'I have been asked to come up with a sedation protocol for sterile placement of venous lines for haemodialysis in a feline patient with renal failure'. This is the type of question that veterinary anaesthetists are asked. To give the answer we need not only to know the clinical pharmacology of the drugs we use, but also to be a physician, to understand the disease process so that we can anticipate the problems. Will the side effects of the sedatives make the condition worse? Will the condition influence the pharmacokinetics or side effects of the agents we use? Do we actually need sedation or would careful handling suffice? Would a carefully administered anaesthetic, allowing maximal support, be preferable? In contrast is the situation where the animal is fit, well, but possibly vicious, and the sedative is being give for our safety. We are very fortunate in having a range of agents, (and often also antagonists) which alone, or in combination can guarantee to enable us to carry out the required procedures in relative safety, but this safety remains dependant on the animal receiving full 'anaesthetic' care.

There is little very 'new' in terms of sedative drugs available, but the modes by which we employ them is changing. This presentation will (very briefly) revise the clinically relevant pharmacological points; discuss the newest available agent, dexmedetomidine then, in the verbal presentation, discuss some case examples.

General Points

For the full clinical pharmacology of the sedative agents:¹

1.  The anti-anxiety and sedative agents we have available are the phenothiazines (e.g., acepromazine), the benzodiazepines (e.g., diazepam, midazolam) and the alpha 2 adrenoceptor agonists (xylazine, medetomidine and dexmedetomidine). Sometimes anaesthetic agents (e.g., propofol, ketamine) may be used to sedate, particularly in the intensive case situation, - but these will be covered in the presentation on intravenous anaesthesia.

2.  Drugs of the three groups have totally different 'sedative' actions:

a.  Phenothiazines calm the animal and in some individuals may make them sleepy, but however high the dose, 'hypnosis' is not achieved. Maximum effects are usually gained at low doses. Although limited sedation on its own, it remains a good premedicant, reducing the dose of subsequent anaesthetic and improving quality of recovery.

b.  Benzodiazepines are very variable in their actions (species and individual effects). In some cases a state close to anaesthesia is achieved, in others there can be paradoxical excitement. For sedation they are most usually used in combination with opioids or ketamine.

c.  Alpha 2 adrenoceptor agonists cause dose-dependant deep sedation, and in the case of medetomidine and dexmedetomidine, high doses can produce a state close to anaesthesia.^2,3 This degree of sedation is accompanied by prolonged cardiovascular and other side effects, and is often not required. Low doses, well below label dose (for example 5 mcg/kg medetomidine) can be very effective in enabling procedures such as radiography to be carried out dogs, or can be an effective premedicant.

3.  The major clinically important side effects at clinical doses (there are a lot more - see references) of each group are as follows:

a.  Acepromazine - Alpha 1 adrenoceptor blockade - vasodilation resulting in hypotension.

b.  Benzodiazepines cause muscle relaxation, and in humans, retrograde amnesia. They have minimal cardiopulmonary effects when used on their own, but can be depressant in various combinations.

c.  Alpha 2 adrenoceptor effects are numerous.^2,3 Positive effects are sedation and analgesia. Major unwanted effects are bradycardia, peripheral vasoconstriction, fall in cardiac output (much due to bradycardia); at high doses respiratory depression - late onset centrally mediated vasodilatation, insulin release blocked so hyperglycaemia; ADH block and high urine output, cessation of gut motility. The bradycardia can be corrected by use of an anticholinergic (atropine, glycopyrrolate) but often there is still peripheral vasoconstriction, and arterial blood pressure becomes unacceptably high (over 300 mm Hg)

4.  Antagonists:

a.  There is no antagonist to acepromazine.

b.  Benzodiazepines are agonist at the GABAA receptor. Their effect can be reversed by flumazenil or sarmazenil.

c.  Alpha 2 adrenoceptor agonists can be antagonised by atipamezole (or the less specific yohimbine). This will antagonise both central and peripheral actions, including sedation and analgesia.

L-659,066 (also known as MK-467),a peripherally acting alpha 2 adrenoceptor antagonist, is not new but recently has been 'looked at' again; the advantage is that it can antagonise the peripheral unwanted side effects whilst allowing sedation and analgesia to remain.^4,5

Medetomidine or Dexmedetomidine?

Dexmedetomidine is the active isomer of medetomidine.^2,3 It has been available and tested in human medicine for some years, where it has found a place for sedation in intensive care and for analgesia. In Europe it is now marketed for use in dogs and cats as a sedative.

Dexmedetomidine is the most potent and most specific alpha 2 adrenoceptor agonist that is available, and as such, the unwanted side effects caused by stimulation of receptors other than alpha 2 agonists should be reduced. However, at clinical doses, most research in veterinary anaesthesia suggests that the actions of dexmedetomidine and of medetomidine, when used at equipotent doses (dexmedetomidine at half the doses of medetomidine) any differences are not clinically significant.

Sedative Combinations

In veterinary practice sedative agents are rarely used alone, but in combination with opioids, with ketamine, or as premedication prior to other anaesthetic agents. When sedatives of any of the three major groups are combined with opioids, the sedative effect is synergistic - the degree of sedation, as judged by lack of response to stimulation, being greater than the additive effect. Common combinations in small animal use butorphanol, buprenorphine, or morphine with alpha 2 adrenoceptor agonists. Where such combinations are used, side effect of the opioids may also be additive, or even synergistic - the most common problem being respiratory depression. Benzodiazepines are combined with potent opioids such as fentanyl to induce anaesthesia (see later presentation). Fentanyl and similar potent opioids cause marked bradycardia, and if this is contraindicated in the case, the use of an anti-cholinergic may be required.

In veterinary anaesthesia, ketamine is used as an anaesthetic, but at sub-anaesthetic doses can be used for sedation and for analgesia. Its stimulatory 'side effects' make it beset used in combination with benzodiazepines, or a low dose of an alpha 2 adrenoceptor agonist.

Sedative Premedication

Sedatives are used as pre-anaesthetic mediation for a number of reasons, not least of which is to make the experience more pleasant for the veterinarian and patient. However, in a survey of anaesthetic deaths in small animal practice, Brodbelt and co-workers⁶ demonstrated that the use of sedative premedication significantly decreased the anaesthetic risk. All the sedatives or combinations discussed greatly reduce the subsequent dose of anaesthetic required.

Clinical Examples

In the verbal presentation, case studies of sedation protocols for a number of situations will be discussed. Examples covered will include dogs and cats with circulatory insufficiency, thoracic trauma, renal failure and diabetes mellitus. The 'pitfall's of the regimens suggested will be highlighted as will be the methods to counteract anticipated problems.

References

1.  Hall LW, Clarke KW, Trim CM. Veterinary Anaesthesia. 10th edition, WB Saunders. London. 2001:75–107.

2.  Murrell JC, Hellebrekers LJ. Medetomidine and dexmedetomidine: a review of cardiovascular effects and antinociceptive properties in the dog. Vet Anaesth Analg 2005;32:117–27.

3.  Kuusela E. Dexmedetomidine and levomedetomidine, the isomers of medetetomidine in dogs. Dissertation for the degree of PhD, University of Helsinki, Finland. 2004. Viewed April 2011 at http://ethesis.helsinki.fi/julkaisut/ela/kliin/vk/kuusela/dexmedet.pdf

4.  Honkavaara JM, Raekallio MR, Kuusela EK, et al. The effects of L-659,066, a peripheral alpha2-adrenoceptor antagonist, on dexmedetomidine-induced sedation and bradycardia in dogs. Vet Anaesth Analg 2008;35:409–13.

5.  Honkavaara JM, Restitutti F, Raekallio MR, et al. The effects of increasing doses of MK-467, a peripheral alpha(2)-adrenergic receptor antagonist, on the cardiopulmonary effects of intravenous dexmedetomidine in conscious dogs. J Vet Pharmacol Ther 2010;33:1365–288.

6.  Brodbelt D. Perioperative mortality in small animal anaesthesia. Vet J 2009;182:152–61.