ABSTRACT
Amitraz acts on α
2-adrenergic receptors in a competitive and
reversible way, leading to some xylazine-like effects. To evaluate the
left ventricular function index after amitraz or xylazine
administration, eight mongrel cats were submitted to intravenous
injection: group X (xylazine), group A (amitraz) or group D (diluent).
The same cats were used in all groups, after a 15-day interval. Heart
rate (HR) and rhythm, shortening fraction (%SF), ejection fraction
(%EF) and cardiac index (CI) were measured by echocardiography
immediately before and during 60 minutes after drug injection. Amitraz
and xylazine induced first-degree atrioventricular block (1st AVB) and
decreases in HR, %SF, %EF and CI. The mean values of HR and all
echocardiographic parameters of group X were significantly lower
comparing to group A. It was concluded that both α
2-agonists produce bradycardia and 1st AVB, but xylazine causes greater depression of the cardiac contractility.
KEYWORDS: Amitraz, xylazine, echocardiography, electrocardiography, cats.
RESUMO
AVALIAÇÃO ECOCARDIOGRÁFICA DE GATOS APÓS A ADMINISTRAÇÃO INTRAVENOSA DE AMITRAZ OU XILAZINA
O amitraz age de forma competitiva e reversível em receptores adrenérgicos do tipo α
2,
desencadeando efeitos similares aos da xilazina. Com o objetivo de
avaliar a função ventricular esquerda após a administração de amitraz
ou xilazina, oito gatos SRD foram submetidos a injeções intravenosas:
grupo X (xilazina), grupo A (amitraz) ou grupo D (diluente). Os mesmos
animais foram utilizados em todos os grupos após um intervalo mínimo de
quinze dias. Foram avaliados frequência cardíaca (FC), ritmo cardíaco,
fração de ejeção (FE), fração de encurtamento (FS) e índice cardíaco
(IC), por meio de eletrocardiografia e ecocardiografia, imediatamente
antes e durante os primeiros sessenta minutos após a aplicação. Tanto o
amitraz quanto a xilazina induziram bloqueio atrioventricular de
primeiro grau (1º BAV) e diminuição de FC, FE, FS e IC. As médias da FC
e de todos os parâmetros ecocardiográficos do grupo X foram
estatisticamente menores do que as do grupo A. Concluiu-se que ambos os
agonistas adrenérgicos de receptores tipo α
2 causaram bradicardia e 1º BAV; contudo, a xilazina produziu maior depressão na contratilidade cardíaca.
PALAVRAS-CHAVES: Amitraz, xilazina, ecocardiografia, eletrocardiografia, gatos.
INTRODUCTION
The α
2-agonists have been widely used in veterinary medicine
since the 1960´s, after xylazine synthesis in Germany, due to their
dose-dependent effects on sedation, miorelaxation and analgesia (ALLEN
et. al., 1986; GROSS, 2003). Their mechanisms of action are related to
the activation of presynaptic α
2-adrenoreceptors leading to
an inhibitory effect on noradrenaline release and by stimulation of
different G proteins (MUIR & MASON, 1996; Vital, 2002).
Previous studies have shown that the stimulation of central and peripheral α
2-adrenoreceptors agonists affect cardiovascular and myocardial function in small animals (MUIR & PIPER, 1977; GOLDEN
et al., 1998; PADDLEFORD & HARVEY, 1999). The main cardiovascular effects of all α
2-agonists
include bradycardia and associated bradyarrhythmias (1st and 2nd degree
atrioventricular heart block), reduction in cardiac output (CO), and an
initial increase in systemic vascular resistance (SVR) (Sinclair,
2003).
Amitraz is an insecticide used in veterinary medicine as an acaricide
and tickicide (SHARMA & DABAS, 1993), whose mechanism of action are
similar to other α
2-adrenoreceptors agonists (HSU & KAKUK, 1984; QUEIROZ-NETO
et al., 2000; FARIAS
et al., 2005). Sedation, analgesia and cardiovascular depression similar to the α
2-adrenoreceptors agonists have been described in several species after amitraz intravenous injection (QUEIROZ-NETO
et al., 2000; ALMEIDA
et al., 2004; FARIAS
et al., 2005; MENDES
et al., 2007; LINARDI
et al., 2008).
In cats, the intravenous administration of 1 mg/kg of a 1.5% amitraz
commercial solution induced sedation, bradycardia, first degree
atrioventricular heart block (1st AVB) and hypotension (ANDRADE
et al.,
2007). In addition, both yohimbine (0.1 mg/kg) and atipamezole (0.2
mg/kg) were effective in the treatment of amitraz injection symptoms,
although atipamezole, which has a higher selectivity to α
2-adrenoreceptors, was more effective in reversing arrhythmias and sedation (ANDRADE
et al., 2006).
Considering the risks and costs to determine the cardiac function by
invasive techniques in cats, echocardiography has been used as the only
non-invasive method to accurately verify cardiac dimensions and
function indexes on basis of directly measured values (PIPERS and
HAMLIN, 1980; DUNKLE
et al.,
1986). However, there are few echocardiographic reports in cats and
none of them describes the effects of amitraz injection. Thus, the aim
of this study was to evaluate the heart rhythm and cardiac function
after intravenous amitraz or xylazine injection in cats.
MATERIAL AND METHODS
This study was approved by the Animal Care Committee at São Paulo State
University (protocol number 007133-07). Eight healthy mongrel cats
weighting 4.1 ± 1.1 kg were selected after physical, hematological,
thoracic radiographic, electrocardiographic and echocardiographic
evaluations. Only cats which had no contact with amitraz during the six
months prior the study were used.
After hair clipping between the right 3rd and 6th intercostal spaces,
each cat was electrocardiographically and echocardiographically
evaluated before (T0 – baseline under physical restraint) and at 5
(T5), 10 (T10), 15 (T15), 20 (T20), 30 (T30), 40 (T40), 50 (T50) and 60
(T60) minutes after treatments. A 24G intravenous catheter was inserted
in the cephalic vein for drug administration. After measurement of
baseline data, an intravenous injection of 1.0 mg/kg of xylazine (group
X), or 1.0 mg/kg of amitraz diluted in a lipid solution (group A)
(FARIAS
et al., 2005), or the
same volume of the lipid solution used for the previous treatment
(group D) was performed in each cat. The order in which each treatment
was given was randomly assigned and at least 15 days were allowed
between the treatments of each cat.
Electrocardiographic leads were attached to the body of the animals to
capture a standard lead II tracing in order to obtain the heart rate
(HR) and possible arrhythmias. Simultaneously, M-mode echocardiographic
measurements were made with a Pandion S300 echocardiograph (PieMedical,
Maastricht, The Netherlands), using a 5- or 7.5-MHz transducer directed
towards the heart within the 4th or 5th intercostal space. The cats
were positioned in right lateral recumbency, on a table specifically
designed for veterinary echocardiography, for imaging of the right
paraesternal short-axis view at chordae tendineae level from below
through an aperture. All echocardiographic measurements used for
analysis represent a resultant mean of at least three cardiac cycles.
To evaluate the echocardiographic left ventricular function, the
following parameters were measured: left ventricular diameter at
end-diastole (LVDd) and at end-systole (LVDs) in cm, interventricular
septal thickness at end-diastole (IVSd) and at end-systole (IVSs) in
cm, left ventricular free wall thickness at end-diastole (LVWd) and at
end-systole (LVWs) in cm, shortening fractional (%SF), ejection
fractional (%EF) and cardiac index (CI) in L/m² x min, determined by
the use of several echocardiographic indexes shown below.
End-systolic left ventricular volume index (ESLVVI) was calculated as
((7 × LVDs3)/(2.4 + LVDs)) divided by body surface area (BSA) in square
meters. End-diastolic left ventricular volume index (EDLVVI) was
calculated by the formula ((7 × LVDd3)/(2.4 + LVDd))/BSA.
M-mode-derived stroke volume (SI) resulted from EDLVVI – ESLVVI, and
M-mode-derived CI was calculated as SI × HR.
The data were normally distributed and expressed as the mean ± SD. The
variables were compared by one way repeated measures analysis of
variance followed by Tukey test. The significance level of all tests
was set at 5% (P<0.05).
RESULTS
Compared with mean baseline values, the HR was significantly reduced in
all moments during treatment with xylazine (X) and amitraz (A) (
Figure 1).
Heart rate (HR) was reduced only at 20 minutes 1n the animals treated
with the diluent. At 5 minutes, HR reduced 47% in the group X and 21%
in the group A; values were reduced during all observation time. The
mean HR values of group X were significantly lower comparing to group
A. Although the ECG average values were normal at all times in all
experimental groups, one cat (number 2) in group X at 50 and 60
minutes, and one cat (number 5) in group A at 20, 40, 50 and 60 minutes
presented first-degree atrioventricular block (1st AVB), characterized
by a PR interval above 90 ms.
The values and significant changes of LVDd, LVDs, SWTd, SWTs, LVTd and LVTs are shown in
Table 1.
The % SF and % EF in group X were significantly reduced in all moments
compared to baseline measurements (59% and 42% lower at 5 minutes,
respectively) (
Figure 2).
They were also decreased in group A at 5, 10 and 15 minutes (26% and
16% lower at 5 minutes, respectively). However, all echocardiographyc
values of group X were significantly lower compared to group A. Data
for CI of group X were below baseline values in all moments (68% lower
at 10 minutes) (
Figure 1).
Cats treated with amitraz had a significant decrease of CI at 15, 20,
30 and 60 minutes (46% lower at 30 minutes). After 10 minutes, all CI
values of group X were significantly lower than group A.
DISCUSSION
The dosage of 1.0 mg/kg of amitraz used was based on previous reports by ANDRADE
et al. (2006) and ANDRADE
et al.
(2007) that showed the effects caused by intravenous amitraz injection
in cats. In one study, sedation, loss of reflexes, mydriasis,
bradycardia, bradyarrhythmias and bradypnea were effectively reversed
with 0.2 mg/kg of atipamezole, an α
2-adrenergic antagonist with high affinity (ANDRADE
et al. 2006). There are few studies with amitraz diluted in lipid vehicle in large animals (ALMEIDA et at., 2004; MENDES
et al., 2007; LINARDI
et al., 2008) and the only report in small animals using this vehicle was made by FARIAS
et al. (2005), who tested a dosage of 1.0 mg/kg.
Due to inherent anatomic and physiologic properties such as elevated
heart rates, purring, and variable positions of the heart in the
thorax, echocardiographic evaluation in cats seems to be more reliable
than traditional cardiovascular assessment such as auscultatory,
electrocardiographic, radiographic, and clinical laboratory findings
(PIPERS & HAMLIN, 1980). It was described that %EF taken from
M-mode echocardiogram may lead to errors, however the results are
similar to the %SF, which is a trustworthy evidence of the cardiac
performance (DUNKLE
et al., 1986). There are few echocardiographic reports in cats after administration of α
2-agonists (ALLEN & DOWNEY, 1983; DUNKLE
et al., 1986; LAMONT
et al., 2002). Considering the myocardial depressor effect of the α
2-agonists,
the evaluation of the left ventricular function after administration of
these drugs is important due to their broad use in veterinary medicine
(ALLEN & DOWNEY, 1983).
The cardiac performance decreased after intravenous administration of
xylazine or amitraz. Reduction in left ventricular function was
previously reported in cats (DUNKLE
et al., 1986), dogs (MUIR & PIPER, 1977), horses (LINARDI
et al., 2008), and calves (CAMPBELL
et al.,
1979) sedated with xylazine. Despite the decrease of %SF, %EF and IC in
cats sedated with amitraz, the reduction on cardiac performance was not
as intense as in those sedated with xylazine. When a low %SF is
calculated, it may be secondary to poor preload, increased afterload or
decreased contractility (BOON, 1998). However, an indication of poor
preload or increased afterload is a decreased left ventricular
diastolic chamber size (BOON, 1998), which did not occur in the present
study. Central nervous system (CNS) depression in both treatments
appeared to be severe enough to induce HR and ventricular dysfunction.
Several studies have demonstrated that a decrease in CO values is not
due to a direct negative action of the α
2-agonist on
myocardial contractility, but is secondary to the increased systemic
vascular resistance and reduced HR (MUIR & PIPER, 1977; AUTRAN de
MORAIS & MUIR, 1995; LINARDI
et al.,
2008). A similar study in horses showed reduction in CO after xylazine
or amitraz administration; however, as the %SF and the %EF did not
change significantly, the reduction in CO was probably due to a
decrease in HR mediated by a reduction of sympathetic activity by α
2-agonist action in the CNS (LINARDI
et al., 2008).
It has been reported that α
2-agonists can produce
bradycardia and dysrhythmias, including sinoatrial block, 1st and 2nd
AVB and sinus arrhythmia (PADDLEFORD & HARVEY, 1999; CANOLA
et al.,
2007). These effects are most likely to occur secondary to the initial
increase in blood pressure and reflex increase in vagal tone (LEMKE,
2004). First AVB in cats sedated with amitraz was first related by
ANDRADE
et al. (2006);
however, the present study demonstrated that it may occur with
different diluent preparations. Amitraz diluted in lipid solution
causes AVB in horses (LINARDI
et al., 2008) but not in dogs (FARIAS
et al.
2005), and it has been associated with bradycardia in both of them. A
delay in the electrical conduction system of the heart has been related
with those dysfunctions (CANOLA
et al., 2007).
The results compared in this study should be interpreted in view of two
main limitations. First, we don’t know if the amitraz dose was
equipotent to the xylazine dose, then amitraz depression effects on
cardiac contractility could had been underestimated. Secondly, the HR
reduction in the group D at 20 minutes could indicate that the diluent
used in this study may have potentiated the cardiac side effects caused
by amitraz administration.
This study showed that either amitraz or xylazine
induce reduction on left ventricular contractility and cardiac index
associated with the bradycardia and 1st AVB caused by the
α2-adrenoreceptor interaction.
ACKNOWLEDGEMENT
We thank the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) for supporting this study.
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Protocolado
em: 8 nov. 2009. Aceito em: 25 out.
2010.