Beths2017 Tiva TCI

TIVA/TCI in Veterinary Practice
31
Thierry Beths
Introduction New Zealand College of Veterinary Scientists) colleges. The

specialist in veterinary anesthesia will most likely work in
Once they have graduated, veterinarians are permitted to academia, a referee centre and sometimes in the industrial
provide anesthesia to any patient of almost if not all species sectors. Some may become a consultant for general
(except humans). In general practice, due to the lack of practitioners and drug companies, but very few will work in
health insurance and the resulting higher health cost, general practice.
anesthesia is induced, maintained and monitored by nurses, In veterinary medicine, TIVA, which involves providing
trained or not, under the supervision of a veterinarian who anesthesia using intravenous agents only, is a well-known
might concurrently be performing a surgical procedure. form of anesthesia. In most of the developed countries,
Consequently, the veterinary practitioner is looking for the veterinarians will provide anesthesia using inhalants and
cheapest and easiest way to provide anesthesia to their TIVA will only be used for those specific cases where the
patients and, in most general practices, this will be through technique might bring some advantage to the patient
the use of inhalants (i.e. isoflurane, sevoflurane). Therefore, (i.e. raised intracranial pressure, bronchoscopy, preservation
Total Intravenous Anesthesia (TIVA) or any other form of of the hypoxic pulmonary vasoconstriction reflex). On the
drug infusion will be last on their list of anesthetic choices other hand, a TIVA technique will be preferentially chosen
due to the apparent difficulty of use, time and cost in remote areas where inhalation is not practical or available
constraints. In teaching institutions or in specialised centres (i.e. equine field anesthesia). In shelter medicine and during
(emergency clinic, referral centres), dedicated and/or humanitarian work in countries in need or following
specialised veterinary anesthetists and anesthesia nurses disasters, TIVA will be the technique of choice for providing
will be in charge of providing anesthesia. Consequently, general anesthesia. The different reasons for this include:
the use of a drug infusion to provide muscle relaxation short surgical procedures not needing prolonged anesthesia;
and/or analgesia will be part of the routine, with or without the number of surgeries to be done and the hectic nature of
intravenous based hypnotic anesthesia (as opposed to the environment; the higher risk and technical difficulties
inhalant). associated with anesthesia machines and accessories such as
Specialisation in anesthesia is possible in veterinary medi- O2 cylinders and vaporisers; finally, shelter medicine has a
cine. It can be achieved by undertaking a rotating internship mobile aspect attached to it which makes it very difficult to
(or equivalent experience) followed by a 3 year residency move around bulky equipment [1].
program in an approved clinic at the end of which, if his/her Balanced anesthesia is a technique where a hypnotic
credentials are accepted, the resident will be eligible to sit the agent (inhalant or intravenous) is administered concurrently
board exam of either the American (ACVAA—American with other drugs (sometimes referred to as adjuvants) to
College of Veterinary Anesthesia and Analgesia), European deliver more analgesia, muscle relaxation and cardiovascu-
(ECVAA—European College of Veterinary Anesthesia and lar stability in order to decrease the amount of hypnotic used
Analgesia) or Australian (ANZCVS—Australian and and associated side effects [2]. This technique of co-infusion
of agents during intravenous or inhalation anesthesia has
been used for quite some time in small animal medicine
T. Beths, MRCVS, PhD, Cert VA, CVA, CVPP (*) (dogs and cats). While in equine medicine, the advantages
U-Vet – University of Melbourne, Veterinary Anesthesiology, of co-infusion have only recently been emphasized and the
250 Princes Highway, Werribee, VIC CODE3030, Australia technique is now becoming more commonly used [3].
e-mail: [email protected]
# Springer International Publishing AG 2017 589

A.R. Absalom, K.P. Mason (eds.), Total Intravenous Anesthesia and Target Controlled Infusions,
DOI 10.1007/978-3-319-47609-4_31
590 T. Beths
In veterinary medicine, when the hypnotic is an inhalant, the horse. When providing continuous infusion, the easiest
technique of using co-infusion to achieve balanced anesthe- method involves a fluid bag containing the hypnotic mix-
sia is also referred to as Partial Intravenous Anesthesia or ture and a giving set attached to an intravenous catheter.
PIVA as opposed to TIVA where the hypnotic as well as the With this system, the flow rate can be adjusted varying the
other agents are all provided intravenously [3]. diameter of the infusion set using a regulating clamp
The distribution of intravenously infused drugs in the (Fig. 31.1). The infusion rate can be calculated from knowl-
body of an animal is governed by the general principles of edge of the volume of each drop of fluid. This methodology
pharmacokinetics (PK). Unfortunately for veterinary is commonly used for “field” anesthesia in the horse
anesthetists, for any given drug those PK parameters will (Figs. 31.2 and 31.3). The veterinarian must remember
vary between species and sometimes even between breeds in that as the fluid disappears from the infusion bag, the
the same species. An example is the slower propofol clear- infusion rate will reduce and will therefore need frequent
ance observed in greyhound dogs by comparison with other re-adjusting. Although this method provides a more consis-
breeds of dogs and beagle dogs in particular [4]. The PK for tent level of anesthesia by comparison with intermittent
most of the intravenous agents used in TIVA (or PIVA), administration, it has a high potential for miscalculation
have been developed in the targeted species, facilitating the and overdose, mainly in smaller patient (i.e. cats) and
adaptation of infusion protocols per species (Tables 31.1, burettes or micro drips are advised for use in those cases.
31.2 and 31.3). In some cases, those infusion protocols have The use of infusion pumps and syringe drivers brings more
not been developed through actual scientific research, but safety and precision to the continuous infusion. These
were instead either simply extrapolated from similar species devices have seen their technology and safety as well as
(i.e. from the horse for the donkey) or were developed from their affordability increase over the last few decades and
clinical experience [53]. their use has therefore become more and more common in
Ideal drugs for intravenous anesthesia and analgesia the veterinary world.
should have a rapid onset of action, quick metabolism, and While most of the veterinarians doing TIVA use recipes
elimination time. Amongst the important PK parameters that or published infusion rates (Table 31.2), veterinary anesthe-
veterinarians need to be familiar with, is the context sensi- sia is seeing the development of pharmacokinetic-dependent
tive half-time of elimination (CSHT). This parameter infusion techniques to allow specific drug plasma
highlights the fact that the elimination half time of a drug concentrations to be reached. Although most of those PK
during an infusion may be dynamic and may vary with the dependent techniques are mainly used in teaching and ref-
duration of the infusion, the context. Very little information eree centres for research purposes, their use has been
exists in veterinary medicine about the CSHT of the drugs described in a few clinical cases. Research groups have
used for infusion. In addition, like any other PK parameters developed stepped infusion systems for different agents
in veterinary medicine it will also vary between species. For such as for medetomidine or dexmedetomidine in the dog
example CSHT for fentanyl in humans increases substan- [35] or ketamine in the horse [22]. Stepped infusion systems
tially after 2–3 h of infusion, while this has not been consist of a group of well-defined different infusion rates
observed in dogs and cats where a steady state is reached which are started at specific times and have been developed
after 2–4 and 6 h of infusion, respectively [54–58]. so that a desired plasma concentration is reached rapidly and
In addition to PK knowledge of the drugs, the (specialist) with little accumulation or hangover. This system unfortu-
veterinary anesthetist must be aware of the pharmacody- nately is very rigid and does not allow for target plasma
namic (PD) differences that can exist between species for concentration changes. Therefore, the Target Controlled
any given agent. In some cases, drugs which are considered Infusion (TCI) system has been introduced where a com-
safe for infusion in some species may have dramatic and puter programmed with the PK of a specific drug for a
even lethal effects in others. For example, lidocaine infusion determined species drives the infusion. The TCI system
may induce cardiovascular depression in the isoflurane will maintain a stable desired drug plasma target concentra-
anesthetized cat [59]. Still in the cat, propofol is suspected tion while adapting the infusion rate to compensate for
to be responsible of Heinz Body formation anaemia when accumulation. Some TCI systems have been developed in
infused daily for 2–3 consecutive days [60]. veterinary medicine, but, they have not yet found their way
The total intravenous techniques used to maintain anes- into clinical anesthesia. This is mostly due to the limited
thesia in animals are not different in principle from those availability of hardware and software and due to the paucity
described for human (see Chaps. 6 and 25). Repeated bolus of evaluation of population pharmacokinetics. Different
dose administration (intermittent administration) is the sim- drugs have been studied and their PK parameters identified
plest technique and the most commonly used for short for use in TCI system for different species: propofol in the
procedures such as skin biopsies, ultrasound or X-ray in dog, and ketamine and detomidine (an α2-adrenoceptor ago-
small animals (dogs and cats), and field castration in the nist licenced in the horse) in the equine patient [61–63].
31
Table 31.1 Pharmacokinetics parameters in commonly used intravenous anaesthetics in different species
Elimination Volume of Total systemic
Drugs Species half-life distribution clearance Comments References
Propofol Dogs 322 min 6.5 L/kg 50.1 mg/kg/min No premed, no co-infusion [5]a
Beagle dogs
486.2 min 3.38 L/kg 34.4 mg/kg/min Premedication medetomidine 10 μg/kg, IM Hall et al. [6]a
Mixed breed dogs
85.3 min 3.27 L/kg 53.35 mg/kg/min Co-infusion Fentanyl 0.1–0.5 μg/kg/min) LD 2 μg/kg, IV Hughes and Nolan [7]a
TIVA/TCI in Veterinary Practice
Greyhound dogs
53 min 6.6 L/kg 34 mg/kg/min Cockshott et al. [8]a
74 min 2.46 L/kg 40 mg/kg/min No premed, no co-infusion Mandsager et al. [9]a
Greyhound dogs
Cats 527.7 min 6.83 L/kg 17.2 mg/kg/min No premed, no co-infusion [10]b
bolus
453 min 7.737 L/kg 11.5 mg/kg/min Co induction Propofol/Ketamine 2 mg/kg each, IV (Ketofol) Zonca et al. [11]a
Co-infusion Propofol/Ketamine 0.17 mg/kg/min each, IV (ketofol)
Ponies 69 min 0.89 L/kg 33.1 mg/kg/min Premed detomidine 20 μg/kg, IV Nolan et al. [12]a
Induction with ketamine 2.2 mg/kg IV
Co-infusion ketamine 50 μg/kg/min, IV
Sheep 56.6 1.037 L/kg 85.4 mg/kg/min Premed acepromazine/papaveretum [13]a
No co-infusion
50.3 min 1.515 L/kg 128 mg/kg/min Same premed as above
Ketamine co-induction 1 mg/kg
Ketamine co-infusion VRI
Swine 1.42–2.72 L/kg 23–32.8 mg/kg/min Isoflurane anesthetized pigs Egan et al. [14]a
Alfaxalone Dogs 24 min 2.4 L/kg 59.4 mg/kg/min Alfaxalone 2 mg/kg IV bolus; no premed [15]b
Beagle dogs
34.3 min 2.4 L/kg 48.5 mg/kg/min Alfaxalone 2 mg/kg IV bolus; no premed [16]b
Greyhound dogs
42.1 min 2.3 L/kg 36.9 mg/kg/min Same as above with acepromazine and morphine, 0.03 and 0.3 mg/kg,
respectively, IM
Alfaxalone Cats 45.2 min 1.8 L/kg 25.1 mg/kg/min Alfaxalone 5 mg/kg, IV bolus [17]b
76.6 min 2.1 L/kg 14.8 mg/kg/min Alfaxalone 25 mg/kg IV, bolus
Horses 33.4 min 1.6 L/kg 37.1 mg/kg/min Alfaxalone 1 mg/kg IV with GGE 35 mg/kg, IV [18]b
Premed acepromazine/xylazine 0.03/1 mg/kg, IV
Neonatal 22.8 min 0.6 L/kg 19.9 mg/kg/min Alfaxalone 3 mg/kg, IV bolus [19]b
foals Premed butorphanol 0.05 mg/kg, IV
(continued)
591
Table 31.1 (continued)
592
Elimination Volume of Total systemic

Drugs Species half-life distribution clearance Comments References
Ketamine Dogs 61 min 1.95 L/kg 39.5 mg/kg/min Ketamine 15 mg/kg, IV, bolus Kaka and Hayton [20]b
Cats 78.7 min 2.12 L/kg 21.33 mg/kg/min Ketamine 25 mg/kg, IV, bolus [21]
Horses 67.4 min 1.03 L/kg 0.076 mg/kg/min Ketamine 0.08–0.025 mg/kg/min (stepped infusion) [22]a
Conscious horses for IV analgesia
42 min 1.63 L/kg 26.6 mg/kg/min Xylazine premed; Ketamine 2.2 mg/kg, IV, bolus Kaka et al. [23]b
66 min 2.72 L/kg 31.1 mg/kg/min Xylazine premed 1.1 mg/kg, IV Waterman et al. [24]b
Induction ketamine 2.2 mg/kg, IV; halothane anaesthesia
90 min 1.43 L/kg 23.9 mg/kg/min Premed detomidine 20 μg/kg, IV Nolan et al. 1996 [12]a
Induction with ketamine 2.2 mg/kg IV
Co-infusion ketamine 50 μg/kg/min, IV
Ponies 15 min 0.012 L/kg 0.6 mg/kg/min Ketamine 0.02 mg/mg/min, LD 0.6 mg/kg, IV [25]a
Conscious horses for IV analgesia PK values for
S- 7.8 min 0.013 L/kg 1 mg/kg/min S-Ketamine 0.01 mg/kg/min, LD 0.3 mg/kg, IV S-ketamine only
Ketamine Conscious horses for IV analgesia
LD loading dose
a
Infusion
b
Bolus only
T. Beths
31 TIVA/TCI in Veterinary Practice 593
Table 31.2 Examples of infusion protocols for analgesic adjuncts in different species
Drugs Species Loading dose IV Infusion rate IV Comments Reference
α2 adrenoceptor agonists
Xylazine Horse 0.035–0.07 mg/kg/min With ketamine 0.09–0.15 mg/kg/min [26]
Horse 1.1 mg/kg 1–1.5 mL/kg/h GKX triple drip with 0.5 mg/mL of xylazine, [27]
1 mg/mL ketamine and 50 mg/mL guaifenesin
Medetomidine Horse 0.007 mg/kg 0.0035 mg/kg/h With propofol 0.01–0.11 mg/kg/min [28]
Dog/cat 0.001–0.002 mg/kg/h [19]
Dexmedetomidine Dog/cat 0.0005–0.001 mg/kg/h [29]
Horse 0.0035 mg/kg 0.0001–0.000175 μg/kg/h [30]
Ketamine Dog/cat 0.2–0.5 mg/kg 5–20 μg/kg/min The author usually uses 5–10 μg/kg/min to [29]
limit possible side effect resulting from
ketamine infusion
Horse 40–50 μg/kg/min With propofol 0.12–0.16 mg/kg min [31, 32]
Opioids
Morphine Dog 0.1–0.2 mg/kg/h [29]
Horse 0.05–0.15 mg/kg 0.03–0.1 mg/kg/h With or without anaesthesia [30, 33,
34]
Fentanyl Dog 0.005 mg/kg 0.2–0.5 μg/kg/min With propofol 0.1–0.3 mg/kg/min [29]
Feline 0.001 mg/kg 0.1 μg/kg/min With propofol 0.1–0.3 mg/kg/min
Remifentanil Dog/cat 0.2–0.6 μg/kg/min With propofol 0.3–0.5 mg/kg/min
Feline 0.2–0.3 μg/kg/min With propofol 0.3 mg/kg/min
Miscellaneous
Lignocaine Dog 2–4 mg/kg 25–80 mic/kg/min [29]
Horse 1.5–5 mg/kg 0.025–0.1 μg/kg/min [2]
For more information, the author refers the reader to more specific veterinary anaesthesia textbook
GKX Guaifenesin Ketamine and Xylazine mixture (triple drip)
The ketamine TCI system for the horse is still in develop- hypnosis and cardiorespiratory function that are improved.
ment and a team from Switzerland has recently determined The most commonly used agents in addition to the hypnotics
and validated a set of PK parameters in ponies [63]. A few to balance anesthesia are the α2-adrenoceptor agonists, keta-
years earlier, in 2006, Knobloch et al., developed a physio- mine, the opioids and lidocaine, to name a few (Table 31.2).
logically based pharmacokinetic (PKPB) model for keta- The α2-adrenoceptor agonists provide in most species
mine in ponies targeting low dose of ketamine (S-ketamine a reliable dose-dependent analgesia, muscle relaxation
1 μg/mL) to provide analgesia [64]. The models provided and sedation. They are therefore ideal agents for balanced
reliable prediction of plasma level of R- and S-ketamine. In anesthesia and are the most widely used sedatives in
the dog, a TCI system for propofol (Figs. 31.4 and 31.5) was veterinary anesthesia. Unfortunately their cardiovascular
developed and validated by Beths et al. in 2001 and has since effects, characterised by an increase in blood pressure
been used in different clinical settings such as neurosurgery and systemic vascular resistance with reduced heart rate
[61, 65]; cardiac surgery in a patient with ductus arteriosus and cardiac output, are limitations to their use. While
[66]; and neutering procedures [67, 68]. In addition, xylazine, romifidine and detomidine are most commonly
combinations with other agents have been studied: used in the equine patient, medetomidine and its active
remifentanil, medetomidine and dexmedetomidine [35, 67, enantiomer dexmedetomidine are used in dogs and cats.
69]. Furthermore, Beths in 2008 and Beier et al., in 2009, The sparing effect of the α2-adrenoceptor agonists has
looked at the influence of medetomidine and been shown on inhalant as well as IV agents such as
dexmedetomidine, and remifentanil infusion, respectively, propofol [35, 77].
on the minimum propofol target concentration needed to Xylazine was synthesize in Germany in 1962 for use in
stop reaction to supramaximal stimulation in dogs human as an antihypertensive. It was the first α2-adrenoceptor
(Table 31.4) [35, 67, 69]. used in veterinary medicine. Although its use is also licenced
To decrease the dose of drugs used and therefore reduce in dogs and in cats, it is mostly used in cattle and horses.
their potential side effects, anesthetists balance their anes- Romifidine is licenced in horses and has a higher potency than
thesia by combining different agents. Doing so, they manage xylazine. Detomidine and medetomidine are more potent than
to not only decrease the amount of drug used, but also give a Romifidine. While detomidine is licenced for use in horses,
more stable anesthesia with muscle relaxation, analgesia, medetomidine is licenced for use in dogs and cats.
594 T. Beths
Table 31.3 Examples of infusion protocols for the most common intravenous hypnotics used for TIVA in veterinary medicine
Drugs Species Premedication Induction IV Infusion rate, IV Comments References
Propofol Dogs As required Propofol Propofol 0.1–0.5 mg/kg/ Dose rate will vary depending on [29]
2–6 mg/kg min analgesia and procedure
Dogs Acepromazine Target of Target 2.7–3.4 μg/mL TCI propofol [35]
0.03 mg/kg, IM 3 μg/mL Dexmedetomidine plasma Stepped infusion
Methadone target of 0.85 ng/mL
0.2 mg/kg, IM
Cats As required Propofol Propofol 0.12–0.5 mg/kg/ Dose rate will vary depending on [29]
4–8 mg/kg min analgesia and procedure
Horses Detomidine Propofol Propofol 0.18 mg/kg/min VRI [36]
2 mg/kg
Horses Xylazine 1 mg/kg, Propofol Propofol 0.16 mg/kg/min VRI [32]
IV 3 mg/kg Ketamine 3 mg/kg/h CRI
Midazolam Poor quality
0.05 mg/kg, IV
Horses Medetomidine Ketamine Propofol 0.1 mg/kg/min VRI [28]
0.007 mg/kg, IV 2 mg/kg Medetomidine 3.5 μg/kg/h CRI
Horses Medetomidine Ketamine Propofol 0.14 mg/kg/min VRI [37]
0.005 mg/kg, IV 2.5 mg/kg Ketamine 1 mg/kg/h CRI
Midazolam Medetomidine 1.25 μg/kg/ CRI
0.04 mg/kg h
Calves Propofol Propofol 0.6–0.6 mg/kg/ VRI [38]
5 mg/kg min
Goats Propofol Propofol 0.2–0.6 mg/kg/ VRI [25, 39,
2.5–6 mg/kg min 40]
Alfaxalone Dogs As required Alfaxalone Alfaxalone 0.07–0.15 mg/ VRI [41, 42]
2–3 mg/kg kg/min
Cats As required Alfaxalone Alfaxalone 0.11–0.18 mg/ VRI Datasheet
1.7–5 mg/kg kg/min [43–45]
Horses Acepromazine Guaiphenesin Alfaxalone 2 mg/kg/h Colt castration [46]
0.03 mg/kg, IV 35 mg/kg Medetomidine 5 μg/kg/h
Medetomidine Alfaxalone
0.007 mg/kg, IV 1 mg/kg
Sheep Alfaxalone 10 mg/kg/h [47]
2 mg/kg
Swine Alfaxalone Alfaxalone 0.08 mg/kg/min VRI [48]
4 mg/kg, IM 1.2 mg/kg Placement of epidural catheter
Medetomidine
0.04 mg/kg, IM
Butorphanol
0.4 mg/kg, IM
Green Ketamine 5 mg/ Alfaxalone 0.15 mg/kg/min VRI [49, 50]
Vervet kg, IM 0.4–1.2 mg/kg Imaging study
monkeys
Ketamine Dogs 2–20 μg/kg/min CRI to provide analgesia in order [29]
to reduce anaesthetic requirements
Cats 0.15–0.46 μg/kg/min CRI to provide analgesia in order [29, 51,
to reduce anaesthetic requirements 52]
Horses α2 agonist Ketamine Triple drip with GGE and α2- See main
Diazepam adrenoceptor agonist text
Medetomidine is a racemic mixture composed of atipamezole. The former was developed to reverse the effects
dexmedetomidine, the active enantiomer and levomede- of xylazine in particular (dogs, cats, ruminants and exotic
tomidine the inactive one. While dexmedetomidine has been species), and the latter is used primarily to reverse the effects
available in human medicine for a long time, it is only in the of medetomidine or dexmedetomidine in dogs, cats and sev-
last decade that it became available to veterinarians. One of eral exotic species. The reversal agents are usually used to
the advantages of this class of drugs is that their effect can be speed up the recovery and/or in an emergency situation.
reversed with the use of α2-antagonists such as yohimbine and While their use is frequent in exotic species and with wild
Fig. 31.1 Regulating clamp used to modify fluid rate through a giving
set
animals where prolonged recumbency may be associated with

higher morbidity and mortality, in equine and small animal
practices, veterinarians tend not to reverse it allowing the
patient to recover slowly and calmly from the anesthesia. In
fact, in horses, following inhalation anesthesia, it is
recommended to give the horse a sedative, usually an α2-
adrenoceptor agonist, while it is still anesthetised in the
recovery box, to smoothen the recovery and to avoid any
excitation which could result in self-induced wound or
worse, limb fracture. Figure 31.6 shows some important
phases of anesthesia in a horse, including recovery. When
using a reversal agent, the analgesic effect of the α2-
adrenoceptor agonists will be reversed and veterinarians
must therefore ensure that analgesia is well under control
using other agents such as opioids or local anesthetics.
Ketamine is a dissociative agent which is used clinically
to provide immobilization or anesthesia (wild animals,
horses). In addition to its hypnotic effect, it also provides
analgesia and is mostly used at low rate infusion for this
effect in different species including dogs, cats and horses.
NMDA antagonism is believed to be the most likely molec-
ular mechanism responsible for most of ketamine’s clinical
properties [78]. Through its NMDA antagonistic properties,
ketamine is known as an antihyperalgesic agent that
decreases wind-up and may provide pain relief in patients
suffering from chronic pain. Infusion schemes have been Fig. 31.2 Equine field anaesthesia—induction of anesthesia
developed in small animals as well as horses and its sparing
596 T. Beths
Fig. 31.3 Equine field

anesthesia—maintenance of
anaesthesia using a triple drip
based protocol
Lidocaine is a sodium channel blocker local anesthetic

that has been used intravenously to provide analgesia sys-
temically. Its analgesic and anti-inflammatory effects are
mediated, among others, by blockade of Na channels, inhi-
bition of glycine receptors, inhibition of NMDA and
neurokinin (NK) receptors, promotion of and the release of
endogenous opioids. Although it is not recommended for
infusion in the cat where severe cardiovascular depression
has been observed when used as an infusion [59], it has been
successfully used peri-and postoperatively in different spe-
cies, including dogs and horses [2, 29].
Hypnotic Agents
Propofol
The properties of propofol differentiate it from other intra-

venous agents. A rapid onset of action, short duration due to
high biotransformation, rapid redistribution and an apparent
lack of accumulation made it the ideal agent for induction
Fig. 31.4 TCI for propofol in the dog—first version and maintenance of anesthesia in human as well as veteri-
nary medicine.
It is a substituted isopropyl phenol which is insoluble in
effects have been well documented with inhalant as well as water and was first formulated with Cremophor EL (1977).
IV agents in different species (Table 31.2) [29, 31, 32, 34]. Pain associated with injection as well as complement
The opioids are known for their analgesic effects. mediated adverse reactions to the Cremophor resulted in
Although agents characterised by short onset and short dura- radical changes in its formulation [80]. Since 1986, it is
tion time such as fentanyl or remifentanil are more appropri- formulated in an oil in water emulsion containing 1 %
ate for constant rate infusion (CRI), longer acting agent such propofol, 10 % soybean oil, 2.25 % glycerol, and 1.2 %
as morphine or methadone have also been used in veterinary purified egg lecithin.
medicine (Table 31.1) [2, 29, 30, 33, 34]. Etorphine, a potent Although this formulation (macro emulsion) is the most
mu-opioid agonist (about 3000 times the potency of mor- popular in human and veterinary medicine, pain on injection
phine), is mostly used for the restraint and the capture of has still been reported in humans [81–83] as well as in dogs
wild animals. Its use as an infusion to maintain a patient and cats [84, 85]. In addition, its lack of preservative allows
under general anesthesia has been described in the elephant for fungal and bacterial growths leading to a very short shelf
(Fig. 31.7) [79]. life of about 12 h after which time any used vials and tubings
Fig. 31.5 TCI for propofol in the

dog—second version
Table 31.4 Examples of minimum infusion rates (MIR) for propofol in different species
Species Premedication Induction IV MIR IV Comments References
Dogs Acepromazine, IM Propofol TCI Propofol TCI, mCp Co-infusion [35]a
Methadone, IM Target 3 μg/mL 3.3 (1.04) μg/mL Dexmedetomidine, Measured Plasma
concentration of 0.83 ng/mL
Propofol TCI, mCP No co-infusion
6.2 (1.35) μg/mL
None Propofol 6 mg/kg 0.51 (0.08) mg/kg/min No co-infusion [70]a
0.42 (0.08) mg/kg/min Co-infusion
Lidocaine 0.25 mg/kg min CRI
(LD 1.5 mg/kg)
0.31 (0.074) mg/kg/ Co-infusion
min Lidocaine 0.25 mg/kg/min, CRI
(LD 1.5 mg/kg)
Ketamine 0.1 mg/kg/min, CRI (1 mg/kg)
None Propofol 6 mg/kg 0.76 (0.1) mg/kg/min No co-infusion [71]a
Propofol 5 mg/kg 0.6 (0.1) mg/kg/min Co-infusion
Ketamine 2 mg/kg Ketamine 0.0.025 mg/kg/min
Propofol 4 mg/kg 0.41 (0.1) mg/kg/min Co-infusion
Ketamine 3 mg/kg Ketamine 0.05 mg/kg/min
Cats None Propofol 0.21 (0.02) mg/kg/min No co-infusion [51]b
0.05–0.1 mg/kg/ 0.14 (0.01) mg/kg/min Co-infusion
min Ketamine 0.023 mg/kg/min
0.14 (0.01) mg/kg/min Co-infusion
Ketamine 0.046 mg/kg/min
Horses Medetomidine Propofol 2 mg/kg 0.06–0.1 mg/kg/min Co-infusion [72, 73]a
0.007 mg/kg, IV Medetomidine 0.0035 mg/kg/h
Xylazine 1 mg/kg, IV Propofol 3 mg/kg 0.1 (0.02) or mCp None [74]a
5.3 (1.4) μg/mL
None Propofol 7 mg/kg 0.2 (0.03) or mCp None [75]a
17.5 (4.0) μg/mL
Rabbit None Propofol 1 mg/kg/ 0.64–1.19 mg/kg/min None [76]c
min
LD loading dose, mCp measured plasma concentration
a
Electric stimulation
b
Toe pinching
c
Tail clamping
598 T. Beths
Fig. 31.6 (continued)
(infusion) should be discarded (Label Diprivan® 451094 F/ Pharmacokinetics

Issued: February 2014). To increase the shelf life of propofol In terms of pharmacokinetics, propofol’s rapid distribution
and possibly decrease pain on administration, other and clearance are mostly responsible for its clinical success
formulations have been developed and tested such as a and make it the drug of choice for maintenance of anesthe-
nano droplet formulation and a propofol containing 2 % sia. In most species (but not cats) propofol does not seem to
benzyl alcohol preservative [10, 86]. Amongst the clinically accumulate after multiple injections or
formulations developed to decrease the pain, the most suc- prolonged infusion resulting in rapid recoveries of rela-
cessful one is fospropofol which is a prodrug of propofol. tively good quality. Following a single bolus IV adminis-
Unfortunately, PK studies in the dog and the rabbit have tration, propofol rapidly reaches the brain and induces
shown longer onset and duration of action when compared anesthesia. Then it will redistribute to other tissues, leaving
with the macro emulsion [76, 87]. the brain and terminating the anesthesia. In most species
Fig. 31.6 Illustration of some important phases of equine box to the surgery table; (e) placement of the horse on the surgery table;
anesthesiaEquine anaesthesiaphases of. (a) Sedation horse placed (f) horse recovering from anesthesia in a padded (wall and floor)
between a wall and a mobile panel to minimize lateral movement recovery box; (g) same horse as previous, recovering from an anesthe-
during induction; (b) induction of anaesthesia; (c) blind endotracheal sia, still intubated and breathing 100 % O2 through a demand valve;
intubation; (d) lifting of a horse under anaesthesia from the induction (h) unassisted recovery; (i) assisted recovery
(but not cats) propofol is extensively and rapidly metabolised Pharmacodynamics

by the liver, resulting in the production of water soluble Regarding the central nervous system (CNS), cerebral blood
sulphide and glucuronide metabolites which will be excreted flow (CBF) regulation is not impaired by propofol adminis-
by the kidneys [88–90]. Propofol’s clearance from the plasma tration while cerebral metabolic rate (CMR) is decreased
far exceeds the hepatic blood flow, which marks the impor- which may protect neuronal function in compromised
tance of the peripheral tissue uptake as well as the possibility patients [96–98]. The decrease in CMR will also result in
of extra hepatic metabolism (lung, kidney). The latter was vasoconstriction, decreasing ICP (intracranial pressure).
confirmed when metabolites of propofol were still detected Therefore the use of propofol has been advised in humans
during the anhepatic phase of orthotopic liver transplantation as well as in dogs with intracranial diseases [99–103].
in man [90]. Although lungs and kidneys have been suggested The cardiovascular (CV) effects of propofol are a dose
as possible sites for the extra hepatic metabolism, it is still dependant decrease in myocardial contractility and a
debated and recent studies have confirmed the importance of decrease in systemic vascular resistance (SVR). The
the role of the kidneys over the lungs in the extra hepatic resulting decrease in blood pressure from baseline
propofol clearance [91–95]. (no hypotension per se) does not usually trigger a
600 T. Beths
Fig. 31.7 Elephant undergoing

tooth surgery and maintained
anesthetized with etorphine
infusion. The patient was
intubated (Murphy style
endotracheal tube ID ¼ 30). The
patient was breathing 100 % O2
and was ventilated (Intermittent
Positive Pressure Ventilation)
using a demand valve
compensatory increase in heart rate as observed with other Propofol lacks analgesic properties, and therefore needs
agents such as thiopental. It has been speculated that in fact to be co-administered with analgesic agents such as opioids.
propofol resets the baroreceptor reflex set point [104]. Propofol is licenced in dogs and cats but its use has also
Respiratory depression is an important side-effect of been reported in other species, either as an induction agent or
propofol and it will dose dependently decrease tidal vol- for TIVA [5, 13, 113–117].
ume and/or respiratory rate leading to apnea [84, 105]. The
incidence of the latter is not only dose dependant, but also Propofol TIVA in Different Species (Table 31.3)
administration rate dependant [105]. The ventilatory
response to hypoxemia and hypercarbia are decreased with Canine
propofol administration and this may be exacerbated with Although propofol may depress the CV system through
co-administration of opioids [18, 106, 107]. To avoid or myocardial depression and arteriolar and venous vasodila-
limit the respiratory depression, it is advised to administer tion, in healthy patient, hemodynamic stability is usually
propofol slowly to effect [84, 108, 109]. well maintained with a lower blood pressure than baseline
It is a great muscle relaxant although myoclonic movements and decrease in cardiac output but with minimal changes in
and muscle twitching as well as opisthotonos have been heart rate [118, 119]. To avoid higher infusion rates to
reported during anesthesia in the dog [84, 110–112]. The compensate for propofol’s lack of analgesia, analgesic
incidence of these reactions is greatly decreased with the use agents (opioids, ketamine) are usually administered in the
of preanesthetic tranquillisers, sedatives or opioids. premedication (bolus) and/or the maintenance (bolus or
more commonly as co-infusion period) phase of anesthesia. tone, swallowing reflexes and presence or absence of limb
Although the aim is to decrease the propofol requirements withdrawal following toe pinching. The authors did not
and therefore the associated cardiovascular depression, in observe any effect on the HR or the SpO2 and PaO2 by
the healthy dog, the addition of potent opioids such as comparison to baseline while mean arterial blood pressure
remifentanil during the maintenance period shows, in addi- (MAP) was lower than baseline, but hypotensive events
tion to the propofol sparing effect, a decrease in the heart (MAP < 60 mmHg) were not reported by the authors (lowest
rate (HR), stroke volume (SV) and cardiac output MAP observed at was 78 7 mmHg at time 40 min). Five of
(CO) while still maintaining good arterial blood pressure the ten dogs of the study had short (15 min) apneic events.
[118, 120]. To limit those CV effects observed with opioid The time to extubation was 9.4 min and the recovery quality
infusion, ketamine infusion has also been used during was scored as smooth or with some paddling of short dura-
propofol based anesthesia: a combination sometimes tion. Other infusion protocols are provided in Table 31.3.
referred to as Ketofol [119, 121]. Ketamine holds a particu- The minimum infusion rate (MIR) and the minimum
lar place amongst anesthetic agents as it maintains or target concentration (TCI) for propofol necessary to block
increases CO in the healthy patient as a result of increased a response to a supramaximal stimulation (tetanic twitch) in
sympathetic tone [122]. In a recent study in healthy beagle 50 % of dogs has been determined with different
dogs, the combination resulted in a decrease of the amount co-infusions including dexmedetomidine, lidocaine and
of propofol used with an increase in HR and arterial blood ketamine [35, 70, 61] (Table 31.4).
pressure [119].
In the healthy dog, the main side-effect resulting from Feline
propofol administration is respiratory depression which The CV and respiratory effects are very similar to those
tends to be exacerbated with the addition of opioids as well observed in the dog. The addition of analgesic agents such
as ketamine and consequently the anesthetists must be ready as potent opioids (fentanyl, alfentanil or sufentanil) in
to provide assisted ventilation [118, 119]. healthy un-premedicated cats undergoing ovariohys-
A recent retrospective study looking at myoclonus in terectomy and maintained under anesthesia with propofol
dogs anesthetised with propofol TIVA reported a 1.2 % TIVA had similar effects as in dogs with a decrease in HR
incidence [123]. This is much lower than the previously and arterial blood pressure as well as a respiratory depres-
described incidences: 21 % [124], 7.5 % [111] or 46.1 % sion (decrease respiratory rate, increase in EtCO2)
[125]. The difference may result from the fact that in the [128]. On the other hand, Padilla and colleagues show
most recent study, myoclonus was precisely defined as that, in acepromazine premedicated cats also undergoing
involuntary muscle contractions which did not cease follow- neutering procedures and receiving either remifentanil or
ing bolus administration of propofol, and due to their inten- alfentanil infusion in addition to propofol TIVA, HR and
sity made continuation of anesthesia difficult without further arterial blood pressure were equal or increased by compari-
treatment [123]. Any uncoordinated movements, tremor, son with baseline while ventilatory parameters were well
paddling (running like movement) that could be explained maintained [129]. In earlier studies, it has been reported
by a lack of hypnosis or analgesia or were present during the that HR and systolic arterial blood pressure (SAP) could
awakening phase were not counted. For example, in the Hall increase in cats secondary to sympathetic activation in
and Chambers study [124] the dogs did not receive any consequence to the administration of high doses of ultra-
analgesia in the premedication or during the procedure and short acting opioids [130, 131]. While we cannot comment
therefore the observed movements could have been on the infusion rate for remifentanil, the alfentanil infusion
attributed to insufficient anesthesia and/or analgesia [124]. rate was higher in the Padilla’s study at 0.5 versus 0.08 μg/
Pain on injection has been described in the dog and the kg/min and could have been responsible for the different
incidence varies between 1 and 7.5 % [84, 85]. In a recent CV parameters in that study. An additional explanation
study (2012), Michou et al. reported a 3 % incidence with could be that as the cats underwent ovariohysterectomy in
the macro emulsion compared with a 20 % incidence with a both studies, it is still possible that the surgical stimulation
new lipid free formulation (propoClear®, Pfizer Animal was different enough to have caused the observed
Health, UK) [126]. Similar results with the lipid free emul- difference.
sion were reported by Minghella in 2010 [127]. In injured cats, cardiorespiratory variables were com-
In a recent study, the induction and maintenance doses in pared between propofol/fentanyl and isoflurane/fentanyl
unpremedicated animals were respectively 5.3 1.1 and anesthesia. A higher requirement for respiratory system sup-
0.6 0.1 mg/kg [119]. In this study dogs were not port through IPPV was found in the propofol group than in
undergoing any surgery and anesthesia was maintained for the isoflurane group (9/11 vs 1/11), but CV parameters such
60 min while the infusion rate was altered up or down as arterial blood pressures in particular were better
following clinical assessment including ocular reflexes, jaw maintained in the propofol group [132].
602 T. Beths
In 2015, Campagna et al. reported that, in medetomidine preparations by comparison to dogs and rats (Fig. 31.8)
premedicated cats undergoing ovariohysterectomy under (unpublished data).
propofol TIVA, 80 % of their patients required controlled In addition to this slower metabolism, the use of propofol
ventilation [44]. In an earlier study in cats premedicated for TIVA in the cat is still controversial. In a study in 1989,
with morphine and medetomidine, undergoing neutering pro- Andress et al. reported, following repeated daily administra-
cedure, Beths et al. did not report post induction apnea or tion of propofol, oxidative injuries to feline red blood cells
patients requiring controlled ventilation [49]. In the latter (Heinz Body formation) as well as facial oedema,
study, propofol based anesthesia was induced with less generalized malaise, anorexia and diarrhoea [60]. Recovery
propofol (0.25 vs. 11.7 mg/kg). Although the propofol main- times were also increased following the second consecutive
tenance infusion rate was higher in the Beths et al. study day of administration. A study performed 12 years later, in
(0.339 vs. 0.178 mg/kg/min), the recovery times were shorter cats repeatedly anesthetised with propofol and undergoing
(33.4 vs. 57 min). This was certainly the result of a shorter radiotherapy, did not report any relevant hematologic
duration of anesthesia in the Beths et al. study (26.1 vs. 74 min) changes [142]. While recovery times were not recorded, it
and the fact that it has been shown, in cats, that recovery was believed that they were not increased. The authors
time increases with longer propofol infusion time [133]. reported similar quality of recovery in all cases without
This is not really a surprise since we know that the PK of any of the side-effects reported in the Andress study
propofol in that species has a longer elimination half time (anorexia and malaises).
which could result from slower metabolism. In humans, about The MIR for propofol necessary to block a response to a
60 % of propofol metabolism is via glucuronidation through supramaximal stimulation (tetanic twitch) in 50 % of cats
the glucuronyl transferase enzyme [134]. In the cat, the gene has been determined with two different ketamine
responsible for that enzyme has been classified as a co-infusions (Table 31.4) [51].
pseudogene and is very likely non-functional [135]. Also in
humans, a proportion of propofol undergoes phase one Equine
metabolism involving cytochrome P450 (CYP) microsomal Due to the lack of analgesic effect of propofol, the doses
enzyme followed by glucuronidation. While the specific required to produce surgical anesthesia are such that while
enzyme has been identified in humans (CYP2B6) and in the CV function is more or less well maintained, respiratory
dogs (CYP2B11), this has not yet been done in the cat [136– depression is of concern and oxygen support is
138]. Moreover, Beths in 2008 did not observe much propofol recommended as well as positive pressure ventilation
related CYP activity in feline hepatic microsomal [5, 31, 36, 143, 144].
Fig. 31.8 Degradation of propofol concentrations (2.5 μg/mL) over 10, 15 30 and 45 min while in cats the incubation times were 0, 1,2 3, 4
time in rat, dog and cat hepatic microsomes. At each time, the mean and 6 h. Isolation of the microsomes followed the methods described by
value of two propofol determinations (HPLC) was calculated. Each Rutten et al. [139] and Correia [140]. Propofol was extracted from the
point is the mean ( SD) propofol concentration from microsomes of microsomes and was analysed by HPLC with fluorescence following
six rats, dogs or cats. The incubation times in rats and dog were 0, 5, the method described by Plummer [141]
As far as the author is aware, propofol is the only IV (0.098–0.108 mg/kg/min) CV parameters were well
anesthetic which, thanks to its pharmacokinetic quality, is maintained (no vasopressor agents required) but still
sufficiently non-cumulative to be used in the equine patient 23 horses needed IPPV. While the anesthesia time varied
for procedures lasting longer than 2 h [73, 145]. Although between 46 and 225 min, the recoveries were reported as
the induction of anesthesia with propofol may be of poor been uneventful with a mean recovery time of 42.2 min.
quality, recoveries are usually good and smooth When adding GGE (100 mg/kg) to a similar protocol
[116, 146]. In unpremedicated horses, a 4 mg/kg IV dose (medetomidine 5 μg/kg and propofol 3 mg/kg, IV) to induce
of propofol is necessary to induce anesthesia [116]. As anesthesia in seven horses, Oku et al. recorded better quality
propofol exists as a 1 % solution, that brings the volume of of anesthesia and considered 3 μg/kg/min of medetomidine
propofol for induction of anesthesia for a 500 kg horse to and 1 mg/kg/min of propofol as the minimum infusion rate
about 2000 mg or about 200 mL, which is a big and expen- (MIR) required to maintain anesthesia in horses undergoing
sive volume. This and the unreliable quality of induction castration [148]. Spontaneous breathing was maintained but
necessitate combinations of different drugs with propofol one horse was apneic at 10 and 15 min and two others at
such as xylazine or detomidine but with little improvement 35 min after receiving a bolus of propofol. Cardiovascular
in the quality of induction [26, 36, 116]. The best results so parameters were well maintained and recoveries were of fair
far seems to have been obtained with the addition of (five horses) good (one horse) and excellent (one horse)
guaiphenesin (GGE), an IV centrally acting muscle relaxant quality. The number of attempts at standing varied from
(74–100 mg/kg), or ketamine in the induction protocol or one to five, with a mean recovery time of about 44 min.
medetomidine in the premedication [37, 73, 147, 148]. Other Similarly to other species (dogs and cats), co-infusion of
authors have even recommended anaesthetising horses using ketamine (20–50 μg/kg/min) allows for a decrease of
a ketamine based protocol followed once anesthesia is propofol infusion rate while maintaining good cardiopulmo-
induced, by a bolus of propofol and propofol TIVA [28, 31]. nary parameters [31, 32, 150].
In two different studies, following premedication with In Flaherty’s study, the protocol consisted of detomidine
medetomidine (7 μg/kg IV) and induction of anesthesia (20 μg/kg IV) premedication followed by induction with
with propofol IV 2 mg/kg, anesthesia was maintained up to ketamine 2.2 mg/kg IV and maintenance of anesthesia with
4 h at an infusion rate between 0.07–0.11 mg/kg/min and ketamine 40 μg/kg/min and propofol 0.12 mg/kg/min (pre-
3.5 μg/kg/h for propofol and medetomidine, respectively ceded with a 0.5 mg/kg, IV) in four ponies [31]. Following a
[72, 73]. In both cases, although all the horses were breath- propofol infusion lasting 65 min (ketamine 60 min) the
ing spontaneously, the rhythm was irregular in the majority recovery was of good quality and lasted about 27.2 min.
of the horses, no apnea was noticed and PaCO2 did not Ohta’s et al., premedicated horses with 1 mg/kg of
change significantly, while hypoxemia was recorded in xylazine, but used a propofol based IV induction (3 mg/kg)
some ponies with PaO2 values as low as 35 mmHg [72]. In with midazolam (0.05 mg/kg) which resulted in unacceptable
terms of CV parameters, those were relatively well induction conditions with some horses paddling [32]. Thereaf-
maintained with a few cases of mild hypotension recorded ter, they maintained anesthesia with a ketamine and propofol
in some ponies with the lowest value recorded for SAP of infusion rate of 50 μg/kg/min and 0.16 mg/kg min, respec-
78 mmHg [73]. Recoveries were smooth and of good quality tively. Ketamine was stopped 20 min before the estimated end
with fewer attempts at standing and better overall recovery of the surgery. While propofol was stopped 112–140 min after
score when atipamezole (specific (dex)medetomidine rever- the start of the infusion, recoveries were of good quality and
sal agent) was not used. The recovery time varied between lasted about 70 (23) minutes.
20 and 38 min between the two studies and was not signifi- Ketamine (2 mg/kg) and diazepam (0.03 mg/kg) IV were
cantly affected by the addition of atipamezole. used to induce acepromazine (0.03 mg/kg, IV) and detomidine
In a similar study to the previous one the replacement of (0.015 mg/kg, IV) premedicated horses [150]. Induction
propofol with ketamine to induce anesthesia allowed for of anesthesia was then followed by a propofol bolus of
better induction quality with more difficult intubation and 0.3 mg/kg and anesthesia was maintained with infusions of
very similar cardiopulmonary parameters. Following 4 h of propofol (0.16 mg/kg/min) and ketamine (20–40 μg/kg/min).
anesthesia, the mean recovery time was of 31.1 min with a The ketamine infusion was started at a rate of 40 μg/kg/min
quality scored of good to excellent [149]. and was decreased by 10 μg/kg/min every 20 min. It was
The addition of diazepam (0.02 mg/kg, IV) to the previ- terminated 30 min before the estimated end of anesthesia.
ous protocol in 50 client owned horses undergoing different After a mean anesthesia time of 59 17 min, recovery time
surgeries, provided excellent induction and endotracheal was 34 7 min and of good quality.
intubation conditions [28]. With a similar medetomidine The addition of medetomidine infusion to ketamine/
CRI, but a propofol variable rate infusion (VRI) propofol anesthesia was studied by Umar et al. [37, 144,
604 T. Beths
151]. The basic protocol was the same between the three cardiopulmonary parameters and recoveries of good to
studies: premedication with medetomidine 5 μg/kg, IV excellent quality [25].
followed by induction of anesthesia with midazolam
0.04 mg/kg and ketamine 2.5 mg/kg IV. To maintain anes- Swine
thesia, ketamine at 1 mg/kg/h and medetomidine 1.25 μg/kg/ In pigs propofol is often combined with a potent short
h was added to a propofol VRI of 0.14 mg/kg/min (2006 and acting opioid such as fentanyl [152]. Schoffmann et al.
2007 studies) and 0.17–0.13 mg/kg/min (2015 study). In all [153] reported the use of propofol for induction (1 mg/kg
the studies the CV parameters were very well maintained. In IV) and maintenance of anesthesia (8 mg/kg/h) with
the first study (2006), apnea was observed in all horses (six) co-infusion of fentanyl (35 μg/kg/h) in midazolam
after the propofol loading dose and therefore IPPV was (0.5 mg/kg, IM), ketamine (10 mg/kg IM) and butorphanol
initiated in this study as well as the following two studies. (0.5 mg/kg, IM) premedicated piglets [153]. They
Once IPPV was started, no respiratory issues were observed reported very stable mean blood pressure and heart rates
in any of the studies. Duration of anesthesia was for 300 min of anesthesia time. There is no information on
115 17 min, 4 h and 175 14 min in the 2006, 2007 the recovery times or quality as it was a non-recovery
and 2015 study, respectively. Recovery quality was good in surgery.
all the studies, with a time to standing of 62 10, 98 21
and 74 28 min, respectively. Miscellaneous
The MIR for propofol necessary to block a response to a Propofol-ketamine in the donkey [154]: Following xylazine
supramaximal stimulation (tetanic twitch) in 50 % of horses premedication (1 mg/kg, IV) and induction of anesthesia
have been determined with different premedication (xylazine, with ketamine (1.5 mg/kg, IV) and propofol (0.5 mg/kg,
medetomidine and no drug) and co-infusion protocols IV), anesthesia was maintained for 1 h in eight healthy
(no drug and medetomidine) (Table 31.4) [73, 74, 145]. donkeys with a CRI of propofol (0.15 mg/kg/min) and keta-
mine (0.05 mg/kg/min). The donkeys were placed in lateral
Ruminants recumbency following induction of anesthesia, their tracheas
Very little information is available on the use of propofol were intubated and they were allowed to breathe room air.
based TIVA in cattle. In 2015, Deschk et al. reported the use While all the donkeys had PaO2 values between 47 and
of propofol in unsedated calves (6–12 months old) for induc- 93 mmHg, ventilation was well maintained (PaCO2 between
tion (5 mg/kg IV) and maintenance (0.6 and 0.8 mg/kg/min 38 and 51 mmHg). Heart rate and mean blood pressure
for 60 min) of anesthesia [38]. The calves were allowed to stayed in acceptable ranges. Recovery was uneventful and
breathe room air. Recoveries were uneventful. No apnea was the donkeys were standing 29 9 min following cessation
noticed at any time while some muscle tremors were of the CRI’s.
observed in three out of eight calves at a propofol infusion Propofol (3.7 mg/kg, IV) was used to induce anesthesia in
rate of 0.6 mg/kg/min but in only one out of eight at a a medetomidine (25 μg/kg, IM) and diazepam (0.38 mg/kg,
propofol infusion rate of 0.8 mg/kg/min. The arterial IM) premedicated King penguin with a history of seizures
pressures decreased in both groups but to a greater extent who was undergoing brain MRI (Figs. 31.9 and 31.10) [38].
in the 0.8 mg/kg/min group which also had a bigger decrease Anesthesia was maintained for 138 min with propofol at a rate
in SVRI (systemic vascular resistance index). Cardiac index of 0.1–0.3 mg/kg/min. IPPV was continued from the start of
(CI) increased in the 0.8 mg/kg/min group while staying anesthesia until the end with 100 % O2. Spontaneous breath-
constant in the 0.6 mg/kg/min group. ing was recorded 10 min after the end of the infusion and
Propofol anesthesia (2.5–6 mg/kg, IV) has been induced extubation was achieved 15 min later when the penguin
in goats either alone or following a premedication [40]. started lifting his head and moving his wings. Recovery was
Maintenance of anesthesia varied with the level of sedation smooth without any excitation or adverse behaviour.
resulting from the premedication (0.2–0.6 mg/kg/min). The MIR for propofol necessary to block a response to a
When compared to fentanyl premedication (0.02 mg/kg) supramaximal stimulation (tail clamping) in 50 % of rabbits
and co-infusion (0.02 mg/kg/h), midazolam premedication has been determined (Table 31.4) [76].
(0.3 mg/kg) and co-infusion (0.3 mg/kg/h) resulted in a
smoother recovery following a 90 min propofol anesthesia
(12–18 mg/kg/h) [39]. In both cases, cardiopulmonary Alfaxalone
parameters were well maintained. When ketamine is used
as a co-infusion (0.03 mg/kg/min) in propofol anesthetised Alfaxalone is a neuroactive steroid which has been used in
goats (0.3 mg/kg/min) following midazolam premedication veterinary medicine since the early 1970s. At that time, the
(0.4 mg/kg IV) and ketamine (3 mg/kg, IV)/propofol (1 mg/ poorly water soluble agent was combined with a weak
kg, IV) induction, the authors reported stable anesthetic alfadolone and formulated in Cremophor EL
[155]. The latter was responsible for hyperaemia in cats, and

histamine release with anaphylactic reactions in dogs
[156]. The formulation was characterised by rapid onset
and offset of action, no irritating effects on the blood vessels,
and minimum CV and respiratory effects with a high thera-
peutic index [157–159]. Athesin (human formulation) or
Saffan (veterinary formulation) were removed from the mar-
ket in the middle of the 1980s [160]. Recently, Jurox, an
Australian drug company reintroduced alfaxalone, without
the alfadolone and this time, formulated in a non-cremophor
vehicle, 2-hydroxpropyl-β-cyclodextrin (Alfaxan CD®).
This drug has now been approved in dogs and cats in
Australia, Canada, and Europe and more recently in the
USA. This new formulation is not associated with histamine
release and has been evaluated in other species (sheep,
horses).
Meanwhile, in humans, alfaxalone in sulfobutyl-
ether-β-cyclodextrin has been developed by another
Australian company, Dawbridge Pharmaceuticals Pty Ltd
(Malver, Victoria, Australia) [160]. Following comparison
of the new formulation with propofol in rats, the authors
concluded that the new formulation had a similar onset and
offset timing as propofol, and a higher therapeutic index.
The new formulation recently went through phase 1c trials
and showed very promising result in humans with a fast
onset and short duration of anesthesia similar to propofol,
but with less reported CV depression and no pain on
Fig. 31.9 Induction of anaesthesia of a King Penguin with propofol injection [161].
prior the MRI examination under propofol TIVA
From now on, all the following information regarding
alfaxalone will concern the new veterinary formulation,
Alfaxan CD®, unless specified otherwise. This formulation
does not contain a preservative and therefore supports
micro-organism growth, but not as readily as does propofol
and any solution remaining after withdrawal should be
discarded [162].
Its mechanism of action is similar to thiopental or
propofol and results from its interaction with the GABAA
receptors and yields a state of anesthesia and provides good
muscle relaxation.
Pharmacokinetics
Alfaxalone shares some PK advantages with propofol
such as fast onset and short duration of action attributable
to the fact that both are rapidly redistributed and metabolized
[15, 16, 163].
The pharmacokinetics of alfaxalone have been deter-
Fig. 31.10 King penguin undergoing MRI examination and mined in different species such as dogs, cats and horses
anesthetized with propofol TIVA (variable rate infusion). The patient (Table 31.1) and has been determined to be non-linear
had an endotracheal tube and was connected to an anesthesia machine (in the dog and the cat), meaning that with increasing
with a universal F breathing system (FiO2 ¼ 1.0)
doses, plasma concentration and the area under the plasma
606 T. Beths
concentration-time curve (AUC) increase out of proportion Although possibly more pronounced in dogs than in cats,
to the change in doses [16, 17]. In the cat, Whittem et al. [17] a dose dependant respiratory depression is observed in both
reported that despite the non-linear kinetic of alfaxalone, at species, with a decrease in respiratory rate leading to apnea,
clinical dose rates, no accumulation of the agent or its effects decreased tidal volume, minute volume and PaO2
were observed [17]. Alfaxalone undergoes both phase I [169, 170]. In both species hypercarbia is also noticed. As
(cytochrome P450 metabolism) and phase II (conjugation for the CV effect, at clinical doses the effects are mild and
dependent) hepatic metabolism. While both dogs and cats manageable. And as for propofol, titration to effect at induc-
seem to produce the same five metabolites following phase I tion will reduce the risk of respiratory depression and post
(allopregnatrione, 3β-alfaxalone, 20-hydroxy-3β-alfaxalone, induction apnea [43, 171].
20-hydroxyalfaxalone and 2α-hydroxyalfaxalone), dogs pre- To the author’s knowledge there are no known contra-
dominantly produce alfaxalone glucuronide in phase indications for the use of alfaxalone but, as it demonstrates
2 whereas cats also produce alfaxalone sulphate [164]. dose-dependant pharmacokinetics and undergoes hepatic
Unlike propofol, it seems that breed has little effect on metabolism, the author would advise caution for its use as
alfaxalone PK as the PK parameters observed in an infusion in patients with liver damage. In both dogs and
un-premedicated greyhounds were very similar to those cats dose-dependant mild CV depression has been observed
observed in un-premedicated beagles [15, 16]. In contrast, after induction of anesthesia with alfaxalone. Therefore the
acepromazine/morphine premedicated greyhounds saw their authors advise caution when used in hemodynamically
anesthesia time, following a bolus of alfaxalone, increased compromised patient and propose dose-titration to effect as
by a factor of 5. A decrease in perfusion due to acepromazine a means of decreasing those CV side-effects.
was thought to be the reason of the observed decrease in
clearance, but this could not be substantiated [16]. Alfaxalone TIVA in Different Species (Table 31.2)
In a study looking at PK in male and female dogs, it
seems that although the agent is derived from the hormone Canine
progesterone, there was no gender effect in the PK and Following acepromazine (0.02 mg/kg, IV) and
therefore it could be administered at the same dose to either hydromorphone (0.05 mg/kg, IV) premedication, anesthesia
sex [15]. was induced and maintained either with alfaxalone or
propofol [41]. The induction dose was 2 mg/kg for
Pharmacodynamics alfaxalone and 4 mg/kg for propofol. Both doses were
Although we do not know the effects of Alfaxan CD® itself administered over 60 s. Anesthesia was then maintained
on cerebral hemodynamic and metabolism, it is very likely for 120 min with alfaxalone 0.07 mg/kg/min for the
that the effect will be similar to those observed with the alfaxalone group and propofol 0.25 mg/kg/min in the
previous alfaxalone-alfadolone formulation: a dose- propofol group. Between the two groups, systemic and pul-
dependent decrease in cerebral blood flow (CBF) and cere- monary artery pressures, HR, CO and CI, stroke volume
bral metabolic rate oxygen (CMRO2) [165–158]. When (SV) and stroke volume index (SVI), and SVR did not vary
maintaining anesthesia in cats via a CRI of the former CT significantly and were well maintained compared to base-
1341 formulation, Baldy-Moulinier and Besset-Lehmann line. Although no significant changes were observed
reported a dose dependent decrease in CBF and intracranial between groups for parameters such as respiratory rate,
pressure (ICP) as well as concurrent vasoconstriction [165]. arterial pH, PaO2, or PaCO2, in both groups, respiratory
Those attributes in relation to the cerebral hemodynamic and depression was evident with low respiratory rate, increased
metabolism supported the use of the new formulation with EtCO2, decreased pH (respiratory acidosis). Post induction
remifentanil CRI in a dog undergoing craniotomy for tumour apnea was observed in one dog in each group and lasted
resection [164]. 210 s in the alfaxalone vs. 82 s in the propofol group. Time
At clinical doses in different species, the CV parameters from end of CRI to standing was 52 10 and 62 18 min
remain quite stable. When given at clinically relevant doses for alfaxalone and propofol respectively. The quality of
in dogs (2 mg/kg, IV) and in cats (5 mg/kg, IV), the CV recovery was good in both groups.
parameters were reported to stay stable [169, 170]. With When comparing their use for surgeries such as
increasing doses, the studied CV parameters deviated from ovariohysterectomy, following acepromazine (0.01 mg/kg
normal, but these changes differed between species. In the IM) and morphine (0.4 mg/kg IM) premedication, induction
cat, when doses of up to 10 times the clinical dose (50 mg/ and maintenance of anesthesia with propofol (5.8 0.3 mg/
kg) were administered IV, HR, CO and ABP decrease while kg and 0.37 0.09 mg/kg/min, respectively) and alfaxalone
in the dog a tenfold clinical dose (20 mg/kg) administration (1.9 0.07 mg/kg and 0.11 0.01 mg/kg/min, respec-
resulted in an increase of HR while ABP decreased tively) showed similar results with no difference between
[169, 170]. groups in the measured cardiopulmonary parameters [42].
Table 31.5 Examples of minimum infusion rates (MIR) for Alfaxalone in different species
Species Premedication Induction IV MIR IV Comments References
Cats Acepromazine 0.1 mg/kg, Alfaxalone 2.57 (0.4) 0.19 (0.02) mg/kg/min Ovariohysterectomy [45]
IM mg/kg
Butorphanol, 0.2, IM
Medetomidine 0.02, IM Alfaxalone 1.87 (0.5) 0.18 (0.02) mg/kg/min
Butorphanol, 0.2, IM mg/kg
Goats Alfaxalone 3 mg/kg 0.16 (0.14–0.18) mg/kg/min None [180]a
Fentanyl 0.005, IV Alfaxalone 2 mg/kg 0.11 (0.11–0.14) mg/kg/min Co-infusion [181]a
Fentanyl 0.005 mg/kg/h
Fentanyl 0.015, IV 0.05 (0.017–0.11) mg/kg/min Co-infusion
Fentanyl 0.015 mg/kg/h
Fentanyl 0.03, IV 0.017 (0.017–0.08) mg/kg/ Co-infusion
min Fentanyl 0.03 mg/kg/h
Midazolam 0.1, IV Alfaxalone 2.3 mg/kg 0.11 (0.11–0.14) mg/kg/min Co-infusion [181]a
Midazolam 0.1 mg/kg/h
Midazolam 0.3, IV Alfaxalone 2 mg/kg 0.11 (0.08–0.11) mg/kg/min Co-infusion
Midazolam 0.3 mg/kg/h
Midazolam 0.9, IV Alfaxalone 2 mg/kg 0.048 (0.016–0.08) mg/kg/ Co-infusion
min Midazolam 0.9 mg/kg/h
a
Clamping proximal part of one digit of the hoof
While HR and blood pressures were well maintained in both alfaxalone CRI was predefined not tailored to the patients’
groups, hypoventilation was observed while maintaining requirements and therefore, boluses of alfaxalone were
good oxygenation (dogs breathed 100 % O2 through an required to be administered to maintain anesthesia. As
appropriate breathing system). Therefore, as a conclusion, alfaxalone clearance is dose dependant (non-linear kinetics)
the authors suggested that ventilatory support should be and as incremental bolus administration results in higher
considered when those protocols were used in bitches peak plasma concentration, it is very likely that the lengthy
undergoing neutering procedure. recovery was due to an “excessive” dose of alfaxalone.
When replacing acepromazine (0.05 mg/kg) with the α2- Similarly the poorer recovery quality observed in the
adrenoceptor agonist dexmedetomidine (10 μg/kg, IM) in a alfaxalone group may have also resulted from the high
buprenorphine (20 μg/kg, IM) based premedication in dogs dose of alfaxalone as this agent has been reported to increase
undergoing similar procedures, the alfaxalone infusion rate noise sensitivity in dog, leading to poor recoveries
was reduced from 0.11 with acepromazine to 0.08 mg/kg/ [179]. Although the alfaxalone TIVA resulted in a lower
min in dexmedetomidine group [172]. The difference APGAR score than isoflurane, puppies’ survival was the
resulted most probably from the analgesic properties of the same in both groups.
α2-adrenoceptor agonist [173, 174]. Similarly to the previ- The MIR for alfaxalone necessary to maintain anesthesia
ous study, the authors reported very good CV parameters in female dogs undergoing ovariohysterectomy has been
while apnea and hypoventilation were commonly observed. determined with two different butorphanol based
After 2 h of anesthesia, recoveries were of short duration premedication protocols (acepromazine vs. medetomidine)
(about 10 min) in both groups, but of better quality in the (Table 31.5) [45].
acepromazine group which could be due to the longer lasting
sedative properties of that agent. Feline
Alfaxalone has been studied in both juvenile (12 weeks of In medetomidine (20 μg/kg, IM) and morphine (0.3 mg/kg,
age) dogs and cats and shown to provide acceptable anesthe- IM) premedicated cats (10 male and 24 female) undergoing
sia [175, 176]. Most recently, it has demonstrated favourable neutering procedure, the reported alfaxalone induction and
characteristics including improved neonatal APGAR scores maintenance doses were 1.7 (0.3–3) mg/kg and 0.18
when used for induction of anesthesia for canine caesarean (0.06–0.25) mg/kg/min [43]. None of the cats became apneic
section by comparison with propofol [177]. Both agents and respiratory and heart rates were well maintained. Hypo-
have similar puppy survival rates. When compared to tensive episodes of short duration and responding to fluid
alfaxalone induction followed by isoflurane anesthesia, therapy and decrease of alfaxalone infusion rate were
alfaxalone TIVA in un-premedicated female dogs reported in 20 cats (59 %). The anesthesia time was longer
undergoing caesarean section resulted in longer recovery of in female cats than in male cats (126.5 24.7 vs. 39.6
poorer quality [178]. Unfortunately, in this study the 21.6 min) resulting in a higher maintenance dose been
608 T. Beths
administered to the female cats (about 22 vs. 7 mg/kg). This Equine

might have resulted in the longer recovery time (time to first The pharmacokinetic of alfaxalone in the adult horses and
head tilt) also observed in the female cats (49 vs. 27 min). neonatal foals have been previously determined following a
Alfaxalone PK, as in the dog, is described as being single IV bolus (Table 31.1) [18, 19].
non-linear and dose-dependant recovery times have been So far, only three studies report the clinical use of
describes in other studies [170, 182]. The quality of the alfaxalone TIVA in the horse [46, 185, 186]. As TIVA is
recovery was good in 31 cats while noise induced excitation mostly used in field anesthesia and as castration is the most
of short duration (10–20 min) was reported in three cats. common surgery done in the field conditions, those three
This side-effect was previously reported in cats with the studies are on horses undergoing field castration.
former alfaxalone-alfadolone formulation [158, 183]. Following romifidine (an α2-adrenoceptor agonist at
In a study in female cats undergoing neutering procedure, 100 μg/kg, IV) and butorphanol (50 μg/kg, IV)
Schwarz et al. [45] compared acepromazine and premedication, anesthesia was induced with diazepam
medetomidine (both with butorphanol) premedication in (0.05 mg/kg, IV) and alfaxalone (1 mg/kg, IV) and
alfaxalone TIVA [45]. While the induction dose was lower maintained with incremental IV dose(s) of alfaxalone
in the medetomidine group (1.87 0.5 vs. 2.57 0.41 mg/ (0.2 mg/kg) as required [186]. Induction and maintenance
kg), the infusion rates were very similar between the two of anesthesia as well as recovery were scored good to excel-
groups (around 0.18 mg/kg/min). Although those results are lent. Horses were standing 34 9 min following induction.
very similar to the previous study, the authors reported Although HR did not change following induction of anes-
inadequate quality of anesthesia and the need for alfaxalone thesia, a slight increase in RR was recorded. Of the 17 ponies
boluses during the procedure. This difference was possibly undergoing castration surgery, one needed four increments
due to the use of butorphanol (a partial μ agonist opioid) while nine needed one.
which has been shown to provide very little analgesia in the When compared to ketamine in a similar setting
cats recovering from neutering surgery by comparison to a (romifidine/butorphanol premedication and diazepam
full agonist opioid such as methadone [184]. Cardiopulmo- co-induction), alfaxalone shows shorter induction time
nary data were similar to the previous study. They reported (18 4 vs. 30 6 s) but needed to be topped up more
neither apneic events nor respiratory depression. Some frequently than ketamine (4/21 vs. 7/20 ponies)
myoclonus, mostly of the hind limbs, was reported during [185]. While both HR and RR increase following ketamine
the recovery period which lasted about 60 min (time to first induction, no changes were observed with alfaxalone. There
head tilt). was no clinical difference in terms of recovery times and
When comparing alfaxalone and propofol TIVA in quality.
dexmedetomidine (15 μg/kg, IM) and morphine (0.3 mg/ Infusion of alfaxalone (2 mg/kg/h) and medetomidine
kg, IM) premedicated female cats undergoing neutering (5 μg/kg/h) has been describes in 11 colts undergoing castra-
procedures, no cardiopulmonary difference (HR and arterial tion surgery [46]. Anesthesia was maintained for about
blood pressure), EtCO2, SpO2, RR)) were noted between the 45 min with this regimen following acepromazine
two groups [49]. No cats required ventilatory support. Nei- (0.03 mg/kg, IV) and medetomidine (7 μg/kg/min)
ther hypotensive nor apneic events were reported. Following premedication and induction of anesthesia with
approximatively 26 min of anesthesia, recovery quality was guaiphenesin (35 mg/kg, IV) and alfaxalone (1 mg/kg, IV).
very good in both groups with a non-significant longer time Quality of induction and recovery were good to excellent,
to reach sternal position with alfaxalone (35 vs 47 min). with only one attempt to stand and a time from end of
In a later study, comparing the same two hypnotic agents infusion to standing of 37 13.5 min. Horses were sponta-
in medetomidine (10 μg/kg, IM) and meloxicam (0.3 mg/kg, neously breathing O2 enriched air and cardiopulmonary data
IM) premedicated female cats undergoing neutering proce- were clinically acceptable with no apneic and/or hypoten-
dure, Campagna et al. also reported very good CV sive events been recorded.
parameters in both groups with no hypotension [44]. With
regards to respiration, the authors reported significantly bet- Ruminant
ter maintained respiratory function in the alfaxalone group While no information exist on the use of alfaxalone in cattle,
where the EtCO2 over time was kept lower and where only a study in un-premedicated sheep induced with alfaxalone
2/10 cats (vs. 8/10) needed ventilatory support. The possible 2 mg/kg IV and maintained anesthetised with a CRI of
difference between those two last studies with regards to the alfaxalone at 10 mg/kg/h, reported clinically acceptable
reported respiratory effects could come from the fact that in hemodynamic results (HR and ABP) with mild respiratory
Campagna et al.’s study, the induction doses were five depression (decreased RR, increased PaCO2, decreased pH)
(propofol) to ten (alfaxalone) times higher than in Beths [47]. Following 72.5 min of anesthesia, recovery was of
et al.’s study. good quality and about 22 min long. In 2015, Ndwanna
et al. determined the MIR of alfaxalone in sheep [180]. In the activity is depressed or disconnected from any incoming
same year, Dzikiti et al. determined the MIR of alfaxalone in signals [189, 190]. The depression of the thalamocortical
sheep with either a fentanyl or a midazolam co-infusion and limbic systems results from NMDA antagonism via the
(Table 31.5) [181, 187]. phencyclidine binding site. This prevents the excitatory neu-
rotransmitter glycine from binding, causing a cataleptic state
Swine where the patient does not respond to external stimuli but
Although alfaxalone based TIVA has not yet been reported does not look asleep either.
in pigs, the author’s group has submitted for publication a Dissociative anesthesia is characterised by: analgesia,
study on the use of alfaxalone TIVA in the pig [48]. light sleep, amnesia, catatonia/catalepsy, poor muscle relax-
In this study, 12 pigs were anesthetised for about 51.5 min ation, hypersensitivity to noise; active cranial nerves reflexes
for epidural catheter placement as part of another study. (palpebral, corneal, gag, nystagmus) [189].
Premedication consisted of 4 mg/kg of alfaxalone, Ketamine exists in most of the preparations as a racemic
medetomidine 40 μg/kg and butorphanol 0.4 mg/kg mixture while a purified S-ketamine formulation is available
IM. Twenty to forty minutes later anesthesia was induced in some countries. The S isomer offers some advantage over
with alfaxalone (1.2 mg/kg, IV) and maintained with the racemic mixture such as quicker metabolism, more
alfaxalone at a rate of 0.08 mg/kg/min. Induction of anes- intense analgesia, less delirium emergence [191].
thesia was smooth and endotracheal intubation was very The pH of the racemic mixture is usually low (3.5–5.5)
easy in all pigs. The cardiorespiratory variables (HR, and pain at injection during IM administration has been
NIBP, RR, and SPO2) remained within normal limits for reported [189].
all animals throughout anesthesia. No pigs developed hypo- Ketamine is very lipophilic and rapidly crosses the blood
tension or apnea. brain barrier. It has a relatively short onset (about 1 min) and
duration of action (15–20 min).
Miscellaneous
Induction and maintenance of anesthesia with alfaxalone Pharmacokinetics
(0.8 0.4 mg/kg, IV and 0.15 0.02 mg/kg/min, IV, In most species (except cats) ketamine undergoes demethyl-
respectively) in ten green vervet monkeys (3.1–6.4 kg) has ation through hepatic microsomal enzymes into the active
been describes [50]. The monkeys underwent X-ray and metabolite, norketamine which has about 10–30 % of the
ultrasound studies. Following 73 13 min of anesthesia, anesthetic potency of ketamine. After repeated doses or long
recoveries were uneventful and time to standing from the infusion of ketamine, accumulation of norketamine
end of infusion was 32.7 12.1 min. HR values were contributes to a prolonged recovery and hangover. After
unchanged from pre-induction values while hypotensive hydroxylation and conjugation, norketamine becomes
event were recorded in six monkeys and responded to fluid water soluble and is excreted by the kidneys [192]. In cats,
therapy and lowering depth of anesthesia. Although RR was although almost all the parent compound is excreted through
decreased from pre-induction values, no apneic events were the kidneys unchanged, some ketamine is bio-transformed
observed. into norketamine that is directly excreted through the
More recently, a study describes the use of alfaxalone kidneys [21]. Caution should therefore be taken when
TIVA (similar rate as in the previous study) in alfaxalone using ketamine in animals with liver and/or renal dysfunc-
(2 mg/kg, IM) and medetomidine (15 μg/kg, IM) tion as prolonged activity and anesthetic time may result.
premedicated cynomolgus monkeys [188]. Those monkeys Recovery following one injection results mainly from
underwent MRI examination and were anesthetised for redistribution and metabolism. Unfortunately, with repeated
about 117 min. At the end of the anesthesia, atipamezole administrations or infusion, the agent tends to accumulate as
(50 μg/kg, IM) was administered and the monkeys were able the redistribution sites become saturated and the recovery
to stand about 20 min after the end of the CRI. Mean arterial becomes more dependant on metabolism and excretion. In
blood pressure, HR and RR were at or below the lower limits cats, as there is no metabolism, redistribution and excretion
of the normal range. are the main pathways for blood ketamine level to
decrease [29].
Ketamine Pharmacodynamics
The delirium emergence, bronchodilation and sympathomi-
Ketamine is a dissociative agent derived from phencycli- metic actions observed with ketamine is believed to be a
dine, and results in a change of awareness by dissociation of product of its antagonistic effect at the muscarinic receptors,
the thalamocortical and limbic systems where the thalamic or to be a direct stimulating effect of the drug on the sympa-
and limbic system seem to be stimulated while cortical thetic system [193].
610 T. Beths
Ketamine increases cerebral blood flow which with the Ketamine TIVA in Different Species (Table 31.2)
observed increase in blood pressure will result in increase in
ICP. Caution is therefore advised when using ketamine in Canine
patients with increased risk of abnormal ICP. This effect can Ketamine is used at a low infusion rate (5–10 μg/kg/min) to
be attenuated by maintaining in normocapnia and/or provide analgesia during inhalation and TIVA (propofol or
co-administering drugs such as the benzodiazepines. In addi- alfaxalone) anesthesia [189, 196–199].
tion, due to increased EEG activity observed with ketamine, Due to possible accumulation over time and associated
it is usually advised not to use ketamine in patients with a rough recoveries, ketamine is not commonly used as the
history of seizures. main hypnotic agent for TIVA in dogs. Still, different keta-
Abnormal behaviours have been reported in the recovery mine based TIVA protocols have been describes using dif-
period, ranging from ataxia, hyper-reflexivity, increased ferent combinations aiming to alleviate the poor muscle
motor activity to frank hyperexcitability where the animals relaxation usually observed with ketamine anesthesia
are hyperresponsive to noise, light and handling [29]. The [200]. These include: guaiphenesin (GGE) and xylazine
incidence or intensity of those reactions can be decreased by [201]; medetomidine premedication [202, 203]; propofol
the addition of benzodiazepines and/or α2 adrenoceptor co-administration [119, 204]; midazolam xylazine/
agonists [192]. medetomidine co-administration [205].
Ketamine has a direct negative inotropic effect on the In all those studies, the quality of anesthesia was of good
myocardium partly through its Ca channel blocking effect. quality and the measured CV functions were well
These effects are usually overcome by the centrally maintained while some respiratory depression was observed.
mediated ketamine stimulation of the sympathetic system. The quality of recovery was only reported as good in two
Therefore, increases in ABP, CO, HR are more commonly studies [119, 205]. Fdo et al. used midazolam infusion as
observed following its administration. Although the keta- previously describes in a human study with ketamine based
mine effect very likely originates from increased sympa- TIVA where recovery was also graded as good and better
thetic nervous system outflow, ketamine also inhibits than following halothane N2O anesthesia [206]. In addition
noradrenaline reuptake at the postganglionic sympathetic to midazolam, Fdo et al. used an α2-adrenoceptor agonist
nerve endings, increasing plasma catecholamine xylazine or medetomidine for premedication and
[122, 194]. Consequently, the administration of ketamine co-administration. Those agents are known to provide good
in a critically ill patient where the catecholamine stores muscle relaxation and are usually recommended while using
and the sympathetic compensatory mechanism are ketamine based anesthesia [189]. Although medetomidine
exhausted may unveil ketamine’s negative inotropic effects. was also used in Hellebrekers (2 studies) and Selikar’s
With regards to the respiratory system the administration studies, it was only used in the premedication. As the anes-
of ketamine usually results in bronchodilation and a thesia in those three studies lasted longer than 60 min, this
maintained ventilatory response to hypoxia and hypercarbia. may have led to having little to no medetomidine left in
Apneustic breathing has been reported where a pause those dogs at the time of the awakening, resulting in rougher
appears after the inspiratory time of the breathing cycle. recoveries being reported.
Minute ventilation and CO2 level are usually stable.
Please note that although pharyngeal and laryngeal Cats
reflexes are maintained, they are usually uncoordinated and In 1991, Brown et al. describes the use of ketamine as part of
endotracheal intubation to secure the airways is strongly a GGE/xylazine combination for a 6 h anesthesia in the cat
advised. [207]. The recorded CV and respiratory parameters stayed
Ketamine is known for its analgesic effect, even at sub within the normal ranges and the cats were back in sternal
anesthetic doses, which has resulted in many protocols hav- recumbency exhibiting voluntary movement in just over 2 h
ing been developed where the infusion rate of the agent is following cessation of the infusion.
below anesthetic levels (i.e. 2–20 μg/kg/min) [189]. As in dogs, ketamine based TIVA is seldom used in cats
Although some of its analgesic effect is possibly due to due to accumulation as well as the poor recovery quality. It is
activity on opioid receptors, it is believed that most of its therefore most commonly used at lower doses for its analge-
effect is through its activity as an NMDA receptor antagonist sic and sparing effects as well its possible sympathomimetic
at the level of the dorsal horn limiting central sensitization effects [51]. Studies in humans have shown that the CV and
and wind-up [29, 195]. respiratory depressing effects of IV drugs such as propofol
could be offset by the addition of ketamine [208, 209]. In a Although the above combinations can be used to induce
study looking at the minimum infusion rate (MIR) of anesthesia after a premedication with an α2-adrenoceptor
propofol in cats when ketamine was added, Ilkiw et al. [51] agonist, it is not advised. This is to avoid using too much
showed that the addition of ketamine (0.23 or 0.46 μg/kg/ GGE before the start of the procedure and therefore limit-
min) allowed a decrease of the propofol infusion rate for a ing the infusion time to maintain anesthesia. It is instead
number of end points such as response to toe pinch, tetanic more common to use an induction protocol such as keta-
stimulation or tail clamp [51]. In addition, CV and respira- mine and diazepam and then start the triple drip. The triple
tory functions were very well maintained. In a similar study, drip is considered a safe way to anesthetise horses and is
Ilkiw and Pascoe showed (2003) that the addition of keta- characterised by smooth recoveries, with the horse going
mine (0.23 μg/kg/min) and the resulting decrease in propofol into sternal recumbency, followed later on by standing.
infusion rate did not change measurements such as MAP, While the CV function is well maintained, the respiratory
CVP, SI, CI, SVRI, O2 delivery index, O2 consumption, function although of good quality at the beginning of the
PvO2, pH or arterial blood PaCO2, base deficit by compari- anesthesia tends to decrease with anesthesia of 45 min or
son to propofol alone [210]. However, the application of longer. It is therefore advised to allow the patient to be
noxious stimulation for MIR determination resulted in an breathing an oxygen-enriched gas mixture and to be
increase of the HR and PaO2 in the propofol alone group. intubated [215]. The combination including an α2-
Ravasio et al. [52] reported the use of “ketofol’, an extempo- adrenoceptor agonist will result in copious amounts of
raneous combination of a low dose of ketamine and propofol urine being produced which may be of concern when work-
in the same syringe (1:1 ratio) [52]. Following an induction ing in hot weather conditions [215].
dose of the mixture at 2 mg/kg of each drug, and a mainte- Other ketamine based TIVA regimens have been
nance infusion rate set at 10 mg/kg/h each, with or without describes such as the MKX where the GGE is replaced by
dexmedetomidine premedication (0.003 mg/kg, IM), cats another muscle relaxant agent, midazolam (0.05 mg/mL)
underwent neutering surgery. Following a 25 min infusion, [216]. The main finding from that study was a prolonged
cats were extubated sooner (7 vs 29 min) in the group without ataxia observed in the recovery period and therefore the
dexmedetomidine and also had a lower sedation score for the authors proposed a reduction of the midazolam concentra-
first hour post-surgery. With or without the premedication tion to minimize the observed side-effect.
with dexmedetomidine, all cardiopulmonary parameters Combinations of xylazine (2–4 mg/kg/h) and ketamine
were well within normal ranges, with HR and SpO2 being (5–7 mg/kg/h) have been evaluated by Mama et al. in 2005.
lower and MAP been higher in the dexmedetomidine group. Oxygen supplementation was advised with that protocol [217].
All the cats breathed spontaneously. Yamashita et al. in 2007 reported the use of a mixture of
midazolam (01.8 mg/mL) ketamine (40 mg/mL) and
Equine medetomidine (0.1 mg/mL) to maintain anesthesia in
Ketamine is the most commonly used IV agent with the medetomidine premedicated (5 μg/kg, IV) horses undergoing
equine patient not only to induce general anesthesia but castration [218]. Following induction of anesthesia with
also to maintain general anesthesia when a TIVA based midazolam (0.04 mg/kg, IV) and ketamine (2 mg/kg, IV),
technique is needed (i.e. field anesthesia) [211]. general anesthesia was maintained with the mixture at a rate
Due to the risk of accumulation, it is usually advised not of about 0.09 mL/kg/h. Following 38 (8) minutes of infu-
to keep the patients under ketamine TIVA for longer than sion, recoveries of satisfactory (3/9) to good (6/9) qualities
90 min as longer anesthesia has been associated with longer lasted about 33 (13) minutes. In the same study, five horses
and rougher recoveries [145]. were anesthetised using the same protocol, but with an infu-
TIVA techniques in equine anesthesia are principally sion rate of 1 mL/kg/h, for 1 h without a surgical procedure
used for surgical procedures in the field where anesthesia being performed so that the cardiopulmonary effects could be
machine are impractical [212]. Greene and co-workers first assessed. It was concluded that although there was mild
describes a combination of ketamine (1 mg/mL), xylazine cardiopulmonary depression, MKM-TIVA provided clini-
(0.5 mg/mL) and guaiphenesin (GGE) 5 % (1 L) [27]. This cally acceptable general anesthesia. Oxygen supplementa-
became the so called “triple drip” or GKX which is given at a tion was advised as hypoxemia was observed during the
rate of 1.5 mL/kg/h. Since then, modifications of the original study with PaO2 values of around 50–60 mmHg.
triple drip have been made by either changing the α2- Recently, the use of S-ketamine (2.5 mg/kg, IV) along
adrenoceptor agonist to detomidine (GKD) or to romifidine with diazepam (0.05 mg/kg, IV) was describes to induce
(GKR) [213, 214]. To increase the time of infusion and as general anesthesia in horses premedicated with romifidine
the GGE is the main cumulative agent, people have (0.1 mg/kg, IV) and L-methadone (0.05 mg/kg, IV) and
increased the dose of xylazine to 1 mg/mL and the ketamine undergoing field castration [219]. It was concluded that
to 2 mg/mL. although the inductions and recoveries were of good
612 T. Beths
qualities, the duration of the surgical anesthesia following The actual use of TIVA or PIVA techniques to help maintain
one single injection tended to be insufficient to complete a patient under general anesthesia will depend upon factors
surgical castration and that general anesthesia could there- such as the veterinarian’s qualification (general practitioner
fore be maintained by an additional doses of S-Ketamine of vs. specialist in anesthesia), the veterinarian’s practice
1 mg/kg, IV, at 10–15 min, without impairing the quality and (equine vs. dogs and cats vs. wildlife) and the veterinarian’s
duration of the recoveries. location (general practice, referee centre, outdoor, third
More information about the use of ketamine TIVA in world country, disaster zone).
equine patients can be found in more specialized literature In human anesthesia, the development of PK dependant
[145, 211, 215]. infusion systems such as the TCI for propofol revolutionised
TIVA by making propofol an IV agent as simple to admin-
Ruminant ister and as rapid to titrate as an inhalational anesthesia.
Similarly to horses, the triple drip mixture has been used Although TCI systems have been developed for propofol
successfully in cattle, sheep, and even lamas [220]. Although in the dog or detomidine and ketamine in the horses, the use
the concentration of ketamine in the mixture will be similar of this technology stayed mostly at the research level. Beside
to that in horses (1–2 mg/mL), xylazine is often reduced to the lack of enough knowledge/availability of population
0.1 and even to 0.05 mg/mL for prolonged anesthesia due to pharmacokinetics for individual target agents, the actual
the risk of accumulation and the increased sensitivity to this cost associated with the infusion of drugs such as propofol
agent observed in ruminants. In all cases, the GGE concen- and even more alfaxalone to maintain anesthesia is very
tration is 50 mg/mL. The reported infusions of mixtures of likely to be the main reason if not the only factor responsible
0.1 mg/mL of xylazine, 1–2 mg/mL of ketamine in GGE for this lack of movement to the clinical world. It is impor-
50 mg/mL are as follow: 1.5–2.5 mL/kg/h in calves, 2 mL/ tant to remember that in veterinary medicine, the health cost
kg/h in adult cattle, 2–2.6 mL/kg/h in sheep and 1.2–2.4 mL/ are not supported by health insurance and therefore
kg/h in lama [220]. veterinarians need to be very cautious with their charges,
keeping their clients happy while still making a living. Using
Swine propofol or alfaxalone instead of isoflurane to maintain a
A triple drip combination of ketamine (1–2 mg/mL), dog under general anesthesia would increase the cost to
xylazine (1 mg/mL) in GGE (50 mg/mL) has been used in the small animal (dogs and cats) veterinarian by a factor of
pigs at rates of about 2.2 mL/kg/h for anesthesia up to 2 h 4 and 8, respectively while in horses, the factor would be of
[221, 222]. Recoveries although of good qualities are about 12 and 24, respectively. Therefore, as most of the
prolonged (30–45 min) and yohimbine (a xylazine specific veterinarians in practice will be using inhalation anesthesia
reversal agent (0.06–1 mg/kg)) could be administered to to maintain their patient anesthetised, it is very unlikely that
shorten the recovery, but with the potential consequence of the TCI system or similar system will become popular soon.
diminishing post-operative analgesia. Another very interesting evolution in human anesthesia
was the linking of the TCI system with monitors of depth of
Miscellaneous anesthesia such as the BIS (Bispectral Index) resulting in a
A triple drip protocol using 0.5 mg/mL of xylazine, 2 mg/mL “closed loop anesthesia” or CLAN [223–226]. As far as the
of ketamine and 50 mg/mL of GGE at a 2 mL/kg/h rate has author is aware, such a system has not yet been tested in
been used to maintain anesthesia for 1 h in the spontaneously animal even so BIS monitoring has been used in
breathing donkey [154]. Although hypoxemia (oxygen sup- dogs and other species with more or less some success
plementation was not provided) was observed, no other [75, 227–235].
cardiorespiratory or metabolic changes were observed. Drug companies are still looking for the “ideal” IV agent.
Recoveries took on average 32 min with some epiphora While some are developing completely new agents, others
and salivation with good quality score in all the donkeys are revisiting old agents and making them more TIVA
(7/8) but one who only scored acceptable. This protocol still friendly [236]. This revamping of old drugs involved
needs to be evaluated for surgical conditions. techniques such as: isolation of active enantiomers
(dexmedetomidine, s-ketamine, l bupivacaine); replacement
of less suitable excipient (Cremophor EL with cyclodextrin
Conclusion for alfaxalone); transforming an agent into a prodrug to
make it more water soluble (fospropofol). More information
Veterinary anesthetists are very familiar with drug infusions can be found elsewhere in the literature [236, 237].
either as a means to maintain a patient under general anes- Will TIVA supersede inhalational anesthesia in human
thesia (TIVA) and/or to provide extra analgesia, sedation or anesthesia? It is difficult to predict, but some seems to think
muscle relaxation (co-infusion, balanced anesthesia, PIVA). it will, or at least in some specific areas such as paediatric
[238]. Although this seems very unlikely to happen in veter- 18. Goodwin WA, Keates HL, Pasloske K, et al. The pharmacokinet-
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in the horse. Vet Anaesth Analg. 2011;38:431–8.
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veterinary market economically viable to keep producing the intravenous bolus of alfaxalone following premedication with
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TIVA/TCI in Veterinary Practice

Introduction New Zealand College of Veterinary Scientists) colleges. The

# Springer International Publishing AG 2017 589

Elimination Volume of Total systemic

animals where prolonged recumbency may be associated with

Fig. 31.3 Equine field

Lidocaine is a sodium channel blocker local anesthetic

The properties of propofol differentiate it from other intra-

Fig. 31.5 TCI for propofol in the

Fig. 31.6 (continued)

(infusion) should be discarded (Label Diprivan® 451094 F/ Pharmacokinetics

(but not cats) propofol is extensively and rapidly metabolised Pharmacodynamics

Fig. 31.7 Elephant undergoing

[155]. The latter was responsible for hyperaemia in cats, and

administered to the female cats (about 22 vs. 7 mg/kg). This Equine

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