Inflammation Clinical Trial
Official title:
Phase 1 Study of the Impact of Propofol vs. Sevoflurane on Brain Damage and Inflammatory Response During Brain Tumour Surgery
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, Endpoint Classification: Pharmacodynamics Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment
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