<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT02229201</url>
  </required_header>
  <id_info>
    <org_study_id>UMCL-NKG-01</org_study_id>
    <nct_id>NCT02229201</nct_id>
  </id_info>
  <brief_title>Comparison of Two Anaesthetics on Brain During Brain Tumour Surgery</brief_title>
  <official_title>Phase 1 Study of the Impact of Propofol vs. Sevoflurane on Brain Damage and Inflammatory Response During Brain Tumour Surgery</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University Medical Centre Ljubljana</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University Medical Centre Ljubljana</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Anaesthesia and surgical stress during craniotomy can lead to brain damage and activation of&#xD;
      inflammatory response. Consequently inflammatory cytokines (IL6, IL8, IL10) are released.&#xD;
      Cell mediated immune balance can increase postoperative complications (infections, wound&#xD;
      healing, multiple organ dysfunction). Many studies have shown that volatile anaesthetics&#xD;
      reduce systemic and local inflammatory response during major surgery, but animal studies have&#xD;
      shown that volatile anaesthetics can induce neuroinflammation (IL6, NF-κB) that leads to&#xD;
      decline of cognitive function in rodent and possible human.&#xD;
&#xD;
      Our aim was to investigate how anaesthetic technique for craniotomy influences the release of&#xD;
      inflammatory cytokines. Our hypothesis was that when optimal neuroprotective strategies are&#xD;
      followed during surgery intravenous anaesthesia attenuates inflammatory response comparing to&#xD;
      inhalational anaesthesia.&#xD;
&#xD;
      The investigators included 40 patients anaesthetised with remifentanil based anaesthesia with&#xD;
      sevoflurane (S group) or propofol (P group).&#xD;
&#xD;
      Plasma levels of IL6, IL8, IL10 were measured during preoperative, perioperative and&#xD;
      postoperative periods of both groups of patients. The investigators also noted emergence&#xD;
      parameters, postoperative (pain, shivering, vomiting) and neurological complications after&#xD;
      surgery.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Anaesthetic technique for craniotomy has to provide optimal cerebral perfusion, oxygenation&#xD;
      and prevent brain oedema (1). It also has to lower the stress response on pain during&#xD;
      intubation and surgical manipulation. Emergence from anaesthesia has to be rapid and smooth&#xD;
      to permit early postoperative neurological evaluation. The most likely opioid in the last&#xD;
      decade is short acting opioid remifentanil that can be easy titrated during the procedure and&#xD;
      provides early recovery (2, 3, 4, 5). Currently the propofol-remifentanil and&#xD;
      sevoflurane-remifentanil are the most frequently used combinations for craniotomy (6, 7).&#xD;
      Recently a multicentre study was published that did not show differences in early recovery&#xD;
      between three groups (propofol-remifentanil: TIVA, sevoflurane-remifentanil,&#xD;
      sevoflurane-fentanyl). Either technique provided optimal surgical conditions. The group&#xD;
      received TIVA had attenuated changes in stress biomarkers (cortizol in plasma and urine,&#xD;
      cateholamines. (8).&#xD;
&#xD;
      Anaesthesia and surgical stress during craniotomy can lead to brain damage and activation of&#xD;
      inflammatory response (9, 10). Consequently inflammatory cytokines (IL6, IL8, IL10) are&#xD;
      released. Cell mediated immune balance can increase postoperative complications (infections,&#xD;
      wound healing, multiple organ dysfunction). Many studies have shown that volatile&#xD;
      anaesthetics reduce systemic and local inflammatory response during major surgery (11, 12,&#xD;
      13, 14), but animal studies have shown that volatile anaesthetics can induce&#xD;
      neuroinflammation (IL6, NF-κB) that leads to decline of cognitive function in rodent and&#xD;
      possible human (15,16).&#xD;
&#xD;
      Our aim was to investigate how anaesthetic technique for craniotomy influences the release of&#xD;
      inflammatory cytokines. Our hypothesis was that when optimal neuroprotective strategies are&#xD;
      followed during surgery intravenous anaesthesia attenuates inflammatory response comparing to&#xD;
      inhalational anaesthesia.&#xD;
&#xD;
      Plasma levels of IL6, IL8, IL10 were measured during preoperative, perioperative and&#xD;
      postoperative periods of both groups of patients. The investigators also noted emergence&#xD;
      parameters, postoperative (pain, shivering, vomiting) and neurological complications after&#xD;
      surgery.&#xD;
&#xD;
      Patients and methods&#xD;
&#xD;
      Anaesthesia regimen:&#xD;
&#xD;
      On arrival in the operating room, the patients were randomly assigned to either Group P or&#xD;
      Group S. Randomisation was done according to computer-generated order.&#xD;
&#xD;
      All patients were on a regimen of dexamethasone 4x4mg/day with the first dose given at least&#xD;
      one day before surgery.&#xD;
&#xD;
      After arriving to the operating room the standard monitoring was instituted. An arterial&#xD;
      catheter was placed in the radial artery to continuously monitor blood pressure. For extended&#xD;
      haemodynamic monitoring Vigileo system was used.&#xD;
&#xD;
      Patients were premedicated with midazolam (2-3 mg i.v.) and ondansetron (4-8 mg i.v.).&#xD;
      Antibiotic prophylaxis with intravenous cefazolin 2g/100 ml 0.9% NaCl was invariably used in&#xD;
      all patients.&#xD;
&#xD;
      Anaesthesia induction in Group P was performed with propofol (Propoven, Fresenius Kabi) and&#xD;
      in Group S with sevoflurane (Sevorane, Abbott Laboratories). Before intubation all patients&#xD;
      received remifentanil (Ultiva, GlaxoSmithKline) and rocuronium (Esmeron, MSD).&#xD;
&#xD;
      After intubation, patient's lungs were ventilated mechanically, with 1:2 oxygen-air mixtures&#xD;
      in P and S group. Ventilation was adjusted to maintain normocapnia. Anaesthesia was&#xD;
      maintained by continuous infusion of propofol 4-6 mg/kg/h in the P group and with sevoflurane&#xD;
      0,8-1 MAC in the S group. Remifentanil was adjusted regarding to anaesthesia response (0.1 -&#xD;
      2 μg/kg/min). The depth of anaesthesia was measured by a bispectral index (BIS) monitor; BIS&#xD;
      values were maintained at 40-60.&#xD;
&#xD;
      For haemodynamic management the following algorithm was used: continuous infusion of 0.9%&#xD;
      NaCl 6 mL kg-¹ for the first hour, followed by 2.5 ml kg-¹h-¹ . If CI &lt; 2 L/min/m2and SVV &gt;&#xD;
      10%, 6% hydroxyethyl starch (Voluven, Fresenius Kabi) until SVV-10% ; if there is no&#xD;
      improvement after 250 ml 6% HES-a, ephedrine (0.5% Efedrin, UMC Ljubljana Pharmacy) 5-10 mg&#xD;
      iv or fenilefrin 50-100 μg (0.01%, UMC Ljubljana Pharmacy). If CI &lt; 2 L/min/m2, SVV &lt; 10% and&#xD;
      heart beat &lt; 40/min, atropine 0,5 mg. If the mean arterial pressure increases by more than&#xD;
      30% and the heart rate by more than 30% from baseline, the infusion of remifentanil is&#xD;
      increased. Any adverse hemodynamic events that did not respond to changes in anaesthetic&#xD;
      regimen could be managed with urapidil or metoprolol, as appropriate. Hypotension following&#xD;
      blood losses was maintained with colloids (6% HAES) and blood replacement. Hemodynamic&#xD;
      parameters were monitored continuously at 5-min intervals from the beginning of induction&#xD;
      until the patients were discharged from the PACU.&#xD;
&#xD;
      30 minutes before the end of the surgery (at the time of dura closer) piritramid 5-10 mg was&#xD;
      administered. Continuous intravenous infusion of piritramid was started postoperatively as&#xD;
      patient control analgesia (PCA). The time of the operation was determined as the time from&#xD;
      pin head-holder placement to its removal. The time from the end of the operation to the&#xD;
      tracheal extubation was also noted. All patients were extubated in the operating theatre and&#xD;
      then transferred to the recovery room.&#xD;
&#xD;
      Postoperative management:&#xD;
&#xD;
      After surgery, the patients stayed in the recovery room for one hour and were then&#xD;
      transferred to the intensive care unit of the Department of Neurosurgery.&#xD;
&#xD;
      Standard postoperative monitoring generally used in these procedures was implemented. Oxygen&#xD;
      titrated to the lowest level needed to achieve the target arterial oxygen saturation of 96%,&#xD;
      was administered via a Venturi mask. Post anaesthetic adverse events and medication in ICU&#xD;
      were recorded for a period of 24 h after anaesthesia. Adverse events were defined as any&#xD;
      unintended changes in body function or well being, such as hypertension, postoperative nausea&#xD;
      and vomiting, pain, neurological complications, in particular if clinical intervention or&#xD;
      drug therapy was required.&#xD;
&#xD;
      Hospital stay was also recorded.&#xD;
&#xD;
      Study design:&#xD;
&#xD;
      This prospective randomised single centre study was conducted at the Department of&#xD;
      Anaesthesiology and Surgical Intensive Care and at the Department of Neurosurgery, in close&#xD;
      cooperation with the Department of Clinical Chemistry and Biochemistry, University Medical&#xD;
      Centre Ljubljana. The investigators included 40 patients anaesthetised with remifentanil&#xD;
      based anaesthesia with sevoflurane (S group) or propofol (P group). The study was approved by&#xD;
      the National Medical Ethics Committee of the Republic of Slovenia. All the procedures were&#xD;
      performed in accordance with Helsinki declaration. The written informed concern was obtained&#xD;
      from all included patients. The patients included in the study were given anaesthesia by the&#xD;
      same anaesthesiologist.&#xD;
&#xD;
      The data recorded included demographic characteristics, time of surgery, time to extubation,&#xD;
      hemodynamic parameters.&#xD;
&#xD;
      Arterial blood samples for the determinations of cytokines (IL 6, IL 8, IL 10) were drawn at&#xD;
      the following time points: 1. before induction, 2. During tumor resection 3. at the end of&#xD;
      the surgery, and 4. 24 hours after surgery 5. 48 hours after surgery.&#xD;
&#xD;
      For analyses of serum interleukin-6 (IL-6), interleukin-8 (IL-8) and interleukin-10 (IL-10),&#xD;
      blood samples were collected in tubes without additive. After centrifugation serum samples&#xD;
      were stored at -20 ºC until analysis. Analyses of samples were performed in one batch.&#xD;
      Chemiluminescent immunometric assay (Immulite analyzer; Siemens Healthcare, Erlangen,&#xD;
      Germany) was used to measure the concentrations of IL-6, IL-8, and IL-10.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>May 2010</start_date>
  <completion_date type="Actual">December 2013</completion_date>
  <primary_completion_date type="Actual">December 2013</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Interleukin 10 plasma concentrations</measure>
    <time_frame>Within 48 hours (1. Before surgery and anaesthesia 2. During surgery, 3. At the end of surgery 4.First postoperative day 5.Second postoperative day)</time_frame>
    <description>The interleukin 10 plasma concentrations during craniotomy (preoperative, perioperative and postoperative periods)</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Hospital stay</measure>
    <time_frame>within the first 15 days after surgery</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pulmonary complications</measure>
    <time_frame>within the first 15 days after surgery</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cardiovascular complications</measure>
    <time_frame>within the first 15 days after surgery</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Neurological complications</measure>
    <time_frame>within the first 15 days after surgery</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Reoperation</measure>
    <time_frame>within the first 15 days after surgery</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Death</measure>
    <time_frame>within the first 15 days after surgery</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Postoperative nausea and vomiting (PONV)</measure>
    <time_frame>within the first 24 hours after surgery</time_frame>
    <description>Post anaesthetic adverse events and medication in ICU were recorded for a period of 24 h after anaesthesia. Adverse events were defined as any unintended changes in body function or well being.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pain using VAS score</measure>
    <time_frame>within the first 24 hours after surgery</time_frame>
    <description>Post anaesthetic adverse events and medication in ICU were recorded for a period of 24 h after anaesthesia. Adverse events were defined as any unintended changes in body function or well being, in particular if clinical intervention or drug therapy was required.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change of blood pressure from the baseline</measure>
    <time_frame>within the first 24 hours after surgery</time_frame>
    <description>Post anaesthetic adverse events and medication in ICU were recorded for a period of 24 h after anaesthesia. Adverse events were defined as any unintended changes in body function or well being, in particular if clinical intervention or drug therapy was required.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Consumption of Propofol (mg)</measure>
    <time_frame>within first 12 hours from the time before the surgery until the end of surgery</time_frame>
    <description>Drugs consumption, volume loading, blood loss and post anaesthetic adverse events and medication were recorded:</description>
  </other_outcome>
  <other_outcome>
    <measure>Consumption Remifentanil (mg)</measure>
    <time_frame>within first 12 hours from the time before the surgery until the end of surgery</time_frame>
    <description>Drugs consumption, volume loading, blood loss and post anaesthetic adverse events and medication were recorded.</description>
  </other_outcome>
  <other_outcome>
    <measure>Consumption of efedrin (mg)</measure>
    <time_frame>within first 12 hours from the time before the surgery until the end of surgery</time_frame>
    <description>Efedrin was used for correction of low blood pressure</description>
  </other_outcome>
  <other_outcome>
    <measure>Total loss of blood (ml)</measure>
    <time_frame>within first 12 hours from the time before the surgery until the end of surgery</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Time to extubation (min)</measure>
    <time_frame>within first 12 hours from the end of surgery until release from the recovery room</time_frame>
    <description>Post anaesthetic adverse events and medication:</description>
  </other_outcome>
  <other_outcome>
    <measure>Vomiting (yes/no)</measure>
    <time_frame>within first 12 hours from the end of surgery until release from the recovery room</time_frame>
    <description>Post anaesthetic adverse events and medication:</description>
  </other_outcome>
  <other_outcome>
    <measure>Lowering of arterial pressure (yes/no)</measure>
    <time_frame>within first 12 hours from the end of surgery until release from the recovery room</time_frame>
    <description>Post anaesthetic adverse events and medication:</description>
  </other_outcome>
  <other_outcome>
    <measure>Additional piritramid (yes/no)</measure>
    <time_frame>within first 12 hours from the end of surgery until release from the recovery room</time_frame>
    <description>Post anaesthetic adverse events and medication:</description>
  </other_outcome>
  <other_outcome>
    <measure>Consumption of fenilefrin (mikrog)</measure>
    <time_frame>within first 12 hours from the time before the surgery until the end of surgery</time_frame>
    <description>Fenilefrin was used for low blood pressure correction</description>
  </other_outcome>
  <other_outcome>
    <measure>Volume loading (ml)</measure>
    <time_frame>within first 12 hours from the time before the surgery until the end of surgery</time_frame>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">40</enrollment>
  <condition>Inflammation</condition>
  <arm_group>
    <arm_group_label>Propofol</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>intravenous anaesthetic</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Sevoflurane</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>volatile anaesthetic</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Propofol</intervention_name>
    <description>4-6 mg/kg/h during anaesthesia</description>
    <arm_group_label>Propofol</arm_group_label>
    <other_name>Propoven 1%</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Sevoflurane</intervention_name>
    <description>0.8 MAC</description>
    <arm_group_label>Sevoflurane</arm_group_label>
    <other_name>Sevorane</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  age 18-80 years&#xD;
&#xD;
          -  American Society of Anaesthesiologists (ASA) physical status I-III&#xD;
&#xD;
          -  Scheduled for brain tumour surgery&#xD;
&#xD;
          -  Glasgow Coma Score 15&#xD;
&#xD;
          -  Cooperative&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  No written informed consent&#xD;
&#xD;
          -  Eendocrine systematic disease&#xD;
&#xD;
          -  Ddrugs that alter endocrine metabolism&#xD;
&#xD;
          -  History of drug hypersensitivity&#xD;
&#xD;
          -  Drug addiction&#xD;
&#xD;
          -  Perioperative blood derivatives.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Jasmina Markovic Bozic, MD, MSC</last_name>
    <role>Principal Investigator</role>
    <affiliation>CD of Anaesthesiology and Intensive Therapy, University Medical Centre Ljubljan</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Blaz Karpe, PHD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Faculty of Natural Science and Engineering, University of Ljubljana</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Iztok Potocnik, MD, MSC</last_name>
    <role>Principal Investigator</role>
    <affiliation>CD of Anaesthesiology and Intensive Therapy, University Medical Centre Ljubljan</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Ales Jerin, PHD</last_name>
    <role>Principal Investigator</role>
    <affiliation>CLINICAL INSTITUTE OF CLINICAL CHEMISTRY AND BIOCHEMISTRY, University Medical Centre Ljubljana</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Andrej Vranič, MD, PHD</last_name>
    <role>Principal Investigator</role>
    <affiliation>CD of Neurosurgery, University Medical Centre Ljubljana</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Vesna Novak Jankovic, PROF, PHD</last_name>
    <role>Study Chair</role>
    <affiliation>CD of Anaesthesiology and Intensive Therapy, University Medical Centre Ljubljana</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University Medical Centre Ljubljana</name>
      <address>
        <city>Ljubljana</city>
        <zip>1000</zip>
        <country>Slovenia</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Slovenia</country>
  </location_countries>
  <reference>
    <citation>Blum FE, Zuo Z. Volatile anesthetics-induced neuroinflammatory and anti-inflammatory responses. Med Gas Res. 2013 Aug 1;3(1):16. doi: 10.1186/2045-9912-3-16.</citation>
    <PMID>23915963</PMID>
  </reference>
  <reference>
    <citation>El Beheiry H. Protecting the brain during neurosurgical procedures: strategies that can work. Curr Opin Anaesthesiol. 2012 Oct;25(5):548-55. doi: 10.1097/ACO.0b013e3283579622.</citation>
    <PMID>22895122</PMID>
  </reference>
  <verification_date>August 2014</verification_date>
  <study_first_submitted>August 11, 2014</study_first_submitted>
  <study_first_submitted_qc>August 27, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 1, 2014</study_first_posted>
  <last_update_submitted>August 27, 2014</last_update_submitted>
  <last_update_submitted_qc>August 27, 2014</last_update_submitted_qc>
  <last_update_posted type="Estimate">September 1, 2014</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University Medical Centre Ljubljana</investigator_affiliation>
    <investigator_full_name>Jasmina Markovic Bozic</investigator_full_name>
    <investigator_title>MD, MSC</investigator_title>
  </responsible_party>
  <keyword>propofol</keyword>
  <keyword>sevoflurane</keyword>
  <keyword>Interleukin 6</keyword>
  <keyword>Interleukin 10</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Inflammation</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Propofol</mesh_term>
    <mesh_term>Sevoflurane</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02229201
org study id: UMCL-NKG-01
nct id: NCT02229201
lead sponsor: 
has dmc: Yes
Anaesthesia and surgical stress during craniotomy can lead to brain damage and activation of
      inflammatory response. Consequently inflammatory cytokines (IL6, IL8, IL10) are released.
      Cell mediated immune balance can increase postoperative complications (infections, wound
      healing, multiple organ dysfunction). Many studies have shown that volatile anaesthetics
      reduce systemic and local inflammatory response during major surgery, but animal studies have
      shown that volatile anaesthetics can induce neuroinflammation (IL6, NF-κB) that leads to
      decline of cognitive function in rodent and possible human.

      Our aim was to investigate how anaesthetic technique for craniotomy influences the release of
      inflammatory cytokines. Our hypothesis was that when optimal neuroprotective strategies are
      followed during surgery intravenous anaesthesia attenuates inflammatory response comparing to
      inhalational anaesthesia.

      The investigators included 40 patients anaesthetised with remifentanil based anaesthesia with
      sevoflurane (S group) or propofol (P group).

      Plasma levels of IL6, IL8, IL10 were measured during preoperative, perioperative and
      postoperative periods of both groups of patients. The investigators also noted emergence
      parameters, postoperative (pain, shivering, vomiting) and neurological complications after
      surgery.
Anaesthetic technique for craniotomy has to provide optimal cerebral perfusion, oxygenation
      and prevent brain oedema (1). It also has to lower the stress response on pain during
      intubation and surgical manipulation. Emergence from anaesthesia has to be rapid and smooth
      to permit early postoperative neurological evaluation. The most likely opioid in the last
      decade is short acting opioid remifentanil that can be easy titrated during the procedure and
      provides early recovery (2, 3, 4, 5). Currently the propofol-remifentanil and
      sevoflurane-remifentanil are the most frequently used combinations for craniotomy (6, 7).
      Recently a multicentre study was published that did not show differences in early recovery
      between three groups (propofol-remifentanil: TIVA, sevoflurane-remifentanil,
      sevoflurane-fentanyl). Either technique provided optimal surgical conditions. The group
      received TIVA had attenuated changes in stress biomarkers (cortizol in plasma and urine,
      cateholamines. (8).

      Anaesthesia and surgical stress during craniotomy can lead to brain damage and activation of
      inflammatory response (9, 10). Consequently inflammatory cytokines (IL6, IL8, IL10) are
      released. Cell mediated immune balance can increase postoperative complications (infections,
      wound healing, multiple organ dysfunction). Many studies have shown that volatile
      anaesthetics reduce systemic and local inflammatory response during major surgery (11, 12,
      13, 14), but animal studies have shown that volatile anaesthetics can induce
      neuroinflammation (IL6, NF-κB) that leads to decline of cognitive function in rodent and
      possible human (15,16).

      Our aim was to investigate how anaesthetic technique for craniotomy influences the release of
      inflammatory cytokines. Our hypothesis was that when optimal neuroprotective strategies are
      followed during surgery intravenous anaesthesia attenuates inflammatory response comparing to
      inhalational anaesthesia.

      Plasma levels of IL6, IL8, IL10 were measured during preoperative, perioperative and
      postoperative periods of both groups of patients. The investigators also noted emergence
      parameters, postoperative (pain, shivering, vomiting) and neurological complications after
      surgery.

      Patients and methods

      Anaesthesia regimen:

      On arrival in the operating room, the patients were randomly assigned to either Group P or
      Group S. Randomisation was done according to computer-generated order.

      All patients were on a regimen of dexamethasone 4x4mg/day with the first dose given at least
      one day before surgery.

      After arriving to the operating room the standard monitoring was instituted. An arterial
      catheter was placed in the radial artery to continuously monitor blood pressure. For extended
      haemodynamic monitoring Vigileo system was used.

      Patients were premedicated with midazolam (2-3 mg i.v.) and ondansetron (4-8 mg i.v.).
      Antibiotic prophylaxis with intravenous cefazolin 2g/100 ml 0.9% NaCl was invariably used in
      all patients.

      Anaesthesia induction in Group P was performed with propofol (Propoven, Fresenius Kabi) and
      in Group S with sevoflurane (Sevorane, Abbott Laboratories). Before intubation all patients
      received remifentanil (Ultiva, GlaxoSmithKline) and rocuronium (Esmeron, MSD).

      After intubation, patient's lungs were ventilated mechanically, with 1:2 oxygen-air mixtures
      in P and S group. Ventilation was adjusted to maintain normocapnia. Anaesthesia was
      maintained by continuous infusion of propofol 4-6 mg/kg/h in the P group and with sevoflurane
      0,8-1 MAC in the S group. Remifentanil was adjusted regarding to anaesthesia response (0.1 -
      2 μg/kg/min). The depth of anaesthesia was measured by a bispectral index (BIS) monitor; BIS
      values were maintained at 40-60.

      For haemodynamic management the following algorithm was used: continuous infusion of 0.9%
      NaCl 6 mL kg-¹ for the first hour, followed by 2.5 ml kg-¹h-¹ . If CI < 2 L/min/m2and SVV >
      10%, 6% hydroxyethyl starch (Voluven, Fresenius Kabi) until SVV-10% ; if there is no
      improvement after 250 ml 6% HES-a, ephedrine (0.5% Efedrin, UMC Ljubljana Pharmacy) 5-10 mg
      iv or fenilefrin 50-100 μg (0.01%, UMC Ljubljana Pharmacy). If CI < 2 L/min/m2, SVV < 10% and
      heart beat < 40/min, atropine 0,5 mg. If the mean arterial pressure increases by more than
      30% and the heart rate by more than 30% from baseline, the infusion of remifentanil is
      increased. Any adverse hemodynamic events that did not respond to changes in anaesthetic
      regimen could be managed with urapidil or metoprolol, as appropriate. Hypotension following
      blood losses was maintained with colloids (6% HAES) and blood replacement. Hemodynamic
      parameters were monitored continuously at 5-min intervals from the beginning of induction
      until the patients were discharged from the PACU.

      30 minutes before the end of the surgery (at the time of dura closer) piritramid 5-10 mg was
      administered. Continuous intravenous infusion of piritramid was started postoperatively as
      patient control analgesia (PCA). The time of the operation was determined as the time from
      pin head-holder placement to its removal. The time from the end of the operation to the
      tracheal extubation was also noted. All patients were extubated in the operating theatre and
      then transferred to the recovery room.

      Postoperative management:

      After surgery, the patients stayed in the recovery room for one hour and were then
      transferred to the intensive care unit of the Department of Neurosurgery.

      Standard postoperative monitoring generally used in these procedures was implemented. Oxygen
      titrated to the lowest level needed to achieve the target arterial oxygen saturation of 96%,
      was administered via a Venturi mask. Post anaesthetic adverse events and medication in ICU
      were recorded for a period of 24 h after anaesthesia. Adverse events were defined as any
      unintended changes in body function or well being, such as hypertension, postoperative nausea
      and vomiting, pain, neurological complications, in particular if clinical intervention or
      drug therapy was required.

      Hospital stay was also recorded.

      Study design:

      This prospective randomised single centre study was conducted at the Department of
      Anaesthesiology and Surgical Intensive Care and at the Department of Neurosurgery, in close
      cooperation with the Department of Clinical Chemistry and Biochemistry, University Medical
      Centre Ljubljana. The investigators included 40 patients anaesthetised with remifentanil
      based anaesthesia with sevoflurane (S group) or propofol (P group). The study was approved by
      the National Medical Ethics Committee of the Republic of Slovenia. All the procedures were
      performed in accordance with Helsinki declaration. The written informed concern was obtained
      from all included patients. The patients included in the study were given anaesthesia by the
      same anaesthesiologist.

      The data recorded included demographic characteristics, time of surgery, time to extubation,
      hemodynamic parameters.

      Arterial blood samples for the determinations of cytokines (IL 6, IL 8, IL 10) were drawn at
      the following time points: 1. before induction, 2. During tumor resection 3. at the end of
      the surgery, and 4. 24 hours after surgery 5. 48 hours after surgery.

      For analyses of serum interleukin-6 (IL-6), interleukin-8 (IL-8) and interleukin-10 (IL-10),
      blood samples were collected in tubes without additive. After centrifugation serum samples
      were stored at -20 ºC until analysis. Analyses of samples were performed in one batch.
      Chemiluminescent immunometric assay (Immulite analyzer; Siemens Healthcare, Erlangen,
      Germany) was used to measure the concentrations of IL-6, IL-8, and IL-10.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Interleukin 10 plasma concentrations
time frame: Within 48 hours (1. Before surgery and anaesthesia 2. During surgery, 3. At the end of surgery 4.First postoperative day 5.Second postoperative day)
description: The interleukin 10 plasma concentrations during craniotomy (preoperative, perioperative and postoperative periods)
measure: Hospital stay
time frame: within the first 15 days after surgery
measure: Pulmonary complications
time frame: within the first 15 days after surgery
measure: Cardiovascular complications
time frame: within the first 15 days after surgery
measure: Neurological complications
time frame: within the first 15 days after surgery
measure: Reoperation
time frame: within the first 15 days after surgery
measure: Death
time frame: within the first 15 days after surgery
measure: Postoperative nausea and vomiting (PONV)
time frame: within the first 24 hours after surgery
description: Post anaesthetic adverse events and medication in ICU were recorded for a period of 24 h after anaesthesia. Adverse events were defined as any unintended changes in body function or well being.
measure: Pain using VAS score
time frame: within the first 24 hours after surgery
description: Post anaesthetic adverse events and medication in ICU were recorded for a period of 24 h after anaesthesia. Adverse events were defined as any unintended changes in body function or well being, in particular if clinical intervention or drug therapy was required.
measure: Change of blood pressure from the baseline
time frame: within the first 24 hours after surgery
description: Post anaesthetic adverse events and medication in ICU were recorded for a period of 24 h after anaesthesia. Adverse events were defined as any unintended changes in body function or well being, in particular if clinical intervention or drug therapy was required.
measure: Consumption of Propofol (mg)
time frame: within first 12 hours from the time before the surgery until the end of surgery
description: Drugs consumption, volume loading, blood loss and post anaesthetic adverse events and medication were recorded:
measure: Consumption Remifentanil (mg)
time frame: within first 12 hours from the time before the surgery until the end of surgery
description: Drugs consumption, volume loading, blood loss and post anaesthetic adverse events and medication were recorded.
measure: Consumption of efedrin (mg)
time frame: within first 12 hours from the time before the surgery until the end of surgery
description: Efedrin was used for correction of low blood pressure
measure: Total loss of blood (ml)
time frame: within first 12 hours from the time before the surgery until the end of surgery
measure: Time to extubation (min)
time frame: within first 12 hours from the end of surgery until release from the recovery room
description: Post anaesthetic adverse events and medication:
measure: Vomiting (yes/no)
time frame: within first 12 hours from the end of surgery until release from the recovery room
description: Post anaesthetic adverse events and medication:
measure: Lowering of arterial pressure (yes/no)
time frame: within first 12 hours from the end of surgery until release from the recovery room
description: Post anaesthetic adverse events and medication:
measure: Additional piritramid (yes/no)
time frame: within first 12 hours from the end of surgery until release from the recovery room
description: Post anaesthetic adverse events and medication:
measure: Consumption of fenilefrin (mikrog)
time frame: within first 12 hours from the time before the surgery until the end of surgery
description: Fenilefrin was used for low blood pressure correction
measure: Volume loading (ml)
time frame: within first 12 hours from the time before the surgery until the end of surgery
arm group label: Propofol
arm group type: Experimental
description: intravenous anaesthetic
arm group label: Sevoflurane
arm group type: Active Comparator
description: volatile anaesthetic
intervention type: Drug
intervention name: Propofol
description: 4-6 mg/kg/h during anaesthesia
arm group label: Propofol
other name: Propoven 1%
intervention type: Drug
intervention name: Sevoflurane
description: 0.8 MAC
arm group label: Sevoflurane
other name: Sevorane
criteria: 
gender: All
minimum age: 18 Years
maximum age: 80 Years
healthy volunteers: No
last name: Jasmina Markovic Bozic, MD, MSC
role: Principal Investigator
affiliation: CD of Anaesthesiology and Intensive Therapy, University Medical Centre Ljubljan
last name: Blaz Karpe, PHD
role: Principal Investigator
affiliation: Faculty of Natural Science and Engineering, University of Ljubljana
last name: Iztok Potocnik, MD, MSC
role: Principal Investigator
affiliation: CD of Anaesthesiology and Intensive Therapy, University Medical Centre Ljubljan
last name: Ales Jerin, PHD
role: Principal Investigator
affiliation: CLINICAL INSTITUTE OF CLINICAL CHEMISTRY AND BIOCHEMISTRY, University Medical Centre Ljubljana
last name: Andrej Vranič, MD, PHD
role: Principal Investigator
affiliation: CD of Neurosurgery, University Medical Centre Ljubljana
last name: Vesna Novak Jankovic, PROF, PHD
role: Study Chair
affiliation: CD of Anaesthesiology and Intensive Therapy, University Medical Centre Ljubljana
facility: 
country: Slovenia
citation: Blum FE, Zuo Z. Volatile anesthetics-induced neuroinflammatory and anti-inflammatory responses. Med Gas Res. 2013 Aug 1;3(1):16. doi: 10.1186/2045-9912-3-16.
PMID: 23915963
citation: El Beheiry H. Protecting the brain during neurosurgical procedures: strategies that can work. Curr Opin Anaesthesiol. 2012 Oct;25(5):548-55. doi: 10.1097/ACO.0b013e3283579622.
PMID: 22895122
responsible party type: Principal Investigator
investigator affiliation: University Medical Centre Ljubljana
investigator full name: Jasmina Markovic Bozic
investigator title: MD, MSC
mesh term: Inflammation
mesh term: Propofol
mesh term: Sevoflurane