Anaesthesiological strategies in elective craniotomy: randomized, equivalence, open trial – The NeuroMorfeo trial
Maria Grazia Franzosi
Department of Experimental Medicine University of Milan-Bicocca
Department of Cardiovascular Research, Istituto di Ricerche Farmacologiche Mario Negri
Neuroanaesthesia and Neurointensive Care Unit, Department of Perioperative Medicine and Intensive Care, San Gerardo Hospital
Internal Medicine II, Department of Clinical Sciences, Ospedale Luigi Sacco
Via GB Grassi 74, 20157 Milano
Background: Many studies have attempted to determine the "best" anaesthetic technique for neurosurgical procedures in patients without intracranial hypertension. So far, no study comparing intravenous (IA) with volatile-based neuroanaesthesia (VA) has been able to demonstrate major outcome differences nor a superiority of one of the two strategies in patients undergoing elective supratentorial neurosurgery. Therefore, current practice varies and includes the use of either volatile or intravenous anaesthetics in addition to narcotics. Actually the choice of the anaestesiological strategy depends only on the anaesthetists' preferences or institutional policies. This trial, named NeuroMorfeo, aims to assess the equivalence between volatile and intravenous anaesthetics for neurosurgical procedures. Methods/Design: NeuroMorfeo is a multicenter, randomized, open label, controlled trial, based on an equivalence design. Patients aged between 18 and 75 years, scheduled for elective craniotomy for supratentorial lesion without signs of intracranial hypertension, in good physical state (ASA IIII) and Glasgow Coma Scale (GCS) equal to 15, are randomly assigned to one of three anaesthesiological strategies (two VA arms, sevoflurane + fentanyl or sevoflurane + remifentanil, and one IA, propofol + remifentanil). The equivalence between intravenous and volatile-based neuroanaesthesia will be evaluated by comparing the intervals required to reach, after anaesthesia discontinuation, a modified Aldrete score 9 (primary end-point). Two statistical comparisons have been planned: 1) sevoflurane + fentanyl vs. propofol + remifentanil; 2) sevoflurane + remifentanil vs. propofol + remifentanil. Secondary end-points include: an assessment of neurovegetative stress based on (a) measurement of urinary catecholamines and plasma and urinary cortisol and (b) estimate of sympathetic/ parasympathetic balance by power spectrum analyses of electrocardiographic tracings recorded
during anaesthesia; intraoperative adverse events; evaluation of surgical field; postoperative adverse
events; patient's satisfaction and analysis of costs.
411 patients will be recruited in 14 Italian centers during an 18-month period.
Discussion: We presented the development phase of this anaesthesiological on-going trial. The
recruitment started December 4th, 2007 and up to 4th, December 2008, 314 patients have been
Anaesthesia for neurosurgical procedures should ideally
provide optimal surgical conditions while maintaining
appropriate cerebral oxygen supply and stable systemic
haemodynamics. Rapid emergence from anaesthesia is
also desirable to allow a quick neurological examination
at the end of procedure.
Over the years, several studies have demonstrated that in
patient with intracranial hypertension the best strategy is
based on intravenous anaesthesia for its beneficial
cerebral haemodynamic effects, for its "neuroprotective" role
and for its action on cerebral metabolism .
On the other hand no studies have been able to determine
the "best" anaesthetic technique for neurosurgical
procedures in patients without signs of cerebral hypertension.
The choice of volatile or intravenous strategy is still
actively debated .
Current practice seems to vary and includes the use of
either volatile or intravenous anaesthetics in addition to
various narcotics . The most frequently administered
anaesthetics during neurosurgical procedures are either
propofol-opioid or sevoflurane-opioid . Inhaled agents
are preferred by some neuroanaesthetists because of the
ease of their administration, the availability of end-tidal
agent monitoring and lack of evidence of outcome
compared with intravenous hypnotics. Other anaesthetists
prefer, on the other hand, intravenous anaesthesia.
The drugs studied in this neuroanaesthesia trial include:
Sevoflurane is a halogenated inhalational anaesthetic
agent administered by vaporization and used in induction
and maintenance of anaesthesia. Minimum Alveolar
Concentration (MAC) in oxygen mixture for a 40 years old
adult is 2.1%; MAC decreases with age. Sevoflurane has a
direct vasodilator effect that increase cerebral blood flow
(CBF) while reduce cerebral metabolic rate (CMRO2).
CBF normalizes approximately 3 hours after the initial
exposure to 1.3 MAC of anaesthetic.
Propofol is an intravenous sedative-hypnotic agent used
during anaesthesia induction and maintenance.
Intravenous injection of a therapeutic dose of propofol induces
hypnosis usually within 40 seconds from the start of
injection, the interval request for one arm-brain circulation.
Steady-state propofol blood concentrations are generally
proportional to infusion rates. Propofol has many of the
properties of an ideal agent for neuroanaesthesia, with
beneficial cerebral haemodynamic effects reducing CBF,
favourable pharmacokinetics and high-quality recovery
profile despite prolonged duration of infusion. It reduces
CMRO2 to a similar extent as Sevoflurane .
Opioids that are usually associated with intravenous and
volatile anaesthesia are remifentanil and fentanyl.
Remifentanil is an antagonist of opioid -receptor and it
has a peculiar pharmacokinetic property due to its
metabolism mediated by a non specific esterase with rapid onset
and termination effects, independently by the duration of
administration. It's commonly used as analgesic for
induction and maintenance of anaesthesia as synergistic
agent with other anaesthetics.
Fentanyl is an opioid analgesic. It interacts predominately
with the opioid -receptor and exerts its principal
pharmacologic effects on the central nervous system. Its
primary actions of therapeutic value are analgesia and
sedation. Fentanyl may increase the patient's tolerance for
pain. Its analgesic activity is, most likely, due to its
conversion to morphine.
Few studies compared propofol-based anaesthesia with
other types of anaesthesia in neurosurgical patients. Todd
 compared propofol/fentanyl with nitrous
oxide/fentanyl and isoflurane/nitrous oxide in 121 patients
undergoing craniotomy for supratentorial mass lesions. There
were minor differences in adverse effects, but no
significant differences in neurological outcome. Nitrous oxide/
fentanyl patients had more hypotension during induction
and more post-operative vomiting, but were quicker to
awaken in recovery. Isoflurane/nitrous oxide patients had
more tachycardia during induction, higher ICP prior to
dural opening and longer emergence times. Finally,
propofol/fentanyl patients had less haemodynamic
instability during induction and less postoperative vomiting, but
were slower than the nitrous oxide/fentanyl patients to
wake-up. Recently Magni  evaluated emergence time
and early postoperative cognitive function in patients
who received either a volatile-based anaesthetic or a total
intravenous anaesthetic. The authors demonstrated no
differences in intraoperative brain volume, emergence
time, early postoperative cognitive abilities, or the
incidences of postoperative shivering, pain, or nausea and
vomiting. However, both intraoperative hypertensive and
hypotensive episodes were more common in patients
anaesthetized with propofol and remifentanil.
Based on current evidence, carefully administered
anaesthesia with any of a variety of agents will result in a similar
outcome. To evaluate the "anaesthesia quality", we must
therefore use surrogate combined endpoints. A score used
in anaesthesia is the modified Aldrete score  that
analyzes motility, respiration and oxygenation,
cardiovascular stability and consciousness. The sum of the scores
ranges between 0 and 10 and a adequate score at the
emergence from anaesthesia is 9.
In some recent articles the modified Aldrete score has
been applied to patients anaesthetized for a craniotomy.
Balakrishnan  compared the effects of remifentanil
versus fentanyl during surgery for intracranial
space-occupying lesions. Anaesthesia maintenance doses of isoflurane,
nitrous oxide, and opioid were at the anaesthesiologist's
discretion for both groups. The percentage of patients
with a normal recovery score (alert or arousable to quiet
voice, oriented, able to follow commands, motor function
unchanged from their preoperative evaluation, not
agitated, and had modified Aldrete Scores of 910) at 10 min
after surgery was significantly higher for remifentanil
(45% vs. 18%; P = 0.005). By 20 min, the difference
between groups was not maintained (P = 0.27).
Talke  compared three anaesthetic techniques
(inhalation, intravenous, mixed) in patients undergoing
craniotomy for supratentorial intracranial surgery. None of the
recovery event times (open eyes, extubation, follow
commands, oriented, Aldrete score) or psychomotor test
performance differed significantly. Mean interval to obtain
an Aldrete score 9 was 15 minutes in all three groups.
This prospective, randomized clinical study found that the
three anaesthetics did not differ in intra- or postoperative
haemodynamic stability or early postoperative recovery
Boztug  investigated the role of using the bispectral
index (BIS) in recovery from anaesthesia and altering drug
administration in patients undergoing craniotomy.
Times to first spontaneous breathing, eye opening, and
extubation (P = 0.035, P = 0.001, and P = 0.0001,
respectively) were significantly shorter in the BIS-guided group.
Time to an Aldrete score of 910 (24 6 vs. 27 6
minutes) and adequate neurological assessment was similar
between the groups.
Del Gaudio  compared the use of remifentanil and
fentanyl during elective supratentorial craniotomy in a
target controlled infusion (TCI)-propofol anaesthesia
regimen and evaluated the quality of recovery from
anaesthesia. Intervals for an Aldrete score of 910 were respectively
about 8.6 1.6 minutes and 14.6 2.6 minutes.
Lauta, in a preliminary report presented at the 2003
SNACC meeting , demonstrated similar times to an
Aldrete 9 (median 5 minutes) for both volatile and
Since the impact of both anaesthesiological strategies on
the outcome of neurosurgical procedures is similar, we
decided to compare different endpoints such as time to
reach consciousness. So far, in patients undergoing
elective supratentorial neurosurgery, no study comparing
intravenous with volatile-based neuroanaesthesia has
been able to demonstrate neither major outcome
differences nor a superiority of one of the two strategies [3,5].
Rather contrasting results has been published concerning
secondary anaesthesia effects like intraoperative brain
volume, early postoperative cognitive ability, incidence of
postoperative shivering, pain, nausea and vomiting .
This paper presents the design of the NeuroMorfeo study,
an open trial comparing volatile versus intravenous
anaesthesia strategies in patients undergoing elective
The NeuroMorfeo study is a multicenter randomized,
open label, controlled trial, with equivalence design ,
evaluating volatile anaesthesia vs. intravenous
anaesthesia strategies in patients undergoing supratentorial
elective neurosurgery. Enrolment criteria, evaluated in all
patients during a routine preoperative assessment and
physical examination, are summarized in the appendix.
Before anaesthesia induction, patient is premedicated
with Midazolam (5 mg IV). An isotonic crystalloid saline
solution (710 mL/kg) is infused through a peripheral
intravenous catheter and a second line is inserted for drug
administration. All patients are preoxygenated for 3
minutes with a reservoir bag in 100% O2.
nyl is stopped at skin dressing and remifentanil reduced at
skin dressing by 30% every 34 minutes.
In all patients, anaesthesia is induced with:
- Propofol (23 mg/kg IV),
- Fentanyl (2 to 4 g/kg IV) in the group 1 and
remifentanil (0.25 g/kg/min IV infused for 3 minutes before
induction) in groups 2 and 3.
- Cisatracurium (0.10.2 mg/kg IV).
After intubation of the trachea, patients are mechanically
ventilated with an inspired mixture of air and oxygen
(2:1). Ventilation, using a closed breathing system (fresh
gas flow of 0.75 L/min oxygen and 1.5 L/min air during
anaesthesia), is adjusted to achieve an end-tidal carbon
dioxide of 3035 mmHg. No local anaesthesia is allowed.
Therefore anaesthesia is maintained according to one of
these three different study groups:
1. (IF) sevoflurane + fentanyl: sevoflurane is
maintained in a 0.75 to 1.25 MAC range and fentanyl (23
g/kg/hr or 0.7 g/kg boluses). Just before incision of
the scalp, fentanyl (12 g/kg/hr) can be
supplemented, if necessary;
2. (IR) sevoflurane + remifentanil: sevoflurane is
maintained in a 0.75 to 1.25 MAC range and remifentanil
(0.050.25 g/kg/min reduced to 0.050.1 g/kg/min
after dural opening). Just before incision of the scalp,
remifentanil can be supplemented, if necessary;
3. (ER) propofol + remifentanil: propofol is maintained
with continuous infusion at 10 mg/kg/h for the first
10 minutes, then reduced to 8 mg/kg/h for the
following 10 minutes and reduced to 6 mg/kg/h thereafter
and remifentanil 0.050.25 g/kg/min reduced to
0.050.1 g/kg/min after dural opening. Just before
incision of the scalp, remifentanil could be
supplemented, if necessary.
During surgery all patients are paralyzed with
cisatracurium (0.1 mg/kg/h), stopped once the bone flap is
At the end of surgery, residual neuromuscular blockade
will be antagonized with neostigmine 2.5 mg and
atropine 1 mg.
Sevoflurane and propofol infusions are reduced once the
bone flap is secured and stopped at skin dressing.
FentaAnalgesia is started before bone flap repositioning with
paracetamol and morphine 0.030.1 mg/kg IV in
Patients are randomly assigned to one of these three
strategies with equal probability. Balanced randomization is
maintained at each clinical site using a stratified
randomization scheme. Patients are randomized the day before
surgery, once the patient has provided written informed
consent and satisfied all the study eligibility criteria. The
patient identification and treatment allocation are
provided by the central randomization service through an
interactive voice response system (IVRS). After
randomization a confirmation e-mail with randomization details
is automatically sent to the center. In order to minimize
the possibility of bias in reporting and assessing primary
and secondary endpoints, the trial adopted a PROBE
design (Prospective Randomized Open trial with Blinded
Evaluation of outcomes).
The primary end point is the post-anaesthesia recovery,
assessed as the interval required to reach an Aldrete score
9 . The Aldrete Recovery Score, which sets the
standards for post-anaesthesia discharge criteria for patients, is
a score (range 010, Table 1) used by doctors and nurses
in the operating rooms. Interval (minutes; seconds)
required from patient extubation to reach a modified
Aldrete score 9 is evaluated in each patient.
The following comparisons are planned:
- Sevoflurane + remifentanil versus propofol + remifentanil;
- Sevoflurane + fentanyl versus propofol + remifentanil [7,10].
The Aldrete score is assessed by a trained
anaesthesiologist, blinded to allocation treatment group. Every 3060
seconds the anaesthesiologist checks the patients' activity
(ability to move extremities), respiration (ability to cough
and breath), circulation (level of blood pressure
compared to patient personal baseline), consciousness (ability
to keep himself awake), colour (level of peripheral oxygen
Every anaesthesiologist involved in the evaluation of the
score has been trained and certified with a dedicated
software course developed to use the Aldrete score.
Secondary end points are:
1. Anaesthesia-related neurovegetative stress evaluation through the measurement of:
2 = Able to move spontaneously or on command 4 extremities
1 = Able to move voluntarily or on command 2 extremities
0 = Unable to move any extremities
2 = BP + 20 mmHg of pre-sedation level
1 = BP + 2050 mmHg of pre-sedation level
0 = BP + 50 mmHg of pre-sedation level
SFcigheumree 1of blood and urine samples for stress biomarkers (cortisol and catecholamines)
Scheme of blood and urine samples for stress biomarkers (cortisol and catecholamines). For each patient samples
are collected before the induction, during surgical procedure and after awakening to evaluate within-patient changes.
a) Haemodynamic stability.
b) Stress biomarkers (cortisol and catecholamines)
. Blood and urine samples are collected before the
induction, during surgical procedure and after
awakening to evaluate within-patient changes in
biomarkers (as shown in figure 1). [14-18]
c) Cardiac autonomic function (dynamic analysis of the ECG)[19,20] Cardiac autonomic function tracings and biomarkers are assessed in central facilities by expert personnel blinded to the assigned treatment.
2. Intraoperative adverse events assessment: arterial hypotension and hypertension, bradycardia and tachycardia, osmotics and hyperventilation requirements .
3. Brain relaxation is assessed at dural opening, by the neurosurgeon, blinded to the study group, using a 4-point brain relaxation score [22,23]:
a) Relaxed brain.
b) Mild brain swelling, acceptable.
c) Moderate brain swelling, no therapy required.
d) Severe swelling, requiring treatment.
4. Post-operative adverse events assessment as seizures, cough, shivering, agitation, cerebral haematoma and post-operative pain.
5. Evaluation of patient's satisfaction through the filling of
the The Iowa Satisfaction with Anaesthesia Scale (ISAS, table
2) 24 hours after surgery.
6. Evaluation of the costs of the three strategies.
Baseline characteristics of the patient (including
demographics, medical history, physical exam, vital signs and
serial lab tests, ASA, Body Mass Index (BMI), planned
intracranial surgery) and all the variables registered during
and after the neurosurgery as haemodynamic parameters
(arterial pressure and heart rate), diuresis, body
temperature, arterial saturation, blood gas analysis, end-tidal
concentrations of anaesthetic vapour, oxygen, and carbon
dioxide, intraoperative and post-operative adverse events,
are recorded on a Case Report Form (CRF). Data
collection ends 24 hours after the end of surgery.
A CRF, software based, has been develop and distributed
to the centers. Data are inputted at each centre and are
sent in an encrypted format to the coordinating centre for
storage in a central database and for statistical analysis. A
I threw up or felt like throwing up
I was too cold or hot
I was satisfied with my anaesthetic care
I felt pain during surgery
Agree very much
monitoring program, according to GCP rules, has been
planned. It includes a central monitoring activity for
efficacy and safety and an on-site monitoring. Central and on
site monitoring activity are carried out by Mario Negri
Institute's experienced personnel and includes CRFs
reviewing in term of completeness and accuracy, errors
and omissions. All corrections are entered on data query
forms that are sent to the Investigator. On-site monitoring
consists in at least four visits for each participating site: a)
an initiation visit before starting the recruitment, b) a visit
after the third randomized patient, c) a visit after 15
recruited patients and d) a close-out visit. During this visit
the clinical monitor reviews on site all CRF and written
informed consents. Accuracy of the key data is verified
reviewing the source documents filed at the Investigator's
site and the clinical records.
An International Data and Safety Monitoring Board
(DSMB) guarantee the patients' safety during the study.
Serious adverse events (SAEs) are collected on the CRF
and evaluated by the DSMB. Investigators are required to
report to the Coordinating Centre all the SAEs suspected
to be related to the study medications within 24 hours
from their occurrence.
Fourteen Italian neuroanaesthesia departments have
agreed to participate to the study. These centers have been
selected on the basis of participation to previous
multicenter studies coordinated by San Gerardo
Neurointensive Care, Monza. These multicenter studies are Neurolink
, a survey on head injury in 28 Italian Neurosurgical
Hospitals (1997), Neurolink Domestic (on more than
1600 severely head injured patients, recruited from 1997
still ongoing), BrainIT  (coordination of the Italian
centers, project supported by the EU framework V (EEC
ESAnet (data collection in subarachnoid haemorrhage
patients in 23 Neurosurgical Departments ).
A web blog http://neuromorfeo.ning.com/ has been
developed for facilitating the communication between the
This trial has the objective to evaluate if IR, as well as IF, is
equivalent to ER. As described previously, this objective
will be addressed by evaluation of the interval required to
reach an Aldrete score 9. To test for equivalence two
comparisons are planned:
1. IR vs. ER,
2. IF vs. ER.
The difference between the groups has been estimated on
a clinical judgment basis.
The estimate for the mean value and the standard
deviation of each group integrates also information from the
limited published literature.
Having a mean duration of the neurosurgical procedures
in the enrolling centers (and this information is available
because we did monitor > 100 neurosurgical procedures
in the 14 centers) of >300 minutes, for both the
comparisons, it has been estimated that plausible equivalence
limits for the mean difference in the time to reach an Aldrete
score 9 range from 3 minutes with pooled standard
deviation equal to 7.
This evaluation comes from:
The need of a rapid emergence from anaesthesia to
allow a quick neurological examination at the end of
procedure. Nevertheless this emergence is not
instantaneous because prolonged administration of
anesthesiological drugs (> 300 minutes) and their
pharmacokinetic properties requires variable interval
from their discontinuation to obtain an Aldrete score
9. This score considers many items as motor activity,
adequate respiration, normal circulation and
peripheral perfusion and recover of consciousness. For
reaching the maximum values (910) the patient have to be
completely awake, with normal circulation and
respiratory, and be cooperative. On a pure clinical
judgment, 180 seconds, after > 300 minutes of
anaesthesia are a very short period. Based on a pure
clinical judgment this interval is extremely reasonable.
The evaluation that this value is less than 1% of the
total surgical duration.
We selected an equivalence design because these
differences aren't clinically significant and in our opinion the
strategies, according the primary endpoint, are similar.
Differences between the strategies will be evaluated
analyzing multiple secondary endpoints.
The study assumes a 1218 months of patients'
enrolment, a 10% drop-out rate and a overall significance level
0.05, taking into account that each comparison will be
tested at the significance level = 0.025.
A study sample size of 411 patients (137 in each group) is
estimated, since it will provide at least a power 84% to
reject the equivalence hypothesis. Sample size calculation
has been performed applying a two-group t-test of
equivalence in means performed with the statistical package
Nquery Advisor 6.01.
The intention to treat (ITT) population, consisting of all
randomized patients originally allocated to therapy
specific anaesthesia arm at the time of randomization will be
used for the efficacy analysis. In addition a per protocol
(PP) analysis will be performed on the efficacy endpoint.
If the results of the two approaches will be somehow
controversial, the PP analysis will be regarded as the definitive
one being in the context of an equivalence trial. The
primary efficacy outcome of the study is the time to reach an
Aldrete score 9. The conclusion that IR as well as IF are
equivalent to ER will be drawn if the lower limit of the
one-sided 95% interval around the mean difference is
greater than -3 minutes and the upper limit of the
onesided 95% confidence interval around the mean
difference is lower than 3 minutes. [28-30] Differences between
the two randomized groups will be analyzed by means of
analysis of variance or by a non-parametric approach if
distributional assumptions are not satisfied. Any clinically
significant imbalance between the randomized groups
will be considered for use as covariates. Secondary and
other efficacy outcomes of the study will be analyzed
using the same statistical methodology adopted for the
primary efficacy outcome. Safety analysis will be carried
out using the ITT population to allow a benefit/risk
assessment within the same study population.
The first patient has been recruited on December 4, 2007.
In the following 6 months, all the centers have obtained
local IRB approval and the initiation visit. To date (4th,
December 2008) 314 patients have been enrolled in the
study. The enrolment should be completed during the
second quarter of 2009.
NeuroMorfeo trial has been designed and initiated in the
context of an absence of evidence about the "best"
anaesthetic strategy for supratentorial elective neurosurgical
procedures. Several studies have compared intravenous
with volatile-based neuroanaesthesia without conclusive
results in favour of one of the two strategies. Clinical
research is usually based on the concept of developing
new therapeutic strategies able to demonstrate a better
efficacy compared with those available, testing a null
hypothesis. Under certain circumstances, however, it may
be inappropriate to plan a trial around a null hypothesis.
The NeuroMorfeo study is a model case. Knowing that
several studies have tried to demonstrate a superiority of
one anaesthesiological strategy without conclusive results,
we decided to plan a study based on an equivalence
design and that is the innovative part of this protocol.
Some conditions have to be satisfied before choosing an
equivalence design. First, the treatment under
consideration exhibits therapeutic non-inferiority to the active
control, that means in our field that no evidence about the
best anaesthesiological practice in elective neurosurgery is
available. Moreover, the tested treatment could offer
ancillary, even important, advantages in safety,
tolerability, cost, or convenience. These all are the relevant aspects
that this study is going to investigate.
An ideal neuroanesthesia should maintain an appropriate
cerebral oxygen supply and stable systemic
haemodynamic as well as rapid emergence time to allow a quick
neurological examination at the end of procedure.
This is the main reason for choosing the Aldrete score as
first, simple, measurable, endpoint. The Aldrete score is
the principal score used in literature to evaluate the post
Secondary end points have no less importance than the
first one. This research will allow exploring many aspects
of modern neuroanaesthesia, as secondary endpoints. In
fact, we will compare these strategies in terms of
neurovegetative activation (haemodynamic stability, essay of
biomarkers of stress, cardiac autonomic function),
intraoperative and post-operative adverse events, state of brain
relaxation, patient's satisfaction and costs of the three
To minimize bias in assessing the treatment effects, we
adopted a PROBE design: all the evaluation of
haemodynamic stability, biomarkers of stress, cardiac autonomic
function, surgical field and post-operative adverse events
are done by personnel blinded to the assigned treatment.
The design and formulation of this protocol will enable us
to reach a conclusion about the "best" elective
neurosurgical anaesthesiological strategy.
The authors declare that they have no competing interests.
Study Committees and Investigators
Data and Safety Monitoring Board
Gianni Tognoni, Consorzio Mario Negri Sud, S. Maria Imbaro, Chieti, Italy.
Roberto Malacrida, Lugano Hospital, Swizerland.
Sergio Maria Gaini, University of Milan, Italy.
David Menon, University of Cambridge, UK.
Barbara Gregson, Newcastle University U/T, UK.
Biohumoral and Electrocardiographic Substudies
GC, principal investigator, is responsible for coordinating
the NeuroMorfeo study. All authors contributed to the
design of the study and to draft the manuscript, and
approved the final version. SB is responsible for statistics
and data analysis. All authors will participate in
interpretation of results.
- physical state, evaluated with the ASA (American Society
of Anaesthesiologists, http://www.asahq.org/clinical/
physicalstatus.htm) classification I (normal healthy
patient), II (patient with mild systemic disease), or III
(patient with severe systemic disease);
- age 1875 years;
- normal preoperative level of consciousness, i.e. Glasgow
Coma Scale (GCS) equal to 15;
- no clinical signs of intracranial hypertension.
- Severe cardiovascular pathology, as uncontrolled arterial
hypertension and documented reduced coronary reserve;
- Known allergies to any anaesthetic agent;
- Reduced preoperative level of consciousness, i.e.
Glasgow Coma Scale (GCS) < 15;
- Body weight greater than 120 kg;
- History of drug abuse or psychiatric conditions;
- Documented disturbance of the hypothalamic region;
- Refusal to sign consent form;
- Participation in other clinical trials in the last 2 months;
- Planned awakening in ICU, due to the location and/or
size of the lesion, postoperative sedation and
postoperative mechanical ventilation requirements.
Database Management and Statistics
Regulatory, Administrative and Secretariat
We acknowledge all the enthusiastic staff of the 14 participating Italian
Ospedale San Gerardo (Monza): Francesca Sala, Stefano Carenini, Silvia Villa;
IRCCS-San Raffaele (Milano): Luigi Beretta, Gloria Licini, Elisa Nicelli, Marco
Fabio Gemma; Policlinico "A. Gemelli" (Roma): Massimo Antonelli, Valerio
Perotti, Anselmo Caricato; Azienda Ospedaliera (Padova): Carlo Ori, Marina
Munari, Sandra Volpin, Massimo Sergi, Elisa Michieletto; Ospedale Bellaria
(Bologna): Marco Zanello, Simona Gualdani, Matteo Vincenzi, Giulia
Marzolla, Alessandra Razzaboni, Vincenzo Stellino, Marzia Mingarelli, Caterina
Testoni, Tiziana Urli; Ospedale della Carit (Novara): Francesco Della Corte,
Petra Konrad, Claudia Montagnini; Ospedale di Circolo (Varese): Giulio
Minoja, Rita Pradella, Giovanna Inzigneri, Benedetta Franchi; Ospedale S.
Giovanni Bosco (Torino): Sergio Livigni, Carlo Alberto Castioni, Raffaele Potenza;
Ospedale S. Giovanni Battista (Torino): Maurizio Berardino, Claudio Borio,
Simona Cavallo, Orsola Morrone, Marco Gabarino, Fulvio Agostini; Azienda
Ospedaliera (Siena): Ettore Zei, Rebecca Tinturini; Azienda Ospedaliera
(Verona): Francesco Procaccio, Gloria Stofella, Daniela Cappelletti,
Francesca Casagrande;Azienda Ospedaliera (Parma): Mario Mergoni, Patrizia
Ceccarelli, Tiziana Serioli; Policlinico Umberto I (Roma): Gianni Rosa, Federico
Bilotta, Policlinico Consorziale (Bari): Enrico Lauta, Crescenza Abbinante.
We also thank Enzo Vigutto and Mariangela Fumarola, R&D office, Azienda
San Gerardo for their technical support. Paola Fasoli for secretarial
AIFA (Agenzia Italiana del Farmaco) fully financed the trial (year 2006,
FARM6FKJKK) that has been registered at Eudract (2007-005279-32) and
on http://www.clinicaltrials.gov (NCT00741351).