KNOWLEDGE SUMMARY

Keywords: ANAESTHESIA; ANALGESIA; HYPOXAEMIA; MEDETOMIDINE; PHARMACOLOGY; SHEEP

In sheep undergoing general anaesthesia does the inclusion of medetomidine result in hypoxaemia?

Rachael Gregson, BVM&S FHEA CertAVP Dip.ECVAA MRCVS^1*

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¹ Large Animal Research and Imaging Facility, The Roslin Institute, The University of Edinburgh, EH25 9RG
* Corresponding author email: rachael.gregson@ed.ac.uk

Vol 10, Issue 2 (2025)
Submitted 29 Sep 2023; Published: 06 May 2025
DOI: https://doi.org/10.18849/ve.v10i2.708

PICO question

In healthy adult female non-pregnant sheep undergoing general anaesthesia for research studies does the inclusion of intravenous medetomidine as part of the anaesthetic protocol cause hypoxaemia?

Clinical bottom line

Category of research

Treatment.

Number and type of study designs reviewed

Four papers were available for critical appraisal. The quality of the evidence is weak. There were four experimental studies; three of which were cross-over studies and one study which was run in parallel with primary orthopaedic research. None of the studies were specifically focussed on the potential hypoxaemic effects of medetomidine.

Strength of evidence

Weak.

Outcomes reported

Sheep across all four studies developed hypoxaemia (indicated by arterial oxygen tension; either P_aO₂ < 80 mmHg/10 kPa when breathing room air, or a statistically significant fall in P_aO₂ compared with baseline, when breathing oxygen enriched gases), when medetomidine was administered intravenously and in combination with various drugs (i.e. midazolam, propofol, ketamine, halothane, and isoflurane). However, as the sheep were receiving various doses of medetomidine at various timepoints, different quantities of supplemental oxygen (if any), varying ventilatory management (two studies used mechanical ventilation and two studies allowed sheep to breathe spontaneously), and different agents were used to maintain anaesthesia, the clinical significance of the P_aO₂ values was difficult to assess.

Conclusion

In clinically healthy (judged by clinical examination) adult female non-pregnant sheep undergoing general anaesthesia (characterised by placement of an endotracheal tube and/or the use of anaesthetic induction agents i.e. barbiturates, ketamine, propofol), the weak evidence presented here suggests that use of intravenous medetomidine can be expected to cause hypoxaemia. However, hypoxaemia is variable and its clinical effects can be lessened with anaesthetic techniques such as the provision of supplemental oxygen.

How to apply this evidence in practice

The application of evidence into practice should take into account multiple factors, not limited to: individual clinical expertise, patient’s circumstances and owners’ values, country, location or clinic where you work, the individual case in front of you, the availability of therapies and resources.

Knowledge Summaries are a resource to help reinforce or inform decision making. They do not override the responsibility or judgement of the practitioner to do what is best for the animal in their care.

Clinical scenario

You are a Named Veterinary Surgeon for a facility which uses large animals. A group of sheep will be receiving general anaesthesia for detailed computed tomography (CT) scanning as part of a Home Office licensed project. The principal investigator is concerned that medetomidine, which is administered as part of the facility’s standard anaesthetic protocol, will cause hypoxaemia, and wants advice as to how relevant this may be.

The evidence

Hypoxaemia develops in healthy adult female non-pregnant sheep following intravenous medetomidine administration as part of a general anaesthetic protocol. The quality of the evidence is weak; there are four experimental studies; three cross-over studies (Raekallio et al., 1998; Celly et al., 1999a; Raisis et al, 2021) and one study which was run in parallel with primary orthopaedic research (Kästner et al., 2001). All four studies varied as to their anaesthetic and ventilatory management of the sheep. Although the evidence shows that hypoxaemia occurs following the intravenous administration of medetomidine in sheep in the peri-anaesthetic period, the severity and clinical consequences of this hypoxaemia are difficult to determine. This is due to the variation in protocols between the studies. The evidence suggests that when intravenous medetomidine is administered to healthy adult female non-pregnant sheep hypoxaemia (partial pressure of arterial oxygen [P_aO₂] < 80 mmHg/10 kPa when breathing room air or a statistically significant fall in P_aO₂ from baseline when breathing oxygen enriched gases) develops. The drug’s effects on P_aO₂ are minimised by anaesthetic techniques such as the administration of supplemental oxygen, tracheal intubation, and adequate monitoring. Therefore, intravenous medetomidine could be used cautiously alongside appropriate anaesthetic management in healthy adult female non-pregnant sheep undergoing research procedures. However, medetomidine is not licensed in food-producing animals in the UK and adherence to relevant legislation in the country of use is advised.

Summary of the evidence

Celly et al. (1999a)

Cardiopulmonary Effects of the α2-Adrenoceptor Agonists Medetomidine and ST-91 in Anesthetized Sheep

Aim: To investigate the relative contributions of the cardiovascular and respiratory systems to alpha2-agonist-induced hypoxemia in halothane anaesthetised, ventilated sheep by comparing the effects of incremental doses of the central and peripheral acting a2-agonist, medetomidine, the peripherally acting a2-agonist, ST-91, and a saline placebo.

 

Kästner et al. (2001)

Comparison of Medetomidine and Dexmedetomidine as Premedication in Isoflurane Anaesthesia for Orthopaedic Surgery in Domestic Sheep

Aim: To determine the potency of dexmedetomidine in relation to medetomidine in sheep undergoing orthopaedic surgery by comparing the anaesthetic requirements and cardiovascular effects of equipotent doses of both drugs in healthy adult female sheep.

 

Raekallio et al. (1998)

Medetomidine-Midazolam Sedation in Sheep

Aim: To investigate the effects (on sedation, arterial oxygenation and haemoglobin oxygen saturation) on healthy adult female sheep of a low dose of medetomidine combined with midazolam; the effects of this combination were compared to the effect of each drug when used alone.

 

Raisis et al. (2021)

Comparison of pulmonary function in isoflurane anaesthetized ventilated sheep (Ovis aries) following administration of intravenous xylazine versus medetomidine

Aim: To compare the effects of equipotent intravenous doses of two alpha-2 adrenoreceptor agonist drugs (xylazine and medetomidine) on pulmonary function (as assessed by spirometry, volumetric capnography and arterial blood gases) on isoflurane anaesthetised, mechanically ventilated, healthy adult female sheep.

 

Appraisal, application and reflection

Sheep are commonly used as experimental research animals for translational biomedical research, particularly orthopaedic and neurological research due to “its large body size, gyrencephalic brain, long lifespan, more extended gestation period, and similarities in neuroanatomical structures to humans” (Banstola & Reynolds, 2022). The provision of balanced anaesthetic protocols which provide analgesia are therefore required in these procedures. Alpha-2 adrenoreceptor agonist drugs (hereafter referred to as alpha-2 agonists) such as medetomidine, have analgesic, sedative, and anaesthetic sparing effects and are very useful as part of balanced anaesthetic techniques in sheep (Lizarraga & Chambers, 2012). Alpha-2 agonists are known to cause hypoxaemia in sheep but there is variation between individual animals and the degree of hypoxaemia is dependent upon dose and route of administration; the causal mechanism is proposed to be alpha-2 adrenoreceptor (hereafter called “α2”) mediated pulmonary vasoconstriction and bronchoconstriction leading to alveolar oedema (Kästner, 2006). Medetomidine is the most specific alpha-2 agonist with an alpha-2:alpha-1 adrenoreceptor selectivity ratio of 1620:1 (Dugdale, et al., 2020) meaning that side effects due to alpha-1 receptor stimulation are less likely to occur than when less α2 specific drugs, such as xylazine, are used. This Knowledge Summary therefore aims to investigate if treatment with intravenous medetomidine in healthy adult non-pregnant sheep causes hypoxaemia, defined as P_aO₂ < 80 mmHg/< 10 kPa when breathing room air, or a statistically significant fall from baseline when supplemental oxygen is administered.

A literature review was performed to answer the PICO question, which yielded four peer-reviewed papers for critical appraisal, after applying article exclusion criteria (Raekallio et al., 1998; Celly et al., 1999a; Kästner et al., 2001; Raisis et al., 2021). All the studies are experimental; three were cross-over studies (Raekallio et al., 1998; Celly et al., 1999a; Raisis et al., 2021) and one was run in parallel with an orthopaedic study (Kästner et al., 2001). There was blinding of evaluators to treatment in only one of the studies (Kästner et al., 2001), and randomisation in only three of the studies (Celly et al., 1999a; Kästner et al., 2001 and Raisis et al, 2021). The articles retrieved covered a time period, from 1998 to 2021.

Synergism between alpha-2 agonists and other anaesthetic drugs is well recognised. Chemical immobilisation using large doses of medetomidine (0.125 mg/kg) and ketamine (2.5 mg/kg) has been shown to cause significant hypoxaemia (P_aO₂ < 40 mmHg) in sheep during the initial phases of immobilisation (Caulkett et al., 1994). However, the authors of this study suggest this could be mitigated with supplemental oxygen administration and reversal of the medetomidine with atipamezole, although this may render the chemical immobilisation ineffective.

Celly et al. (1999a) found hypoxaemia while increasing doses of medetomidine (0.5 µg/kg to 4.0 µg/kg, intravenously) were administered to mechanically ventilated sheep anaesthetised with halothane (Celly et al. 1999a). The alveolar-arterial oxygen tension gradient (P(A-a)O₂) and shunt fraction (Q_s/Q_t) increased, signifying pulmonary dysfunction in these animals, which is offered as the explanation for the fall in arterial oxygen tension (P_aO₂). The pulmonary dysfunction is suggested to be caused by the development of pulmonary oedema which has been shown to occur after xylazine administration (Celly et al., 1999b). As both xylazine and medetomidine are alpha-2 agonists with a comparable mode of action, it is reasonable to agree with the authors that the development of pulmonary oedema could also be occurring here. However, none of the papers discussed here described evidence of pulmonary oedema. The P_aO₂ in the region of 200 mmHg following medetomidine administration in these sheep is in excess of the P_aO₂ of approximately 100 mmHg a healthy animal breathing room air would achieve, according to the alveolar gas equation [P_AO₂ = F_IO₂(P_B-P_H2O) - (P_ACO₂/RQ)]; Dugdale et al., 2020. However, as the sheep in this study were breathing 100% oxygen (Celly et al., 1999a), and their P_aO₂ was 509 mmHg when the placebo was administered, the sheep receiving medetomidine can be considered to have a relative hypoxaemia, the effects of which were lessened by oxygen supplementation; this fall in P_aO₂ was statistically significant (P < 0.05).

Hypoxaemia was found, with the P_aO₂ reaching a lowest level of 58.5 mmHg, in sheep premedicated with medetomidine (10 µg/kg intravenously) during isoflurane anaesthesia for experimental hip replacement surgery (Kästner et al., 2001). However, it is difficult to assess these numbers as the F_IO₂ was not stated, the sheep were breathing spontaneously, and their respiratory function under anaesthesia was sub-optimal, as indicated by a raised P_aCO₂ in the region of 50 mmHg; normal being 35–45 mmHg (Dugdale et al., 2020). This paper did not include a negative control group for ethical reasons. It is therefore difficult to prove that the hypoxaemia is due to the alpha-2 agonist, and not due to another reason, such as effects of recumbency or surgery. Also, the paper concludes with the statement that there is “development of severe hypoxaemia and pulmonary oedema in individual animals” yet no individual animal data is included, only ranges, and no histology was performed to confirm the presence of pulmonary oedema or fat emboli (Kästner et al., 2001); fat emboli can develop after bone surgery and cause hypoxaemia, and these sheep had had hip replacement surgery (Lindeque et al., 1987).

The most recent paper yielded by the literature search was Raisis et al., (2021). This considered respiratory function in isoflurane anaesthetised, mechanically ventilated sheep administered either xylazine or medetomidine (2.5–5 µg/kg intravenously). Like the paper by Kästner et al. (2001), this was performed concurrently with another experimental study, in this case a nutritional study, and as such was restricted in terms of timeline, numbers and endpoints by the primary study. No dose finding pilot to choose appropriate doses of alpha-2 agonist drugs could therefore be performed, and the alpha-2 agonist doses had been extrapolated from a study using conscious sheep (Celly, et al., 1997). The methodology of the study was altered on discovery that the chosen initial dose of intravenous xylazine (75 µg/kg) caused significant hypoxaemia (assessed as SpO₂ < 90% or marked tachypnoea and confirmed by a P_aO₂ of 51.2 [37.4–64.9] mmHg) necessitating reversal of the xylazine with atipamezole. The dose of both alpha-2 agonists was subsequently halved to maintain equipotent doses and the data from the sheep given higher doses was excluded. No sheep receiving medetomidine required administration of atipamezole. The data from the animals eventually included in the paper shows that the sheep receiving medetomidine in comparison with xylazine did experience a fall in P_aO₂, from 63.1 kPa (473.3 mmHg) before drug administration to 56.1 kPa (420.8 mmHg) at 10 minutes after drug administration (P < 0.05). Again, the animals are reported to be mechanically ventilated with 100% oxygen at this point, mitigating the effects of any pulmonary dysfunction caused by the medetomidine, as shown by the increase in carbon dioxide elimination (VCO₂). The study concludes with the statement that medetomidine is preferred over xylazine as it better maintains pulmonary function but suggests that more work is required in other sheep breeds.

In a cross-over experimental study (Raekallio et al., 1998), sedation in sheep was investigated using medetomidine, midazolam, and a combination of the two agents; only the combination of medetomidine and midazolam met the criteria for general anaesthesia in this Knowledge Summary (allowing tracheal intubation). This study showed that 15 µg/kg medetomidine and 0.1 mg/kg midazolam administered intravenously caused profound sedation leading to lateral recumbency accompanied by marked hypoxaemia (on the basis of P_aO₂ measurement) unrelated to ventilation (assessed by P_aCO₂ values). However, although there are graphs of the P_aO₂ values over time, due to the granular nature of the scale and lack of numerical table of values, it is difficult to determine exactly the level of hypoxaemia in these sheep, although it speculated to be in the region of 5–7 kPa (37.5–52.5 mmHg). As the definition of clinical hypoxaemia for the purposes of this Knowledge Summary is P_aO₂ < 80 mmHg or < 10 kPa when breathing room air (Dugdale et al., 2020), it is possible that if these sheep received supplemental oxygen, and perhaps if the lungs had been mechanically ventilated, which would have been possible as their tracheas had been intubated, their P_aO₂ would not have fallen to this level. One sheep in this group suffered cardiac arrest and had to be resuscitated; although out with the remit of this Knowledge Summary to discuss the ethics of the experimental studies appraised, it raises the topic of humane end points for this study. The main conclusion of the paper is that the synergism between midazolam and medetomidine causes such profound cardiorespiratory effects that their use cannot be recommended.

All the papers discussed here found that hypoxaemia, as assessed by P_aO₂, occurs after the administration of intravenous medetomidine in the peri-anaesthetic period in healthy adult female non-pregnant sheep of various breeds. The severity and clinical significance is, however, not easy to determine, as none of the studies was primarily interested in the development of hypoxaemia following the administration of intravenous medetomidine. There was a wide variation in doses of medetomidine administered, ventilatory support provided and levels of oxygen supplementation administered, meaning the hypoxaemia identified may not have been relevant in a clinical situation. The evidence, although weak, suggests that in answer to the PICO question, intravenous medetomidine administered to adult female sheep judged healthy on clinical exam during the anaesthetic period causes hypoxaemia.

Methodology

Search Strategy

 

Exclusion / Inclusion Criteria

 

Search Outcome

 

Acknowledgements

The author would like to acknowledge that this Knowledge Summary was initially conceived as part of a Certificate of Advanced Veterinary Practice (CertAVP) module studied at the University of Liverpool.

ORCiD

Rachael Gregson: https://orcid.org/0000-0003-2704-1825

Conflict of Interest

The author declares no conflicts of interest.

References

1. Banstola, A. & Reynolds, J.N.J. (2022). The Sheep as a Large Animal Model for the Investigation and Treatment of Human Disorders. Biology. 11(9), 1251. DOI: https://doi.org/10.3390/biology11091251
2. Caulkett, N.A., Cribb, P.H. & Duke, T. (1994). Cardiopulmonary effects of medetomidine-ketamine immobilization with atipamezole reversal and carfentanil-xylazine immobilization with naltrexone reversal - A comparative study in domestic sheep (Ovis-Ovis). Journal of Zoo and Wildlife Medicine. 25(3), 376–389.
3. Celly, C.S., McDonell, W.N., Young, S.S. & Black, W.D. (1997). The comparative hypoxaemic effect of four alpha 2 adrenoceptor agonists (xylazine, romifidine, detomidine and medetomidine) in sheep. Journal of Veterinary Pharmacology and Therapeutics. 20(6), 464–471. DOI: https://doi.org/10.1046/j.1365-2885.1997.00097.x
4. Celly, C.S., McDonell, W.N. & Black, W.D. (1999a). Cardiopulmonary Effects of the α2-Adrenoceptor Agonists Medetomidine and ST-91 in Anesthetized Sheep. Journal of Pharmacology and Experimental Therapeutics. 289(2), 712–720. DOI: https://doi.org/10.1016/S0022-3565(24)38192-3
5. Celly, C.S., Atwal, O.S., McDonell, W.N. & Black, W. D. (1999b). Histopathologic alterations induced in the lungs of sheep by use of alpha2-adrenergic receptor agonists. American Journal of Veterinary Research. 60(2), 154–161.
6. Dugdale, A.H.A., Beaumont, G., Bradbrook C. & Gurney M. (2020). Veterinary Anaesthesia: Principles to Practice. Hoboken, New Jersey: Wiley-Blackwell.
7. Lindeque, B., Schoeman, H., Dommisse, G., Boeyens, M. & Vlok, A. (1987). Fat embolism and the fat embolism syndrome. A double-blind therapeutic study. The Journal of Bone & Joint Surgery British Volume. 69-B(1), 128–131. DOI: https://doi.org/10.1302/0301-620X.69B1.3818718
8. Lizarraga, I. & Chambers, J.P. (2012). Use of analgesic drugs for pain management in sheep. New Zealand Veterinary Journal. 60(2), 87–94. DOI: https://doi.org/10.1080/00480169.2011.642772
9. Kästner, S.B.R. (2006). A(2)-agonists in sheep: a review. Veterinary Anaesthesia and Analgesia. 33(2), 79–96. DOI: https://doi.org/10.1111/j.1467-2995.2005.00243.x
10. Kästner, S.B.R., Von Rechenberg, B., Keller, K. & Bettschart-Wolfensberger, R. (2001) Comparison of Medetomidine and Dexmedetomidine as Premedication in Isoflurane Anaesthesia for Orthopaedic Surgery in Domestic Sheep. Journal of Veterinary Medicine Series A. 48(4), 231–241. DOI: https://doi.org/10.1046/j.1439-0442.2001.00354.x
11. Raekallio, M., Tulamo, R.M. & Valtamo, T. (1998). Medetomidine-Midazolam Sedation in Sheep', Acta Veterinaria Scandinavica. 39(1), 127–134. DOI: https://doi.org/10.1186/bf03547814
12. Raisis, A.L., Hosgood, G.L., Crawford, N., Kästner, S., Musk, G.C., Herrmann, P. & Mosing, M. (2021). Comparison of pulmonary function in isoflurane anaesthetized ventilated sheep (Ovis aries) following administration of intravenous xylazine versus medetomidine. Laboratory Animals. 55(5), 443–452. DOI: https://doi.org/10.1177/0023677220983366

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