Continuous non-invasive hemodynamic assessment – adding essential value to pharmacological research projects
During the past decades the non-invasive continuous measurement of blood pressure and advanced vital parameters by means of a finger sensor has established itself as a useful and highly appreciated method in various research areas, as devices available on the market are easy to use, reliable and clinically validated. [>> publications]
Seamless information on the cardiovascular response of humans to specific interventions is of special interest in pharmacological research. There exists quite a range of studies in this area, where non-invasive technologies were used for the assessment and the evaluation of different pharmacological issues, especially related to the administration of drugs and medication control.
> Evaluating the tolerability, feasibility and safety of the administration of certain drugs
Hutson et al. performed a phase I study to evaluate the tolerability and safety of a gel formulation containing capsaicin, phenylephrine HCL and caffeine citrate in normal adult volunteers. Secondary objectives were to characterize the pharmacokinetics of the caffeine citrate formulation and the highest dose of phenylephrine needed to achieve a target increase in systolic blood pressure of at least 40 mmHg. The results suggested that the caffeine citrate drug mixture is well tolerated. The early increase in blood pressure within the first 15 minutes was mainly attributed to the oral pain associated with capsaicin, one of the hottest substances on earth. The late increase after up to 120 minutes was caused by phenylephrine and caffeine.1
Another study assessing the feasibility and safety of drugs was published by Fagermoen at al. who tested clonidine, an antihypertensive drug, in adolescents suffering from the chronic fatigue syndrome (CFS) by non-invasively and continuously measuring cardiovascular variables during tilt-testing. The results confirmed that clonidine seems to be safe enough to proceed from a pilot study to a controlled trial in a select group of adolescents with CFS. 2
> Evaluating efficacy and effects of drugs in different settings
Doering et al. assessed the efficacy profile of a natural pharmaceutical product for the treatment of sleep disorders and inner restlessness in an acute experimental stress setting. The study group investigated whether the medication could mitigate the individual perception of stress and reduce stress reaction. Subjective stress ratings as well as cardiovascular and neuroendocrine parameters were analyzed before and after stress exposure. The results suggest an alleviated response to neuroendocrine stress in healthy volunteers induced by the medication, but did not ease the subjective stress ratings. 3
Zgola et al. compared the hemodynamic effects of etomidate and propofol as well as electrical shock during ICD testing in a prospective, randomised trial. Hemodynamic parameters such as continuous blood pressure, stroke volume, cardiac output and total peripheral resistance were measured using non-invasive methods before and after injection of etomidate or propofol as well as immediately after internal defibrillation of ventricular fibrillation (VF). Propofol significantly decreased blood pressure by both reducing cardiac output and causing vasodilatation whereas etomidate only slightly decreased diastolic and mean blood pressure without affecting other parameters. Induction of VF and internal defibrillation did not cause clinically significant changes apart from very modest drops in diastolic and mean blood pressure values. 4
Bendixen et al. investigated the effect of a single dose of the non-selective β-adrenergic receptor antagonist propranolol on hypertonic saline-evoked masseter muscle pain and autonomic activity during rest and during a mental arithmetic task in comparison to a placebo group. Hypertonic saline-evoked pain intensity was scored on a numeric rating scale (NRS) while heart rate variability and hemodynamic measures were recorded non-invasively. Propranolol did not reduce NRS pain scores compared with placebo but did induce significant autonomic changes with reduced heart rate and increased heart rate variability independent of the mental task. 5
Beat-to-beat heart rate (HR), blood pressure (BP), and cardiac hemodynamics were recorded using non-invasive techniques and stroke volume modelling by Sheldon et al., for testing the hypothesis that atomoxetine, a highly selective norepinephrine transporter inhibitor, prevents tilt-induced syncope. Atomoxetine significantly decreased the risk of tilt-induced syncope in vasovagal syncope subjects. Hemodynamic monitoring showed that atomoxetine decreased terminal reflex bradycardia, thereby preventing final falls in cardiac index and blood pressure, normally associated with presyncope or syncope. 6
> Evaluating the achievement of a targeted hemodynamic value or other outcome
Melik et al. determined whether the dietary supplement L-arginine improves the endothelial function of microvessels by increasing nitric oxide production, which is a vasodilator to relax and widen the blood vessels. Noninvasive hemodynamic measurement was used to assess heart rate, blood pressure and cardiac output. The results demonstrated that a single dose of L-arginine influences endothelium-dependent vasodilation predominantly in young, trained individuals. Heart rate and cardiac output decreased after L-arginine administration, whereas blood pressure did not change. 7
Nomoto et al. compared the effects of two different blood sugar lowering agents in type 2 diabetes patients on the glycemic status and on the endothelial cell function, which is important for the prevention and improvement of atherosclerosis, a common risk factor associated with cardiovascular events in this patient group. Drugs such as GLP-1 analogues have been approved not only to improve glycemic control, but also to have protective impact on atherosclerosis. A comprehensive panel of hemodynamic parameters and serum metabolic markers were assessed before and after the treatment period. The results showed that sitagliptin had a favorable anti-inflammatory effect and positive effects on lipid metabolism compared with glimepiride, while effects on endothelial function did not differ between groups. 8
> Evaluating patient-specific effects of a drug on hemodynamics
A further example for evaluating the effect of drug administration on hemodynamics is the study by Matsumoto et al. who monitored cardiac output and cardiac index using a noninvasive impedance cardiac output monitor in electroconvulsive therapy patients. The study group investigated the relationships between cardiac output values before succinylcholine chloride administration and the onset of succinylcholine chloride action to find the appropriate interval between administration and electrical stimulation. Results showed that “the onset of muscle relaxation varies among patients receiving in electroconvulsive therapy and is related to cardiac index before succinylcholine chloride administration.” 9
> Value of continuous hemodynamic assessment in pharmacological research
It is obvious that rapid changes in blood pressure and hemodynamics might be missed by intermittent methods, such as oscillometric NBP upper arm measurement.10
On the other hand, continuous hemodynamic measurement, including cardiac output, is readily available non-invasively which enables researchers to assess the complex impact of drugs on patients by showing them the complete hemodynamic picture.
Without non-invasive continuous measurements, the listed pharmacological effects could not be observed in sufficient detail, so the devices significantly contribute to the investigation of new drugs in different settings and the identification of the necessary dosages. In addition to basic research, the devices also offer the possibility of patient-specific treatment. 9
References:
- Hutson, P. et al. Safety, Pharmacokinetic, and Pharmacodynamic Study of a Sublingual Formula for the Treatment of Vasovagal Syncope. Drugs R. D. (2022) doi:10.1007/s40268-021-00378-9.
- Fagermoen, E; Sulheim, D; Winger, A. W. et al. Clonidine in the treatment of adolescent chronic fatigue syndrome: a pilot study for the NorCAPITAL trial. BMC Res. Notes 5, 418 (2012).
- Doering, B. K. et al. Effects of Neurexan ® in an experimental acute stress setting – An explorative double-blind study in healthy volunteers. Life Sci. 146, 139–47 (2016).
- Zgoła, K. et al. Hemodynamic effects of etomidate, propofol and electrical shock in patients undergoing implantable cardioverter-defibrillator testing. Kardiol. Pol. 72, 707–715 (2014).
- Haugaard Bendixen, K., Juhl Terkelsen, A., Baad-Hansen, L., Cairns, B. E. & Svensson, P. Effect of Propranolol on Hypertonic Saline-Evoked Masseter Muscle Pain and Autonomic Response in Healthy Women During Rest and Mental Arithmetic Task. J. Orofac. Pain 7, 243–255 (2013).
- Sheldon, R. S. et al. A proof of principle study of atomoxetine for the prevention of vasovagal syncope: the Prevention of Syncope Trial VI. EP Eur. (2019) doi:10.1093/europace/euz250.
- Melik, Z., Zaletel, P., Virtic, T. & Cankar, K. L-arginine as dietary supplement for improving microvascular function. Clin. Hemorheol. Microcirc. 65, 205–217 (2017).
- Nomoto, H. et al. A Randomized Controlled Trial Comparing the Effects of Sitagliptin and Glimepiride on Endothelial Function and Metabolic Parameters: Sapporo Athero-Incretin Study 1 (SAIS1). PLoS One 11, e0164255 (2016).
- Matsumoto, N. et al. Relationship Between Cardiac Output and Onset of Succinylcholine Chloride Action in Electroconvulsive Therapy Patients. J. ECT 25, 246–249 (2009).
- Wagner, J. Y. et al. Noninvasive continuous versus intermittent arterial pressure monitoring: evaluation of the vascular unloading technique (CNAP device) in the emergency department. Scand. J. Trauma. Resusc. Emerg. Med. 22, 8 (2014).
