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Ketanserin Effects on Peripheral Temperature and Lactate (KoPTaL)

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ClinicalTrials.gov Identifier: NCT03646318
Recruitment Status : Not yet recruiting
First Posted : August 24, 2018
Last Update Posted : August 24, 2018
Sponsor:
Collaborator:
Medical Centre Leeuwarden
Information provided by (Responsible Party):
PHJ van der Voort, Onze Lieve Vrouwe Gasthuis

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Critical Illness Drug: Ketanserin Other: Placebo Phase 4

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 120 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Randomised controlled trial (blinded)
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Placebo medication
Primary Purpose: Treatment
Official Title: Ketanserin Effects on Peripheral Temperature and Lactate (KoPTaL)
Estimated Study Start Date : September 1, 2018
Estimated Primary Completion Date : April 1, 2019
Estimated Study Completion Date : May 1, 2019

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




Primary Outcome Measures :
  1. Delta Temperature [ Time Frame: 8 hours (after start of the study medication) ]
    Delta Temperature is calculated from the difference between central (rectal) and peripheral (forefoot) temperature


Secondary Outcome Measures :
  1. Lactate clearance [ Time Frame: 8 hours (after start of the study medication ]
    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

  2. hospital length of stay [ Time Frame: 6 months after start of study medication ]
    Length of stay hospital

  3. mortality [ Time Frame: 6 months after start of study medication ]
    mortality at hospital discharge

  4. ICU length of stay [ Time Frame: 6 months after start of study medication ]
    length of stay in the ICU

  5. ICU mortality [ Time Frame: 6 months after start of study medication ]
    mortality at ICU discharge



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

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Responsible Party: PHJ van der Voort, Prof. dr. P. H. J. van der Voort, Onze Lieve Vrouwe Gasthuis
ClinicalTrials.gov Identifier: NCT03646318     History of Changes
Other Study ID Numbers: WO 17.123 oost
First Posted: August 24, 2018    Key Record Dates
Last Update Posted: August 24, 2018
Last Verified: August 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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

Additional relevant MeSH terms:
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Critical Illness
Disease Attributes
Pathologic Processes
Ketanserin
Antihypertensive Agents
Platelet Aggregation Inhibitors
Serotonin Antagonists
Serotonin Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs