Ketamine hydrochloride is a general anaesthetic deriving from the cyclohexamine phencyclidine. This latter molecule was synthesised in 1956 by Harold Maddox, a pharmacologist of the Parke-Davis pharmaceutical company, and became the first molecule to be used in anaesthesia, in 1958 by Greifenstein and colleagues. However, phencyclidine caused negative effects on awakening from anaesthesia. Ketamine was synthesised in 1962 by Stevens, it was first used in humans in 1965 by Corssen and Domino and later, in 1970, it was adopted for the anaesthesia in the cat. To date, it has been used in humans, primates, cats, dogs, horses, pigs, ruminants, birds, reptiles, laboratory rodents and in several species of exotic animals.
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PHYSICOCHEMICAL CHARACTERISTICS
From a chemical point of view, ketamine hydrochloride, an analogue of phencyclidine, can be considered as the hydrochloride of 2-(o-chlorophenyl)-2-(methylamino)–cyclohexanone. This chemical compound is slightly acid, whereas the hydrochloride solution has a pH of 3.5-5.5 and for this reason it cannot be mixed with alkaline solutions. For veterinary use it isformulated as a solution containing a preservative, benzethonium hydrochloride.It is relatively stable for three years, but it must be protected from light and excessive heat.
The preparation is a racemic mixture, composed of equal parts of two stereoisomers S-(+) and R-(-). The isomer S-(+) is stronger, and causes less adverse events: a recent study on human patients has in fact shown that the administration of this isomer alone resulted in less fatigue and in an inferior drop in mental concentration compared to the administration of the racemic mixture. On the contrary, the physiological effects on blood pressure and on the heart rate are similar with the administration of the racemic mixture compared to the two stereoisomers inoculated separately. The duration of hypnosis with the positive isomer is twice as long compared to the one induced by the negative isomer and the analgesia is also deeper. The combination of the two isomers presents intermediate effects.
METABOLISM
In the dog, ketamine is mainly and rapidly metabolised by liver microsomes. The biotransformation of the compound occurs in the liver, where the cyclohexane ring is N-demethylated and hydroxylated, resulting in water-soluble glucuronides eliminated through the urine. The principal metabolite, norketamine, has hypnotic properties (approximately one fifth of the power of ketamine) and also a longer half-life compared to ketamine. This explains why the animals receiving high and repeated doses of ketamine exhibit occasional sleepiness and prolonged awakening times. Instead, the activity of the other metabolites is not well known.
In the cat, the hepatic metabolism is lower than in other species and the majority of ketamine is excreted unchanged through the kidneys or it is partially biotransformed with the formation of norketamine.
PHARMACOKINETICS
The pharmacokinetics of ketamine has not yet been extensively studied; nevertheless, it can be explained with a two-compartment model. In the cat, the distribution is very fast (t1/2 = 3 minutes) and is then followed by a slower phase of elimination. The t1/2 of ketamine (66.9÷24.1 minutes) is independent from the parenteral route of administration. The bioavailability after parenteral administration is of 51% in the cat and of 43% via the endorectal route. Absorption from the site of intramuscular administration is so rapid that the plasma level is reached within 10 minutes. Due to its high liposolubility, ketamine diffuses throughout the organism (especially in the adipous tissue, the liver, the lungs and the brain) even after intramuscular inoculation, and therefore the Vd is relatively high (10 times higher than thiopental). Clearance is also quite high (12-17 ml/kg/min) and this explains the short half-life (2-3 h) of ketamine. The onset of action after intravenous administration is 30-40 seconds. The rather quick awakening time is determined especially by the fast redistribution (as is the case for other anaesthetic drugs such as propofol) rather than by its metabolism. The binding to plasma proteins is of approximately 50%.
MECHANISM OF ACTION
Ketamine can induce a dissociative anaesthesia. This term is indicative of a cataleptic and hallucinatory state characterised by muscle rigidity, muscle hypertonus, coordinated muscle movements not connected to painful stimuli, preserved laryngeal and palpebral reflex, absence of ocular ventroflexion, mild nystagmus and blinking, loss of the pedal and pinnal reflex. The resulting effects are deep somatic analgesia, tachycardia and hypertension, associated with a minimum level of unconsciousness, while the animal appears instead to be dissociated from the environment. The resulting anaesthesia must be considered as incomplete. The mechanism of action of ketamine is not completely known, but a selective depression of the neuronal function of the neocortico-thalamic axis and of the central nuclei of the thalamus may be hypothesised together with the contemporary stimulation of some parts of the limbic system, including the hippocampus. Ketamine acts like a non-competitive receptor antagonist of glutamate receptors (NMDA); glutamate is the most important excitatory neurotransmitter in the CNS. The action on these receptors is probably the mechanism responsible for ketamine-induced analgesia and the cause of its anaesthetic and neuroprotective effects. Even at sub-anaesthetic doses, ketamine has proved to be effective in treating chronic pain characterised by allodynia or hyperalgesia, as well as painful conditions deriving from CNS hyperexcitability.
In addition to the above, the analgesic effects of ketamine can also be explained by some other mechanisms:
- blocking of the transport of dopaminergic neurotransmitters such as serotonine, dopamine and noradrenaline;
- blocking of the signals that travel along the spino-reticular tracts;
- depression of the acetylcoline receptors; action on sodium, potassium and calcium voltage-dependent channels;
- strengthening of the g-aminobutyric acid bond in the CNS and strengthening of inhibitory mechanisms through the gaba system;
- direct action of ketamine on the first and fifth laminae of the dorsal horn;
- depression of the nuclei in the medialmedullaryreticular formationofthe medulla;
- possible interaction with opioid receptors.
EFFECT ON THE CENTRAL NERVOUS SYSTEM
The functional and electrophysiological dissociation between the neocortico-thalamic and the limbic systems gives the name to the type of anaesthesia induced by ketamine.
Ketamine significantly increases brain perfusion, intracranial pressure and cerebrospinal fluid pressure, as the result of brain vasodilatation and of the increase in systemic pressure. The administration of ketamine to patients with a reduced intracranial compliance (e.g. tumors, haematoma) should be avoided or, in any case, associated with controlled ventilation.
Ketamine causes an increase in cerebral metabolism: despite the fact that the anaesthetic has different effects on the brain, inhibiting some areas and stimulating others, the general effect is an increased cerebral oxygen consumption.
Low doses of ketamine are likely to induce an anticonvulsant effect, even if weak, through the antagonism on NMDA receptors. Nevertheless, while waiting for more detailed studies on this issue, ketamine should not be used in animals having a history of seizures.
Awakening from ketamine anaesthesia may be followed by abnormal behaviours and hallucinations, that can progress to delirium, such as ataxia, increased motor activity, dissociative conditions, hyper-reactivity to stimuli, hyper-reflexia or violent reactions. These reactions generally disappear in a few hours; premedication with tranquillizers, sedatives or opioids drastically reduces their incidence.
ANALGESIA
Ketamine is the only general injectable anaesthetic agent able to guarantee a good level of analgesia.
When anaesthesia is induced with ketamine, or when ketamine is added to general anaesthesia before surgical stimulation, postoperative pain diminishes and a better pain management is achieved.
The analgesic properties of ketamine seem to reduce the sensitisation of pain pathways and allow to cover also the postoperative period.
Recently, ketamine has been used at sub-anaesthetic doses by continuous infusion and combined with other analgesic drugs for the prevention of postoperative pain [6] in both animals and humans and has resulted in a reduced need for opioids in patients subjected to abdominal surgery, nephrectomy and other types of major surgery.
The preoperative administration of ketamine, which acts as a powerful antagonist of NMDA receptors, may therefore prevent the wind-up phenomenon and reduce postoperative pain.
However, ketamine induces a greater degree of analgesia at somatic level than at visceral level and for this reason it is more effective for anaesthesia induction and in the postoperative analgesia of patients undergoing surgery of the skeletal and integumentary system and of the extremities than in animals undergoing other types of surgery.
CARDIOVASCULAR EFFECT
Ketamine causes an indirect stimulation of the cardiovascular system.
In an animal in optimal clinical conditions, the increasein cardiac output and the decrease in coronary vascular resistancecompensate for the deficiency of oxygen, meaning that the coronary circulationis appropriate for the increased oxygen consumption.
Unfortunately, however, in the presence of a patient with a myocardial disorder the increaseof coronary blood flow may not be sufficient to compensate for the oxygen demand of the myocardium.
For this reason, ketamineshould be used carefully in patients with heart problems.
The increasein heart rate and blood pressure is linked to the stimulation of central adrenergic control structures or to the inhibition of the neuronal catecholaminereuptake.
In the dog, immediately after the administration of ketamine a transient decrease in blood pressure is observed, because the drug determines a direct, but temporary myocardial depression. This aspect is evident during anaesthesia when ketamine, due to specific and different reasons, is administered intravenously. Aftera few seconds, an evident but temporary reduction in blood pressure and, sometimes, even a reduction in heart rateoccurs. Generally,the negative inotropic effect is masked by the stimulation of the sympathetic nervous system and, normally, hypertensive effects are predominant until high doses of ketamine are used.
The stimulationof the autonomic nervous system (ANS) causes an increase in left ventricular work and oxygen consumption: ketamine must therefore be avoided in cases of severe hypertrophic cardiomyopathy, hyperthyroidism, pulmonary andsubaortic stenosis and myocardial alterations in which oxygen supply is critical.
The administration of ketamine can cause life-threatening cardiovascular depression in patients with damaged left ventricular function or in patients whose sympathetic tone is not increased.
Current indications for the anaesthesia of patients with cardiovascular failure specify that diazepam and ketamine should be used in the presence of the following conditions: mitralor tricuspid insufficiency, dilated cardiomyopathy, atrioventricular block, patent ductus arteriosus, while it is not considered appropriate in patients with hypertrophic cardiomyopathy, ventricular septal defect, or aortic stenosis.It is also recommended to insert equal volumes of the two drugs inside the same syringe and to slowly inject intravenously 1 ml/10 kg. Inhypovolemic patients, the administration of ketamine causes an increase in heart rate and blood pressure; cardiac output, however, does not increase.
It is extremelyimportant to consider that in protracted states of shock the stimulating actionof the ANS may not occur in view of the depletion of endogenous catecholamines (the exhaustion phase of the shock), caused by the body's response to prolonged stress. Therefore, also in this case, ketamine can have a direct depressant effect on the heart.
EFFECT ON THE RESPIRATORY SYSTEM
Unlike other anaesthetics, ketamine does not depress the ventilatory response to hypoxia.
In general, cardiac output, which allows to maintain a satisfactory oxygenation of tissues, and arterial oxygen tension (in comparison with barbiturates) are maintained within standard values.High doses of ketamine can induce apneustic breathing (a respiratory pattern characterised by a prolonged suspension of ventilation for 30-40 seconds after inhalation, followed by close, deep breaths) (Video 1).
Ketamine, just like propofol, has a bronchodilating effect which makes the drug suitable for patients with asthma.
Pharyngealand laryngeal reflexes are partially or completely maintained during dissociative anaesthesia, however the swallowing reflex may be masked, since animals anaesthetised with ketamine are intubated.
Ketaminedetermines an increase in salivary and tracheobronchial secretions (which may be partially controlled with the use of atropine) and this effect, associated with the lack of depression of the laryngeal and pharyngeal reflexes, can make endotracheal intubation difficult, especially in cats when ketamine is used as the only anaesthetic.
EFFECT ON THE LIVER
After the administration of ketamine, no liver function alterations are reported, neither in human patients nor in dogs.
Ketamine is rapidly metabolised; any possible prolongation of the action of the drug is more dependant on the reduction of hepatic perfusion than on specific changes in liver function.
In the cat, hepatic metabolismis however inferior to that of other species and the main emunctory organ is the kidney through which large amounts of norketamine, an active metabolite, and unchanged ketamine are eliminated. Therefore, in the cat, in case of impairment of renal excretion activity (e.g. renal failure, urinary obstruction) ketamine may perhaps not be the drug of first choice.
EFFECT ON THE KIDNEYS AND ON THE URINARY SYSTEM
Inhealthy animals, ketamine can increase renal perfusion due to its stimulating effect on the cardiovascular system. In case of hypovolemic shock, however, renal perfusion is more appropriately maintained by thiopental than by ketamine or diazepam, because with the last two drugs a marked renal arterial vasoconstriction may occur. Cats with renal or urinary obstruction have prolonged awakening times.
Ketaminein association with diazepam is not suitable for sedation and anaesthesia induction in patients undergoing tests to assess the functionality of the distal urinary tract: in fact, ketamine abolishes the detrusor contraction reflex in all dogs.
GASTROINTESTINAL EFFECT
Ketaminehas mild effects on gastrointestinal motility. In the dog, the effect of ketamine on the gastroesophageal sphincter pressure is not reported, while in the cat the sphincter tone is better preserved with ketamine than with propofol or thiopental. Diazepam associated with ketamine may increase the incidence of vomiting.
HAEMATOLOGICAL EFFECT
The effectof ketamine on the blood has not yet been fully studied in the dog; however, in the cat, the reduction in the haematocrit is less evident after the administration of ketamine than with thiopental, probably due to a lower sequestration of red blood cells by the spleen.
METABOLIC, ENDOCRINE AND IMMUNE SYSTEM EFFECT
Ketaminecauses an increased release of adrenocorticotropic hormone (ACTH) and of B-endorphin in piglets with an ongoing haemorrhage. Both these hormones represent two sides of the opioid/anti-opioid system and the increase in the ACTH anti-opioid effect under ketamine anaesthesia can be seen as an advantage for the endocrine system, which is associated with those that ketamine has on the cardiovascular system in cases of severe haemorrhage. Clinical experiences in humans have revealed the existence of interactions between thyroid hormones and ketamine. Patients undergoing a replacement therapy for thyroid insufficiency have experienced severe hypertension and tachycardia after the administration of ketamine. In such cases a treatment with β-adrenergic blockers is effective. According to a recent research, ketamine causes a dose-dependent inhibition of mast cell exocytosis.
OPHTHALMOLOGIC EFFECT
Inhuman patients ketamine causes a significant increase in intraocular pressure. A recent study has confirmed that ketamine (5 mg/kg i.v.) causes an increase in intraocular pressure in dogs which have not been premedicated; therefore, ketamine must be avoided in dogs suffering from glaucoma, corneal trauma or during intraocular surgery. This effect seems to be related to the increased extra-ocular muscle tone induced by ketamine. In the cat, lacrimal production is not decreased, however the failure to close palpebral rims favours the drying of the cornea. It is therefore good veterinary practice to moisten the cornea with some gel or with lubricating eye drops during anaesthesia with ketamine.
Ketamine causes nystagmus, which may persist even after the administration of xylazine; this side effect makes the drug unsuitable for ophthalmic surgery if used without myorelaxant drugs such as benzodiazepines.
After administering the anaesthetic, the eyelid remains open, the pupil remains dilated and the corneal and eyelid reflexes are maintained.
EFFECT OF KETAMINE ON PREGNANCY AND USE IN CESAEREAN SECTION
Ketaminecauses an increased frequency of uterine contractions and it crosses the placenta, therefore even low doses of ketamine (> 2 mg/kg i.v.) induce neonatal depression.
By increasing the uterine tone, ketaminedecreases uterine perfusion at the time of delivery and the vigor of puppies and kittens immediately after birth is lower compared to what happens when propofol is used. Neurological reflexes are also more depressed after the use of ketamine (2 mg/kg i.v.) in association with midazolam (0.5 mg/kg i.v.).
EFFECT ON THE MUSCOLOSKELETAL SYSTEM
As previouslydescribed, ketamine causes muscle hypertonus and myoclonus (involuntary muscle movements and tremors) which can result in tonic-clonic spasm of limb muscles. The incidence of these effects may bereduced with an adequate premedication with sedatives or tranquillizers.
NEGATIVE EFFECTS OF KETAMINE
Ketamine side effects consist in convulsive episodes, especially in the dog: seizures may be related to a dopamine release and for this reason ketamine should be avoided in epileptic animals.
The administrationof ketamine by itself results in muscular hypertonus and spontaneous, almost continuous movements. Pharyngeal and laryngeal reflexes (although they cannot be considered protective for the airways) persist and salivation is abundant.
Anotherproblem associated with the use of ketamine is, for an untrained observer, the difficulty in evaluating correctly the depth of anaesthesia; in fact, the persistence of (ocular) reflexes and muscle tone may raise the suspicion of a superficial effect of the anaesthetic plan and the possible addition of other unnecessary anaesthetics could lead to a severe cardio/respiratory depression.
Ketamine mustalways be associated with other analgesics. Moreover, as it does notguarantee adequate visceral anaesthesia, even in routine surgery (e.g. ovariectomy) ketamine must always be preceded by drugs with an analgesic effect.
Contraindicationsin the use of ketamine include:
- animals with head injury or high intracranial pressure;
- animals with liver failure and cats with renal failure;
- patients with certain types of heart problems;
- patients in whom the increased demand and consumption of oxygen and the increased contractility cause serious side effects on the heart
Another problem is represented by the prolonged awakening time and by hypothermia, that may occur especially in the cat following an excessive intramuscular administration of the drug. Episodes of delirium may occur with vocalisations, incoordination, agitation and a gesture of closing the mouth with the paws. The administration of tranquillizers can reduce these effects.
Finally, because of its acidic pH, after intramuscular administration ketamine causes pain and irritation at the injection site.
CLINICAL USE
Ketamineis used as a drug for the induction of anaesthesia in both the dog and the cat (Video 2). Being a dissociative anaesthetic, it can cause muscle hypertonia, restless awakenings, involuntary movements and occasional convulsions which are simply triggered by noises, lights or manipulation. To compensate for these and other side effects, ketamine is used in combination with sedatives and tranquillizers.
The use of ketamine by infusion is still not very common in the dog and cat, but it may be helpful in preventing hyperalgesia.
Repeated doses of the drug (one fourth of the initial dose every 10-15 minutes as needed) result in minimal accumulation of the anaesthetic, but in these conditions the quality of the awakening is worsened and excitatory phenomena, muscle tremors and hallucinations may occur.
Tiletamine
Tiletamine,or 2-ethylamino-2-(2-thienyl) cyclohexanone, is chemically similar to ketamine.
The mainanaesthetic and analgesic effects of tiletamine are very similar to those of ketamine, although this compound is more powerful, has a greater duration of action and it causes more evident side effects (apneustic breathing, muscle rigidity, tonic-clonic movements).
As withketamine, tiletamine causes immobilisation and dissociative anaesthesia, the eyeballs stay in place and the eyelids do not close, leaving the cornea exposed to the outside. Most of the reflexes remain active and ocular, laryngeal and eyelid response is present.
Normally, thisdrug is not used as the only anaesthetic agent and in fact on the market only combinations with a benzodiazepine (zolazepam) are present. The association is formed by the combination of the two agents in a 1:1 ratio (tiletamine 50 mg/kg and zolazepam 50 mg/kg) and it induces rapid anaesthesia via the intramuscular or intravenous route. Zolazepam has the prerogative of being a tranquillizer, a muscle relaxant and an anticonvulsant drug, which can minimise some of the side effects induced by tiletamine.
Particular attention must be paid when usingthe combination tiletamine/zolazepam in the dog; the tranquillizing effect of the benzodiazepine is often of a shorter duration than that of tiletamine and could therefore lead to agitated awakenings due to the residual effects of cyclohexamine, especially if the animals are not premedicated before receiving zolazepam or if they are not sedated at the end of the procedure. In the cat, the opposite usually happens, meaning that the duration of tiletamine is shorter than that of zolazepam and awakenings will be more gentle and prolonged. Respiratory depression is dose dependent and at high doses apneustic breathing often occurs (some deep breaths, pauses of apnoea of approximately 30-60 seconds, more deep breaths, etc.).
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