High definition oscillometry (HDO): A novel method for non-invasive blood pressure measurements in cynomolgus monkeys

Cynomolgus monkeys are commonly used in toxicological research including the determination of drug effects on the cardiovascular system. Accurate and reproducible determination of blood pressure (BP) in conscious, manually restrained or chemically restrained animals is a challenge with current non-invasive cuff techniques. The HDO (high-definition oscillometry) technique enables real time measurements that are visible on a computer screen for immediate determination if the measurement is valid. Further, the HDO measurement is considerably faster (up to15 seconds) than other cuff methods. Measurements taken with HDO and were compared for accuracy and reliability with simultaneously recorded direct blood pressure data from telemetry implants. Six animals, implanted with a telemetry transmitter, were used and data were compared under manual constraint, with or without administration of a BP lowering drug (hexamethonium bromide) or ketamine sedation. For each animal, systolic, diastolic, mean arterial pressure, and pulse rate (PR; HDO and Telemetry only) were determined. Simple linear regression revealed substantially larger R2 values for HDO-Telemetry than Cardell-Telemetry comparisons. R2 values were up to 0.69 for HDO and up to 0.15 for Cardell for BP data. For PR, R2 values were up to 0.98 for HDO. In conclusion, HDO data revealed a close correlation with telemetry data indicating that this novel, non-invasive technique produces reliable blood pressure data in manually or chemically restrained monkeys for a wide blood pressure range. Introduction This study was designed to evaluate the use of the Memo Diagnostic equipment, which is based on the high-definition oscillometry technique (HDO) for blood pressure measurement in nonhuman primates for future toxicology studies. This novel technique allows real time visualizing of measurements and immediate determination if a measurement was valid and artifact-free (Figures 1A and 1B). Blood pressure measurements were taken using HDO or the Cardell BP Monitor Model 9401 to evaluate accuracy and reliability when compared with the “gold standard”, telemetry implants. Blood pressure measurement data were taken from conscious, manually restrained animals, ketamine sedated animals, and from conscious animals with and without a blood pressure lowering drug (hexamethonium bromide). Figure 1A. Valid BP measurement; SYS and DIA are marked in blue. Figure 1B. Invalid BP measurement; a moving artifact occurred during SYS. High-Definition Oscillometry (HDO): A Novel Method for Non-Invasive Blood Pressure Measurements in Cynomolgus Monkeys Andrea Mitchell1, Tom Cleven1, Beate Egner2 and R. Dustan Sarazan1 1Covance Laboratories Inc., Madison, Wisconsin; 2S+B medVet GmbH, Babenhausen, Germany Material and Methods Study A To evaluate intraand inter-run precision and inter-staff robustness for the HDO method, two investigators measured 6 animals in block order. Cuff measurements, taken on the tail root, were compared with simultaneously recorded telemetry data. No. of Animals Investigators Method 3 Males and 3 Females 2 HDO versus Telemetry Intra-Run Precision Blood pressure/pulse rate was measured in triplicate by the same investigator from all animals. Inter-Run Precision Three triplicate measurements (9 readings) were performed by the same investigator from all animals. Inter-Staff Robustness Three triplicate measurements (9 readings) were performed by two different investigators from all animals. Study B Blood pressure measurements were obtained from ketamine (10 mg/kg i.m.) sedated animals by telemetry, with the Cardell, and with the HDO cuff on the tail root. Cuff measurements were compared with simultaneously recorded telemetry data. No. of Animals Investigators Method 3 Males and 3 Females 1 Covance standard and HDO versus Telemetry Study C Blood pressure measurements were obtained from conscious, manually restrained animals with the Cardell and with the HDO cuff on the tail root with alternating measurements. Both cuff measurements were compared with simultaneously recorded telemetry data before, during, and after administration of hexamethonium bromide. Individual doses of hexamethonium ranged between 2.9 and 10 mg/kg i.v. until a substantial drop in BP was observed. No. of Animals Dose (3 Males and 3 Dose Level a Concentration Group Females per Group) (mL/kg/dose) (mg/mL) Method 1 (Control) b 6 0 0 Cardell and HDO versus Telemetry 2 (Hexamethonium) 6c up to 10 1 Cardell and HDO versus Telemetry a Animals were dosed at a volume of up to 10 mL/kg over an approximately 5-minute period. b The control group received 0.9% saline. c The same animals as in Group 1 were used but on a different day. Data Analysis Telemetry parameters (SYS, DIA, MAP, PR) were evaluated using the DSI-PONEMAH software. For all phases, Bland and Altman plots as well as regression plots were generated for the hemodynamic data. The hemodynamic data were also analyzed by factorial analysis of variance techniques with repeated measures (where appropriate). For the post hoc analyses, where applicable, the method comparisons (Telemetry versus Cardell method or HDO method) were evaluated by Dunnett-Hsu adjusted t-test at the 5.0%, two-tailed probability level when indicated by a significant method effect. Results were reported as significant at the 5 or 1% significance level, where applicable. A significance level of p < 0.05 was used for the actual evaluation of the data. All analyses were performed using the SAS System (2003). Results and Discussion Study A Intraand inter-run precision results revealed that individual subsequent measurements taken by the same investigator were reproducible and not significantly different. Inter-staff robustness analysis showed that measurements taken by different investigators on the same animal were comparable with each other indicating that the person handling the equipment per se did not alter the measurement process and that reliable and reproducible blood pressure and pulse rate values could be obtained. Study B HDO data collected during Ketamine anesthesia revealed a closer correlation with telemetry data than Cardell data using simple linear regression for DIA and MAP, while the correlation for SYS was similar for both cuff methods. R2 values for HDO were up to 0.41 and for Cardell up to 0.13. For PR, the regression plot for telemetry and HDO revealed a R2 value of 0.98. Examples for collected data in one animal are depicted in Figures 2A through 2D. Figures 2A, B, C, D. Ketamine was injected i.m. after the second reading. Study C HDO data collected during hexamethonium-induced decrease in BP revealed a closer correlation with telemetry data than Cardell data using simple linear regression for SYS, DIA and MAP. R2 values for HDO were up to 0.69 and for Cardell up to 0.07. For PR, the regression plot for telemetry and HDO revealed a R2 value of 0.89. Examples for collected data in one animal are depicted in Figures 3A through 3D. Figures 3A, B, C, D. Hexamethonium was injected i.v. after the second reading.