Vasopressor Effects in Anesthetized Patients
Condition: Brain Tumor
MeSH terms: Brain Neoplasms
Study type: Interventional
Phase: Phase 4

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.
    

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:

        1. 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

        2. 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.
    

Intervention name(s): Ephedrine; Phenylephrine
Intervention type(s): Drug; Drug
Intervention description(s): 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%
Intervention MeSH terms: Phenylephrine; Oxymetazoline; Ephedrine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment