Ketanserin Effects on Peripheral Temperature and Lactate (KoPTaL)

Ketanserin Effects on Peripheral Temperature and Lactate (KoPTaL)

A high blood lactate and a high peripheral to central temperature difference (deltaT) are associated with a higher mortality in critically ill patients. Both measures are signs of a reduced microcirculatory bloodflow or vasoconstriction and are associated with shock. It is unknown which medication can best be used to improve deltaT and lactate clearance.

Ketanserin is being used in the intensive care setting for decades to optimize circulatory parameters. Ketanserin is a serotonin type 2-receptor blocker (5-HT2). Blocking the 5-HT2 receptor with ketanserin can attenuate pathological vasoconstriction. In these ways ketanserin can reduce vasoconstriction and can improve the microcirculation. As a consequence, the enhanced blood flow in the skin will increase the peripheral temperature and decrease deltaT. At the same time an increased flow in the microcirculation may lead to a reduction in lactate production.

Objective:

To determine the effects of a continuous ketanserin infusion on peripheral temperature and lactate clearance in critically ill patients with either a high lactate or a high deltaT.

Study Overview

• Status: Unknown
• Conditions: Critical Illness
• Intervention / Treatment: Drug: Ketanserin; Other: Placebo

Detailed Description

Rationale:

A high blood lactate and a high peripheral to central temperature difference (deltaT) are associated with a higher mortality in critically ill patients. Both measures are signs of a reduced microcirculatory bloodflow or vasoconstriction and are associated with shock. On the other hand, it has not been shown yet that interventions leading to improvement of this temperature gap reduces mortality or improves any other outcome measurement. Moreover, it is unknown which medication can best be used to improve deltaT and lactate clearance.

Ketanserin is being used in the intensive care setting for decades to optimize circulatory parameters. Ketanserin is a serotonin type 2-receptor blocker (5-HT2). Blocking the 5-HT2 receptor with ketanserin can attenuate pathological vasoconstriction. In these ways ketanserin can reduce vasoconstriction and can improve the microcirculation. As a consequence, the enhanced blood flow in the skin will increase the peripheral temperature and decrease deltaT. At the same time an increased flow in the microcirculation may lead to a reduction in lactate production.

Objective:

To determine the effects of a continuous ketanserin infusion on peripheral temperature and lactate clearance in critically ill patients with either a high lactate or a high deltaT.

Study design:

A multicentre double blind randomized controlled trial.

Study population:

All adult intensive care patients above 17 years old with a deltaT of >6°C with informed consent given by the patient or legal representative.

Intervention (if applicable):

The intervention is a continuous pump driven Ketanserin infusion of 0.75 ug/kg/min for eight hours.

The control group will receive the same volume of glucose 5%.

Main study parameters/endpoints:

Change in DeltaT (measured per hour) Change in lactate (measured per 2 hours)

Nature and extent of the burden and risks associated with participation, benefit and group relatedness:

The risks of ketanserin infusion are limited but can be a QTc prolongation and a slight decrease in blood pressure. The study needs an arterial blood sample on inclusion, and after 2, 4, 6 and 8 hours of 1.5 ml each. In addition, a 6 ml blood sample at T=4 and T=8 hours.

• Study Type: Interventional
• Enrollment (Anticipated): 120
• Phase: Phase 4

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• DeltaTemperature greater that 6.0 °C.
• Age 18 years or older
• Admitted to the ICU for any reason
• Signed informed consent from the patient or legal representative

Exclusion Criteria:

• Pregnancy
• No possibility to obtain informed consent
• QTc above 550 msec,
• Arrhythmias, including bradycardia defined as a heart rate below 50/min; 2nd and 3rd degree AV block; ventricular tachycardia
• Blood Potassium level < 3.5 mmol/l
• Blood Magnesium level <0.5 mmol/l
• Allergy for ketanserin
• DeltaT less than 6°C.
• Patients undergoing therapeutic hypothermia
• Patients admitted after cardiac arrest
• Patients admitted after cardiac surgery

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ketanserin; Ketanserin is a serotonin type 2-receptor blocker (5-HT2). In normal endothelium, the 5-HT1 effects (vasodilation) are the most prominent [Dabire 1990]. In endothelium that is damaged, which is the case in sepsis, the 5HT2 effects (vasoconstriction) surpass the 5-HT1 effects. Blocking the 5-HT2 receptor with ketanserin can attenuate this pathological vasoconstriction. In addition, ketanserin has favourable α1-adrenergic blocking properties in the endothelium (vasodilation) that may further reverse the pathological vasoconstriction. In these ways ketanserin can reduce vasoconstriction and can improve the microcirculation.	Drug: Ketanserin; The dose of 0.75 ug/kg/min is a dose that has been used frequently in critically ill patients. The concentration of the study drug infusion will be 40 mg/40 ml glucose 5%. The maximum dose however will be 4.5 mg per hour for patients with a weight more than 100 kg. The pre-filled 50 ml syringes will be filled with 40 ml of a solution containing 40 mg ketanserin or 0 mg ketanserin in glucose 5%. The minimum number of ketanserin vials (2 ml with 5 mg/ml) that are needed is 240 (40 mg = 4 vials per patient). Duration of intervention: 8 hours
Placebo Comparator: Placebo; The placebo is a standard glucose 5% solution.	Other: Placebo; Glucose 5% solution

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Delta Temperature	Delta Temperature is calculated from the difference between central (rectal) and peripheral (forefoot) temperature	8 hours (after start of the study medication)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Lactate clearance	Lactate clearance is defined as :(Lactate (admission) - Lactate (8 hours))*100 / Lactate (admission) (Lactate (admission) - Lactate (8 hours))*100 / Lactate (admission) A lactate clearance of 10% or more is regarded as clinical relevant	8 hours (after start of the study medication
hospital length of stay	Length of stay hospital	6 months after start of study medication
mortality	mortality at hospital discharge	6 months after start of study medication
ICU length of stay	length of stay in the ICU	6 months after start of study medication
ICU mortality	mortality at ICU discharge	6 months after start of study medication

Collaborators and Investigators

• Sponsor: Onze Lieve Vrouwe Gasthuis
• Collaborators: Medical Centre Leeuwarden

Study record dates

Study Major Dates

• Study Start (Anticipated): September 1, 2018
• Primary Completion (Anticipated): April 1, 2019
• Study Completion (Anticipated): May 1, 2019

Study Registration Dates

• First Submitted: April 11, 2018
• First Submitted That Met QC Criteria: August 22, 2018
• First Posted (Actual): August 24, 2018

Study Record Updates

• Last Update Posted (Actual): August 24, 2018
• Last Update Submitted That Met QC Criteria: August 22, 2018
• Last Verified: August 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Critical Illness; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Platelet Aggregation Inhibitors; Serotonin Agents; Serotonin Antagonists; Ketanserin
• Other Study ID Numbers: WO 17.123 oost

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No