Anaesthesia and physiological monitoring during in vivo imaging of laboratory rodents: considerations on experimental outcomes and animal welfare

The implementation of imaging technologies has dramatically increased the efficiency of preclinical studies, enabling a powerful, non-invasive and clinically translatable way for monitoring disease progression in real time and testing new therapies. The ability to image live animals is one of the most important advantages of these technologies. However, this also represents an important challenge as, in contrast to human studies, imaging of animals generally requires anaesthesia to restrain the animals and their gross motion. Anaesthetic agents have a profound effect on the physiology of the animal and may thereby confound the image data acquired. It is therefore necessary to select the appropriate anaesthetic regime and to implement suitable systems for monitoring anaesthetised animals during image acquisition. In addition, repeated anaesthesia required for longitudinal studies, the exposure of ionising radiations and the use of contrast agents and/or imaging biomarkers may also have consequences on the physiology of the animal and its response to anaesthesia, which need to be considered while monitoring the animals during imaging studies. We will review the anaesthesia protocols and monitoring systems commonly used during imaging of laboratory rodents. A variety of imaging modalities are used for imaging rodents, including magnetic resonance imaging, computed tomography, positron emission tomography, single photon emission computed tomography, high frequency ultrasound and optical imaging techniques such as bioluminescence and fluorescence imaging. While all these modalities are implemented for non-invasive in vivo imaging, there are certain differences in terms of animal handling and preparation, how the monitoring systems are implemented and, importantly, how the imaging procedures themselves can affect mammalian physiology. The most important and critical adverse effects of anaesthetic agents are depression of respiration, cardiovascular system disruption and thermoregulation. When anaesthetising rodents, one must carefully consider if these adverse effects occur at the therapeutic dose required for anaesthesia, if they are likely to affect the image acquisitions and, importantly, if they compromise the well-being of the animals. We will review how these challenges can be successfully addressed through an appropriate understanding of anaesthetic protocols and the implementation of adequate physiological monitoring systems.

[1]  Christoph Groden,et al.  Application of micro-CT in small animal imaging. , 2010, Methods.

[2]  G. Nikiforidis,et al.  In vivo small animal imaging: current status and future prospects. , 2010, Medical physics.

[3]  R Mark Henkelman,et al.  Systems biology through mouse imaging centers: experience and new directions. , 2010, Annual review of biomedical engineering.

[4]  Nikola Cesarovic,et al.  Isoflurane and sevoflurane provide equally effective anaesthesia in laboratory mice , 2010, Laboratory animals.

[5]  Christian M. Kerskens,et al.  Propofol allows precise quantitative arterial spin labelling functional magnetic resonance imaging in the rat , 2010, NeuroImage.

[6]  Wolfhard Semmler,et al.  Gating in small-animal cardio-thoracic CT. , 2010, Methods.

[7]  J. Hodgin,et al.  A noninvasive computerized tail-cuff system for measuring blood pressure in mice. , 1995, Hypertension.

[8]  Alexandra Badea,et al.  Small animal imaging with magnetic resonance microscopy. , 2008, ILAR journal.

[9]  W. Erhardt,et al.  The use of pulse oximetry in clinical veterinary anaesthesia , 1990 .

[10]  Steven J. Schapiro,et al.  Handbook of Laboratory Animal Science, Volume II : Animal Models , 2003 .

[11]  J. Bulte,et al.  In vivo tracking of cellular therapeutics using magnetic resonance imaging. , 2009, Expert opinion on biological therapy.

[12]  P. White,et al.  Biodisposition of ketamine in the rat: self-induction of metabolism. , 1976, The Journal of pharmacology and experimental therapeutics.

[13]  Sushil K. Sharma,et al.  SPECT neuroimaging in translational research of CNS disorders , 2008, Neurochemistry International.

[14]  Andreas Bruns,et al.  Validation of cerebral blood perfusion imaging as a modality for quantitative pharmacological MRI in rats , 2009, Magnetic resonance in medicine.

[15]  S. Madala,et al.  Effects of isoflurane on coronary blood flow velocity in young, old and ApoE(-/-) mice measured by Doppler ultrasound. , 2007, Ultrasound in medicine & biology.

[16]  Urs Utzinger,et al.  Task-based imaging of colon cancer in the Apc(Min/+) mouse model. , 2006, Applied optics.

[17]  Ciprian Catana,et al.  Small-Animal Molecular Imaging Methods , 2010, Journal of Nuclear Medicine.

[18]  Jerald Silverman Anesthetics in GEM: Does TBE Make the Grade? , 2003, Lab Animal.

[19]  M. Robinson,et al.  Immuno-positron emission tomography in cancer models. , 2010, Seminars in nuclear medicine.

[20]  A. S. Hall,et al.  Magnetic resonance for the anaesthetist , 1992, Anaesthesia.

[21]  R. Gruetter,et al.  Deep thiopental anesthesia alters steady‐state glucose homeostasis but not the neurochemical profile of rat cortex , 2010, Journal of neuroscience research.

[22]  Ralph Müller,et al.  Guidelines for assessment of bone microstructure in rodents using micro–computed tomography , 2010, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[23]  S. Levine,et al.  Feeding sugar overnight maintains metabolic homeostasis in rats and is preferable to overnight starvation , 2000, Laboratory animals.

[24]  Michael L Lipton,et al.  Imaging devices for use in small animals. , 2011, Seminars in nuclear medicine.

[25]  Andreas Hess,et al.  On the use of α-chloralose for repeated BOLD fMRI measurements in rats , 2011, Journal of Neuroscience Methods.

[26]  S. Wolfensohn,et al.  Handbook of Laboratory Animal Management and Welfare , 1994 .

[27]  Xiaoping P. Hu,et al.  Comparison of alpha-chloralose, medetomidine and isoflurane anesthesia for functional connectivity mapping in the rat. , 2010, Magnetic resonance imaging.

[28]  K. Field,et al.  Anaesthetic effects of chloral hydrate, pentobarbitone and urethane in adult male rats , 1993, Laboratory animals.

[29]  J. Roughan,et al.  Evaluation of a short duration behaviour‐based post‐operative pain scoring system in rats , 2003, European journal of pain.

[30]  W. Smith Responses of laboratory animals to some injectable anaesthetics , 1993, Laboratory animals.

[31]  H. M. Swartz,et al.  The effects of ketamine–xylazine anesthesia on cerebral blood flow and oxygenation observed using nuclear magnetic resonance perfusion imaging and electron paramagnetic resonance oximetry , 2001, Brain Research.

[32]  P. Flecknell,et al.  Effects of repeated anaesthesia with ketamine/medetomidine and of pre-anaesthetic administration of buprenorphine in rats , 2000, Laboratory animals.

[33]  A. Nagy Manipulating the mouse embryo , 2013 .

[34]  A. Verkman,et al.  Analysis of organ physiology in transgenic mice. , 2000, American journal of physiology. Cell physiology.

[35]  R. Remie,et al.  Food deprivation: common sense or nonsense? , 1997 .

[36]  Joanne Tetens-Woodring,et al.  Safety and efficacy of various combinations of injectable anesthetics in BALB/c mice. , 2008, Journal of the American Association for Laboratory Animal Science : JAALAS.

[37]  Patrick L Chow,et al.  Monte carlo simulations of dose from microCT imaging procedures in a realistic mouse phantom. , 2005, Medical physics.

[38]  Z. Lee,et al.  Imaging Stem Cell Implant for Cellular-Based Therapies , 2008, Experimental biology and medicine.

[39]  A. S. Hall,et al.  Magnetic resonance for the anaesthetist , 1992, Anaesthesia.

[40]  O. Schober,et al.  Small animal PET in preclinical studies: opportunities and challenges. , 2008, The quarterly journal of nuclear medicine and molecular imaging : official publication of the Italian Association of Nuclear Medicine (AIMN) [and] the International Association of Radiopharmacology (IAR), [and] Section of the Society of....

[41]  Jann Hau,et al.  Handbook of Laboratory Animal Science , 2004 .

[42]  P. Flecknell,et al.  Laboratory animal anaesthesia , 1996 .

[43]  David Borsook,et al.  A role for fMRI in optimizing CNS drug development , 2006, Nature Reviews Drug Discovery.

[44]  D. Brodbelt,et al.  Arterial blood pressure monitoring in anesthetized animals. , 1997, Journal of the American Veterinary Medical Association.

[45]  M. Khalil,et al.  Molecular SPECT Imaging: An Overview , 2011, International journal of molecular imaging.

[46]  Aart J. Nederveen,et al.  Lasting effects of chronic fluoxetine treatment on the late developing rat brain: Age-dependent changes in the serotonergic neurotransmitter system assessed by pharmacological MRI , 2012, NeuroImage.

[47]  M Wright,et al.  Pharmacologic effects of ketamine and its use in veterinary medicine. , 1982, Journal of the American Veterinary Medical Association.

[48]  J. Hickson In vivo optical imaging: preclinical applications and considerations. , 2009, Urologic oncology.

[49]  R. L. Baldwin,et al.  Establishing an appropriate period of acclimatization following transportation of laboratory animals. , 2006, ILAR journal.

[50]  François Hallouard,et al.  Iodinated blood pool contrast media for preclinical X-ray imaging applications--a review. , 2010, Biomaterials.

[51]  A. Gozzi,et al.  A robust experimental protocol for pharmacological fMRI in rats and mice , 2012, Journal of Neuroscience Methods.

[52]  P. Cozzone,et al.  Cine-MRI assessment of cardiac function in mice anesthetized with ketamine/xylazine and isoflurane , 2004, Magnetic Resonance Materials in Physics, Biology and Medicine.

[53]  P. Pagel,et al.  Mechanism of Myocardial Protection by Isoflurane: Role of Adenosine Triphosphate‐regulated Potassium (K sub ATP) Channels , 1996, Anesthesiology.

[54]  D. Lovell Variation in pentobarbitone sleeping time in mice 2. Variables affecting test results , 1986, Laboratory animals.

[55]  Timothy Q Duong,et al.  Cerebral blood flow MRI in mice using the cardiac‐spin‐labeling technique , 2008, Magnetic resonance in medicine.

[56]  E. Melby,et al.  CRC handbook of laboratory animal science , 1974 .

[57]  P. Herrero,et al.  Measurement of input functions in rodents: challenges and solutions. , 2005, Nuclear medicine and biology.