A Phase 4 interventional study of Ephedrine and Phenylephrine in Brain Tumor, sponsored by University of Aarhus. Completed at 1 site in Denmark. Open to participants aged 18 Years to 75 Years. Per ClinicalTrials.gov, last updated 2018-10-26.
Sponsored by University of Aarhus · Phase 4, Interventional, and Treatment
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.
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:
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
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.
1,960 studies on the registry are indexed under Brain Neoplasms; 516 are open to participants now.
This study's enrollment of 48 is above the median of 40 across 1,458 interventional studies indexed under Brain Neoplasms.
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Exclusion Criteria:
Drug: Ephedrine
Drug: Phenylephrine
Infusion of Ephedrine 2mg/ml until MAP above 60 mmHg or until MAP has raised 20%
Infusion of Phenylephrine 0,1mg/ml until MAP above 60 mmHg or until MAP has raised 20%
Capillary Transit Time Heterogeneity
Time frame: 4 Years
Cerebral Metabolic Rate of Oxygen
Time frame: 4 Years
Plan to share: No
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