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Having their best interests at HEART: Coronary collateral circulation in the rabbit, stress & the effects of alpha-2 agonists, phenothiazines and volatiles.


In the United Kingdom rabbits are now the third most commonly anaesthetised household pet after cats and dogs, but they are still regarded as a challenge by many veterinary professionals.  In the 2008 CEPSAF study by Broadbelt et al, it was determined that rabbits were 7 times more likely to die during the perioperative period than dogs. Several factors influence this including: the health status of the patient; the sedative/anaesthetic/analgesia protocol selected; the procedure being undertaken; and nurse/veterinarian familiarity with the species. 

In this article we will discuss the unique coronary circulation of the rabbit and the effects stress and sedative or anaesthetic drugs may have on the heart of this increasingly popular patient.  

Coronary Collateral Circulation

It has been well established that coronary artery-to-artery anastomoses, also known as coronary collateral circulation (CCC), are important in determining the rate of myocardial cell death following an ischaemic event (Maxwell et al, 1987).  In 1912 Herrick recognised that coronary collateral circulation varied between species and that in the pig, which has no CCC, areas of ischaemia that were not rapidly re-perfused progressed to irreversible damage. However, in species where there is extensive CCC there may be sufficient blood flow to slow post-ischaemic cell damage with the potential for partial or full recovery of the ischaemic area. One such species is the guinea pig: in studies performed by Johns & Olsen (1954), Flores et al, (1984); and Rosen et al, (1984) it was demonstrated that grossly visible and substantial coronary collateral circulation was present in this species, and that even after 6 hours of complete coronary artery occlusion myocardial ischaemia did not develop. 

Compared to dogs and cats the rabbit has minimal collateral coronary circulation and this was demonstrated very clearly by Maxwell et al, (1987).  The study examined the CCC and myocardial perfusion of several species, including the rabbit, using radioactive imaging. The results for CCC were presented as a percentage of blood flow to normal myocardium (i.e. non-ischaemic flow).  CCC was 15.9% of normal blood flow in the dog and 11.8% in the cat.  For rats the collateral blood flow was less than dogs or cats but was still detectable indicating a low level of CCC (6.1%). However, 6.1% was not considered sufficient to permit tissue survival during ischaemic events.  The rabbit and ferret showed minimal CCC (2% and 2.4% respectively) and this verifies the findings of Flores et al, (1984) who established the presence of abundant CCC in the guinea pig but none in the rabbit or ferret.

The minimal CCC in the rabbit demonstrates the susceptibility of the heart in this species to reductions in myocardial perfusion, whether from disease, stress or drug administration.

Stress and catecholamines

In 1973 paper by Weber & VanderWalt cardiomyopathy and sudden deaths were reported in groups of rabbits housed in high densities: the deaths were considered to be related to the stress experienced by the animals. Even in modern veterinary practice stress is a very common occurrence in rabbits presented to the clinic, with the endogenous release of catecholamines potentially responsible for inducing significant myocardial changes (Downing & Chen, 1985).  Indeed, Downing & Lee (1983) concluded that endogenous release of catecholamines produced myocardial injury in rabbits, with the severity of myocardial injury a function of the levels, and duration of action, of noradrenaline in the circulatory system.  Noradrenaline causes sustained coronary vasoconstriction, mediated via stimulation of the alpha-adrenergic pathways, and reduced blood flow to the myocardium (Downing & Lee, 1983).  If this occurs in the rabbit, which has minimal collateral coronary circulation, it may rapidly progress to myocardial necrosis and inflammation.  

Therefore, when combined with the minimal CCC in the rabbit, the coronary vasoconstriction as a consequence of catecholamine release during periods of stress may result in myocardial injury.

Alpha-2 agonists

Alpha-2 adrenergic agonists (A2-agonists) are commonly used in many species, including the rabbit, for sedation, analgesia, their minimal respiratory effects at clinical doses, and for their dose sparing effects on other sedative/anaesthetic drugs (Segal et al, 1989; Pascoe et al, 2006; Rioja et al, 2006, Pypendop et al, 2011; Duke-Novakovski et al, 2016).  

The administration of an A2-agonist produces peripheral vasoconstriction which in turn may initiate a biphasic effect on the cardiovascular system: 

Phase 1. An initial increase in blood pressure with a compensatory decrease in heart rate and cardiac output (up to 50%).  

Phase 2. The phase 1 effects begin to wane after approximately 20 minutes followed by a centrally mediated reduction in peripheral vasoconstriction. Heart rate and blood pressure return to normal or just below normal. 

The constriction of coronary arteries by A2-agonists via activation of the A2 receptors in the vessels appears to be dose dependent (Pascoe et al, 2015) and most pronounced in the smaller coronary vessels.  If this vasoconstriction fails to permit an adequate blood flow to meet myocardial oxygen demands then cell death will result (Teng et al, 1995). Mimuro et al, (2010) confirmed this by administering dexmedetomidine to perfused isolated rat hearts with pre-existing ischaemic injuries: the size of the infarct increased following dexmedetomidine administration. Indeed, the vasoconstriction and reduced coronary blood flow subsequent to administration of the alpha-agonist methoxamine produces an identical pattern of lesions to those caused by the catecholamine noradrenaline (Downing & lee, 1983; Simons & Downing, 1985).  In a study by Hurley et al, (1994) coronary vasoconstriction following administration of the A2-agonist detomidine was believed to be the most likely cause of myocardial injury in 5/6 rabbits, although other causes were also considered (hypovitaminosis E, free radical injury). 

In addition to the cardiovascular effects of A2-agonists hepatic blood flow may also be reduced (Lawrence et al, 1996) in a dose-dependent manner thus decreasing the hepatic metabolism of the drug and prolonging the cardiovascular effects (Dutta et al, 2000; Pypendop et al, 2013)

Although cardiac output can diminish by up to 50% following A2-agonist administration, in healthy dogs and cats with a relatively good CCC (15.9% in the dog and 11.8% in the cat) this is not generally considered to be an issue. However, if the canine or feline patient has a reduced organ reserve, when blood flow to the vital tissues may be compromised, the administration of A2-agonists should be carefully considered. In contrast, the limited CCC of the rabbit (2%) predisposes the myocardium to ischaemic injury following coronary vasoconstriction, during episodes of hypotension (e.g. following the use of phenothiazines such as acepromazine or volatile inhalation agents), and/or following hypoxic events.  

Phenothiazines and volatile inhalation agents

Acepromazine is the most commonly administered phenothiazine in the UK and acts mainly as dopamine receptor (D1 & D2) antagonist in the basal ganglia, medulla and hypothalamus with a resultant reduction of motor function and responsiveness to external stimuli.  It also blocks α1 adreno-receptors peripherally producing vasodilation and has anticholinergic & antihistamine activity (muscarinic receptor & H1 receptor blockades) (Duke-Novakovski et al, 2016). Non-antagonisable depression of the central and peripheral nervous system results in peripheral vasodilation and hypotension. Although this may be well tolerated in the healthy dog and cat the hypotension produced in animals with limited cardiac reserve can lead to cardiovascular collapse (Dugdale, 2010). Acepromazine can also potentiate the cardiovascular effects of co-administered drugs.

Inhalation induction using volatile agents such as isoflurane and sevoflurane, either by mask or chamber can be very distressing for the patient and can potentially increase circulating catecholamines with the resultant effects on the heart as described above.  Additionally, even following the administration of premedicants, rabbits may refuse to breathe during volatile induction: hypoxia and collapse can result (Flecknell et al, 1999; Meredith & Lord, 2014).  All volatile agents, whether used for induction or maintenance of anaesthesia, can cause a dose dependent hypotension, mainly as a result of depressed myocardial contractility, and a subsequent reduction in stroke volume.  Blood pressure should therefore be carefully monitored and managed in the rabbit where reduced myocardial perfusion as a result of hypotension could be detrimental.  The use of MAC sparing drugs as part of the premedication protocol should be considered (Meredith & Lord, 2014).

In the rabbit patient with minimal CCC and with potentially high levels of circulating catecholamines the use of drugs that promote reduced cardiac output, cause coronary vasoconstriction, or result in hypotension or hypoxia should be carefully considered and the doses minimised. Attentive monitoring and management of the patient must be performed. 

Stress, drug distribution and unexpected responses

Unexpected responses to sedative, analgesic and anaesthetic drugs are occasionally seen in veterinary patients, particularly if excited, and it has been demonstrated that that blood brain barrier permeability to some drugs can be increased when patients are stressed (Sharma et al, 1991; Friedman et al, 1996). This suggests stress could influence the distribution and brain concentration of sedative or anaesthetic drugs and explain the unexpected responses seen in some animals that have received clinical doses of these agents.  In an equine study performed by Raekallio et al, (1992) the sedative effects of the A2 agonist detomidine was less in nervous horses than those that were calm: high plasma adrenaline concentrations (indicating sympathetic stimulation and adrenal activity) corresponded to a reduced sedative state. There may also be individual variations in the number of A2 adrenergic receptors present in each patient together with differences in occupation of those sites by circulating catecholamines when the animal is stressed.  If the A2 adrenergic receptors are already occupied by catecholamines drugs such as alpha-2 agonists may be less effective than in patients not experiencing stress (Raekillio et al, 2002).

Therefore, stress may have a role to play in the distribution and metabolism of sedative/anaesthetic drugs in rabbits and their subsequent clinical effects.

Individual variation

In addition to the effects of stress on the clinical effectiveness of sedative and anaesthetic drugs rabbits of different strains or breeds can also demonstrate a wide variability in response (Aeschbacher 2001) making it difficult to select appropriate doses (Avsaroglu et al, 2003).  Strain and breed differences have been observed in mice & rats (Simpson & Johnson 1996) & ethnic variability has been observed in humans (Ortolani et al, 2001).  This was illustrated in rabbits in a study performed by Avsaroglu et al, (2003) where two different strains (IIIVO/JU and AX/JU) received solo infusions of propofol, ketamine or medetomidine over 30 seconds.  When propofol or ketamine were administered the righting reflex was lost for longer in the IIIVO/JU rabbits than the AX/JU animals. When medetomidine was administered there was a loss of righting reflex for the IIIVO/JU rabbits but not the AX/JU patients, although reduced movement and lowering of the head were seen.  This suggests the IIIVO/JU strain is “more sensitive” to the three drugs assessed and may be attributed to differences in action of the drugs at their respective receptors, individual variations in the number of receptors (Raekillio et al, 2002), or due to differences in biotransformation. 

It should be noted that many sedation/anaesthesia/analgesia studies in rabbits are performed on laboratory strains which tend to be very healthy and genetically similar, and the procedures performed by familiar personnel and in a familiar environment (reducing stress). Therefore, laboratory rabbit data may not directly reflect the reality of anaesthetising the pet rabbit in a multi-species clinic.


The rabbit heart has minimal CCC making it susceptible to reductions in myocardial perfusion, whether from stress, drug administration or disease. There is individual variability in the response to sedative and anaesthetic drugs.

For information on the use of Alfaxan Multidose in rabbits please download your Rabbit User Guide here.

Article by
Karen Heskin BVSc CertSAO MRCVS & John Chitty BVetMed CertZooMed CBiol MSB MRCVS

Karen Heskin qualified from the University of Liverpool and has a vast experience of small animal practice, orthopaedic referrals, anaesthesia and research.

John Chitty qualified from the RVC in 1990 and gained the RCVS Certificate in Zoological Medicine in 2000. He is director of a small animal and exotics practice in Hampshire, with an exotics and zoo caseload and is also a past president of BSAVA.

Originally published: Thursday, 5th December 2019

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​Peri-anaesthetic mortality and nonfatal gastrointestinal complications in pet rabbits

This recent retrospective study looks at the cases of 185 pet rabbits admitted for sedation or general anaesthetic and evaluates the incidence and risk factors contributing to peri-anaesthetic mortality and gastrointestinal complications.

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Pain, what a Pain! How Locoregional Anaesthesia can Improve the Outcome and Welfare of Veterinary Patients (Part 1)

In this first article out of a series of two, Dan takes us through an introduction and practical tips for appropriate local anaesthesia delivery. Find out why these anaesthesia techniques, that are well recognised in human medicine, have seen an increase in popularity in veterinary medicine over the recent years

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Perspectives on Premeds – Opioids

Perspectives on Premeds is a series of articles touching on different pharmacological, physiological and clinical aspects of pre-anaesthetic medication. This second article aims to provide a refresher on opioids.

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Effects of Dexmedetomidine with Different Opioid Combinations in Dogs

Read the highlights of a recently published research paper that evaluates cardiorespiratory, sedative and antinociceptive effects of dexmedetomidine alone and in combination with morphine, methadone, meperidine, butorphanol, nalbuphine and tramadol. 

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Preoxygenation Study Highlights

This study evaluates the effectiveness of two methods of preoxygenation in healthy yet sedated dogs and the impact of these methods on time taken to reach a predetermined haemoglobin desaturation point (haemoglobin saturation (SpO2) of 90%) during an experimentally induced period of apnoea.

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Capnography – Not Just a Load of Hot Air

Capnography is the measurement of inhaled and exhaled carbon dioxide (CO2) concentration. The graphical illustration of CO2 within respired gases versus times is known as the capnogram.

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Perspectives on Premeds – Alpha-2 Agonists

Perspectives on Premeds is a series of articles touching on different pharmacological, physiological and clinical aspects of pre-anaesthetic medication. This first article aims to provide a refresher on α2 agonists.

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Alfaxan - now licensed for use in pet rabbits

Jurox Animal Health is delighted to announce that Alfaxan is now licensed for cats, dogs and pet rabbits. This is an exciting advance and could change the way rabbits are anaesthetised in the U.K.

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