Combined Cardiopulmonary Assessments Using Impedance and Digital Implants in Conscious Freely Moving Cynomolgus Monkeys, Beagle Dogs, and Göttingen Minipigs: Pharmacological Characterization and Social Housing Effects

Abstract

Respiratory monitoring, using impedance with implanted telemetry in socially housed animals, was not possible until the recent development of digital signal transmission. The objective of this study was to evaluate digital telemetry monitoring of cardiopulmonary parameters (respiratory rate, tidal volume, minute volume, electrocardiography (DII), systemic arterial blood pressure, physical activity, and body temperature) in conscious, single-housed, non-rodent species commonly used in toxicology studies following administration of positive/negative controls (saline, dexmedetomidine, morphine, amphetamine, and doxapram), and also, the effects of various social housing arrangements in untreated female and/or male cynomolgus monkeys, Beagle dogs, and Göttingen minipigs (n = 4 per species). Aggressions were observed in socially housed male minipigs, however, which prevented pair-housed assessments in this species. All tested pharmacological agents significantly altered more than one organ system, highlighting important inter-organ dependencies when analyzing functional endpoints. Stress-related physiological changes were observed with single-housing or pair-housing with a new cage mate in cynomolgus monkeys and Beagle dogs, suggesting that stable social structures are preferable to limit variability, especially around dosing. Concomitant monitoring of cardiovascular and respiratory parameters from the same animals may help reduce the number of animals (3 Rs) needed to fulfill the S7A guidelines and allows for identification of organ system functional correlations. Globally, the data support the use of social housing in non-rodents for safety pharmacology multi-organ system (heart and lungs) monitoring investigations.

Effect of single housing on innate immune activation in SIV-infected pigtail macaques (Macaca nemestrina) as a model of psychosocial stress in acute HIV infection

“…It is important to note that, although numerous studies report positive behavioral outcomes from social housing of macaques, which is currently the standard for assessment of animal welfare, measurement of cortisol as a biomarker of stress has yielded highly inconsistent results (60,(63)(64)(65)(66). There are a number of factors that may contribute to this variability, including method and timing of measurement as well as the numerous physiological factors that affect cortisol levels (67)(68)(69).…”

Guidelines for assessment of cardiac electrophysiology and arrhythmias in small animals

“…Implantable telemetry allows researchers to assess HR, quantify standard ECG parameters, detect arrhythmias, and monitor other variables including body temperature, activity, arterial blood pressure, the electroencephalogram, the electromyogram, and respiration in a wide range of animal models, including rats and mice ( 156 , 178 – 185 ). A major advantage of telemetry is that physiological variables are measured in freely moving animals that behave normally in their cages, an important distinction from other in vivo measurements described later ( Acute In Vivo ECG Recording ).…”

“…Long-term ECG recordings allow for investigations of time as a biological variable, including studies of ECG changes during the light or dark cycle ( 186 ), biological time (i.e., the time relative to the start of the light) ( 187 ), or circadian time (time in constant conditions) ( 188 – 190 ). Telemetry can also be used to determine the impact that changes in the environment or behavior have on physiological variables ( 191 – 195 ), including temperature, activity, feeding, diet, and exposure to environmental compounds ( 185 , 196 ).…”

Blood Pressure Monitoring Through Radiotelemetry: Exploring the Viability of Its Application in Multihoused Small Laboratory Animals

“…It is important to integrate the measured signals with observations of behavior. For example, in large animals, feeding results in excitement and, hence, changes in heart rate and blood pressure, 9 while measurements repeated over time show consistent diurnal patterns. 14 This should be taken into account when setting up the measurements.…”

“…Also, changes in group composition were shown to affect behavior and cardiopulmonary function. 9 Both nonhuman primates and dogs showed signs of stress, such as increased respiration and heart rate when housed solitarily, 9 but also when exposed to a new cage mate, until the new hierarchy was established. Dogs were also more active when housed with a cage mate.…”