Potent non-hypnotic, non-narcotic
sedative, analgesic for horses.
The chemical name of detomidine is 4-[(2,3-dimethylphenyl) Methyl]
-1H-imidazole, with chemical formula: C12H14N2.HCl Detomidine
hydrochloride is a centrally acting alpha-2 adrenergic receptor agonist,
similar in pharmacology to clonidine. Its central depressive action
produces sedation without any hypnotic effect. Detomidine produces
analgesia by inhibition of CNS-mediated transmission of pain impulses
and sensation. Detomidine is non-narcotic. An increase in blood pressure
and a decrease in heart rate are alpha-adrenergic effects of Detomidine.
* Rapid onset of reliable sedation and/or
analgesia
* Reliable dose related response
* Positive
* Predictable sedation, with
* Potent analgesic properties
* Minimal tissue irritation
Ranvet’s CALMANT provides veterinarians with predictable, effective
patient management, and reduced injury risk to patient, veterinarian and
assistants.
* A low dose rate renders most horses tractable for simple diagnostic
procedures such as radiography or ultrasound, stomach tubing, dentistry,
endoscopy or rectal examination.
* When higher doses of detomidine are used, profound sedation and
analgesia such as that elicited by the various sedative/narcotic
combinations currently used, is obtained, thus rendering horses
tractable for more prolonged and painful procedures such as wound
repair, gynaecological surgery and castration, scintigraphy, etc.
Ranvet’s CALMANT - Indications
Detomidine is a dose dependent sedative and analgesic for all
indications, including dose dependent control of visceral pain.
The potent sedative and analgesic properties facilitate handling of
horses during;
* Examination
* Transport
* Diagnostic procedures
* Radiographic examination
* Manipulation
* Minor surgical intervention
* Dental work
* Stomach tubing
* Endoscopy
* Wound treatment & minor surgery
* Gynaecological examination & surgery
* Castration
* Hoof care & surgery
Plus: - CALMANT provides rapid analgesia in colic cases, with an ability
for prolonged analgesia
Ranvet’s CALMANT
* Enables veterinarians to completely control sedation and analgesia of
horses.
* Effects of detomidine are dose-related, and initial dose can be
“topped up” with no break in activity.
* Use CALMANT in adult horses, foals, and pregnant mares, either alone
or in combination with other sedative, analgesic or anaesthetic drugs.
There are multiple techniques for inclusion of detomidine into your
treatment regime.
Ranvet’s CALMANT Dosage range:
* At low dose rates sedation is reliable, and at high dose rates
analgesia is remarkably profound, providing an extremely useful option
for analgesia in colic management.
* As a pre-anaesthetic agent, detomidine significantly reduces the
dosages of other anaesthetic agents.
* Excellent sedation for simple non-invasive procedures in most horses
is achieved at the lowest dose rate: i.e: 5-10microgram/kg bodyweight
(0.25 -0.5mL per 450-500kg horse).
* Pure anxiolysis with few clinical signs of sedation can be achieved
with extremely low doses of detomidine (less than 10micrograms/kg
bodyweight).
* For a significant analgesic effect, higher dose rates of
10-20microgram/kg (0.5 - 1.0mL per 450-500kg horse) are employed. If
analgesia is the primary requirement, it is recommended that doses above
15microgram/kg bodyweight are used. A dose rate of 20microgram/kg will
show strong sedation which increases with dose (10).
* The effect of administration can be gauged by a number of measurable
parameters, including dropping of the head, lower lip and eyelid. The
horses become apparently unconcerned and disinterested in the
environment and any surrounding activity.
* Animals treated with higher doses of detomidine (40, 60, 80,
160microgram/kg) show an increase in the duration of sedation without a
significant increase in the degree of sedation ( 20microgram/kg - 1
hour, 80microgram/kg - 2.5 hours, and 160microgram/kg approximately 3
hours). By comparison, xylazine at a dose rate of 1.1mg/kg produces
sedation of 15-30 minutes (13)
* The analgesic effects of detomidine have been found to be strongly
related to dose and route of administration. A difference in regional
anaesthesia has also been noted with an increased duration of analgesia
noted in the fore limbs, and in the perineal region at dose rates of 5 -
160microgram/kg.
* When intramuscular administration of detomidine is used, dose rates of
80-160microgram/kg bodyweight are required to raise the pain threshold
of both fore and hind limbs while the perineal region shows no change in
pain threshold.
A maximum dose of 80microgram/kg has been recommended, as no further
analgesia is elicited beyond this dose.
Grade of Degree of Average mcg/kg mL/100kg
Effect Sedation Duration
1 MILD (adequate sedation, mild analgesia) 30-60 minutes 10-20 0.1 - 0.2
11 MODERATE (moderate sedation & analgesia) 1-2 hours 20-40 0.2 - 0.4
111 HEAVY (heavy sedation, profound analgesia) 2 - 6 hours 40-80 0.4 -
0.8
* Some clinicians find that a dosage range even lower than that listed
above provides adequate effect in many instances.(33,34)
Horses recover quickly from detomidine administration. The duration of
sedation is dose-dependent.
Daunt (1995) (34) of Stanford University, provides a detailed series of
recommended uses of detomidine in Annexure A of the Compendium of
Continuing Veterinary Education, Vol. 17, No. 11, November 1995, as
follows;
Uses Intravenous Dose Total Dose and Volume
(mg/kg) 450kg horse
Dose (mg) Volume (mL)
Diagnosis
Radiography or ultrasonography 0.005 - 0.01 2.2 - 4.5 0.2 - 0.45
Endoscopy 0.01 -0.02 4.5 -9.0 0.45 - 0.9
Rectal/vaginal examination 0.01 - 0.02 4.5 - 9.0 0.45 - 0.9
Wound assessment 0.005 - 0.02 2.2 - 9.0 0.2 - 0.9
Therapy
Transportation, clipping, shoeing
and hoof care, bandage change,
Stomach tubing 0.005-0.01 2.2 - 4.5 0.2 - 0.45
Intra-articular injection 0.005 - 0.015 2.2 - 6.7 0.2 - 0.67
Dentistry 0.005 - 0.02 2.2 - 9.0 0.2 - 0.9
Wound/sinus irrigation 0.01 - 0.02 4.5 - 9.0 0.45 - 0.9
Mild colic pain 0.01 - 0.02 4.5 - 9.0 0.45 - 0.9
Moderate/severe colic pain 0.02 - 0.04 9-18 0.9 - 1.8
Anaesthesia
Premedication for general 0.005 - 0.02 4.5 - 9.0 0.45 - 0.9
anaesthesia (inhalation maintenance)
Suture wounds, elective standing
surgery (with local) 0.01 - 0.03 4.5 - 13.5 0.45 -1.35
Injectable general anaesthesia
Detomidine 0.02 - 0.03 9.0 - 13.5 0.9 - 1.35
Plus
Ketamine 2.2 1000 10
Detomidine 0.02 - 0.03 9.0 - 13.5 0.9 - 1.35
plus
Tiletamine-zolazepam 2.0 900 9.0
Detomidine 0.01 9.0 - 13.5 0.9 - 1.35
plus
Gualifensin-thiobarbiturate 30-80 guaifensin 5% solution for
foals/ponies
10% solution for adults
2.0 - 5.0 thiobarbiturate 5% solution for foals
10% solution for adults
Detomidine 0.01 9.0 - 13.5 0.9 - 1.35
plus
Guaifensin-ketamine 30-80 guaifensin 5% solution for foals, ponies
10% solution for adults
1.5 - 2.2 ketamine 700 - 1000 7 - 10
Notes: Detomidine is 10mg/mL. ketamine is 100mg/mL
Tiletamine-zolazepam label recommends reconstituion in sterile water to
a concentration of 100mg/mL
Guaifensin is usually rapidly infused IV until the patient begins to
sway (for sedated horses, this usually requires 30-60mg/kg). The
infusion is interrupted, and an IV bolus of a thiobarbiturate (thiamylal
or thiopental) or ketamine is administered. Alternatively, a mixture of
guaifensin-thiobarbiturate or guaifensin-ketamine can be infused as a
solution.
Chemical Restraint For Standing Procedures in the Horse
Hubbell (2006) (44) describes three groups of chemical agents commonly
used to produce standing chemical restraint in the horse;
phenothiazines, alpha-2 agonists, and opioids. The alpha-2 agonists,
including detomidine and xylazine, produce sedation with muscle
relaxation, ataxia and analgesia when given orally, IV or IM to horses.
Arterial blood pressure is initially increased due to drug-induced
increases in peripheral vascular resistance. Hypertension may be
sustained (20-60 minutes), particularly when detomidine is used. Heart
rate decreases and sinus arrhythmia, plus first and second degree
atrioventricular blockade are common. Decreases in heart rate can
produce significant decreases in cardiac output. Respiratory rate is
usually decreased, but tidal volume increases. Alpha-2 agonist use also
decreases salivation, gastric secretions and gastrointestinal motility,
as well as urine volume.
The level of sedation produced by alpha-2 agonists is more pronounced
than that of phenothiazines.
Horses that have received detomidine are recognised to assume a “head
down” or saw-horse stance, and frequently shift their weight from side
to side.
Hubbell (2006) continues, to observe that detomidine is a more specific
alpha-2 receptor agonist than xylazine, with an alpha-2 / alpha-1
specificity of 260:1 compared to 160:1 for xylazine.
Detomidine is approximately 100 times more potent than xylazine, and has
a duration of activity approximately twice as long. Detomidine is
frequently used alone, or in combination with opioids (butorphanol,
nalbuphine) to produce standing chemical restraint for a wide variety of
procedures.
The administration of a combination of ketamine (0.5mg/kg),
tiletamine-zolazepam (0.7mg/kg), and detomidine (0.01mg/kg) was
investigated for anaesthesia for castration by Muir et al (2000).(48)
The combination was prepared by reconstituting 500mg of
tiletamine-zolazepam powder with 4mL of ketamine (100mg/mL) and 1mL of
detomidine (10mg/mL). The mixture has been administered after xylazine
sedation at a rate of 0.007mL/kg IV (approx. 3mL/450kg). This
combination produces excellent induction of anaesthesia with
intraoperative blood pressures higher than those seen with most other
techniques. Duration of anaesthesia is longer than xylazine and
ketamine, and recoveries may need assistance
Use of Detomidine in Equine Colic
It must always be emphasised that while use of detomidine in horses
exhibiting severe abdominal pain provides effective sedation and
analgesia, which allows safe monitoring, evaluation, and medical
treatment, the normal indicators for surgical intervention, such as
heart rate and degree of discomfort, may not be present (34).
The alpha-2 agonists commonly used in horses with abdominal pain include
xylazine and detomidine. Both are potent analgesics and cause muscle
relaxation and sedation. Detomidine has more potent analgesic effects
than xylazine , and has the potential to mask abdominal pain associated
with surgical disease for an extended period, particularly if
administered repeatedly. It should possibly be reserved for horses with
marked abdominal pain in which surgical exploration is not an option, or
those which must be transported long distances for surgery The dose of
detomidine is approximately 10-20microgram/kg IV or IM, and it should be
remembered that the alpha-2 agonists can have inhibitory effects on
gastrointestinal motility (43).
Jochle (1989) (73) reports an uncontrolled clinical study in which 12
investigators co-operated to evaluate the analgesic and sedative effect
of detomidine in 234 horses with abdominal pain caused by colic. The
study used each horse as its own control, and evaluated response to the
drug over 60 minutes. Detomidine was given IV once in 169 cases (167
horses, 1 mule, 1 donkey) at a dose of 20microgram/kg bwt, and to 65
horses at 40microgram/kg. the higher dose was predominantly in horses
with severe pain which were most often in poor health and given a poor
prognosis. Sedation and analgesia, rated as satisfactory or highly
satisfactory, was achieved in 96% of cases, with obvious differences
between sex, doses, breed and species. First clinical signs of sedation
and analgesia were recorded within 2.5 and 3.2 minutes, respectively,
and deep sedation and analgesia were achieved by 4.2 and 5.1 minutes.
Objective evaluation of analgesia was based on clinical scores relating
to behaviour (sweating, kicking, pawing, head and body movement,
stretching, lip curling, attitude and appetite) In 5 of 7 of these
parameters the 40microgram/kg dose scored higher initially and took
longer to return to normal. Although most cases treated with
20microgram/kg returned to almost normal levels by 15 minutes, those
treated with 40microgram/kg required 30 minutes. Horses not responding
to either dose of detomidine went to surgery or were destroyed. These
involved intestinal strangulation, incarceration, and torsion or
rotation of the gut. No differences were found between doses in the
occurrence of side effects. As expected, heart rates and respiratory
rates decreased and recovered slowly. Other side effects were recorded
in approximately 37% cases and consisted of instability (27.1% of all
other side effects), sweating (14.5%), cardiovascular abnormalities
(arrhythmias 15.1%), and abnormal reactions to sensorial stimuli (6.6%).
Less than 20% of the side effects were classified as strong or very
strong, and none was considered serious. No deaths were attributed to
this drug.
Experimental studies using a balloon-induced colic model (as reported at
the AAEP Annual Meeting, 1969) have been used to test the efficacy of
detomidine in the management of pain in equine colic. At dose rates
greater than 20microgram/kg, reliable analgesia was obtained in all
experimental cases where pain was induced by inflating a caecal balloon
catheter (14). Pain relief at 20ug/kg varied from 20 to 85 minutes; at
80ug/kg from 30 to 225 minutes; at 160ug/kg from 20 to 300 minutes.
It was evident that caecal contractions in response to inflation of the
balloon catheter ceased under the influence of detomidine. It was found
that complete obliteration of caecal pain at the highest dose rate of
160ug/kg may be undesirable for the clinician if he is to properly
monitor and evaluate the resolution (or otherwise) of the colic episode.
A 152 horse trial by Jochle et al (1989) (74) evaluated detomidine,
butorphanol, flunixin and xylazine in a blind multi-centre clinical
trial using horses exhibiting abdominal pain. The drugs were
administered as follows; detomidine 20 or 40microgram/kg, butorphanol
0.1mg/kg, flunixin meglumine 1mg/kg, xylazine 0.5mg/kg. each centre
compared responses to two doses of detomidine with those of the other
analgesics. The drugs were administered IV after clinical assessment of
the degree of sweating, kicking, pawing, head and body movement,
attitude, lip curling, stretching to urinate, pulse rate, respiratory
rate and rectal temperature. Similar assessments were repeated at 15
minute intervals for at least one hour. The investigators ranked the
response to treatment from not satisfactory to highly satisfactory.
Significant differences in sweating, kicking, pawing, head and body
movement, attitude, pulse rate and respiratory rate were noted between
the horses receiving butorphanol and either dose of detomidine. The
investigators’ subjective evaluation of the analgesic and sedative
effects of either dose of detomidine were significantly better than for
butorphanol. Analgesia was rated as highly satisfactory or satisfactory
in 93.3% and 6.7% of the horses receiving 40microgram/kg detomidine,
73.3% and 26.7% of horses receiving 20microgram/kg detomidine, and none
of the horses receiving butorphanol. There were no differences in the
incidence of side effects with the two compounds. Significant
differences were noted in kicking, pawing, head and body movement and
attitude between the horses receiving flunixin meglumine and either dose
of detomidine. Flunixin provided significantly less analgesia than
either dose of detomidine. Analgesia was rated as highly satisfactory or
satisfactory in 73.7% and 21% of horses receiving 40microg/kg
detomidine, 42.9% and 21.4% of horses receiving 20microg/kg detomidine,
and 6,3% and 37.5% of the horses receiving xylazine. Sedation was
considered to be at least satisfactory in 84.2% of horses receiving
40microg/kg detomidine, 71.5% horses receiving 20microg/kg detomidine,
and 53.3% horses receiving xylazine.
Detomidine has been found to be a superior analgesic to butorphanol in
the management of equine colic, regardless of the cause.. When two dose
rates of detomidine (20 and 40ug/kg) were used, and the recommended dose
level of butorphanol in the treatment of 40 clinical colic cases (18),
detomidine provided onset of sedation in all patients within 2-3
minutes, and analgesia was evident in all animals in 2.6 minutes, with
deep analgesia seen within 4.6 and 5.5 minutes for the lower and higher
dose respectively. Butorphanol was found to be less efficient and took
longer to exert any effect.
Alpha-2 agonists reduce blood flow of obstructed large intestine and
decrease intraluminal pressure (50, 51,) There is a transient increase
in urine production, which may complicate dehydration and circulatory
shock.
Detomidine can produce complete cessation of colic for up to 3 hours,
and, during experimental caecal distention, provide analgesia for a mean
of 45 and 105 minutes at a dose rate of 20microgram/kg and
40microgram/kg, respectively. (50)
Treating and Shipping the Violent Colic Case
Belknap (2006), (42) of Ohio State University, in a review on treating
and shipping the violent colic case, notes that the most potent NSAID
for visceral pain is flunixin meglumine, which should be given at the
maximal dose (1.1mg/kg) for severe pain. The sedatives with the more
potent analgesic properties include the alpha-2 adrenergic agonists,
including detomidine, as well as opioids such as butorphanol or
morphine.
Belknap recommends that detomidine can be given at a dosage of 0.011 to
0.022mg/kg IV or IM (4.95mg and 9.9mg, respectively); and that both
routes may be used to allow for a rapid effect from the IV dose, and a
more sustained effect from the IM dose.
The effect of detomidine is usually 1-2 hours, however, the duration of
efficacy varies with the severity of pain. He further suggests that
opioid antagonists such as butorphanol (0.01 to 0.03mg/kg IV or IM) or
morphine (0.1mg/kg IV) can be valuable additions to the detomidine,
keeping in mind that morphine decreases GI motility to a greater degree.
Another option for addition to an alpha-2 antagonist is small ketamine
boluses (0.22mg/kg IV or 100mg/450kg IV) which are reported to provide
potent short-term relief of 15-20 minutes) This may be an option to
control a horse for enough time to examine and place an IV catheter.(42)
Belknap further advises that a constant rate IV infusion of detomidine
(5-10mg/450kg/hour) and ketamine (270mg/450kg/hour) has recently been
presented as an alternative for transportation of painful colic cases
for long distances by E. Abrahamson, BEVA Proc, 2005. Abrahamson
suggested the use of an IV flow control device to ensure constant rate
of administration regardless of whether the horse becomes recumbent
Use of Detomidine in Anaesthesia
Detomidine can be used safely with a wide variety of anaesthetic
combinations provided careful patient monitoring and reduction of
anaesthetic doses is carried out.
In cases where horses have been sedated with detomidine for clinical
evaluation or diagnostic procedures, or as a premedicant, it is
recommended that at least 30 minutes elapse before induction of
anaesthesia. Cardiopulmonary depression is most prominent 15-30 minutes
following administration (29). Studies have shown that detomidine may
produce an anaesthetic sparing effect of up to 50% when induction is
followed by Halothane administration (29,30,33,41)
Recovery times from anaesthesia using detomidine are reported as longer
than observed with other combinations, depending on the duration of
inhalation anaesthesia, but the quality (that is; successful,
co-ordinated attempts to stand) is reportedly good (34). Similar
recovery times, but with more ataxia, are reported with
detomidine-ketamine anaesthesia as compared to xylazine-ketamine (22,23)
Matthews et al (1991) (56) compared 6 combinations of injectable
anaesthetic agents administered to 6 adult horses in a Latin square
design. The drug combinations were xylazine-ketamine,
xylazine-butorphanol-ketamine, xylazine-tiletamine-zolazepam,
xylazine-butorphanol-tiletamine-zolazepam, detomidine-ketamine, and
detomidine-butorphanol-ketamine. Measured variables were heart rate,
respiratory rate, systolic blood pressure, arterial pH (pHa), PaCO2,
PaO2, recumbency time, and the number of attempts to stand. Quality of
induction and recovery, muscle relaxation, and response to stimulus were
examined subjectively. The horses required significantly more attempts
to stand after administration of xylazine-tiletamine-zolazepam,
xylazine-butorphanol-tiletamine-zolazepam, and detomidine-ketamine than
after xylazine-ketamine, xylazine-butorphanol-ketamine, or
detomidine-butorphanol-ketamine. Mean recumbency times varied from 23
minutes with xylazine-ketamine to 41.3 minutes with
xylazine-butorphanol-tiletamine-zolazepam. There were significant
differences in mean heart rates at 15 minutes, in mean respiratory rates
at 5, 10, 15 minutes, and mean systolic blood pressures at 10 minutes of
anaesthesia. There were no significant differences in pHa, PaCO2 or
Pa02.
Wan et al (1992) (57) anaesthetised 8 horses three times, by IV
administration of xylazine (1.1mg/kg) and ketamine (2.2mg/kg),
detomidine (0.02mg/kg) and tiletamine-zolazepam (1.1mg/kg), or
detomidine (0.04mg/kg) and tiletamine-zolazepam (1.4mg/kg). The
sequences were randomised. Duration of analgesia and the times to
sternal and standing positions were recorded. Heart rate, arterial
pressure, pHa, PaC02, and Pa02 were measured before and during
anaesthesia. Duration of analgesia with the two doses of
detomidine-tiletamine-zolazepam (26 +/- 4 minutes and 39 +/- 11 minutes,
respectively) was significantly longer than the 13 +/- 6 minutes
obtained with xylazine-ketamine. Bradycardia occurred after
administration of detomidine, but heart rates returned to base values 5
minutes after administration of tiletamine and zolazepam. Arterial
pressure was significantly higher, and Pa02 significantly lower during
anaesthesia with detomidine-tiletamine-zolazepam than with
xylazine-ketamine. The authors concluded that
detomidine-tiletamine-zolazepam can provide comparable anaesthesia of a
longer duration than xylazine-ketamine, but hypoxaemia may develop in
some horses.
Detomidine - Anaesthesia Immediately After Hard Exercise
Hubbell et al (1999) (58) determined the sedative, cardiorespiratory and
metabolic effects of xylazine, detomidine, and a combination of xylazine
and acepromazine administered IV at twice the standard doses in 6
Thoroughbred horses recuperating from maximal exercise. Each horse ran 4
simulated races at treadmill speeds that caused horses to exercise at
120% of their maximal oxygen consumption until horses were fatigued or a
maximum of two minutes, with a minimum 14 days between races. One minute
after the end of exercise, horses were treated with IV xylazine
(2.2mg/kg), detomidine (0.04mg/kg), or xylazine (2.2mg/kg)-acepromazine
(0.04mg/kg), or saline. Treatments were randomised so each horse
received each treatment once. Cardiopulmonary indices were measured, and
samples of arterial and venous blood were collected immediately before
and at specific times for 90 minutes after the end of each race. All
sedatives produced effective sedation. The cardiopulmonary depression
that was induced was qualitatively similar to that induced by
administration of these sedatives to resting horses and was not severe.
Sedative administration after exercise prolonged the exercise-induced
increase in body temperature. The authors concluded that administration
of xylazine, detomidine, or a combination of xylazine-acepromazine at
twice the standard doses produced safe and effective sedation in horses
that had just undergone a brief, intense bout of exercise.
Rankin et al (1999) (59) examined 6 healthy Thoroughbred horses to
evaluate whether prior exercise affects anaesthesia induction, recovery,
or both. Horses were trained to run on a treadmill until fatigued, then
sedated immediately with detomidine hydrochloride and anaesthetised with
a zolazepam-tiletamine combination. Anaesthesia was maintained with
isoflurane in oxygen for 90 minutes. Blood samples were taken before,
during and after exercise and during anaesthesia. During exercise,
changes in heart rate, core body temperature, plasma lactate
concentration, arterial pH and PaCO2 were significant. Plasma ionised
calcium concentration was lower after exercise, and remained lower at 30
minutes of isoflurane anaesthesia. Compared to baseline values plasma
chloride concentration decreased significantly during anaesthesia after
exercise. Cardiac output during anaesthesia was significantly lower than
during pre-exercise, and arterial blood pressure during anaesthesia was
also significantly lower, but both indices were still at acceptable
levels. The authors concluded that administration of detomidine followed
by zolazepam-tiletamine appeared to be safe and effective for sedation
and anaesthesia of horses immediately after strenuous exercise, and that
anaesthetic given according to this protocol can be used to anaesthetise
horses injured during athletic competition to assess injuries,
facilitate first aid, and possibly allow salvage of injured horses
Detomidine - Use in Foals
Oijala et al (1988) (69) administered detomidine twice to 6 foals (14-94
days old) using three different doses (10, 20, 40microgram/kg IV) in a
double blind trial. Sedation, analgesia, heart rate and clinically
observed side effects were recorded. Detomidine showed strong sedative
effects at all doses tested. Sedation deepened very little by increasing
the dose from 10 to 40microgram/kg, but the duration of the effect was
longer. Analgesia was considered good with the largest dose
(40microgram/kg), and moderate or non-existant at lower doses.
Detomidine caused a decrease in heart rate at all doses and other
observed effects included ataxia, heavy breathing, arrhythmia, sweating
and frequent urination. No adverse effects were observed.
Ohnesorge et al (1991) (72) conducted field trials using detomidine as a
sedative and analgesic for laryngoscopic examinations in a total of 193
foals and 806 mature Hanoverian horses. Detomidine was administered
either IV in foals 3-11 months old (20microgra/kg) and in mature horses
915microgram/kg), or IM in foals below 6 months of age (35microgram/kg).
After IV administration, laryngoscopy was tolerated in more than 90% of
all animals without additional use of a twitch, while in foals treated
IM more than 70% required a twitch in order to complete the procedure.
The effectiveness of detomidine was influenced by dose, route of
administration, the time interval between treatment and examination, and
the degree of excitement before treatment, but not by sex. Profound
bradycardia was evident in all treated horses, but arrhythmias were seen
only in animals older than 4 months, and were more pronounced in horses
with a lower resting heart rate. These cardiovascular responses never
endangered any of the treated animals. A transient dyspnoea was seen in
13 foals (6.7%) and 10 horses (1.2%). Other side effects were rare. The
foaling rate of 297 mares treated at any time during the first 8 months
of pregnancy was 66.7%. A comparison with 5499 untreated, contemporary
controls revealed a foaling rate of 61%, hence treatments with
detomidine had no effect on pregnancies.
Ranvet’s CALMANT - Route of Administration
Intravenous, Intramuscular
Administration is most commonly by either Intravenous or intramuscular
injection. The intravenous route provides a more rapid response and
profound analgesic effect. Onset of effect by intravenous administration
is usually seen in 2 to 5 minutes, whereas intramuscular injection
effect usually takes 5-10 minutes.
For dosage accuracy, and to minimise wastage, a tuberculin syringe or
other small volume syringe is recommended.
At the lowest recommended dose of detomidine (20 microgram/kg), depth of
sedation and analgesia is more pronounced when injection is administered
by the intravenous rourte. At higher doses differences in response
between routes of administration disappear.
Xylazine has been found to be less efficient as a sedative and analgesic
than the lowest recommended dose of detomidine. Acepromazine shows good
sedative effects for 60 to 90 minutes, but lacks any analgesic effect.
Peak levels of analgesia with the two highest dose rates of detomidine
(80 and 160 micrograms/kg) occur after intravenous administration within
15 minutes; after intramuscular administration from 30 to 45 minutes.
Elevations of pain threshold after intramuscular injections are about
half those seen after intravenous injection.
Oral
Alpha-2 agonists can be administered by IV, IM, or oral routes. The
intensity of the cardiorespiratory side effects after IM administration
is reduced, presumably due to lower plasma concentration of unbound
drug. IV administration produces a more rapid onset of action, an
increased intensity of effect, but a shorter duration of effect.(44)
Oral administration of detomidine is usually saved for situations where
a horse is not amenable to injections. Oral (sublingual) administration
at a dose of 0.06mg/kg bodyweight has been shown to produce profound
sedation 45 minutes after administration (45)
Continuous Rate Infusion
In addition to single dose administrations, detomidine may be used as
continuous rate infusions to provide prolonged periods of sedation and
analgesia. For example, following an IV loading dose of 5-7 microgram/kg
of detomidine, a continuous infusion of 0.6 microgram/kg/minute is
initiated. After 15 minutes the infusion rate is decreased by half to
0.3microgram/kg. By continuing to decrease the infusion rate by half
every 15 minutes, a moderate to deep degree of sedation and analgesia
can be maintained for prolonged periods (49)
Van Dijk (1994) (61) maintained anaesthesia in 10 elective surgery
horses at Utrecht University with an intravenous infusion of
guaiphenesin (100mg/mL), ketamine (2mg/mL) and detomidine (0.02mg/mL).
The infusion rate was 1mL/kg/hour. The author concluded that this
combination was safe and useful for the maintenance of total anaesthesia
in horses.
Ranvet’s CALMANT - Side Effects / Tolerance
• At all dose rates of detomidine, some slight unsteadiness can be
expected within 2-5 minutes after administration, particularly if high
doses are used. Despite this unsteadiness, horses will seek a well
balanced footing.
• Occasional dropping of the head (horses requiring dental work or
gastroendoscopy may need some head support for short periods)
• Reports of occasional and transient sweating, snoring, slight
salivation and muscle tremor, but no response to sharp auditory stimuli
• Some piloerection at onset
• May occasionally cause relaxation of the prepuce and penis, rarely as
pronounced as seen with other sedatives and tranquillisers. No cases of
penile prolapse have been reported (15)
• Injection site tolerance is high with minimum tissue reaction
• Withold feed until detomidine effect has worn off
• Bradycardia is noted in most patients at onset of activity. This
normalises within several minutes.
• As with any patient, monitor for untoward reactions.
Ranvet’s CALMANT - Contraindications & Safety
• Not recommended for use in pregnant mares, though limited work has
shown no embryo-toxicity
• Not recommended for use with sympathomimetic amines
• Detomidine is primarily excreted via urine (voluminous urination is
normal within approximately one hour of administration, with a transient
hyperglycaemia). Horses with impaired renal function or concurrent use
of drugs which reduce renal function will prolong sedative/analgesic
effects
• Possible interactions with potentiated sulphonamide and detomidine
usage have been reported. Two deaths occurred following intravenous
administration of trimethoprim/sulphadoxine in horses under heavy and
light detomidine sedation respectively during routine wound repair (23,
24) The pharmacological basis for untoward reaction (including some
fatalities) is not known. The use of potentiated sulphonamide in sedated
or anaesthetised horses is NOT recommended, regardless of sedative or
anaesthetic agent employed.
Detomidine has a wide safety margin. Doses of 300micrograms/kg
bodyweight (20 times the recommended dose) have resulted in long periods
of sedation but uneventful recovery after 8-10 hours
If complications from the use of detomidine in horses do occur, they are
most likely relative to overdose of drug combinations. Excessive
depression of respiratory rate with associated hypoxia, slow heart rates
or heart block, changes in blood pressure, elevation of blood glucose,
excessive urination if the horse is dehydrated, are potential
complications, as with other anaesthetic drug combinations.
Detomidine - Effect on Pregnant Mares
Detomidine, as is the case with other alpha-adrenoreceptor agonists,
increases the contractility of the pregnant and non-pregnant bovine
uterus at high dose rates but not at low dose rates (up to 20ug/kg)
(16), and even causes a decrease in electrical activity and thus
contractility. Levels of steroid hormones such as oestrogens influence
the changes in cell membrane potential mediated by various ions,
principally calcium, as well as increasing sensitivity of
alpha-adrenoreceptors.
Trials in mares where 20 pregnant mares received an intravenous or
intramuscular injection of detomidine at doses of 20, 80 or 150ug/kg
bodyweight, resulted in no untoward effects on the pregnancies or on
subsequent parturition (17)
Katila et al (1988) (52) administered detomidine by IV injection of 20
micrograms/kg bodyweight weekly from day 14 to day 60 of pregnancy, and
thereafter every four weeks until parturition, throughout 10 pregnancies
in eight mares, to observe that repeated administration of detomidine
had no specific adverse effects on pregnancies.
Luukanen et al (1997) (53) administered detomidine to 11 pregnant mares
at 3 week intervals during the last trimester of pregnancy. Maternal and
foetal electrocardiographs were recorded and foetal activity monitored
by transabdominal ultrasonography before, and 2 hours after injection.
After parturition, the foals were examined and weighed. Maternal and
foetal heart rate showed an initial decline after detomidine
administration, with the mare heart rate declining in 2 minutes, and
foetal heart rates dropping in 5 minutes after injection. The mares
exhibited conductive disturbances 2 minutes after injection, but foetal
heart rhythm remained regular. Foetal activity was decreased at 5
minutes, but had reverted to control values about 90 minutes after
detomidine administration. The authors concluded that administration of
detomidine (0.015mg/kg) to healthy pregnant mares at 3 week intervals
during the last trimester had no measurable detrimental effects on the
outcome of pregnancy.
Jedruch et al (1989) (54) studied the effect of detomidine on the
electrical activity of the uterus during the last trimester of pregnancy
in 6 mares. The effect was observed in 3-5 minutes after IM injection,
and lasted for 50-70 minutes. 20 and 40 microgram/kg bodyweight doses of
detomidine decreased the myometrial electrical activity, whereas 60
microgram/kg doses did not have any effect on the activity. The results
suggested that 20, 40, and 60 microgram/kg bodyweight doses of
detomidine can be administered to mares during the last trimester of
pregnancy without the risk of abortion induced by increased uterine
electrical activity.
Schatzmann et al (1994) (55) compared the effect of 3 alpha-2 agonist
sedatives, detomidine (0.04mg/kg), romifidine (0.08mg/kg) and xylazine
(1.1mg/kg) and placebo (NaCl) on intrauterine pressure with an
intrauterine balloon model in 4 non-pregnant warmblood mares. Within 6.0
(+/- 2.2) minutes mean pressure increases of 9.80 (+/- 3.74), 6.88 (+/-
3.95) and 13.95 (+/- 5.19) mmHg were recorded for detomidine, romifidine
and xylazine respectively. The mean duration of pressure increase was
30.0 (+/- 5.10), 17.67 (+/- 9.87) and 19.50 (+/- 13.78) minutes for the
three drugs respectively. There was no significant difference in the
degree and duration of sedation between the three treatment groups. It
is concluded that alpha-2 agonists exert a marked pressure increase in
the uterus with no statistically significant differences in degree and
duration between the three drugs.
Ranvet’s CALMANT - Pre-Anaesthetic Use
Detomidine has been used as an effective pre-anaesthetic agent for
intravenous anaesthesia or for intravenous induction followed by gaseous
anaesthetic maintenance (20).
It is recommended that at least 30 minutes elapse following intravenous
administration of detomidine at a dose rate of 10microgram/kg bodyweight
before induction due to quite dramatic reduction in the required dosages
of the other anaesthetic agents that may be used. Careful patient
monitoring is required for safety.
Induction with intravenous combinations such as Guaifenesin and
thiopentone sodium in a 5% solution was found to be smooth, with horses
gradually sinking into sternal recumbency. Halothane concentrations for
maintenance are markedly reduced (21)
Prior to ketamine anaesthesia, when detomidine is used at a dose rate of
20microgram/kg followed at least 5 minutes later by ketamine (2.2mg/kg),
the type and quality of induction and anaesthesia is similar to that of
xylazine-ketamine, however while the xylazine-ketamine recoveries are
sudden and complete, detomidine-ketamine takes significantly longer (22)
Although the hypertension and bradycardia induced by detomidine is
reduced after administration of ketamine, arterial blood pressure has
been shown to remain significantly above that before sedation.
The occurrence of bradycardia and heart block is reduced if horses
receive atropine 0.02mg/kg as a premedicant before administration of
detomidine.
• If detomidine is used in combination with ketamine it is normal to
note bradycardia in the patient
• Detomidine / ketamine combinations, if used for induction, tend to
produce a ‘smoother” induction, however recovery is longer than normally
seen with xylazine/ketamine.
• Clinical observations suggest that anaesthetic agents (gaseous or
parenteral) may be used at lower than normal dose levels if detomidine
is used for pre-medication.
Taylor et al (2000) (64) evaluated detomidine and romifidine as
premedicants in 100 horses undergoing elective surgery. After
administration of acepromazine (0.03mg/kg IV) 50 horses received
detomidine (0.02mg/kg IV) and 50 received romifidine (0.1mg/kg IV)
before induction and maintenance of anaesthesia with ketamine (2mg/kg)
and halothane, respectively. Arterial blood pressure and blood gases,
ECG, and heart and respiratory rates were recorded. Induction and
recovery were timed and graded. Mean duration of anaesthesia for all
horses was 104 +/- 28 minutes. Significant differences in induction and
recovery times or grades were not detected between groups. Mean arterial
blood pressure decreased in both groups 30 minutes after induction, and
from 40-70 minutes after induction was significantly higher in
detomidine-treated horses, compared to romifidine treated horses. In all
horses mean respiratory rate ranged from 9-11 breaths per minute, paO2
from 200-300mmHg, PaCO2 from 59-67mmHg, arterial pH from 7.33 to 7.29,
and heart rate from 30-33 beats/min, with no significant differences
between groups. Detomidine and romifidine were both satisfactory
premedicants, with romifidine leading to more severe hypotension than
detomidine, despite administration of dobutamine to more
romifidine-treated horses.. detomidine was the preferable alpha-2
agonist when maintenance of blood pressure is particularly important.
Matthews et al (1999) (65) at Texas A & M University, evaluated propofol
for induction and maintenance of anaesthesia after detomidine
premedication (0.015mg/kg IV), in 12 horses undergoing abdominal
surgery. 20 to 25 minutes after detomidine administration a propofol
bolus (2mg/kg IV) was administered for induction, then propofol infusion
(0.2mg/kg/min) was used to maintain anaesthesia. The authors concluded
that detomidine-propofol anaesthesia in horses in dorsal recumbency was
associated with cardiovascular depression, but hypoxaemia and
respiratory depression occurred and some excitement was seen on
induction. This technique is not recommended for surgical procedures in
horses in dorsal recumbency and if supplemental oxygen is not available
(eg, field anaesthesia)
Further, Mama et al (1996) (66) at University of California, Davis,
administered detomidine (15 and 30 microgram/kg) and xylazine(0.5 and
1mg/kg) to two groups of 6 horses as premedicants to propofol
anaesthesia (2mg/kg), and concluded that neither xylazine or detomidine
prevented the excitation associated with propofol injection in horses
Combined Use of Detomidine with Xylazine /Ketamine
Hubbell (2006) (45) notes that, since the introduction of xylazine -
ketamine anaesthesia, three new alpha-2 agonists have arrived in
veterinary medicine: detomidine, medetomidine and romifidine. The
combination of these agents with ketamine for short term anaesthesia has
been investigated.
Detomidine (0.02mg/kg, IV) in combination with ketamine produces
induction of anaesthesia similar to that of xylazine-ketamine, with
potentially better muscle relaxation (45, 46). The depth of anaesthesia
as evidenced by the ease of continuing anaesthesia with thiopental was
thought superior to xylazine-ketamine, but the recoveries from
anaesthesia tended to be rougher when detomidine was used., presumably
because of its greater duration of action than xylazine.(47, 48)
Taylor et al (1995 (60) examined the pharmacokinetics and some
pharmacological effects of anaesthesia induced by a combination of
detomidine, ketamine and guaiphenesin in eight ponies, with the ponies
taking on average 68 minutes to recover to standing, with uneventful
recoveries.
Bennett et al (1998) (62) compared the physiological effects of two
commonly used anaesthetic induction techniques in horses maintained with
halothane. One hundred horses admitted to the Animal Health Trust,
Newmarket, for elective surgery were randomly allocated to receive
either guaiphenesin (to effect) and thiopentone (5mg/kg), or detomidine
(20microgram/kg) and ketamine (2mg/kg) for induction of anaesthesia
after acepromazine premedication. Anaesthesia was maintained with
halothane in oxygen. Immediately after induction of anaesthesia, heart
rate was higher after guaiphenesin/thiopentone, and arterial blood
pressure was higher after detomidine and ketamine. Therafter,
hypotension developed in both groups. Arterial blood gases and
respiratory rates were similar in both groups, and there were no
significant differences between groups in the subjectively scored
quality of induction and recovery, or recovery time.
Combined Use of Detomidine With Opiates
The use of opiates following low dose administration of detomidine has
been investigated.
Clarke et al (1988) (19) examined the effects of administration of one
of four opiates,
pethidine 1mg/kg, morphine 0.1mg/kg, methadone (physeptone) 0.1mg/kg and
butorphanol 0.05mg/kg administered by intravenous injection to horses
already sedated with detomidine (10microgram/kg bodyweight).
Behavioural, cardiovascular and respiratory effects of the combinations
were compared to those of detomidine alone. Addition of the opiate
increased the apparent sedation and decreased the response of the horse
to external stimuli. At the doses used, butorphanol produced the most
reliable response. Side effects seen were increased ataxia (greatest
with methadone and butorphanol), and excitement (usually muzzle tremors
and muscle twitching). Following pethidine, generalised excitement was
sometimes seen. Marked cardiovascular changes occurred in the first few
minutes after morphine or pethidine injection, but these changes were
minimal within 5 minutes. Following morphine or pethidine there was a
significant increase in arterial carbon dioxide tension. Fourteen
clinical cases were successfully sedated using detomidine/butorphanol
combinations in this trial.
Physeptone (methadone) 0.05 to 0.1mg/kg is frequently used in Australia,
following sedation with xylazine or detomidine (27).
Butorphanol (0.1 to 0.5mg/kg) following sedation with detomidine is
possibly the most effective drug combination to facilitate standing
surgery in the horse (40)
At higher dose rates of detomidine, sedation plus potent analgesia
elicited would, in most cases, obviate the need for an opiate
combination.
Taylor et al (1988) (70) of the Animal Health Trust, Newmarket, used
combinations of detomidine (mean dose rate 13microgram/kg) and
butorphanol (mean dose rate 26microgram/kg) to sedate 61 horses for a
variety of surgical or diagnostic procedures in general equine practice.
Three horses were sedated on more than one occasion. The degree of
sedation was graded from 3 to 0 (deep sedation to no effect), and any
side effects were recorded. 43% of horses were graded 3, 46% were graded
2, 8% were graded 1, and 3& were graded 0. Bradycardia and ataxia were
the major side effects. The combination was judged to be effective and
safe for use in general practice. In 56 horses (92%) the necessary
procedure was carried out under excellent conditions and in only one
horse was the degree of sedation considered to be totally
unsatisfactory.
Schatzmann et al (2001) (71) measured the analgesic potency of
butorphanol 25microgram/kg bodyweight and levomethadone 100microg/kg,
administered together with detomidine 10microg/kg, in 12 Warmblood
horses in a randomised, blinded, crossover study. The nociceptive
threshold was determined using a constant current and a pneumatic
pressure model. Detomidine alone and in combination with butorphanol or
levomethadone caused a significant temporary increase of the nociceptive
threshold with a maximum effect within 15 minutes and a return to
baseline levels within 90 minutes. Butorphanol and levomethadone
increased the nociceptive threshold and prolonged duration of anti-nociception
significantly from 15 to 75 minutes (P<0.05) after drug administration
compared with detomidine alone. No significant difference between
butorphanol and levomethadone was registered. It is concluded that the
addition of butorphanol or levomethadone to detomidine increases the
nociceptive threshold to somatic pain and prolongs the analgesic effect
of detomidine in the horse.
Kruluc et al (2006) (75) studied the influence of detomidine used alone
and in combination with butorphanol on brain activity. The authors found
that both alone and in combination, detomidine significantly caused
brain wave changes, and the detomidine-butorphanol combination provided
greater and longer muscle relaxation, and is safer and more appropriate
for painless and non-painless procedures on standing horses
Ranvet’s CALMANT - Pharmacological Profile
• Effects produced by inhibition of noradrenaline mediated transmission
of nerve impulses in CNS
• A potent alpha-2 receptor agonist
• No hypnotic effect. Non-narcotic
• ECG shows prolongation of PR-interval and A-V block
• Minimal effect on respiration
• Detomidine has been demonstrated to be approximately 25 times more
potent than xylazine in it’s action at both pre- and post-synaptic
receptors
Detomidine is a highly specific and potent agonist at pre- and post
synaptic alpha-2 adreno receptors (1,2) both in vitro and in vivo. Its
main mechanism of action is direct activation of central alpha-2 sites
inducing a dose-dependent inhibition of noradrenaline release and
turnover mediated by a local feedback control mechanism (3,4,5). This
has been shown to lead to a characteristic pattern of sedation,
increased pain threshold, hypothermia and mydriasis.
In experimental models, these responses are significantly inhibited by
alpha-2 adreno receptor blocking agents such as idazoxan while
antagonists of alpha-1 sites have no effect. High doses of atropine are
able to partially counteract the sedative but not the analgesic effects
of the compound.
Of all the synthesized imidazole derivatives having alpha-2 binding
properties, detomidine was found to have only mild anti hypertensive
properties, and exhibits a strong peripheral vasopressor effect through
post synaptic alpha-2 receptor stimulation.
Xylazine has also been observed to be a rather specific alpha-2
adrenoreceptor agonist (6) but has been shown to be approximately 40
times less potent in its action at both pre and post synaptic receptors
(7).
At high concentrations after high doses, detomidine also has some
partial alpha-1 stimulatory activity leading to some sympathomimetic
effects including piloerection and sweating
Detomidine - Pharmacokinetics and Pharmacodynamics
Studies in rats, horses, dogs and cattle have shown that detomidine is
rapidly absorbed following intravenous, intramuscular and subcutaneous
administration, and is rapidly distributed to the brain. Thereafter, a
redistribution follows with a half life of approximately 2 hours into
all tissues, leading to disappearance of CNS effects. The final
elimination of detomidine is via kidneys, predominantly as metabolites
with half lives of 12-22 hours in the different species.
Raekallio et al(1991) (67) evaluated single doses of detomidine at 10
and 20microgram/kg dose rates IV to adult horses. Plasma concentrations
of adrenaline, noradrenaline, the catecholamine metabolites 3,4
dihydroxyphenylglycol and 3,4-dihydroxyphenylacetic acid and cortisol
were determined before medication and 30 minutes after. The plasma
concentrations of noradrenaline and the catecholamine metabolites
decreased significantly after administration at both dose rates of
detomidine. Plasma adrenaline level tended to increase but plasma
cortisol levels were not influenced. The findings suggested a reduction
in sympatho-adrenal activity in horses treated with detomidine.
Further work by Raekallio et al (1992) (68) was undertaken on 39 horses
given detomidine at 10microgram/kg IV, where the behaviour of the horse
at the time of detomidine injection, and the extent of sedation were
evaluated. Plasma adrenaline, noradrenaline and the catecholamine
metabolites listed above, plus cortisol concentrations decreased
significantly after administration of detomidine. A high plasma
adrenaline concentration before detomidine injection, indicative of a
high level of stress, seemed to correlate with a reduced sedative effect
of detomidine. The extent of sedation was also related to the
concentrations of adrenaline, noradrenaline and metabolites in plasma
after the detomidine injection. Detomidine influences the plasma
catecholamine concentrations by reducing directly sympatho-adrenal
activity, and there may also be an effect due to the sedative actions of
detomide whereby the reductions in plasma catecholamine concentrations
may partly be due to decreased secretion of catecholamines by detomidine
administration.
Detomidine - Cardiovascular and Pulmonary Effects
The effects of detomidine on the cardiovascular system are attributable
to its effects on the autonomic nervous system.
Administration of detomidine causes a decrease in heart rate and an
initial increase in blood pressure. At a dose rate of 20microgram/kg
there is an initial drop in blood pressure and heart rate (8).
Compensation for drops in heart rates of experimental horses to as low
as 10-15 beats per minute was made by an increase in systemic blood
pressures at dose rates of 20, 80 and 160microgram/kg
.
A temporary change in the conductivity of the myocardium also occurs,
accompanied by partial or complete atrioventricular and sinoatrial
blocks. The incidence of arrhythmias has been observed to be less
following intramuscular administrations than after intravenous
administrations. These arrhythmias vary in their incidence and duration
between individual horses, and can persist for up to 3 hours following
administration (9), depending on the dose level. With xylazine, A-V and
S-A blocks were found to disappear after 5 minutes following
administration.
Respiratory responses include an initial slowing of respiratory rate and
reduction in tidal volume within a few seconds to one or two minutes
following administration. Normal, or slightly increased respiratory
rates and tidal volumes commonly occur thereafter: the respiratory
pattern is frequently described as pauses of up to 30 seconds, followed
by 3-8 breaths in a close pattern. At the highest experimental dose of
160microgram/kg, reduced arterial oxygen level results in observed
alterations in mucous membrane colour. The arterial pH remains normal or
slightly elevated at all dose rates.
Taylor et al (1998) (63) examined 16 colts premedicated with
acepromazine, and anaesthesia induced with detomidine/ketamine. Colts
were randomly allocated to receive halothane or infusion of
detomidine-ketamine-guaiphenesin (DKG) to maintain anaesthesia for a
mean of 90 minutes during surgical castration. Mean arterial blood
pressure with DKG was significantly higher than with halothane, and,
with halothane, the mean arterial blood pressure increased from
pre-surgery (64 +/- 6mmHg) to mid-surgery (80 +/- 5mmHg) but did not
change with DKG. Recovery was smooth in both groups, and the authors
concluded that DKG was likely to lead to better tissue perfusion than
halothane
Ranvet’s CALMANT - Presentation
• Clear, colourless liquid for injection
• Potency: Detomidine hydrochloride 10mg/mL
• 5mL multi-dose glass vial
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