Anaesthetic agents and associated drugs
For further information on dose rates and the indications for use of these drugs see Induction of anaesthesia and Anaesthetic complications and resuscitation techniques
SEDATIVES AND TRANQUILISERS (drugs which reduce anxiety and produce mild sedation):
Diazepam and midazolam are tranquilisers of the benzodiazepine class. These drugs do not immobilize animals, but when used alone they produce a calming effect with muscle relaxation without affecting consciousness. Benzodiazepines generally cause minimal respiratory or cardiovascular depression and have the advantage of producing retrograde amnesia.
Diazepam used at 0.15 – 0.45 mg/kg orally can produce a degree of sedation. More importantly it is used to control seizures (convulsions or fits) caused by ketamine or tiletamine at 0.05 – 0.1 mg/kg by slow intravenous injection. Diazepam is not water soluble and only slowly absorbed from muscle. Intramuscular injections can be painful. Diazepam should not be given by very rapid intravenous injection as the propylene glycol used as a solubilising agent may produce hypotension, bradycardia, apnoea and cardiac arrest.
Midazolam is water soluble and is rapidly absorbed from muscle. In field anaesthesia, midazolam is used to control seizures and can be given by the intramuscular or intravenous routes at 0.05 – 0.1 mg/kg. “Hypnovel” is a 5mg per ml solution of midazolam. To control seizures give 0.1ml /10kgs intravenously or 0.2ml per 10kg intramuscularly. In countries in which midazolam is not available diazepam can be used as an alternative as above. Rapid intravenous injections of midazolam will not cause the adverse cardiac or respiratory side effects of diazepam solutions.
Medetomidine is a very potent sedative drug of the alpha-2 adrenoceptor agonist type with analgesic properties. Although in all species high doses will produce a sleep-like state with marked muscular relaxation, it should never be used alone to handle dangerous animals as stimulation will cause arousal and animals which appeared to be sedated may react aggressively with little or no warning. Disadvantages include significant respiratory depression, bradycardia, hypotension, vomiting and disruption of thermoregulation. The effects of medetomidine can be reversed with a range of alpha-2 adrenoceptor antagonist including atipamezole, yohimbine and tolazoline. Medetomidine is used in combination with low doses of ketamine to produce a reversible state of anaesthesia. While this combination may be used for tigers, there is a significant risk of sudden arousal following minor stimulation, so the animal should be safely restrained with hobbles and depth of anaesthesia monitored more closely than when other anaesthetics or anaesthetic combinations are used. This risk can be significantly reduced by using medetomidine in combination with tiletamine-zolazepam (eg “Zoletil“). Medetomidine is sold under a number of brand names and is usually available as a 1mg/ml solution. Stronger solutions are available in some countries. Medetomidine can cause significant respiratory depression in tigers when used in combination with ketamine. NB – systolic heart murmurs are often often heard in tigers anaesthetised with drug combinations including medetomidine.
Dexmedetomidine is another alpha-2 adrenoceptor agonist more potent than medetomidine by a factor of 2:1, but is not available in strengths higher than 0.5mg / ml. Dexmedetomidine appears to cause less respiratory depression in tigers.
Xylazine is not an anaesthetic but a sedative chemically related to medetomidine although not as potent. It is usually available as solutions of 100 mg/ml or 20 mg/ml. In high doses it causes severe cardiac and respiratory depression, and even death. Xylazine should NOT be used in animals suffering from shock. Its effects are largely reversible with atipamezole at 1 mg atipamezole per 10 mg xylazine used. Used alone it will provide insufficient sedation to handle tigers safely. Low doses of xylazine are used in combination with ketamine or tiletamine-zolazepam to produce anaesthesia in tigers.
ANAESTHETIC DRUGS (drugs which produce loss of consciousness and pain perception):
Ketamine hydrochloride is a dissociative anaesthetic drug, causing chemical separation between the conscious mind and the sensory and motor control mechanisms of the brain. It produces rapid anaesthesia, a trance like state, peripheral analgesia and minimal respiratory depression. The eyes remain open, the swallowing reflex is maintained, and when used alone, there can be pronounced muscle rigidity, which can cause an increase in body temperature. Excessive salivation and seizures (convulsions) are common side effects. Recovery from ketamine anaesthesia can be prolonged and characterised by ataxia (in-coordination). Although ketamine alone has a wide margin of safety it is best used in combination with a tranquilizer (such as midazolam or diazepam) or sedative (such as medetomidine or xylazine) to overcome the adverse side effects. Ketamine solution is acidic and may cause pain on injection. There is no specific reversal agent for ketamine.
Tiletamine + zolazepam combined in equal amounts is sold under the brand name of “Zoletil” or “Telazol“. Tiletamine is a dissociative anaesthetic drug chemically related to ketamine, and zolazepam is a tranquiliser chemically related to midazolam. The combination is used as an animal anaesthetic with properties that include a rapid induction, effective analgesia, a wide safety margin, minimal depression of breathing and a dose dependent effect. (In other words, the more that is given, the deeper and more prolonged the anaesthesia achieved). The combination is very soluble which allows the use of very small volumes of liquid. Disadvantages include a prolonged, ataxic and sometimes stormy period of recovery; lack of a specific reversal agent and instability when reconstituted with water. Use of Zoletil can result in an elevated body temperature , excessive salivation and occasional seizures. Swallowing and gag reflexes are often preserved during anaesthesia which can make intubation difficult if it becomes necessary. Its use alone in tigers has been controversial in recent years owing to the occasional adverse neurological side-effects seen in some captive individuals. These side effects are reduced by using low doses of Zoletil in combination with medetomidine or dexmedetomidine. “Zoletil” is supplied in packs containing one vial of 250 mg (“Zoletil 50”) or 500 mg (“Zoletil 100”) tiletamine/zolazepam powder plus one vial of sterile water. In its powdered form it is extremely stable. Adding all the water in the sterile water vial provided to a vial of Zoletil 100 powder produces a 100 mg/ml solution. Stronger solutions up to 500 mg/ml can be prepared by adding less water. By tradition the dose of Zoletil refers to the mixture of tiletamine + zolazepam, so that 2mg Zoletil = 1mg tiletamine + 1mg zolazepam.
Isoflurane is a volatile liquid which when vaporised at low concentrations in a carrier gas such as oxygen is one of the most widely available gaseous anaesthetic agents used in veterinary medicine. When used correctly isoflurane gas is a reliable anaesthetic but care must be taken to avoid the profound cardiovascular and respiratory depression that are caused by overdosing. In the field, isoflurane and oxygen can be used to prolong or control the depth of anaesthesia, and to smooth ataxic (uncoordinated) or stormy inductions or recoveries. Although carrying substantial amounts of bottled oxygen into the field can be unrealistic, simple equipment can be built that allows the vaporisation of isoflurane in air. (See section on Prolonging and deepening anaesthesia)
Pentobarbital sodium is a high strength barbiturate anaesthetic and is only used for the humane destruction (euthanasia) of animals. It is usually available as a 200mg/ml solution (eg Euthatal”). Intravenous doses of 150 mg/kg will rapidly cause death in any species. This is equivalent to 7.5 ml/10 kg. Far lower doses are usually effective in anaesthetised animals. If veins cannot be accessed in anaesthetised animals, the drug may be injected directly into the heart through the chest wall between ribs, or even into the abdominal cavity.
ANAESTHETIC REVERSAL DRUGS:
There are no drugs that will specifically reverse the effects of ketamine or tiletamine. However, when sedatives such as medetomidine or xylazine are used in combination with these anaesthetic agents, the amount of anaesthetic drug required for immobilisation is low. Therefore by reversing the longer-acting sedatives the time to effective recovery can be dramatically shortened.
Atipamezole is an alpha-2 adrenoceptor antagonist. It is a highly potent and specific antagonist (reversal agent) to medetomidine and can also be used to reverse the effects of xylazine. It is usually given intramuscularly, but in emergencies it can be given intravenously to produce a quicker effect. Most commercial brands of atipamezole (eg “Antisedan” ) are available as a 5mg/ml solution. Doses used range between 3 and 5x the amount of medetomidine given for an anaesthetic (i.e between 3 and 5 mg atipamezole for each mg of medetomidine given). 10mg atipamezole are given per mg dexmedetomidine, and when used to reverse xylazine 1 mg atipamezole is given for every 10 mg xylazine.
Flumazenil (and sarmazenil) are potent and specific benzodiazepine antagonists used to reverse the effects of drugs such as diazepam, midazolam and zolazepam. In tigers and other cats tiletamine is eliminated faster than zolazepam. Therefore flumazenil or sarmazenil can be used to shorten the recovery times of tigers anaesthetised with Zoletil. 1mg flumazenil is given intramuscularly for every 20-25mg benzodiazepine. However, these drugs have a shorter half life than most benzodiazepines and resedation can result. They also tend to be expensive.
Yohimbine also has alpha-2 adrenoceptor antagonist properties, but it is not very specific nor potent and should be used only to reverse xylazine. When used to reverse ketamine-xylazine combinations yohimbine should not be given within 30 minutes of the last ketamine injection. 1mg yohimbine should be given for every 10mg xylazine by intramuscular injection. Intravenous yohimbine may cause seizures (Dushyant, pers. comm., 2020).
DRUGS USED IN ANAESTHETIC EMERGENCIES:
Adrenaline is a cardiac stimulant and is used only in an emergency situation when the heart is failing or has stopped. For this purpose, it is generally given by slow intravenous injection. (Adrenaline can be given by intramuscular or even subcutaneous injection but is far less rapidly effective). In the extreme circumstance of cardiac arrest (i.e. the heart has stopped beating), adrenaline can be given by intracardiac injection combined with external cardiac compressions in an attempt to restart the heart. However, it is far easier and more effective to give adrenaline by intravenous injection before that stage has been reached. Vigilant monitoring of the heart during anaesthesia is therefore essential. “Adrenaline injection 1:1000” is a 1 mg/ml solution of adrenaline and is usually supplied in glass vials of 1ml. Doses of 0.01 mg/kg are generally used which is equivalent to 0.1 ml per 10 kgs of animal.
Atropine sulphate is used to stabilise and increase the heart rate during anaesthetic emergencies. However, atropine also causes a persistent dilation of the pupils and is therefore not appropriate for use in animals to be released to the wild within 24 hrs. (Dilation of the pupils causes disturbances in an animal’s vision). Atropine is available in several strengths including a 0.6 mg/ml solution and a 10 mg/ml solution. It can be given intramuscularly, subcutaneously or even by slow intravenous injection at between 0.02 and 0.06 mg/kg. This is equivalent to between approximately 0.3 and 1 ml of a 0.6 mg/ml solution per 10 kg of animal or between 0.2 and 0.6 ml of a 10 mg/ml solution per 100 kgs of animal.
Dexamethasone is a steroid with potent anti-inflammatory and anti-allergic properties. It is also used in cases of shock. Because dexamethasone suppresses the body’s immune responses, whenever it is given, antibiotics should also be administered to prevent bacterial infections developing. Dexamethasone is available in different strength solutions, but commonly at 2 mg/ml. It is generally given intramuscularly, although in cases of shock intravenous injection is better. For anti-inflammatory and anti-allergic purposes dexamethasone is given at 0.1 mg/kg which is the equivalent of 0.5 ml of a 2 mg/ml solution per 10 kg of animal. For cases of shock, it is given at the much higher dose rate of 1 mg/kg, equivalent to 5 ml of a 2 mg/ml solution per 10kg of animal.
Doxapram hydrochloride is a central nervous system and respiratory stimulant that appears to have some non-specific antagonistic action against some anaesthetic agents. Its primary use is to stimulate the depth and frequency of breathing in animals that are suffering from respiratory depression and in these circumstances should be used intravenously after checking that nothing is obstructing an animal’s airway. However, its effects tend to be short-lived (<20 minutes) and may therefore need repeated administration. Doxapram is commonly available as a 20mg/ml solution (eg “Doxpram-V“) For sub-adult and adult tigers dose rates of between 0.5 and 1mg/kg (equivalent to 0.25 – 0.5 ml “Dopram-V” solution per 10 kg of animal) should be tried first. Given at these dose rates, doxapram may re-establish an acceptable breathing pattern without causing arousal which could lead to a dangerous situation for the operators. In juvenile tigers higher doses of between 2 and 3 mg/kg may be required.
Glycopyrrolate is used to stabilise and increase the heart rate during anaesthetic emergencies and is similar in this respect to atropine. However, unlike atropine, glycopyrrolate does not cause dilation of the pupils and is therefore a better drug to use on animals that are to be released to the wild immediately. (Dilation of the pupils causes disturbances in an animal’s vision). Glycopyrrolate is available as a 0.2mg/ml solution (eg “Robinul”) and is usually supplied in 3 ml glass vials. It is used at 0.01 mg/kg by intramuscular or slow intravenous injection. This is equivalent to 0.5 ml of “Robinul” per 10 kg of animal.
OTHER:
Hyaluronidase is an enzyme which breaks down some components of connective tissue. When mixed with anaesthetic drugs its effect is to accelerate their uptake into the bloodstream and hence shorten the time it takes to induce anaesthesia. Commercially available as “Hyalase”, it comes as a powder in small glass vials containing 1500 international units (iu) hyaluronidase. For adult tigers, dissolve the contents of one vial in the liquid anaesthetic drugs to be loaded into a dart. This will not appreciably increase the drug volume. Hyalase is an expensive drug.
VETERINARY DRUGS should be stored and used safely, in accordance with local legislation and professional guidelines. As a minimum:
- All drugs should be stored in a lockable cabinet maintained at a suitable temperature.
- Access to the drugs should be limited to those qualified and authorised to do so.
- Drug use should be recorded.