Original ContributionEffects of alfaxalone on cerebral blood flow and intrinsic neural activity of rhesus monkeys: A comparison study with ketamine
Introduction
Alfaxalone is a synthetic neuroactive steroid anesthetic and has been used as an induction and maintenance agent for anesthesia of large animals [1]. Alfaxalone-2-hydroxpropyl-β-cyclodextrin (Alfaxalone-HPCD) is its newest formulation and was approved by FDA for use in dogs and cats in the United States in 2012 [2]. Alfaxalone produces satisfactory induction and maintenance of anesthesia such as onset of anesthesia, fast redistribution, short elimination half-life, short duration of action [3], no cardiovascular depression at clinical doses [4,5], and a lower frequency of apnea [6]. In recent years, alfaloxone has been increasingly used in horses [7], dogs [1], pigs [8], cats [3,9], and non-human primates (NHPs) [[10], [11], [12]], suggesting alfaloxone has the potential to become an alternative anesthetic for induction and maintenance anesthesia of large animals. However, alfaxalone's effects on the cerebral blood flow (CBF) physiology and neural activity of large animals remain poorly understood.
CBF quantifies the blood supply to the brain and is highly coupled to brain metabolism and functionality [[13], [14], [15], [16]]. Several non-invasive perfusion MRI techniques can be used to perform quantitative CBF measurement in large animals like macaque monkeys non-invasively [17], and examine the effects of anesthesia on CBF and autoregulation of large animals [18,19]. In addition, resting state functional MRI (rsfMRI) can detect the intrinsic neural activity in the brain and has been widely used to examine the functional connectivity in the brain [20,21] and anesthetized subjects [12,[22], [23], [24]]. Both CBF and rsfMRI techniques are robust and non-invasive approaches to investigate the effects of anesthesia on the brain physiology and functionality in animals and human subjects [16,[25], [26], [27], [28], [29]].
Large animals (like pigs, dogs, rabbits, cats, and NHPs, et al.) are usually required to be sedated for performing invasive procedures or non-invasive imaging scans in biomedical and neuroscience research. As a popular practice in neuroimaging study, the animals are firstly knocked down with an induction agent (like ketamine) and then maintained with inhalational anesthesia (such as isoflurane) for the entire duration of scan session. The anesthesia effects of ketamine and isoflurane on the CBF and neural functionality of the brain have been explored extensively in previous studies [15,19,25,[30], [31], [32], [33], [34], [35]], demonstrating the CBF and neural functionality could be dramatically affected by applied anesthetics in a dose- and duration-related manner. We hypothesized the CBF and neural activity of the brain could be affected by alfaloxone when it is used alone or as an induction agent in veterinary anesthesia of large animals. In the present study, the anesthesia effects of alfaloxone on the CBF and intrinsic neural functionality were investigated using macaque monkeys and compared with the effects of ketamine.
Section snippets
Methods and materials
Healthy female rhesus monkeys (n = 4, 11–15 years old) were employed in the present study. Alfaxalone (Alfaxan, Jurox, MO, USA) was given initially via intramuscular injection (induction, 5 mg/kg) followed by intravenous infusion (0.125 mg/kg/min) for about 50 min during MRI scanning. Then the anesthetic was switched to isoflurane (~0.8% with 100% Oxygen) (IsoThesia, Henry Schein Animal Health, NY, USA) to keep the animal sedated continuously until the end of each scan session (for about one
Results
The temporal changes of mean arterial pressure (MAP) and HR of monkeys during the entire scanning session were examined and illustrated in Fig. 2. No significant MAP change was seen during the entire period of alfaxalone infusion. Continuous reduction of MAP was observed during ketamine and following isoflurane administration. The MAP was always reduced after the anesthetic (alfaxalone or ketamine) was switched to isoflurane. No significant changes of breathing rates were seen in any scenario
Discussion
Alfaxalone has been increasingly used as induction agent or used alone for general anesthesia of large animals in recent years. Our results indicated that alfaxalone had evident suppression effect on CBF compared to ketamine (and isoflurane) and showed comparable suppressive effects on the intrinsic neural activity with ketamine. In particular, alfaxalone resulted in more stable physiological measures when used alone or as induction agent. Also, alfaxalone's residual effect on CBF of the monkey
Conclusion
The present study revealed alfaxalone's effects on CBF physiology and intrinsic neural activities of monkeys when used alone or as induction agent for inhalational anesthesia. The findings suggest alfaxalone can be a good alternative to veterinary anesthesia in biomedical research and neuroimaging study of brain physiology and functionality. As large animals (such as pigs and non-human primates) are increasingly used for study of neurodegenerative diseases (like stroke, traumatic brain injury
Author statement
Li: Investigation, data processing and analysis, draft preparation and writing; Kempf: experimental design, investigation; Howell: conceptualization, supervision; Zhang: experimental design, conceptualization, editing, supervision.
Declaration of Competing Interest
The authors have no conflict of interest to disclose.
Acknowledgements
The authors are grateful to Sudeep Patel and Ruth Connelly for assistance in data acquisition and animal handling, and the Center for Magnetic Resonance Research (CMRR) of University of Minnesota for sharing the multiband EPI pulse sequence with us. The project is supported by the Office of Research Infrastructure Programs (OD P51OD011132).
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