Veterinary Anaesthesia and Analgesia, 2012 doi:10.1111/j.1467-2995.2012.00722.

RESEARCH PAPER

Effects of a constant rate infusion of magnesium sulphate

in healthy dogs anaesthetized with isoflurane and
undergoing ovariohysterectomy

Eva Rioja*, Brighton T Dzikiti*, Geoffrey Fosgate , Amelia Goddard*, Frik G Stegmann* & Johan P Schoeman*
*Department of Companion Animal Clinical Studies, Faculty of Veterinary Sciences, University of Pretoria, South Africa
 Department of Production Animal Studies, Faculty of Veterinary Sciences, University of Pretoria, South Africa

Correspondence: Eva Rioja, Department of Companion Animal Clinical Studies, Faculty of Veterinary Science, University of Pretoria, Private
Bag X04, Onderstepoort, 0110, Pretoria, South Africa. E-mail: eva.riojagarcia@up.ac.za.

was performed pre- and post-anaesthesia. Postoper-

Abstract
Objective To determine the effects of intravenous
(IV) magnesium sulphate (MgSO4) as a bolus
followed by a constant rate infusion (CRI) on
anaesthetic requirements, neuroendocrine stress
response to surgery, haemostasis and postoperative
analgesia in healthy dogs undergoing ovariohyster-
ectomy.
Study design Blinded randomized clinical trial.
Animals Sixteen female dogs.
Methods After intramuscular premedication with
acepromazine (0.05 mg kg)1) and morphine
(0.3 mg kg)1), anaesthesia was induced with diaz-
epam (0.2 mg kg)1) and propofol (2 mg kg)1)
intravenously and maintained with isoflurane in
oxygen in all dogs. Dogs were randomly assigned to
two groups, M and C. Group M received MgSO4
(50 mg kg)1 over 15 minutes, followed by a
15 mg kg)1 hour)1 CRI). Group C received an
equivalent bolus and CRI of lactated Ringer’s
solution. In addition, all dogs received lactated
Ringer’s solution (10 mL kg)1 over 15 minutes
followed by 10 mL kg)1 hour)1). End-tidal isoflura-
ne and carbon dioxide tensions, cardio-respiratory
variables, arterial blood gases, electrolytes, ACTH
and cortisol concentrations were measured at
different time points. Thromboelastography (TEG)
ative pain was evaluated using the short form of the
Glasgow Composite Pain Scale. Data were analysed
with repeated measures ANOVA and Mann–Whitney
U tests (p < 0.05).
Results No statistically significant differences
between groups were found in any of the measured
variables. However, the alpha angle and maximal
amplitude recorded by TEG in group M were
significantly increased post-anaesthesia, but
remained within the reference interval. One dog in
Group M and two in Group C received rescue
analgesia during recovery.
Conclusions and clinical relevance As used in this
study, MgSO4 failed to decrease isoflurane require-
ments, postoperative pain and stress hormone
concentrations; however, it did not produce any
cardio-respiratory or major haemostatic side effects.
Administration of intravenous MgSO4 together with
an opioid during ovariohysterectomy in dogs does
not seem to provide any clinical advantage.
Keywords anaesthesia, canine, magnesium sulphate,
pain, thromboelastography.
Introduction
Magnesium is the fourth most common cation in
the body and the second most common intracellular

1
Intraoperative intravenous magnesium sulphate in dogs E Rioja et al.
cation after potassium (Fawcett et al. 1999). It
serves as a cofactor in many enzymatic reactions
and is involved in several other processes including
gating of calcium channels, transmembrane ion
fluxes, regulation of adenylyl cyclase activity, mus-
cle contraction, cardiac excitability, control of
vasomotor tone, neuronal activity, neurotransmit-
ter release and hormone receptor binding (Fawcett
et al. 1999; Herroeder et al. 2011).
Magnesium may also be able to produce analgesia
and prevent central sensitization by acting as an
antagonist at N-methyl-D-aspartate (NMDA) recep-
tors (Mayer et al. 1984). Conflicting results, how-
ever, have been obtained in investigations of the
analgesic effect of an intraoperative constant rate
infusion (CRI) of magnesium sulphate (MgSO4) in
humans. In some studies, MgSO4 did decrease
postoperative pain scores and opioid requirement
in patients undergoing both orthopaedic (Dabbagh
et al. 2009; Hwang et al. 2010) and soft tissue
surgeries (Tramer et al. 1996; Seyhan et al. 2006;
Mentes et al. 2008; Ryu et al. 2008; Saadawy et al.
2010). However, no beneficial effects were found
when intraoperative MgSO4 was administered to
patients undergoing hysterectomy (Ko et al. 2001),
Caesarean section (Paech et al. 2006) and thora-
cotomy (Kogler 2009).
Intraoperative IV MgSO4 also reduced the
requirement of propofol necessary to maintain
anaesthesia in humans (Choi et al. 2002; Telci
et al. 2002; Gupta et al. 2006; Seyhan et al. 2006;
Ray et al. 2010), but did not decrease intraopera-
tive sevoflurane requirements (Oguzhan et al.
2008) and actually increased its minimum alveolar
concentration (MAC) at the time of skin incision
(Durmus et al. 2006).
Only a few studies have investigated the effects of
an intraoperative CRI of MgSO4 in animals. In dogs
undergoing ovariohysterectomy, MgSO4 reduced
the dose of thiopental and propofol necessary for
orotracheal intubation, and also the halothane
requirement to maintain anaesthesia (Anagnostou
et al. 2008). It also reduced the MAC of halothane
in rats (Thompson et al. 1988), but failed to reduce
the MAC of isoflurane in goats (Queiroz-Castro et al.
2006).
The effects of MgSO4 on coagulation have not been
fully elucidated. Magnesium inhibited platelet func-
tion both in vitro (Ravn et al. 1996a) and in vivo
(Ravn et al. 1996b). Furthermore, MgSO4 attenu-
ated the hypercoagulable state induced by haemod-
ilution (and relative hypomagnesaemia) associated
2  2012 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesiologists
with rapid crystalloid administration in humans
(Ruttmann et al. 2007). Conversely, however, the
IV administration of MgSO4 significantly improved
thromboelastography (TEG) variables in human
patients with a hypocoagulable state and undergoing
liver transplantation (Choi et al. 2005). Both in vitro
and in vivo administration of MgSO4 did not signif-
icantly change TEG variables in healthy human
volunteers (James & Neil 1995; Ames et al. 1999).
The purpose of this study was to determine the
effects of IV administration of MgSO4 on anaesthetic
requirements, neuroendocrine stress response to
surgery, haemostasis and postoperative analgesia in
healthy dogs undergoing ovariohysterectomy.
Material and methods
The study was a blinded, randomized, clinical trial.
A total of 16 healthy female dogs undergoing
elective ovariohysterectomy at the Onderstepoort
Veterinary Academic Hospital were enrolled in the
study after obtaining approval from the Institutional
Animal Use and Care Committee, as well as owner
consent. They were considered to be healthy based
on a physical examination and preoperative (T0)
blood analyses including: blood smear, complete
blood count (CBC), total protein concentration (TP),
serum creatinine, electrolytes (including total mag-
nesium) and TEG. Exclusion criteria were body
weight <10 kg, age >7 years, current drug therapy
and presence of a coagulopathy, pregnancy or
uterine pathology (i.e. pyometra). Surgery was
performed by one of two experienced small animal
surgeons.
All dogs received morphine (Morphine sulphate;
Fresenius Kabi, Bodene Pty Ltd., South Africa)
0.3 mg kg)1 and acepromazine (Neurotranq;
Alfasan BV, Holland) 0.05 mg kg)1, administered
intramuscularly (IM) as pre-anaesthetic medica-
tions. Approximately 20 minutes afterwards, a
20-gauge · 1.25-inch (2.5 cm) cannula was placed
in the cephalic vein for administration of IV drugs
and fluids. Anaesthesia was induced with diazepam
(0.2 mg kg)1, IV, Micro Diazepam; Micro Health-
care Pty Ltd., South Africa) and propofol (2–
4 mg kg)1, IV; Propofol 1%; Fresenius Kabi Pty
Ltd., South Africa); the latter was administered to
effect in order to allow orotracheal intubation.
Anaesthesia was maintained with isoflurane (Isofor;
Safeline Pharmaceuticals Pty Ltd., South Africa)
vaporized in oxygen and delivered through a circle
breathing system with a fresh gas flow rate of
 2012 The Authors. Veterinary Anaesthesia and Analgesia
 Intraoperative intravenous magnesium sulphate in dogs E Rioja et al.

2 L minute)1. An experienced anaesthetist (ER), an equivalent bolus of lactated Ringer’s solution

unaware of treatment groups, adjusted isoflurane
concentration to maintain minimal jaw tone, partial
ventromedial rotation of the eyes and absence of
palpebral reflexes.
A 20-gauge · 1.25-inch (2.5 cm) cannula was
inserted into the dorsal pedal artery for arterial
blood sample collection and arterial pressure mea-
surements. The pressure transducer was positioned
at the level of the right atrium and zeroed to
atmospheric pressure. A multi-parameter monitor
(Datex-Ohmeda S/5 Anesthesia Monitor; GE Health-
care Finland Oy, Finland) was used to record the
following physiological variables: respiratory rate
(fR), expired tidal volume (VE), end-tidal carbon
dioxide tension (PE¢CO2), end-tidal isoflurane con-
centration (FE¢Iso), heart rate (HR), electrocardio-
gram, systolic, diastolic and mean arterial pressures
(SAP, DAP and MAP, respectively), haemoglobin
saturation (SpO2) and oesophageal temperature
(Temp). The gas analyzer was calibrated with a
commercial gas mixture (Quick Cal calibration Gas,
GE Healthcare Finland Oy).
Using a random numbers table, dogs were
assigned to two treatment groups, with each group
containing eight dogs. In Group M, MgSO4 (Sabax
Magnesium Sulphate 50% injection, Adcock Ingram
Critical Care Pty Ltd., South Africa) was diluted with
lactated Ringer’s solution (Intramed Ringer-Lactate
Solution; Fresenius Kabi, Bodene Pty Ltd.) and
administered as an IV bolus (50 mg kg)1 in 50 mL)
over 15 minutes, followed by a CRI (15 mg kg)1
hour)1, equivalent to 25 mL hour)1). In Group C,
(50 mL) was injected IV over 15 minutes and
followed by a CRI (25 mL hour)1). In both groups,
the bolus was administered after induction of
anaesthesia but before start of surgery; the CRIs of
MgSO4 and lactated Ringer’s solution were discon-
tinued immediately after skin closure. Additionally,
both groups received lactated Ringer’s solution IV
throughout anaesthesia (10 mL kg)1 over 15 min-
utes followed by 10 mL kg)1 hour)1).
Physiological variables were continuously moni-
tored and recorded at the following time points:
immediately before the administration of MgSO4 or
lactated Ringer’s bolus (T1); at 5 (T2) and 10 (T3)
minutes during the administration of MgSO4 or
lactated Ringer’s bolus; immediately after the
administration of MgSO4 or lactated Ringer’s bolus
(T4); after skin incision (T5); during the removal of
the first (T6) and second (T7) ovaries; during
closure of the abdominal wall (T8); and immediately
after skin closure (T9). The minute volume index
(VMi) was calculated by multiplying the VE and the
fR and dividing by the body weight in kilograms.
Intraoperative and postoperative serial blood
samples (Table 1) were obtained from the jugular
vein or dorsal pedal artery for comparison to results
obtained at T0. Jugular blood samples were collected
into a 4 mL serum tube (2 mL per sample), a 4.5 mL
trisodium citrate (3.2%) tube (4.5 mL per sample), a
4 mL EDTA tube (Beckton Dickinson Vacutainer
Systems, UK) (2 mL per sample) and a 3 mL
heparinised syringe (PICO50 Radiometer, Arterial
Blood Sampler, 80 IU electrolyte-balanced heparin;

Table 1 Collection times and vari-

ables measured from blood obtained Time points
from the jugular vein and the dorsal Variables
pedal artery in dogs undergoing measured T0 T1 T2 T3 T4 T5 T6 T7 T8 T9 T10
elective ovariohysterectomy

CBC X X
Total serum protein X X
Arterial blood gases X X X
Electrolytes X X
Thromboelastography X X
ACTH and cortisol X X X X X

T0 = preoperatively; T1 = immediately before the administration of a bolus of MgSO4 or

lactated Ringer’s solution; T2 = at 5 minutes and T3 = at 10 minutes after starting
administration of a bolus of MgSO4 or lactated Ringer’s solution; T4 = immediately after
the administration of a bolus of MgSO4 or lactated Ringer’s solution; T5 = after skin
incision; T6 = during the removal of the first ovary; T7 = during removal of the second
ovary; T8 = during closure of the abdominal wall; T9 = immediately after skin closure;
T10 = 30 minutes after extubation.

 2012 The Authors. Veterinary Anaesthesia and Analgesia

 2012 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesiologists 3
Intraoperative intravenous magnesium sulphate in dogs E Rioja et al.

Radiometer Medical ApS, Denmark) (1.5 mL per

sample), in this order. Additionally, jugular blood
samples for measurement of corticotrophin (ACTH)
concentrations were collected into cold 4 mL EDTA
vacutainer tubes (2 mL per sample), maintained at
4 C and centrifuged (also at 4 C) within 15 min-
utes of collection (Heraeus Megafuge 11R centrifuge;
Thermo Scientific, Germany). Jugular venous blood
samples were used for determination of CBC (Advia
2120 Hematology System; Siemens Healthcare
Diagnostics, IL, USA); total serum protein concen-
tration, serum creatinine, total magnesium and
chloride (Cobas Integra 400 Plus; Roche Diagnos-
tics, Switzerland); ionized calcium, sodium and
potassium (Rapidlab 348; Siemens Healthcare Diag-
nostics); and ACTH and cortisol concentrations
(Immulite 1000; Siemens Healthcare Diagnostics).
Arterial blood was collected from the dorsal pedal
artery into 3 mL heparinised syringes (1.5 mL per
sample) for immediate determination of pH, arterial
oxygen and carbon dioxide tensions (PaO2 and
PaCO2 respectively), bicarbonate and base excess
(Rapidlab 348; Siemens Healthcare Diagnostics).
Blood gases were measured at 37 C and not
corrected for body temperature. Haemostasis was
assessed by TEG (TEG 5000 Thromboelastograph
Haemostasis System; Haemoscope Corporation, IL,
USA) performed on the citrated venous blood sam-
ples. Citrated tubes for TEG analyses were main-
tained in a standing position for 30 minutes at room
temperature and analyses were performed using
human recombinant tissue factor as an activator,
which has been validated for use in dogs (Wiinberg
et al. 2005).
Quality of recovery from anaesthesia was scored
always by the same observer (ER) unaware of the
treatment groups using a five-point numerical rating
scoring system (Appendix 1). Postoperative pain was
assessed every 30 minutes from 30 to 180 minutes
after tracheal extubation using the short form of the
Glasgow Composite Measure Pain Scale (SF-GCMPS;
Reid et al. 2007) by the same observer (ER). Mor-
phine (0.2 mg kg)1) and carprofen (4.4 mg kg)1,
Statistical analysis
Data were analyzed using commercially available
software (SPSS version 17.0, SPSS Inc., IL). Data were
assessed for normality through the plotting of histo-
grams, calculation of descriptive statistics and the
Anderson-Darling test for normality. Outcome vari-
ables violating the normality assumption were
transformed using natural logarithms or ranks prior
to statistical analysis. A repeated measures ANOVA was
performed on all outcomes (natural or transformed
scale) to estimate the overall effect of treatment.
Normally-distributed continuous variables employed
post-hoc Bonferroni adjustment for multiple pairwise
comparisons. Mann–Whitney U tests with Bonferroni
p-value adjustment were used for non-normally
distributed outcomes requiring post-hoc compari-
sons. Wilcoxon signed rank tests were used to com-
pare pre- and post-operatively measured outcomes.
Results were considered significant if p < 0.05.
Results
Groups M and C were homogeneous in terms of
number of animals included, body weight, age,
preoperative haematological, biochemical and
TEG variables, amount of fluids administered and
surgery time. Anaesthesia time was statistically
shorter (10 minutes) in Group C (Table 2).
The variables DAP, VE and VMi were trans-
formed using natural logarithms and fR, MAP and
Table 2 Descriptive data, surgery and anaesthesia times,
preoperative creatinine and amount of fluids administered
during surgery, shown as mean ± SD, of dogs undergoing
elective ovariohysterectomy. Group M (n = 8) received an
intravenous bolus of 50 mg kg)1 followed by an infusion
of 15 mg kg)1 hour)1 of MgSO4 during surgery. Group C
(n = 8) received an equivalent volume of lactated Ringer’s
solution
Groups

Rimadyl injectable; Pfizer, South Africa) were admin-

istered IV and subcutaneously, respectively, as rescue C (n = 8) M (n = 8) p value
analgesia when the SF-GCMPS score was ‡6/24, as
previously suggested (Reid et al. 2007). Such dogs Weight (kg) 29.2 ± 7 31.1 ± 5.3 0.645
were subsequently withdrawn from the study. Dogs Age (years) 1.7 ± 1.9 2.2 ± 1.8 0.234
Surgery time (minutes) 27 ± 2 31 ± 9 0.574
that did not require any rescue analgesia during the
Anaesthesia time 93 ± 7 103 ± 6 0.021
180 minute observation period received the same (minutes)
doses of morphine and carprofen at the end of the Fluids (mL kg)1) 20.3 ± 4.3 20.2 ± 3.8 0.959
study, despite low pain scores.
 2012 The Authors. Veterinary Anaesthesia and Analgesia
4  2012 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesiologists
 Intraoperative intravenous magnesium sulphate in dogs E Rioja et al.
PaO2 were rank-transformed for the ANOVA analy-
sis. No statistically significant differences were
found when comparing FE¢Iso and the intraopera-
tive cardiorespiratory variables measured in the
two groups (3). However, in both groups, SAP,
DAP, MAP at T6, T7 and T8, but only MAP at T9,
were significantly higher than at T1. In both
groups, Temp recorded from T3 to T8 was signif-
icantly lower than at T1. At T4 and T9, the pH
was significantly lower and PaCO2 was statistically
higher compared to values at T1 in both groups;
while PaO2 was significantly higher only at T4
compared to T1. In both groups, bicarbonate
concentrations at T9 were significantly higher
than at T1 (Table 4).
Results for ACTH and cortisol are summarized in
Fig. 1. No significant differences were found in
ACTH or cortisol concentrations between the two
groups. No differences between pre- and post-
operative TEG values were identified between the
two groups (Table 5). In Group M, however, the
postoperative values for alpha angle, maximal
amplitude and coagulation index were statistically
higher, but not clinically significant, in comparison
to preoperative values.
A similar degree of haemodilution was detected
when comparing haematological and biochemical
values at T0 and T9 in both groups (Table 6).
Haematocrit, haemoglobin, total protein, potas-
sium, erythrocytes, leukocytes and platelets at T9
were significantly lower than at T0 in both
groups. Total magnesium was significantly lower
postoperatively in Group C in comparison to the
T0 value and in comparison to Group M. No
statistically significant differences were found
between the two groups for any of the other
variables.
There were no significant differences in recovery
scores between groups. The median (range) recov-
ery scores were 1 (1–2) for both groups. There was
a significant effect of time but not of treatment in
the ANOVA analysis of the pain scores. The median
(range) pooled pain scores were 3 (1–5), 3 (1–11),
2 (0–5), 2 (1–5), 2 (0–7) and 1 (0–3), at 30, 60,
90, 120, 150 and 180 minutes post-extubation,
respectively. One dog in Group M and two in Group
C received rescue morphine during recovery. The
dog in Group M was a very excitable Greyhound,
which despite receiving three doses of rescue
morphine (at 30, 150 and 240 minutes post-
extubation), still had a pain score ‡6. One of the
dogs in Group C was a very anxious Labrador that
 2012 The Authors. Veterinary Anaesthesia and Analgesia
 2012 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesiologists
received two doses of rescue morphine (150 and
180 minutes post-extubation) but still had a pain
score ‡6.
No adverse effects were observed during recovery
from anaesthesia in any dogs.
Discussion
This study failed to demonstrate any clinically
beneficial effect of administering MgSO4 in dogs
sedated with acepromazine and morphine, anaes-
thetized with isoflurane and undergoing ovario-
hysterectomy. However, no side effects were found.
These results are in contrast to a previous study in
dogs undergoing ovariohysterectomy, where a pre-
operative IV MgSO4 bolus of 50 mg kg)1 followed
by a CRI of 12 mg kg)1 hour)1 decreased the
induction dose of thiopental and intraoperative
halothane requirements (Anagnostou et al. 2008).
The loading dose (50 mg kg)1) and infusion rate
(15 mg kg)1 hour)1) in the present study were
different to those used by Anagnostou et al.
(2008), but included in the dose range (30–
50 mg kg)1 followed by 6–25 mg kg)1 hour)1)
reported in human medicine (Choi et al. 2002; Telci
et al. 2002; Durmus et al. 2006; Gupta et al. 2006;
Seyhan et al. 2006; Oguzhan et al. 2008; Ryu et al.
2008; Ray et al. 2010; Saadawy et al. 2010).
Theoretically, the doses used here should have
produced a similar or greater anaesthetic sparing
effect compared to the study of Anagnostou et al.
(2008). The discrepancy in the results obtained
might be explained by the different anaesthetic
technique used. While the study of Anagnostou
et al. (2008) used only acepromazine (0.05 mg
kg)1) for pre-anaesthetic medication, our study used
the same dose of acepromazine in combination with
morphine. Both morphine and acepromazine
decrease the MAC of volatile anaesthetics (Heard
et al. 1986; Steffey et al. 1994; Muir et al. 2003).
When lidocaine and ketamine are co-administered
with morphine, isoflurane requirements do not
decrease further, despite the ability of these two
drugs to reduce isoflurane MAC when administered
alone (Muir et al. 2003). It is possible, therefore,
that the administration of acepromazine and mor-
phine produced a maximal anaesthetic sparing
effect, so that a further decrease of isoflurane
requirement was impossible despite MgSO4 admin-
istration. Another possible explanation is that the
study lacked sufficient power to detect significant
differences between groups. According to the results
5
6
Table 3 Cardiorespiratory and temperature results over time, shown as mean ± SD, in dogs undergoing elective ovariohysterectomy. Group M (n = 8) received an intravenous bolus of
50 mg kg)1 followed by an infusion of 15 mg kg)1 hour)1 of MgSO4 during surgery. Group C (n = 8) received an equivalent volume of lactated Ringer’s solution

Time points

Group T1 T2 T3 T4 T5 T6 T7 T8 T9

HR (beats minute)1) M 104 ± 25 101 ± 25 100 ± 26 101 ± 25 98 ± 25 105 ± 23 96 ± 8 99 ± 14 111 ± 19

C 96 ± 36 93 ± 37 94 ± 36 96 ± 35 105 ± 37 118 ± 24 107 ± 20 99 ± 22 111 ± 21
SAP (mmHg) M 86 ± 22 84 ± 14 81 ± 18 84 ± 18 93 ± 22 123 ± 23* 136 ± 15* 115 ± 11.1* 104 ± 18
C 88 ± 11 89 ± 13 88 ± 13 92 ± 11 102 ± 16 119 ± 14* 140 ± 20* 120 ± 18* 113 ± 11
DAP (mmHg) M 52 ± 15 49 ± 9 48 ± 13 49 ± 15 55 ± 16 78 ± 31* 91 ± 25* 72 ± 17* 60 ± 19
C 47 ± 10 45 ± 7 43 ± 6 45 ± 5 52 ± 11 68 ± 8* 87 ± 6* 71 ± 9.4* 64 ± 9
MAP (mmHg) M 63 ± 15 61 ± 9 60 ± 13 62 ± 15 67 ± 15 92 ± 27* 104 ± 21* 84 ± 14* 74 ± 17*
C 58 ± 9 58 ± 8 57 ± 6 59 ± 6 67 ± 11 84 ± 8* 101 ± 6* 84 ± 10* 78 ± 8*
VMi (mL kg)1 minute)1) M 134 ± 59 154 ± 80 155 ± 88 146 ± 57 175 ± 83 227 ± 120 180 ± 84 163 ± 41 171 ± 55
Intraoperative intravenous magnesium sulphate in dogs E Rioja et al.

C 148 ± 118 138 ± 86 134 ± 64 154 ± 86 170 ± 87 189 ± 76 191 ± 106 163 ± 118 174 ± 100
PE¢CO2 (mmHg) M 40 ± 4 40 ± 5 40 ± 4 39 ± 5 38 ± 3 39 ± 4 40 ± 4 42 ± 2 40 ± 2
(kPa) 5.3 ± 0.6 5.3 ± 0.6 5.3 ± 0.6 5.2 ± 0.6 5.1 ± 0.5 5.2 ± 0.5 5.4 ± 0.5 5.6 ± 0.3 5.3 ± 0.3
C 41 ± 5 41 ± 6 42 ± 4 41 ± 4 40 ± 5 39 ± 5 40 ± 4 41 ± 3 41 ± 4
5.5 ± 0.7 5.6 ± 0.8 5.5 ± 0.6 5.5 ± 0.6 5.3 ± 0.7 5.2 ± 0.7 5.3 ± 0.6 5.4 ± 0.4 5.5 ± 0.6
FE¢Iso (Vol%) M 1.4 ± 0.2 1.3 ± 0.2 1.2 ± 0.2 1.2 ± 0.3 1.2 ± 0.3 1.4 ± 0.4 1.4 ± 0.4 1.4 ± 0.4 1.2 ± 0.3
C 1.4 ± 0.4 1.2 ± 0.2 1.1 ± 0.2 1.1 ± 0.3 1.2 ± 0.2 1.3 ± 0.4 1.4 ± 0.4 1.3 ± 0.4 1.2 ± 0.3
Temp (C) M 36 ± 0.9 35.7 ± 1 35.6 ± 1* 35.5 ± 0.9* 35.4 ± 0.8* 35.4 ± 0.8* 35.4 ± 0.7* 35.4 ± 0.7* 35.5 ± 0.7
C 35.5 ± 0.7 35.2 ± 0.7 35 ± 0.6* 35 ± 0.6* 34.9 ± 0.6* 34.9 ± 0.6* 34.8 ± 0.6* 34.8 ± 0.6* 34.9 ± 0.5

*value significantly different (p < 0.05) from T1.

See key of Table 1 for time points.

 2012 The Authors. Veterinary Anaesthesia and Analgesia

 2012 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesiologists
 Intraoperative intravenous magnesium sulphate in dogs E Rioja et al.

Table 4 Arterial blood gas results

over time, shown as mean ± SD, in Time points
dogs undergoing elective ovariohys-
terectomy. Group M (n = 8) received Group T1 T4 T9
an intravenous bolus of 50 mg kg)1
followed by an infusion of 15 mg
pH M 7.36 ± 0.04 7.32 ± 0.03* 7.32 ± 0.02*
kg)1 hour)1 of MgSO4 during sur-
C 7.33 ± 0.04 7.32 ± 0.04* 7.32 ± 0.04*
gery. Group C (n = 8) received an PaCO2 (mmHg) (kPa) M 42.5 ± 4.5 47.7 ± 3.3* 48 ± 1.8*
equivalent volume of lactated Ring- 5.7 ± 0.6 6.3 ± 0.4* 6.4 ± 0.2*
er’s solution C 47.2 ± 4.5 48.5 ± 5.2* 49.2 ± 3.9*
6.3 ± 0.6 6.4 ± 0.7* 6.5 ± 0.5*
PaO2 (mmHg) (kPa) M 427.5 ± 38.4 452.7 ± 44.4* 425.9 ± 69.8
56.9 ± 5.1 60.2 ± 5.9* 56.6 ± 9.3
C 439.9 ± 62.9 490.8 ± 42.7* 489.4 ± 42.2
58.5 ± 8.4 65.3 ± 5.7* 65.1 ± 5.6
Bicarbonate (mmol L)1) M 23.3 ± 1 24.2 ± 1.2 24.3 ± 0.7*
C 24.2 ± 0.9 24.2 ± 2 24.6 ± 1.4*
Base excess (mmol L)1) M )2.2 ± 1 )2.2 ± 1.2 )2.1 ± 0.8
C )2 ± 1.2 )2.2 ± 2 )1.8 ± 1.6

*Value significantly different (p < 0.05) from T1.

See key of Table 1 for time points.

Table 5 Pre-and post-operative throm-

boelastographic values, shown as med- Group M Group C
ian (range), in dogs undergoing elective
ovariohysterectomy. Group M (n = 8) T0 T9 T0 T9
received an intravenous bolus of
50 mg kg)1 followed by an infusion of
R (minutes) 5.9 (4.3–0.5) 6.3 (3.1–9.8) 5.0 (3.9–7.4) 5.5 (3.8–7.4)
15 mg kg)1 hour)1 of MgSO4 during
K (minutes) 2.3 (1.8–4.8) 2.2 (1.5–3.1) 2.2 (1.1–4.0) 1.8 (1.5–2.6)
surgery. Group C (n = 8) received an Angle () 54.5 (40.9–61.8) 59.8 (49.0–69.1)* 59.9 (41.4–74.5) 65.1 (52.8–69.8)
equivalent volume of lactated Ringer’s MA (mm) 55.4 (46.6–63.6) 58.5 (52.9–66.1)* 56.8 (44.5–75.2) 60.9 (49.4–70.0)
solution GI (dynes 6.2 (4.4–8.8) 7.1 (5.6–9.7)* 6.6 (4.0–15.2) 7.8 (4.9–11.6)
second)1)
LY30 (%) 0 (0–6.6) 0 (0–0.1) 0 (0–6.1) 0.2 (0–2.2)
LY60 (%) 1.0 (0–10.4) 0.8 (0–3.6) 2.4 (0.5–8.0) 2.5 (0.3–7.2)

*Value significantly different (p < 0.05) from T1.

Reaction time (R), clot formation time (K), alpha angle (Angle), maximal amplitude (MA),
global clot strength (GI), lysis at 30 minutes (LY30) and lysis at 60 minutes (LY60).
See key of Table 1 for time points.

obtained by Anagnostou et al. (2008), we calcu-
lated that five animals in each group would be
necessary in order to detect an isoflurane concen-
tration difference of 0.2%, considering a two-sided
alpha of 0.05 and a beta of 0.2 (power of 80%). On
the basis of the results obtained in this study,
however, we retrospectively calculated that 40 dogs
per group would be necessary to detect a difference
of 0.2% in isoflurane concentration, with a power of
80%. The clinical significance of a difference of 0.2%
is debatable and it is therefore our opinion that a
larger sample size would not have changed the
results of this study.
 2012 The Authors. Veterinary Anaesthesia and Analgesia
 2012 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesiologists
It is possible that anaesthetic sparing effect of
MgSO4 is volatile agent-dependent. In a study in
rats, a CRI of MgSO4 reduced the MAC of halothane
(Thompson et al. 1988), while it failed to reduce the
MAC of isoflurane in goats (Queiroz-Castro et al.
2006). This is also supported by clinical studies in
humans where the requirements for halothane or
IV anaesthetics, such as propofol, are consistently
reduced by MgSO4 administration, while the
requirements for isoflurane and also sevoflurane
are unchanged or even increased (Choi et al. 2002;
Telci et al. 2002; Durmus et al. 2006; Gupta et al.
2006; Seyhan et al. 2006; Oguzhan et al. 2008;
7
Intraoperative intravenous magnesium sulphate in dogs E Rioja et al.

250 ACTH 400 Cortisol

Control 350
200 Magnesium
300
250

nmol L–1
pg mL–1
150
† 200
100 150
100 *
50 *
* 50 † † †
*† †
0 0
T0 T1 T7 T9 T10 T0 T1 T7 T9 T10
Time points Time points

Figure 1 ACTH and cortisol concentrations over time, expressed as mean ± SD, in dogs undergoing elective ovariohys-
terectomy. Group M (n = 8) received an intravenous bolus of 50 mg kg)1 followed by an infusion of 15 mg kg)1 hour)1 of
MgSO4 during surgery. Group C (n = 8) received an equivalent volume of lactated Ringer’s solution. *Pooled value
significantly different (p < 0.05) from T0.  Pooled value significantly different (p < 0.05) from T1. See key of Table 1 for
time points.

Table 6 Pre-and post-operative electrolytes and haematological values, shown as median (range), in dogs undergoing
elective ovariohysterectomy. Group M (n = 8) received an intravenous bolus of 50 mg kg)1 followed by an infusion of
15 mg kg)1 hour)1 of MgSO4 during surgery. Group C (n = 8) received an equivalent volume of lactated Ringer’s solution

Group M Group C

T0 T9 T0 T9

Total Mg (mmol L)1) 0.80 (0.72–0.84) 1.35 (1.26–1.53)* 0.81 (0.70–0.86) 0.69 (0.65–0.76)*, 
Cl) (mmol L)1) 115 (109–123) 114 (111–121) 112 (108–116) 114 (111–117)
Na+ (mmol L)1) 147 (144–150) 145 (143–150) 148 (144–152) 146 (143–149)*
K+ (mmol L)1) 3.88 (3.65–4.18) 3.58 (3.43–3.95)* 4.05 (3.75–4.47) 3.67 (3.32–3.86)*
Ca+2 (mmol L)1) 1.34 (1.26–1.43) 1.33 (1.31–1.40) 1.40 (1.30–1.49) 1.41 (1.31–1.44)
Ht (%) 53 (43–64) 38 (32–46)* 52 (37–59) 36 (32–41)*
TP (g L)1) 58.9 (54.3–81.1) 48.8 (42.9–67.6)* 54.3 (51.0–70.2) 45.6 (41.6–56.2)*
Hb (g L)1) 179 (151–215) 129 (108–154)* 176 (125–201) 122 (102–144)*
RCC (·1012 L)1) 7.77 (6.05–8.69) 5.56 (4.47–6.43)* 7.64 (5.36–8.27) 5.10 (4.48–5.75)*

*Value significantly different (p < 0.05) from T0;  value significantly different (p < 0.05) from group M.
Haematocrit (Ht), total serum protein concentration (TP), haemoglobin concentration (Hb), red blood cell count (RCC) and platelet count
(Plt).
See key of Table 1 for time points.

Ryu et al. 2008; Ray et al. 2010). This discrepancy 2001). These two in vitro studies were performed
could be due to differences in study design or it using isoflurane and sevoflurane and contradict the
could be related to specific drug interactions at the in vivo observation that magnesium does not change
level of the central nervous system. It has been or increases MAC of these two inhalant anaesthet-
suggested that competitive antagonism by magne- ics. One possible explanation for this discrepancy is
sium at hippocampal presynaptic calcium channels that the magnesium concentrations achieved in
regulates neurotransmitter release in the central vitro may not correlate with the cerebrospinal fluid
nervous system, which could explain, at least in concentrations attained in vivo.
part, the mechanism underlying the anaesthetic- The present study did not suggest an improve-
sparing effects of magnesium (Sasaki et al. 2002). ment in postoperative analgesia in dogs receiving
Moreover, it has been shown that clinically relevant MgSO4 during surgery, as postoperative pain scores
concentrations of volatile anaesthetics inhibit the were similarly low in both groups. In the study by
functioning of NMDA receptors expressed recomb- Anagnostou et al. (2008), none of the dogs that
inantly in Xenopus oocytes and that this inhibition received MgSO4 required rescue analgesia during
is potentiated by magnesium (Hollmann et al. recovery whereas two of the dogs in the control
 2012 The Authors. Veterinary Anaesthesia and Analgesia
8  2012 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesiologists
 Intraoperative intravenous magnesium sulphate in dogs E Rioja et al.
group required rescue analgesia. Three mechanisms
have been suggested for the anti-nociceptive effects
of magnesium: inhibition of calcium influx, antag-
onism of NMDA receptors and prevention of
enhanced ligand-induced NMDA signalling in a
state of hypomagnesaemia (Iseri & French 1984;
Mayer et al. 1984; Nowak et al. 1984). Evidence in
the medical literature is unconvincing in this
respect, as shown by a systematic review in 2007
that included 14 randomized trials (Lysakowski
et al. 2007). The lack of postoperative analgesic
difference between groups could be due to the low
power of this study. Alternatively, it is possible that
the degree of postoperative pain was low in these
dogs due to concomitant administration of mor-
phine or that the period of observation (3 hours
post-extubation) was too short. Moreover, these
dogs did not have preoperative pain and therefore
no activation of the NMDA receptors was present.
Surgery and pain induce a neuroendocrine stress
response, which causes sympathetic activation and
promotes a catabolic state (Desborough 2000).
Magnesium has been shown to possess sympatho-
lytic activity (Shimosawa et al. 2004), which is
evidenced by its ability to attenuate the haemody-
namic responses to endotracheal intubation in
humans (Puri et al. 1998). The sympatholytic effect
of magnesium seems to be due to the blockade of N-
type calcium channels at nerve endings, inhibiting
norepinephrine release (Shimosawa et al. 2004). In
the present study MgSO4 did not attenuate the
neuroendocrine or the haemodynamic response to
surgery as evidenced by similar increases in ACTH
and cortisol concentrations, as well as arterial
pressure, in both groups during ovarian removal.
The reason for this is unclear. It is possible that the
dose of MgSO4 was too low to mitigate the intense
sympathetic stimulation during ovarian ligament
ligation and resection.
Hypermagnesaemia has been reported to cause
hypotension, bradycardia, increased PR and QRS
duration, and fatal arrhythmias in dogs (Nakayama
et al. 1999; Jackson & Drobatz 2004). A study of
incremental magnesium administration to anaes-
thetized healthy dogs revealed that significant
adverse cardiovascular effects occurred when plas-
ma concentrations exceeded 6 mmol L)1 (Nakay-
ama et al. 1999). Total magnesium concentration
was only slightly above the upper limit considered
physiological in dogs in Group M and no adverse
cardiorespiratory effects were observed during and
after IV MgSO4 administration.
 2012 The Authors. Veterinary Anaesthesia and Analgesia
 2012 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesiologists
Postoperative hypomagnesaemia is common in
humans (Chernow et al. 1989), especially after
abdominal surgeries (Lanzinger et al. 2003; Sch-
warz & Nevarez 2005), as well as in critically ill
patients (Ryzen 1989; Tong & Rude 2005). In
veterinary medicine, hypomagnesaemia has been
identified in 6.1% of hospitalized canine patients
(Khanna et al. 1998), 28% of hospitalized feline
patients (Toll et al. 2002) and in 54% of equine
patients undergoing colic surgery (Garcia-Lopez
et al. 2001). Several factors may be involved,
including reduced dietary intake or intestinal
absorption, increased renal or gastrointestinal
losses and iatrogenic causes such as haemodilu-
tion. In healthy humans, it has been shown that
rapid administration of crystalloid solutions with
low or no magnesium causes hypomagnesaemia
and hypercoagulability (Ruttmann et al. 2007).
Moreover, hypomagnesaemia induces activation of
NMDA receptors (Nowak et al. 1984), which could
enhance pain intensity. In the present study,
postoperative serum magnesium concentration
was decreased in the control group, but still
remained within reference intervals. Longer and
more invasive surgical interventions are more
likely to lead to hypomagnesaemia (Lysakowski
et al. 2007).
There are conflicting reports on the effects of
magnesium on coagulation. Magnesium increased
some TEG variables indicating a tendency towards
increased coagulation when administered IV to
healthy human volunteers (Ames et al. 1999),
patients undergoing liver transplant (Choi et al.
2005), as well as when it was added to blood
in vitro (James & Neil 1995). Conversely, magnesium
inhibits platelet function (Ravn et al. 1996a,b),
which may explain its ability to attenuate the
hypercoagulable state induced by rapid crystalloid
infusion secondary to haemodilution in humans
(Ruttmann et al. 2007). In the present study, some
TEG variables increased in both groups, potentially
indicating hypercoagulability, although statistical
significance was only reached in Group M. How-
ever, these variables remained within reference
intervals and the changes are not considered
clinically relevant. The lack of significant effects
of magnesium on coagulation in this study could
be due to differences among species, speed of onset
of haemodilution, volume of fluid or dose of MgSO4
administered, or low sample size. One limitation of
this study to determine the effects of fluids and
magnesium on coagulation is the lack of a
9
Intraoperative intravenous magnesium sulphate in dogs E Rioja et al.
negative control group that did not receive any
fluids.
Some adverse effects reported following IV admin-
istration of magnesium include nausea and vomit-
ing (Jackson & Drobatz 2004; Anagnostou et al.
2008), which seem to occur after rapid bolus
administration in conscious animals. In the present
study MgSO4 was administered when the animal
was unconscious and no episodes of vomiting were
observed postoperatively.
In conclusion, intraoperative administration of a
CRI of MgSO4 in dogs sedated with acepromazine
and morphine, anaesthetized with isoflurane and
undergoing ovariohysterectomy does not produce
any clinical advantage.
Acknowledgements
Funding was obtained from the Department of
Companion Animal Clinical Studies, the Research
Committee of the University of Pretoria and the
National Research Foundation of South Africa.
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Appendix 1
Numerical rating scale for evaluation of the quality of recovery from anaesthesia.

1. Quiet, calm, breathing normally, no excitement or signs of pain during at least 15 minutes after extubation
2. Some vocalization but no excitement during the first 15 minutes after extubation, not painful, relaxes in response to
human contact
3. Mild excitement with some vocalization during the first 15 minutes after extubation, not painful, does get better in response to
human contact but continues vocalizing
4. Vocalizing, thrashing, very excited but not painful, at some point during the first 15 minutes after extubation, does not
get better in response to human contact
5. Painful

 2012 The Authors. Veterinary Anaesthesia and Analgesia

12  2012 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesiologists