The Effect of Phenylephrine and Ephedrine on Microvascular Blood Flow

Study Overview
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Brief Summary
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During operations to treat abdominal problems the blood pressure can fall, resulting in falls in blood flow to the vital organs. This fall can be treated by the administration of drugs that cause constriction of blood vessels. Although these drugs correct falls in blood pressure, it is unclear what effect they have on blood flow from the heart and to the vital organs. In this study of healthy volunteers we aim to better understand the changes in blood flow in both small and large vessels that occur in response to administration of these drugs. To do this we will use two different techniques of ultrasound imaging. A narrow (4-5mm) ultrasound probe will be inserted into the oesophagus via a nostril to measure blood flow in a major blood vessel. A second probe will rest on the abdomen and will record changes in blood flow in small vessels of the liver. Two drugs which raise the blood pressure via different mechanisms will be administered and the changes in flow from the heart and to vital organs will be measured and compared.

Detailed Description
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Optimising the cardiac output is essential to ensure adequate organ perfusion in patients who are undergoing major surgery. To enable this cardiac output (CO) is frequently monitored during operations using a variety of techniques; one such technique is trans-oesophageal Doppler ultrasound also known as oesophageal Doppler monitoring (ODM). ODM measurement of CO is a less invasive technique than many currently used methods, and has recently been recommended by NICE for adoption in clinical practice. The matching of microvascular blood flow and CO is advantageous for visceral organs, in marrying demands for oxygen and nutrients to their delivery. Major surgery and the attendant requirement for general anaesthesia can result in dramatic changes in blood pressure (BP) and CO. These changes can be corrected by the administration of vasoactive drugs such as phenylephrine and ephedrine, although it is unclear what effects these drugs have on microvascular blood flow (MVBF) to the intra-abdominal viscera. Whilst they correct falls in BP, and hence may increase visceral flow, this increased BP is partially mediated via splanchnic vasoconstriction, which may result in decreased blood flow. A greater appreciation of the effect of these vasoactive drugs on the CO and MVBF may help with the development of more refined algorithms for their use in the clinical setting. In our clinical physiology laboratories we regularly employ contrast-enhanced ultrasound (CEUS) using a Phillips iU22, to measure MVBF in healthy males following a variety of physiological challenges. This minimally invasive ultrasound based imaging technique is ideal for gaining an insight into the effect various physiological interventions have on tissue blood flow and could be readily used to chart changes in visceral MVBF and CO following vasoactive drug administration. Transference of this investigative approach to a clinical setting has the potential to greatly improve the care of the surgical patient under anaesthesia.

Official Title
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An Observational Study to Test the Effect of the Vasoactive Drugs Phenylephrine and Ephedrine on the Stroke Volume and Microvascular Blood Flow of Healthy Volunteers

Conditions
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Healthy Volunteers

Intervention / Treatment
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* Drug: Administration of phenylephrine
* Other: Measurement of stroke volume
* Other: Contrast enhanced ultrasound scan
* Drug: Administration of ephedrine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged 18-60 years Male Able to consent in English by themselves Absence of any exclusion criteria Exclusion Criteria: A BMI < 20 or > 28 kg•m2 Active cardiovascular disease: uncontrolled hypertension (BP > 140/90), angina, heart failure (class III/IV), arthymia, right to left cardiac shunt or recent cardiac event Individuals taking alpha or beta-adrenergic blocking agents, monoamine oxidase inhibitors, tricyclic antidepressants, serotonin or noradrenaline selective reuptake inhibitors, quinidine, cardiac glycosides or buspirone (or who have ceased taking them in the previous 14 days¬) Cerebrovascular disease: previous stroke, aneurysm (large vessel or intracranial) Peripheral vascular disease Metabolic disease: hyper and hypo parathyroidism, untreated hyper and hypothyroidism, Cushing's disease, types 1 or 2 diabetes Active inflammatory bowel disease, or renal disease Known prostatic hypertrophy Malignancy Clotting dysfunction Previous oesophageal surgery Individuals with a known history of oesophageal varices Individuals with a known history of epistaxis Family history of early (<55y) death from cardiovascular disease Known sensitivity to SonoVue, ephedrine or phenylephrine Participants who have taken part in any other research study in the last three months which involved: taking a drug; being paid a disturbance allowance; having an invasive procedure (eg blood sample >50ml, muscle biopsies) or exposure to ionising radiation.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Group 1<br>Healthy volunteers | Drug: Administration of phenylephrine<br>* Intravenous phenylephrine will be administered in 50-100 microgram increments until the mean arterial blood pressure has increased by 25% compared to baseline, or until a maximum dose of 1mg has been administered.<br>Other: Measurement of stroke volume<br>* The measurement of stroke volume will be performed using an Oesophageal Doppler Monitor<br>Other: Contrast enhanced ultrasound scan<br>* Microvascular blood flow will be measured using a contrast enhanced ultrasound scan<br>Drug: Administration of ephedrine<br>* Intravenous ephedrine will be administered in 3-6mg increments until the mean arterial blood pressure has increased by 25% compared to baseline, or until a maximum dose of 30mg has been administered.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in microvascular blood flow | Microvascular visceral blood flow is assessed using contrast enhanced ultrasound, and will be assessed before and after the administration of each drug. | 30 minutes | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in stroke volume | The change in stroke volume will be assessed using an Oesophageal Doppler Monitor, and will be assessed before and after the administration of each drug. | 30 mins |