www.ivis.org Proceedings of the 36th World Small Animal Veterinary Congress WSAVA Oct. 14-17, 2011 Jeju, Korea Next Congress: Reprinted in IVIS with the permission of WSAVA http://www.ivis.org
14(Fri) ~ 17(Mon) October 2011 ICC Jeju, Korea 2011 WSAVA FASAVA World Congress www.wsava2011.org AP-C21 AFTER THIOPENTAL? OPTIONS FOR SHORT TERM INJECTABLE ANAESTHESIA KW Clarke, MA, VetMB, DVetMed, DVA, Dip ECVA MRCA, FRCVS Hon Prof. of Veterinary Anaesthesia, Royal Veterinary College Hatfield, Hertfordshire, AL9 7TA, UK Introduction Thiopental, and other barbiturates have been the mainstay for induction of anaesthesia since the 1940s. Over the past 30 years they have been replaced gradually, mainly by propofol and ketamine, and now can be difficult to obtain. This presentation will consider what is currently and easily available for induction of anaesthesia, the advantages and disadvantages for use in both dogs and cats in the practice situation, and will concentrate then on what is (relatively) new or controversial. This presentation will consider (a) Some general principles of use of injectable anaesthetic agents in small animals. (b) Brief revision of most relevant clinical pharmacology, in particular re unwanted side effects. (c) What s new or controversial? (d) In the verbal presentation, some suggested protocols for induction of, or very short-term, anaesthesia. General Principles 1. A cat is not a small dog! The cat s lack of glucuronyl transferes enzymes mean that metabolism of some drugs (in particular propofol) is delayed, and that some of the solvents or preservatives may be cumulative and/or toxic. 2. Once a drug is injected, it can only be removed by metabolism- this may vary with species or breed and may be influenced by disease states. 3. The dose of anaesthetic required will vary with the premedication used (combinations may have synergistic effects), and with the clinical state of the patient. 4. Some agents used in anaesthetic combinations (alpha 2 adrenoceptor agonists, benzodiazepines, opioids) CAN be antagonised-it is important to match duration of antagonist and agonist. 5. Route of administration - Intravenous (IV) best as easiest to judge depth, BUT not all agents work in a circulation time (thiopental does so, but pentobarbitone not), so effect is delayed. IV administration is 2011 WSAVA FASAVA World Congress Proceedings 59
usually best given slowly. Intramuscular (IM) or similar is always second best - depth of anaesthesia achieved is much less controllable and depend is on speed of uptake. 6. ALL anaesthetics are respiratory depressant, even if the animal breaths fast, so using injectable agents still needs OXYGEN, a clear AIRWAY, the ability to VENTILATE if necessary and excellent MONITORING. Anaesthetic agents/combinations A (very) brief resume of the major clinically important pharmacology [1]. Thiopental. Barbiturate, presented as solid to dissolve in water. Irritant extravascularly. IV route only. Rapid onset of anaesthesia (one circulation time) initital recovery by re-distribution, slow metabolism and cumulative. Poor analgesia. Very respiratory depressant. Vasodilates. Increases heart rate. Propofol Presentation usually in lipid, but see below. Non-irritant but sometimes pain on injection. IV route only. Rapid onset anaesthesia, non-cumulative and recovery fast-and complete, except in cats [2}. Poor analgesia. Very respiratory depressant. Cardiovascular effects as thiopental but less tachycardia. Ketamine Presentation in solution with preservatives. Many routes of administration. Non-irritant, but pain on IM injection. Onset of anaesthesia after IV injection not immediate. Excellent analgesia. Respiratory depressant but animal may breath rapidly and shallowly. Technically myocardial depression but sympathetic stimulation result in CV system being well maintained. Hallucinogenic and muscle rigidity so usually used in combination with alpha 2 agonists or benzodiazepines. Etomidate Rapidly acting IV induction agent, with rapid recovery from induction dose. Pain on injection. Venous phlebitis. Poor analgesia. Myoclonic activity. Minimal cardiovascular effects (so popular for the compromised dog). See below for concern re cortisol suppression. Alphaxalone - see detail below. Benzodiazepine/opioids may also be used to induce anaesthesia [3]. Neither of these agents work in a circulation time. What s new or currently controversial (a) Propofol in cats The major route (there are others) of metabolism of propofol is through glucuronidation of the parent drug followed by glucuro conjugation of hydroxylated metabolite via cytochrome P450 to produce other conjugates. Cats lack the enzymes necessary for this, and also are slow to metabolise the lipids in the carrier. As a result, propofol is not as short acting in the cat as in the dog. Its safe use as an induction agent, and use for short duration infusion appears satisfactory, but there is continual controversy as to whether it is suitable for longer infusions or for use several days in succession (when under experimental conditions, toxicity has occurred [2]). (b) Propofol formulations The original lecithin based formulation of propofol had to be used within a very short time of openingmaking it expensive. Since becoming out of patent, a number of new versions have included preservatives of varying efficacy. These versions state on their marketing authorisation the time after opening the vial when the product is considered safe. The most recent on the veterinary market includes benzyl alcholol 60 2011 WSAVA FASAVA World Congress Proceedings
AFTER THIOPENTAL? OPTIONS FOR SHORT TERM INJECTABLE ANAESTHESIA and, in the USA, has authorisation to be open for 28 days (some other countries give a shorter time). There are some questions as to the toxicity of the Benzyl alcohol particularly in cats, but again this is only likely to be a problem with prolonged infusions. An emulsion formulation of propofol that does not include oils and again has a long shelf life after opening has been available, but in the UK has been (possibly temporarily) withdrawn for commercial reasons. Etomidate Etomidate has not been used as a CRI in intensive care for many years since it was realised that the adrenocortical suppression in such patients increased the overall death rate, most usually from infections. In the last few years there has been considerable controversy over whether the short-term (a few hours) adrenocortical suppression it induces means that it should not be used for IV induction of anaesthesia, in particular in patients with sepsis. There is no evidence as to whether this is a potential problem in veterinary anaesthesia. Alfaxalone (3-alpha-hydroxy-5-alpha-pregnane-11,20-dione) solubalized in 2 alpha-hydroxypropyl beta cyclodextrin (HPBCD) Licenced product - Alfaxan Steroid anaesthesia is not new- over the last 50 years a number of agents have been used - the problem has been solubility. Alphaxalone /alphadalone combination solublised in cremaphor was used in humans and in cats (Saffan ) - but the cremaphor caused histamine release. Facts about Alfaxalone as Alfaxan. (a) Originally licenced in Australia, and used there now for some years. Now licenced in many countries for cats and dogs. Licensed dose rates without sedative premedication are 3mg kg-1 dogs and 5 mg kg-1 cats. Administer IV over 60 seconds. Recommended to premedicate healthy animals. (b) Effective anaesthesia on IV use in (close to) a circulation time. Induction quality usually good, but improved by sedation. Advise from practice use is to ensure anaesthesia is adequate before endotracheal intubation, otherwise if the animal is stimulated, it wakes up! (c) Non irritant IV, or if accidental extra-vascular. It could be given IM, but volume too large for use without deep sedation. (d) Short half-life, non-cumulative. Metabolised by the liver. (e) Very good safety margin, especially if ventilate (massive overdose may causes apnoea). (f) No evidence of histamine release. (g) Can be used together (not in same syringe) with most commonly used sedatives, analgesics, or subsequent inhalation agents. (h) Cardiovascular effects - minimal at clinical, or even heavy clinical doses [3,4,5]- after this (supraclinical doses for licensing procedures) dose dependant fall in blood pressure and systemic vascular resistance. (i) transient apnoea if injected fast - more prolonged at massive overdose. (j) Can get some disturbed recoveries. These are much less likely to happen if extubation is whilst anaesthesia is still deep, and the animal allowed to recover somewhere quiet. 2011 WSAVA FASAVA World Congress Proceedings 61
References 1. Hall LW, Clarke KW and Trim CM. 2001. Chapter 5 In Veterinary Anaesthesia. WB Saunders, London. Pgs 113-131. 2. Andress JL, Day TK, Day D. 1995 The effects of consecutive day propofol anesthesia on feline red blood cells. Vet Surg 24, 277-82. 3.Psatha E, Alibhai HI, Jimenez-Lozano A et al,2011. Clinical efficacy and cardiorespiratory effects of alfaxalone, or diazepam/fentanyl for induction of anaesthesia in dogs that are a poor anaesthetic risk. Vet Anaesth Analg 38, 24-36. 4.Muir W, Lerche P, Wiese A et al, 2008. Cardiorespiratory and anesthetic effects of clinical and supraclinical doses of alphaxalone in dogs. Vet Anaesth Analg 35, 1-12. 5. Muir W, Lerche P, Wiese A et al, 2009 Cardiorespiratory and anesthetic effects of clinical and supraclinical doses of alphaxalone in cats. Vet Anaesth Analg 36, 42-54 62 2011 WSAVA FASAVA World Congress Proceedings