characteristics of cases with no statistically significant differences between diabetic and non-diabetic dogs. Data as

presented as mean (and SD) if data was normally distributed or median (and range) if it was not normally distributed

Variable Group n Mean ± SD Median (range) p-value

Age (years) Diabetics 20 9.3 ± 2.7 0.07

Non-diabetics 20 7.5 ± 3.5

Body mass (kg) Diabetics 20 18.1 ± 8.5 0.73

Non-diabetics 20 17 ± 11.2

Time from induction to vecuronium

administration (minutes)

Diabetics 20 17 (9–30) 0.12

Non-diabetics 20 15 (10–20)

Supramaximal stimulation (mA) Diabetics 17 44.0 ± 16 0.33

Non-diabetics 11 37.0 ± 20

HR at onset of NMB (beats minute)1) Diabetics 20 96 ± 25 0.03

Non-diabetics 20 78 ± 23

HR at return T1EMG (beats minute)1) Diabetics 20 90 ± 21 0.07


MAP at onset of NMB (mmHg) Diabetics 19 74 ± 19 0.81


MAP at return T1EMG (mmHg) Diabetics 18 68 ± 16 0.88


FE¢ISO at onset of NMB (%) Diabetics 19 1.2 ± 0.2 0.79


FE¢ISO at return T1EMG (%) Diabetics 19 1.2 ± 0.1 0.56


PE¢CO2 at onset of NMB (kPa) Diabetics 20 5.3 (2.4–7.2) 0.06

Non-diabetics 20 4.9 (3.7–6.3)

PE¢CO2 at return T1EMG (kPa) Diabetics 20 5.3 ± 0.7 0.4


Body temperature onset of NMB (�C) Diabetics 6 37.2 ± 0.7 0.22


Body temperature return T1EMG (�C) Diabetics 5 37.2 ± 0.7 0.26


Glucose at onset of NMB (mmol L)1) Diabetics 20 13.2 ± 5.8 n/a

Glucose at return of T1EMG(mmol L)1) Diabetics 13 13.1 ± 5.2 n/a



was longer than in the male group (p = 0.047),

however this result was affected by one outlier and is

of questionable biological significance.

One diabetic dog was already receiving predniso-

lone treatment at admission and one non-diabetic

received dexamethasone before vecuronium. All

other cases receiving intra-operative dexamethasone

received it after the study period. It was not possible

to examine potential links between blood glucose

stability in diabetic dogs and the duration of action of

vecuronium: there was incomplete serum fructos-

amine data, methodological differences between

laboratories in serum fructosamine evaluation and

lack of consistency in the evaluation of stability.

Discussion

Vecuronium (0.1 mg kg)1) administered to non-

diabetic dogs anaesthetized with isoflurane in the

current study produced a duration of blockade of

16.8 ± 4.2 minutes when evaluated by tactile

response to TOF stimulation, which is similar to that

Table 2 Time to return of tactile and EMG responses following administration of vecuronium to diabetic and non-diabetic

dogs. The duration of action of vecuronium is given by the time to return of T1

Tactile

response Group n

Mean ± SD

(minutes)

Median (range)

(minutes)

Mean

difference

95% Confidence interval

Lower Upper p-value

T1 Diabetics 18 13.2 ± 3.5 12.3 (9.3–21) )3.6 )1.08 )6.19 0.007

Non-diabetics 20 16.8 ± 4.2 15.8 (11.5–27.5)

T2 Diabetics 18 14.9 ± 3.9 13.8 (11.0–23.5) )4.5 )1.57 )7.36 0.004

Non-diabetics 20 19.4 ± 4.8 17.1 (12.0–29.5)

T3 Diabetics 18 16.2 ± 4.1 14.0 (11.5–25.0) )4.6 )1.45 )7.69 0.005

Non-diabetics 20 20.8 ± 5.2 19.0 (12.0–32.0)

T4 Diabetics 18 16.9 ± 4.3 15.8 (12.0–26.0) )4.8 )1.7 )8.0 0.004

Non-diabetics 20 21.8 ± 5.2 20.3 (15.0–32.0)

EMG response

T1 Diabetics 16 13.6 ± 3.4 12.75 (10–23) )2.8 )0.23 )5.38 0.034

Non-diabetics 15 16.4 ± 3.6 15.5 (12.5–24.0)

T2 Diabetics 15 15.4 ± 4.3 14.5 (10.0–26.0) )4.9 )1.6 )8.28 0.005

Non-diabetics 15 20.3 ± 4.7 19.0 (15.0–30.5)

T3 Diabetics 13 15.5 ± 2.9 15.0 (10.0–21.5) )6.5 )3.24 )9.77 0.0004

Non-diabetics 15 22.0 ± 5.0 19.5 (16.0–31.5)

T4 Diabetics 14 16.5 ± 3.4 16.3 (10.0–23.5) )6.0 )2.55 )9.39 0.001

Non-diabetics 15 22.4 ± 5.3 20.5 (16.0–33.0)

Figure 1 Sex distribution of cases overall, in the diabetic and non-diabetic groups.



reported previously. The observed differences may

be attributable to different methodologies. Studies in

dogs have demonstrated a vecuronium ED90 of 14

± 3 lg kg)1 (Booij et al. 1980), as assessed by the

dose which produced a 90% depression of twitch

tension and 35.8 ± 2.5 lg kg)1 (Thut et al. 1994)

derived by mathematical techniques. Using the TOF

count, Jones (1985a) reported a mean time to T1

reappearance of 13.4 minutes and Sarrafzadeh-Re-

zaei & Clutton (2009) reported a duration of total

blockade of 15.2 minutes for vecuronium

0.05 mg kg)1 when using a TOF method on the

ulnar nerve. Kariman & Clutton (2008) demon-

strated duration of effect of 22.2 ± 2.9 [18–

25] minutes for vecuronium 0.1 mg kg)1 using a

TOF method on the ulnar nerve and palpation of

evoked responses. The duration of effect was cal-

culated as loss of T4 to return of T4, whereas the

current study used time from drug administration to

the return of T1.

Other methodological differences that have been

demonstrated to affect results for duration of NMB

include; a lack of consistency of the anaesthetic drugs

administered; the parameters of neuromuscular func-

tionrecorded(Nava-Ocampoet al.2005)andthetypeof

neuromuscular monitoring technique employed (Nak-

ata et al. 1998). Mechanomyography has been estab-

lished as the gold standard for neuromuscular

monitoring and cannot be used interchangeably with

EMG (Engbaek 1996; Hofmockel et al. 1998). Mecha-

nomyography measures a shorter onset, more profound

block with slower recovery than that measured by EMG

and in humans suffering from neuromuscular disease,

these differences are more pronounced. Saitoh et al.

(2003) compared the duration of action of vecuronium

in diabetic and non-diabetic humans using an EMG

assessment of NMB and was subsequently criticized for

the use of a non-validated device (Hemmerling et al.

2003). The current study has similar methodological

limitations. However, subsequent analysis did not

show any significant differences between the paired

responses, and the tactile and EMG responses were

highly correlated with one another. This was true for

both the diabetic dogs and for the non-diabetic dogs,

suggesting that EMG measurement was not signifi-

cantly altered by the presence of diabetes mellitus.

This study demonstrated a shorter duration of

action of vecuronium in diabetic dogs when com-

pared to non-diabetic dogs. This contrasts to human

patients with type II diabetes, where the time to

return of T1EMG–T4EMG was significantly longer

than in non-diabetic patients (Saitoh et al. 2003).

The reason for the decrease in duration of action of

vecuronium in diabetic dogs is unknown, but could

potentially be due to effects on vecuronium metab-

olism, distribution, or clearance.

Altered hepatic metabolism or renal clearance

would provide the most obvious explanations for the

briefer effect of vecuronium in diabetic dogs. Concur-

rent or previous drug administration and pre-existing

pathology have been shown to alter the pharmacoki-

netics of vecuronium in humans, potentially via

changes in hepatic metabolism. Vecuronium is a large

steroidal molecule that undergoes organ dependent

elimination. In humans, 60–90% of vecuronium

elimination is via the hepatic route, either unchanged

in the bile (40–60%) or via hepatic metabolism

(20–30%), where it undergoes deacetylation to phar-

macologically active metabolites (3-desacetyl, 17-

desacetyl and 3,17-desacetyl vecuronium) (Khuenl-

Brady et al. 1992). In the dog renal excretion is

reported as 5–20% and biliary excretion 7–20% (Booij

et al. 1981). In humans, the enzyme responsible for

vecuronium metabolism is most likely to be a hepatic

cytochrome P450 (CYP), possibly CYP3A4. This is a

CYP iso-enzyme responsible for the metabolism of a

large number of steroids and over 120 different drugs

(Sweeney & Bromilow 2006). The effect of diabetes

mellitus on the CYP enzyme system is complex and not

fully elucidated (Sarlis & Gourgiotis 2005). Whether

diabetes influences CYP in a manner that increases the

rate of vecuronium metabolism is unknown at pres-

ent.

Corticosteroid administration has been reported to

cause resistance to NMB (Parr et al. 1991a,b; Fiacch-

ino & Giannini 1992) but the mechanism has not been

determined. Diabetic dogs may present with

pre-existing Cushing’s syndrome and endogenous

corticosteroids may potentially result in resistance to

vecuronium. Pre-anaesthetic biochemical evaluation

aimed to identify any dogs with elevated liver enzymes,

consistent with a pre-existing hepatopathy, and usu-

ally present in Cushing’s syndrome, and thus exclude

such cases from the study. However, biochemical

markers alone may not be effective in identifying all

affected cases. One diabetic dog was already receiving

prednisolone treatment at admission and one non-

diabetic received dexamethasone prior to administra-

tion of vecuronium. Whether this influenced the

duration of NMB in these cases is unknown.

Volume of distribution of vecuronium may be

altered by an increase in body water content.

Anabolic steroid abusers have a decreased sensitiv-

ity to vecuronium, partly resulting from an increase



in total body water content causing a change in

volume of distribution of the drug (Kam & Yarrow

2005). Work in humans suggests that weight gain

resulting from insulin treatment in poorly controlled

type II diabetes mellitus results in a change in total

body water content (Packianathan et al. 2005). To

the authors’ knowledge, body water content in

diabetic dogs has not been investigated. Persistent

mild hyperglycaemia tends to promote water reten-

tion, but hyperglycaemia in excess of the renal

threshold would promote diuresis and subsequent

volume depletion.

Kariman & Clutton (2008) postulated that mede-

tomidine induced diuresis results in an increased

vecuronium clearance and that this might explain

vercuronium’s reduced duration of action in mede-

tomidine recipients compared to control dogs. In

this study, the mean blood glucose of the diabetic

dogs at the time of return of T1(EMG) was

13.1 mmol L)1, in excess of the renal threshold

(Verlander 1997) and likely to promote an osmotic

diuresis. The decrease in duration of action of

vecuronium in diabetic dogs may be due to a

combination of factors including hepatic enzyme

induction, increased volume of distribution or

increased renal clearance. This contrasts with a

documented increase in duration in human type II

diabetics receiving peri-operative insulin.

Human diabetics suffer from pathological changes

at the neuromuscular junction and decreased motor

nerve conduction velocities even where clinical

diabetic neuropathy is not present (Lawrence & Locke

1961). This has been postulated as an explanation for

the reported increased duration of action of vecuro-

nium. In dogs, diabetic neuropathy only sporadically

has been reported (Steiss et al. 1981; Johnson et al.

1983; Katherman & Braund 1983). Canine cases of

diabetic neuropathy present with clinical signs of

neurological dysfunction (Morgan et al. 2008). Thus

it is not known if dogs have histological changes at

the neuromuscular junction and in peripheral nerves

prior to the onset of clinical signs.

In humans, gender has been shown to affect both

time to onset and duration of action of rocuronium,

an amino-steroid NMB. Adamus et al. (2007) dem-

onstrated that women are more sensitive to rocu-

ronium than men; the onset time was shortened

and the clinical duration was increased in female

patients. No mechanism for this sensitivity was

suggested. In this study there was no evidence of

increased sensitivity of females to neuromuscular

blockade. It is therefore unlikely that the sex of the

dogs was an important factor in determining the

duration of action of vecuronium.

No attempt was made to control for skin surface

temperature in the region of m. tibialis cranialis,

although core temperature was supported with an

active warming device. It has been demonstrated that

the duration of action of vecuronium is influenced by

skin surface temperature, in the absence of change in

core temperature, and that this decrease contributes

to the potentiation of NMB (Suzuki et al. 2004). In

this study all dogs were exposed to the same condi-

tions that might influence the degree of surface

cooling.

The investigators in this study were aware of the

disease state of the dogs. This was due to the

necessity for repeat blood sampling in diabetic dogs.

Non-diabetic dogs could not undergo repeat blood

sampling for a non-therapeutic reason, because this

is a licensed procedure.

Conclusion

In this study, based on EMG and tactile assessment, the

duration of action of vecuronium was significantly

shorter in diabetic dogs than in non-diabetic dogs

undergoing isoflurane anaesthesia. The reason for the

decrease in duration of action of vecuronium has yet to

be elucidated. Further studies to investigate whether

this finding is limited to steroidal non-depolarising

neuromuscular blocking agents may be warranted.

Acknowledgements

The authors would like to thank Dr Vicki Adams for

her initial statistical advice, Professor Eddie Clutton

for his assistance with the manuscript and Julia

Freeman for obtaining the EMG data.

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Received 20 April 2011; accepted 21 June 2011.



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Diabetes mellitus affects the duration of action of vecuronium in dogs