J. Vet. Med.
A 50, 530–533 (2003)
Ó 2003 Blackwell Verlag, Berlin
ISSN 0931–184X
Department of Surgery, Faculty of Veterinary Medicine, Uludağ University, Bursa, Turkey
Hepatic Effects of Halothane, Isoflurane or Sevoflurane Anaesthesia in Dogs
_
A. Topal1,3, N. Gül1, Y. Ilçöl2
and O. S. Görgül1
Addresses of authors: 1Department of Surgery, Faculty of Veterinary Medicine, Uludağ University; 2Laboratory of
Biochemistry, Medical Faculty, Uludağ University; 16190 Bursa, Turkey; 3Corresponding author: Tel.: +90 224 234 7655;
fax: +90 224 234 6395; E-mail: atopal@uludag.edu.tr
With 1 table
Summary
The effects of halothane, isoflurane and sevoflurane anaes-
thesia on hepatic function and hepatocellular damage were
investigated in dogs, comparing the activity of hepatic enzymes
and bilirubin concentration in serum. An experimental study
was designed. Twenty-one clinically normal mongrel dogs were
divided into three groups and accordingly anaesthetized with
halothane (n ¼ 7), isoflurane (n ¼ 7) and sevoflurane (n ¼ 7).
The dogs were 1–4 years old, and weighed between 13.5 and
27 kg (18.4 ± 3.9). Xylazine HCI (1–2 mg/kg) i.m. was used
as pre-anaesthetic medication. Anaesthesia was induced with
propofol 2 mg/kg i.v. The trachea was intubated and anaes-
thesia maintained with halothane, isoflurane or sevoflurane
in oxygen at concentrations of 1.35, 2 and 3%, respect-
ively. Intermittent positive pressure ventilation (tidal volume,
15 ml/kg; respiration rate, 12–14/min) was started immediately
after intubation and the anaesthesia lasted for 60 min. Venous
blood samples were collected before pre-medication, 24 and
48 h, and 7 and 14 days after anaesthesia. Serum level of
aspartate aminotransferase (AST), alanine aminotransferase
(ALT), alkaline phosphatase (ALP) and gamma-glutamyl-
transferase (GGT), lactate dehydrogenase (LDH GGT)
activities and bilirubin concentration were measured. Serum
AST, ALT and GGT activities increased after anaesthesia in
all groups. In the halothane group, serum AST and ALT
activities significantly increased all the time after anaesthesia
compared with baseline activities. But in the isoflurane group
AST and ALT activities increased only between 2 and 7 days,
and in the sevoflurane group 7 days after anaesthesia. GGT
activity was increased in the halothane group between 2 and
7 days, and in the isoflurane and sevoflurane groups 7 days
after anaesthesia. All dogs recovered from anaesthesia without
complications and none developed clinical signs of hepatic
damage within 14 days. The results suggest that the use of
halothane anaesthesia induces an elevation of serum activities
of liver enzymes more frequently than isoflurane or sevoflurane
from 2 to 14 days after anaesthesia in dogs. The effects of
isoflurane or sevoflurane anaesthesia on the liver in dogs is
safer than halothane anaesthesia in dogs.
Introduction
Halothane, introduced into clinical practice in 1956, is a widely
used inhalant anaesthetic agent in veterinary medicine. How-
ever, many reports of hepatotoxicosis associated with haloth-
ane administration have been published, for e.g. in people
(Dales, 1976; Williams et al., 1977; Sinclair, 1980; Neuberger
U.S. Copyright Clearance Center Code Statement: 0931–184X/2003/5010–0530 $15.00/0
Received for publication: December 12, 2003
and Williams, 1984; Colin, 1986; Kharasch and Hankins, 1996;
Rodes and Bruguera, 2001), rats (Van Dyke, 1982; Delclaux
et al., 1998; Masaki, 1999), guinea-pigs (Sato et al., 1994;
Farrell et al., 1996), dogs (Gaunt et al., 1984; Frink et al.,
1990; Canpolat et al., 1992) and horses (Gopinath et al., 1970).
In people, severe hepatic necrosis develops following
halothane anaesthesia in one of every 6000–35 000 patients
and is fatal in 75% of these patients. The association between
hepatic necrosis and halothane anaesthesia is responsible for
the decrease in use of this anaesthetic in people (McEven et al.,
2000).
Halothane is metabolized in the microsomal fraction of the
liver via two main pathways: oxidative metabolism is greater in
the presence of high oxygen tension, while reductive metabo-
lism is favoured by hypoxic conditions. The extent of this
metabolism is approximately 20%. Products from reductive
metabolism might be more hepatotoxic than oxidative metab-
olites. CF3CÆHCI free radicals are formed by cytochrome P450,
and some of these radicals then initiate lipid peroxidation in the
endoplasmic reticulum; the damage produced by this process
might ultimately be responsible for cell death (Ray and
Drummond, 1991; Jones and Kenna, 1992, Smith et al., 1993).
Halothane substantially inhibits drug-metabolizing capacity
by the liver with slight to moderate increases in serum activities
of hepatic-derived enzymes such as transaminases (Williams
et al., 1977; Sinclair, 1980; Darling et al., 2000; Rodes and
Bruguera, 2001). There are also several case reports and
studies about fulminant hepatitis induced by halothane
anaesthesia (Kenna et al., 1987; Ray and Drummond, 1991;
Jones and Kenna, 1992; Kharasch and Hankins, 1996; Rodes
and Bruguera, 2001).
In 1986, hepatic necrosis was reported in veterinary medi-
cine in a healthy lactating female goat and seven of 29
hyperimmunized goats after anaesthesia with halothane
(O’brien et al., 1986). Six of the animals died and all the
affected goats had extremely high serum aspartate amino-
transferase (AST) activity and high total bilirubin concentra-
tion. In another experimental study 24 goats were
anaesthetized with halothane and isoflurane. In one goat that
was anaesthetized with halothane serum AST activity was high
at 24 and 48 h after anaesthesia (McEven et al., 2000).
Isoflurane and sevoflurane, two other inhalant anaesthetics
used in animals and human beings, are less hepatotoxic than
halothane. However, recent studies (Shichinohe et al., 1992;
Nishiyama et al., 1998a,b, 1999; Schmidh et al., 1999; Darling
et al., 2000) have reported liver injury after sevoflurane or
isoflurane anaesthesia in man. This included a fulminant liver
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Hepatic Effects of Halothane, Isoflurane or Sevoflurane Anaesthesia in Dogs
failure and necrosis after isoflurane anaesthesia (Nishiyama
et al., 1998a).
There are few studies that have evaluated hepatic function
during halothane and isoflurane anaesthesia in dogs (Gaunt
et al., 1984; Frink et al., 1990; Canpolat et al., 1992). There
are no studies comparing serum activities of liver enzymes after
halothane, isoflurane or sevoflurane anaesthesia in dogs.
The purpose of this study was to compare serum liver
enzyme activities and total bilirubin concentrations in dogs
during halothane, isoflurane or sevoflurane anaesthesia.
Material and Methods
The Faculty of Veterinary Medicine and Medical Faculty of
the Uludağ University approved the experimental protocol.
The animals were housed and treated according to the
guidelines of the National Society of Medical Research
Principles of Laboratory Animal Care.
Twenty-one clinically normal mongrel dogs were used in this
study. These included 10 males and 11 females. The exact age
was unknown but was estimated to be between 1 and 4 years.
Body weight ranged between 13.5 and 27 kg (mean
18.4 ± 3.9 kg). The animals were fed a commercial dog food
(Royal Canin, Randers, Denmark, Medium Adult) and had
free access to water. Food, but not water, was withheld for at
least 12 h before the start of the experiment.
Physical examinations, serum biochemical analyses and
WBC before 2 days from the study were normal in all dogs.
The dogs were divided into three groups of seven animals to
be anaesthetized with halothane, isoflurane and sevoflurane.
Fifteen minutes before the start of the experiment, the dogs
were pre-medicated with xylazine HCI 1–2 mg/kg i.m.
(RompunÒ; Bayer, Istanbul, Turkey) and after an intravenous
catheter was placed in the cephalic vein, a Ringer’s solution
infusion (10 ml/kg/h) was started.
Anaesthesia was induced with propofol 2 mg/kg i.v. (Abbott
PropofolÒ; Abbott, Chicago, IL, USA) and a cuffed endotra-
cheal tube was placed in the trachea.
Anaesthesia was maintained with halothane (FluothaneÒ;
Zeneca, Istanbul, Turkey), isoflurane (ForaneÒ; Abbott, UK)
or sevoflurane (SevoraneÒ; Abbott, Chicago, IL, USA) deliv-
ered via a circle rebreathing system in 4 l of O2. The
anaesthetic vapourizer was then turned to a setting of 1.35%
for halothane, 2% isoflurane and 3% sevoflurane.
Intermittent positive pressure ventilation (tidal volume
approximately 15 ml/kg; respiration rate12–14 breaths/min)
was started immediately after intubation. Tidal volume was
adjusted to maintain an end-tidal CO2 concentration between 35
and 45 mm Hg (measured by continuous capnography, Normo-
cap 200; Datex-Ohmeda Helsinki, Finland) and SpO2 95%
(measured by continuous pulse oxymetry, Vet/OXTM 4403; SDI
Fort Collins, CO, USA). During anaesthesia, heart rate (HR)
and oesophageal temperature were monitored continuously
using a pulse oximeter. These cardiopulmonary responses (HR,
SpO2, ETCO2, temperature) were recorded every 15 min from
the time of anaesthetic induction to the beginning of recovery.
Anaesthesia was continued for 60 min. After anaesthesia, all
dogs were extubated and observed in the post-anaesthesia care
unit for the next 2 h and the animal care unit for 14 days.
Venous blood samples were collected before pre-medication,
24 and 48 h, and 7 and 14 days after anaesthesia. Serum
aliquots were frozen at )20°C until analysis.
531
The activity of aminotransferase was measured during
routine laboratory tests. The serum activity of aspartate
aminotransferase (AST), alanine aminotransferase (ALT),
alkaline phosphatase (ALP) and gamma-glutamyltransferase
(GGT), lactate dehydrogenase (LDH), and the total bilirubin
(Tbil) concentration were measured, using automated chem-
istry analyzer (Aeroset; Abbott). Normal reference values for
AST, ALT, ALP, GGT, LDH and Tbil concentration were
10–88 IU/l, 10–88 IU/l, 20–150 IU/l, 1.0–10 IU/l, 45–235 IU/l
and 0.06–0.10 mg/dl, respectively (Center, 1989).
All data are expressed as mean ± standard deviation (SD).
Differences in AST, ALT, ALP, GGT, and LDH activity and
Tbil concentrations were analysed using Wilcoxon signed
ranks tests within the groups and Mann–Whitney U-test
between groups. Ratios of enzyme activities compared with
baseline values were calculated and analysed between groups
using the Mann–Whitney U-test.
Results
The results of the enzyme activities after anaesthesia with
halothane, isoflurane and sevoflurane are summarized in
Table 1. All groups showed an increase of AST, ALT and
GGT activity. Abnormal AST (P < 0.005) and ALT
(P < 0.05) values were seen in the halothane group all the
time after anaesthesia. But AST and ALT activities were
increased in the isoflurane group between 2 and 7 days and in
the sevoflurane group at 7 days after anaesthesia (P < 0.05;
Table 1). GGT activity was increased in the halothane group
at 2 and 7 days and in the isoflurane and sevoflurane groups at
7 days after anaesthesia (P < 0.05; Table 1). LDH activity
increased on 7 days post-anaesthetic in the halothane group
(P < 0.05; Table 1). ALP activity did not significantly
increase after anaesthesia in any group. Total bilirubin
concentration increased after anaesthesia, but there were no
significant differences among the groups (Table 1).
No patients showed hepatitis or liver failure after anaes-
thesia.
No significant changes in HR were observed in the haloth-
ane group, whereas an increase in HR was observed in the
isoflurane and sevoflurane groups. However, there were no
significant differences in HR among the three anaesthetic
groups. Respiration rate was maintained at the same frequency
using mechanical ventilation. There were no significant chan-
ges in SpO2 during the anaesthesia period between anaesthetic
groups.
Discussion
In this study, the serum activities of AST, ALT and GGT were
higher after administering halothane than after administering
isoflurane and sevoflurane. But AST and ALT values increased
in the isoflurane group between 2 and 7 days, in the sevoflu-
rane group on 7 days after anaesthesia. Although these
changes did not result in liver failure, it is likely that the
enzymes originated from damaged liver cells.
In the present study HR during halothane anaesthesia was
lower than during isoflurane and sevoflurane anaesthesia.
However, there was no significant difference in HR between
isoflurane and sevoflurane groups. These findings might be an
indication for a less depressant effect to baroreceptor-reflex
532 A. Topal et al.

Table 1. Mean activity levels of

Time after anaesthesia (day) serum enzymes and total bilirubin
Test (ref. during and after anaesthesia in
range) Groups Pre 1 2 7 14 dogs (n ¼ 7)
AST H 21 ± 7 48 ± 13* 138 ± 27** 159 ± 36** 123 ± 17**
10–88 I 20 ± 9 36 ± 11 52 ± 18* 69 ± 22* 38 ± 20
(IU/l) S 19 ± 6 23 ± 9 27 ± 11 38 ± 10* 24 ± 12
ALT H 22 ± 7 53 ± 17* 98 ± 19* 138 ± 28* 109 ± 21*
10–88 I 21 ± 7 35 ± 13 52 ± 16* 59 ± 17* 33 ± 15
(IU/l ) S 20 ± 8 31 ± 10 38 ± 12 49 ± 14* 29 ± 9
ALP H 57 ± 16 83 ± 25 78 ± 39 58 ± 37 57 ± 19
20–150 I 55 ± 19 69 ± 28 72 ± 20 51 ± 22 30 ± 12
(IU/l ) S 56 ± 21 62 ± 24 73 ± 24 55 ± 23 32 ± 18
GGT H 3.2 ± 1.7 3.3 ± 2.2 5.4 ± 1.6* 6.1 ± 1.2* 3.8 ± 1.6
1–10 I 3.4 ± 1.1 3.6 ± 1.3 4.4 ± 2.3 6.0 ± 1.8* 3.2 ± 1.3
(IU/l ) S 3.0 ± 1.5 3.2 ± 2.5 3.8 ± 2.1 5.9 ± 1.6* 3.5 ± 2.2
LDH H 150 ± 66 219 ± 61 236 ± 57 297 ± 82* 194 ± 58
45–235 I 145 ± 59 169 ± 52 149 ± 24 138 ± 42 131 ± 71
(IU/l ) S 138 ± 34 147 ± 57 134 ± 38 121 ± 30 120 ± 41
Tbil H 0.38 ± 0.08 0.40 ± 0.11 0.41 ± 0.10 0.38 ± 0.10 0.36 ± 0.13
0.06–0.10 I 0.36 ± 0.13 0.41 ± 0.08 0.42 ± 0.07 0.36 ± 0.11 0.32 ± 0.12
(mg/dl) S 0.30 ± 0.12 0.32 ± 0.04 0.36 ± 0.08 0.32 ± 0.08 0.25 ± 0.12

Mean ± SD, enzyme activities (IU/l) and bilirubin concentrations (mg/dl) for the groups receiving
halothane (H), isoflurane (I) and sevoflurane (S).
*P < 0.05 and **P < 0.005 difference from baseline activities (Wilcoxon rank sum).

function with sevoflurane and isoflurane in comparison with
halothane (Bernard et al., 1990).
Liver function after inhalation anaesthesia depends on
liver blood flow during anaesthesia, increased intracellular
calcium concentration ([Ca++]i), metabolites of anaesthetics,
and other drugs used perioperatively (Kanaya et al., 1995;
Nishiyama et al., 1998a,b). Halothane causes a loss of auto-
regulation and semireciprocal flow such that hepatic arterial
blood flow (HABF) becomes pressure dependent, reducing
hepatic blood flow and O2 delivery (Frink et al., 1990; Farrell
et al., 1996). In contrast, liver blood flow does not differ
between sevoflurane and isoflurane anaesthesia in men
(Kanaya et al., 1995). In greyhounds both sevoflurane and
isoflurane produced comparable effects on total hepatic
arterial blood flow (THBF) and hepatic oxygenation. There
are no reports of ([Ca++]i) in sevoflurane anaesthesia, while
([Ca++]i) was found to be lower in isoflurane anaesthesia than
in halothane anaesthesia (Nishiyama et al., 1998a,b).
Other drugs were not taken into consideration in the present
study because they could not be controlled. Xylazine and
propofol have some effects on liver function and liver blood
flow. However, all dogs in this study received the same amount
of these drugs according to the protocol. Therefore, differences
in liver enzyme activities between the three groups were not
attributed to these drugs.
Serum AST, ALT and GGT concentrations are sensitive
markers for anaesthetic-induced liver damage in man. For this
reason, these enzyme levels have been determined many
human studies (Frink et al., 1992; Shichinohe et al., 1992;
Sato et al., 1994; Nishiyama et al., 1998a,b, 1999; Schmidh
et al., 1999; Darling et al., 2000; Obata et al., 2000; Suttner
et al., 2000; Rodes and Bruguera, 2001). In the same way,
these enzymes activities are sensitive markers for anaesthetic-
induced liver damage in dogs. Therefore, we used the same
enzyme markers.
Halothane, which induces liver damage more than isoflurane
and sevoflurane, exerts a more deleterious effect on liver blood
flow than isoflurane (Kanaya et al., 1995; Darling et al., 2000;
Helmy and Al-Attiyah, 2000). Moreover, isoflurane increases
serum activities of liver enzymes more frequently than
sevoflurane 3–14 days after anaesthesia in human beings
(Nishiyama et al., 1998a,b).
In our study the AST (P < 0.005; Table 1) and ALT
(P < 0.05; Table 1) activities significantly increased in the
halothane group after anaesthesia. But the AST and ALT
activities increased in the isoflurane group between 2 and
7 days and in the sevoflurane group 7 days after anaesthesia in
dogs (P < 0.005; Table 1). In the same way, GGT activity was
increased in the halothane group on 2 and 7 days, and in the
isoflurane and sevoflurane groups 7 days after anaesthesia
(P < 0.05; Table 1). Consequently, hepatic dysfunction or
subclinical hepatic injury might occur especially with haloth-
ane and rarely with isoflurane anaesthesia in dogs. Other
studies dealing with the effects of inhaled anaesthetics on
human hepatic function produced similar results.
Elevated serum levels of aminotransferase activity have been
regarded as the gold standard for anaesthetic-related hepatic
toxicity. In this study, more liver cell damage after halothane
anaesthesia and less after isoflurane anaesthesia compared with
sevoflurane anaesthesia, indicated by higher serum activities of
liver enzymes, could be attributed to the centrolobular necrosis
of the liver by trifluoroacetyl acid (TFA) and deleterious effect
on liver blood flow with halothane and isoflurane anaesthesia.
This view was supported by previous human studies.
Dales in 1976 stated that rapidly repeated exposure to
halothane may cause hepatitis and concluded that if alter-
native satisfactory inhalation agent is available, application of
halothane should be avoided in patients with unexplained
hepatitis after previous exposure. There was strong evidence
that repeated exposure to halothane, especially within a short
period, increases the evidence of jaundice in human. Similarly,
our results demonstrate that serum levels of aminotransferase
activity increased especially after halothane anaesthesia in
dogs. Hence we suggest that when an animal is repeatedly
exposed to an inhalation anaesthesia (e.g. multiple fracture),
an anaesthetic agent other than halothane should be chosen.
Hepatic Effects of Halothane, Isoflurane or Sevoflurane Anaesthesia in Dogs
Even with the small number of animals in this study,
we conclude that halothane is worse than isoflurane and
sevoflurane in terms of post-operative liver function. However,
isoflurane induced an elevation of serum activities of liver
enzymes more frequently than did sevoflurane between 2 and
7 days.
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