Comparison of Two Anaesthetics on Brain During Brain Tumour Surgery
Condition: Inflammation
MeSH terms: Inflammation
Study type: Interventional
Phase: Phase 1

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Propofol; Sevoflurane
Intervention type(s): Drug; Drug
Intervention description(s): 4-6 mg/kg/h during anaesthesia; 0.8 MAC
Other intervention name(s): Propoven 1%; Sevorane
Intervention MeSH terms: Propofol; Sevoflurane
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: propofol; sevoflurane; Interleukin 6; Interleukin 10