Vasopressor Effects in Anesthetized Patients

Sponsor

University of Aarhus (Other)

Overall Status

Completed

CT.gov ID

NCT02713087

Collaborator

(none)

Enrollment

Location

Arms

Duration (Months)

1.8

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Project title: Influence of Vasopressors on Brain Oxygenation and Microcirculation in Anesthetized Patients with Cerebral Tumors

Sponsor-investigator: Klaus Ulrik Koch M.D.

Sponsor: Department of Anesthesia Aarhus University Hospital, Nørrebrogade 44, 8000 Aarhus C, Denmark

Objective:

To investigate whether phenylephrine and ephedrine causes different alterations in microcirculation and oxygenation, as measured with MRI and PET, in anesthetized patients with brain tumors. Using MRI and PET, the study will assess whether there is a difference in deoxyhemoglobin concentration (Bold signal), CTTH, cerebral blood flow (CBF) and cerebral metabolic rate of oxygen (CMRO2) between ephedrine and phenylephrine

Method:

Double blinded controlled randomized clinical trial. Either phenylephrine or ephedrine are infused intravenously under general anesthesia. MRI is performed in 20 patients before and after infusion. PET/CT is performed in 20 patients before and after infusion. BIS and NIRS monitoring will be used in either scanner. After scanning patients are transported to the operating theatre and the craniotomy is performed. After removal of the bone flap subdural ICP is measured and recorded.

MRI to analyze CBF, CTH, max.CMRO2, maxOEF, CBV and grey-scale ADC before and after ephedrine and phenylephrine. PET/CT to analyze CBF and CMRO2 before and after ephedrine and phenylephrine and calculation of OEF. During each PET/CT scan session oxygen saturation and hemoglobin concentration is measured.

Data from the proposed studies will add substantial new knowledge to the investigators current understanding of the effects of vasopressors on cerebral circulation. This information will aid the neuroanesthesiologist, neurointensivist and the neurosurgeon in the choice of the optimal method to manage cerebral perfusion pressure during craniotomy for brain tumor.

Condition or Disease	Intervention/Treatment	Phase
Brain Tumor	Drug: Ephedrine Drug: Phenylephrine	Phase 4

Detailed Description

Background:

During brain tumor surgery the main objective for the neuroanesthesiologist is to maintain a low intracranial pressure (ICP) and a sufficient cerebral perfusion pressure (CPP) (CPP = mean arterial blood pressure [MABP] - ICP) to ensure adequate cerebral oxygenation. Brain tumors are often associated with edema and increased ICP and a specific recommendation for CPP thresholds during brain tumor surgery does not exist. In daily practice vasopressors are used to increase MABP to maintain a CPP between 50-70 mmHg in accordance with current guidelines for management of patients with traumatic brain pathology.

However, recent studies show that arterial blood pressure correlates only poorly with microcirculatory flow. Elevation of blood pressure may result in reduced capillary perfusion and oxygen delivery despite reaching resuscitation end-points with CPP within 50-70 mmHg. This is supported by an experimental study demonstrating vasopressor-induced mismatch between cerebral perfusion and oxygenation, possibly due to microvascular heterogeneity, as suggested by the authors. In addition, recent studies in healthy anesthetized subjects demonstrate that, despite an increase in MABP, cerebral oxygenation simultaneously decreases after phenylephrine but remains unchanged after administration of ephedrine. Thus, increasing CPP with vasopressors may lead to paradoxical microcirculatory response with vasopressor-induced tissue hypo-perfusion and hindered tissue oxygenation.

Brain microcirculation is the primary site of oxygen exchange. The investigators have recently proposed that red blood cell capillary transit time heterogeneity (CTTH) may affect tissue oxygen tension in patients with ischemic stroke, subarachnoid hemorrhage and traumatic brain injury. According to this theory capillary compression due to edema and elevated ICP may cause redistribution of capillary flows into patterns with functional shunting of oxygenated blood through the cerebral capillary bed. This capillary dysfunction may further hinder oxygen diffusion into cerebral tissue and ultimately cause cerebral ischemic damage. The dissimilar effects of phenylephrine and ephedrine on cerebral oxygenation may be caused by a different influence on brain capillary perfusion or alternated CTTH. Currently there are no studies available on the effects of commonly used vasopressors on brain microcirculation and oxygenation in patients undergoing craniotomy for brain tumors.

Hypothesis:

The use of phenylephrine is associated with a reduction in brain oxygenation and microcirculation compared to ephedrine in anesthetized patients with brain tumors.

Specifically the investigators hypothesize that:

In peritumoral areas phenylephrine is associated with a local increase in CBF, increased CTTH, decreased oxygen extraction fraction and increase in the BOLD signal compared to ephedrine
Phenylephrine is associated with a reduction in oxygen extraction fraction (OEF) compared to ephedrine

Materials and methods:

Overall Study design:

Double blinded controlled randomized clinical trial.

Studies:

Study 1 (MRI study). 20 patients are randomized to infusion of either ephedrine or phenylephrine until MAP >60 mmHg

Study 2 (PET study). 20 patients are randomized to infusion of either ephedrine or phenylephrine until MAP >60mmHg

MRI and PET measurements are performed after induction of general anesthesia with propofol and remifentanil. The MRI or PET sequence is then performed before administration of study-drug and again after the infusion of either phenylephrine or ephedrine results in MAP > 60mmHg. Depth of anesthesia is monitored with BIS in both studies to ensure equal level of anesthetic depth in the two groups. NIRS is monitored in both studies to compare measurements of brain oxygenation determined by PET/CT. NIRS measurements are not possible during MR scan and will be measured either before or after the scan. BIS and NIRS are registered in each patients case report form (CRF). After the MRI/PET study the patient is transported to the operating theatre and the craniotomy is performed. After removal of the bone-flap, subdural ICP is measured and recorded as previously described.

The overall experimental setup is the same for the two studies. The patient is anesthetized and MRI or PET is performed before and after administration of a study-drug. The specific MRI and PET protocols are mentioned below

MRI protocol
Conventional MRI sequences on a high quality research scanner
Diffusion-weighted MRI incl. diffusion kurtosis imaging
Perfusion-weighted MRI before and after ephedrine or phenylephrine, respectively
The duration of the entire MRI scan is estimated to 60 min. Two and a half standard doses of gadolinium MRI contrast are administered ( 0.25 mmol/kg).
PET protocol
Cerebral Blood Flow (CBF): 500 MBq of [15O]H2O is injected intravenously. At injection a three minute PET image acquisition of the brain is started together with arterial blood sampling (also three minutes) with an automated blood radioactivity sampler that draws 7 ml blood per minute. The PET acquisition is done on a Siemens High Resolution Research Tomograph (HRRT) in list mode.
Cerebral Metabolic Rate of Oxygen (CMRO2): 1000 MBq of [15O]O2 is inhaled and immediately exhaled. At inhalation PET acquisition and blood sampling are performed with protocols identical to CBF.
During each scan session oxygen saturation and haemoglobin concentration will be measured.

Physiological parameters (blood pressure and ICP) are documented in the CRF corresponding to each patient. BIS and NIRS data are stored on a portable computer and subjected to offline analysis. Parametric and non-parametric statistics will be used to compare MRI and PET. Physiological data will be recorded during stimulation with study-drugs. The sample size is based on previous publications where a MRI protocol was performed before and after drug administration in anesthetized patients. The exact form of applied statistics are not yet decided. This kind of study with new parameters from MRI and PET has never been done and statistical help will be consulted along the process.

Perspectives:

Data from the proposed studies will add to the investigators understanding of the cerebral microcirculation and its importance for brain oxygenation in patients of different age and comorbidity. Meanwhile, the study will provide new insights into the effects of vasopressors on the cerebral circulation. The study will thus provide direct observations for the investigators recent efforts to understand the role of the microcirculation in neurological disorders, and help the investigators chose the optimal method to manage CPP during craniotomy for brain tumor.

These insights may have implications for the future management of increased intracranial pressure and CPP after TBI and SAH.

Applicant´s part in the research:

Applicant Klaus Ulrik Koch is sponsor-investigator on this study and the responsible person of finishing the PhD thesis.

Study Design

Study Type:

Interventional

Actual Enrollment :

48 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Triple (Participant, Care Provider, Investigator)

Primary Purpose:

Treatment

Official Title:

Influence of Vasopressors on Brain Oxygenation and Microcirculation in Anesthetized Patients With Cerebral Tumors

Study Start Date :

Sep 1, 2015

Actual Primary Completion Date :

Nov 1, 2017

Actual Study Completion Date :

Nov 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Ephedrine	Drug: Ephedrine Infusion of Ephedrine 2mg/ml until MAP above 60 mmHg or until MAP has raised 20%
Active Comparator: Phenylephrine	Drug: Phenylephrine Infusion of Phenylephrine 0,1mg/ml until MAP above 60 mmHg or until MAP has raised 20%

Arm

Intervention/Treatment

Active Comparator: Ephedrine

Drug: Ephedrine

Infusion of Ephedrine 2mg/ml until MAP above 60 mmHg or until MAP has raised 20%

Active Comparator: Phenylephrine

Drug: Phenylephrine

Infusion of Phenylephrine 0,1mg/ml until MAP above 60 mmHg or until MAP has raised 20%

Outcome Measures

Primary Outcome Measures

Capillary Transit Time Heterogeneity [4 Years]

Secondary Outcome Measures

Cerebral Metabolic Rate of Oxygen [4 Years]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Patients scheduled for supine-positioned elective craniotomy for supratentorial malignant and non-malignant brain tumors 3 cm or larger (measured as the largest diameter in any plane on MR images)
ASA (American Society of Anesthesiologist) status 1-3 (27)
Written informed consent from participating patients

Exclusion Criteria:

Age younger than 18 yrs. or older than 75 yrs.
Pregnancy or nursing (negative pregnancy blood test)
History of allergic reactions to phenylephrine or ephedrine
eGFR < 60ml/min/1.73m2

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Aarhus University Hospital	Aarhus	Jylland	Denmark	8000

Sponsors and Collaborators

University of Aarhus

Investigators

Study Director: Leif Oestergaard, Professor, University of Aarhus

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

Publications

Responsible Party:

University of Aarhus

ClinicalTrials.gov Identifier:

NCT02713087

Other Study ID Numbers:

Vasobrain01

First Posted:

Mar 18, 2016

Last Update Posted:

Oct 26, 2018

Last Verified:

Oct 1, 2016

Individual Participant Data (IPD) Sharing Statement:

Plan to Share IPD:

Additional relevant MeSH terms:

Study Results

No Results Posted as of Oct 26, 2018