Download Propofol Sedation During Awake Craniotomy for Seizures

Propofol Sedation During Awake Craniotomy for
Seizures: Patient-Controlled
Administration
Versus
Neurolept Analgesia
Ian A. Herrick, BSC, MD, FRCW, Rosemary A. Craen, MBBS, FANZCA*,
Adrian W. Gelb, MB, ChB, FRCPC*, Laurie A. Miller, PhDt, Cynthia S. Kubu, PhDt,
John P. Girvin, MD, FRCSCS, Andrew G. Parrent, MD, FRCSCS, Michael Eliasziw, PhD§, and
Joyce Kirkby, RNA*
Departments
of *Anaesthesia, tPsychology,
SClinical Neurological
Sciences, and §Epidemiology
Health Sciences Centre, University of Western Ontario, J. I’. Robarts Research Institute, London,
This prospective study evaluated the safety and efficacy of patient-controlled
sedation (PCS) using propofol during awake seizure surgery performed under bupivacaine
scalp blocks. Thirty-seven
patients were
randomized
to receive either propofol PCS combined
with a basal infusion of propofol (n = 20) or neurolept
analgesia using an initial bolus dose of fentanyl and
droperidol
followed by a fentanyl infusion (n = 17).
Both groups received supplemental
fentanyl and dimenhydrinate
for intraoperative
pain and nausea, respectively. Comparisons
were made between groups
for sedation, memory, and cognitive function, patient
satisfaction, and incidence of complications.
Levels of
C
ortical resection
for the management
of refractory seizures or cerebral
lesions located in close
proximity
to eloquent
areas of the brain is often
performed
with the patient awake. Anesthesia is usu-
ally provided using a combination of local anesthesia
(local infiltration and regional blockade) and intravenous (IV) medications to provide sedation, anxiolysis, and supplemental analgesia during these long
procedures.
The need to minimize interference with intraoperative electrocorticography (ECoG), when this is used,
limits the repertoire of drugs available for sedation.
Traditionally, neurolept analgesia using a combination of opioid (often fentanyl) and droperidol has been
This study was supported
by a grant from
vices Incorporated
(PSI) Foundation.
Accepted
for publication
March
6, 1997.
Address
correspondence
to Ian A. Herrick,
Anaesthesia,
London
Health Sciences Centre,
339 Windermere
Road, London,
Ontario
N6A
01997 by the International
0003.2999/97/$5.00
Anesthesia
Research
the Physicians’
and Biostatistics,
Ontario, Canada
London
intraoperative
sedation and patient satisfaction were
similar between groups. Memory and cognitive function were well preserved in both groups. The incidence
of transient episodes of ventilatory
rate depression
(~8 bpm) was more frequent among the propofol patients (5 vs 0, P = 0.04), particularly
after supplemental
doses of opioid. Intraoperative
seizures were more
common among the neurolept
patients (7 vs 0, P =
0.002). PCS using propofol represents an effective alternative to neurolept analgesia during awake seizure surgery performed in a monitored
care environment.
(Anesth Analg
1997;84:1285-91)
a popular technique (1,2). Recently, the use of propofol sedation during these procedures has been reported (3,4) and has become popular at our hospital.
Patient-controlled sedation (PCS) with propofol, using patient-controlled
analgesia (PCA) technology,
has been reported to be safe, to provide effective sedation, and to be associated with a high degree of
patient satisfaction and acceptance (5-7). Most of the
available data involving PCS relate to surgical procedures of relatively short duration.
This prospective, randomized study was designed
to evaluate the safety and efficacy of propofol PCS
during awake craniotomy for seizure surgery. The
impact of propofol sedation on intraoperative ECoG is
addressed in an accompanying article.
Ser-
Methods
MD, Department
of
University
Campus,
5A5, Canada.
After institutional ethics approval and acquisition of
written, informed consent, adult patients (aged 18-65
Society
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1997;84:1285-91
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yr) scheduled for cortical resection for refractory seizures were randomized to receive either propofol PCS
or neurolept analgesia (fentanyl and droperidol).
Sedation for the PCS group consisted of patientadministered propofol using a bolus dose of 0.5 mg/
kg, a lockout interval of 3 min, and a basal infusion of
0.5 mg * kg-’ * h-’ via a standard PCA device (Baxter,
McGaw Park, ILPCAII). Patients were shown how to
use the device preoperatively and were instructed to
administer sedation if they wished to be more
“sleepy” or if they experienced anxiety or discomfort.
Patients were encouraged to use the PCS device early
in the operative procedure (to ensure that they understood how to use it and what effect it would have on
them) and were reminded that they could use the
pump if they requested more sedation or became restless during the operation. They were also told that
supplemental analgesia was available from their anesthesiologist if they were uncomfortable and that the
anesthesiologist would take over administration of
sedation if they were unable or unwilling to do so at
any point in the operation. To avoid potential interference with ECoG recordings, propofol administration (both the PCS boluses and the basal infusion) was
suspended 15 min prior to ECoG recording and functional cortical mapping.
For the neurolept group, sedation consisted of initial IV boluses of droperidol (0.04 mg / kg) and fentanyl (0.7 pg/kg) followed by an anesthesiologistcontrolled
continuous
infusion
of fentanyl
at
0.7 pg - kg-’ . h-‘. Administration
of supplemental
droperidol was performed at the discretion of the
attending anesthesiologist.
Both groups received supplemental anesthesiologistadministered fentanyl (25-pg boluses) and dimenhydrinate (25-mg boluses) as needed for intraoperative pain
and nausea or vomiting, respectively.
Regional blockade of the scalp was performed by
the surgeon l-2 h preoperatively using bupivacaine
0.5% with epinephrine. Supplemental local anesthetic
solution (bupivacaine 0.33% with epinephrine) was
used to infiltrate along the incision lines prior to surgery. During craniotomy, dura mater was anesthetized using a mixture of lidocaine 1% and 0.25% bupivacaine without epinephrine. Our block technique
for craniotomy under local anesthesia has been previously described in detail (8).
All patients received supplemental oxygen via nasal
prongs during surgery. Intraoperative monitoring included ECG, pulse oximetry, noninvasive automated
blood pressure measurements, and capnography via
the nasal prongs.
On the day before surgery, patients were visited to
obtain demographic data and to perform baseline cognitive function and memory testing. Memory for objects was evaluated using recall and recognition tests
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preoperatively, intraoperatively (at 1 h after the commencement of sedation), postoperatively in the postanesthesia care unit (PACU), and on postoperative
day (POD) 1. Memory was also evaluated on POD 1
and 2 by free recall of specific intraoperative events.
Cognitive functioning was assessed preoperatively,
intraoperatively at 1 h, in the PACU, and on POD 1
using examination questions listed in Appendix 1.
Intraoperative sedation was assessedprior to sedation (baseline) and then hourly by the attending anesthesiologist based on a 5-point scale (Appendix 2). The
technical difficulty associated with each surgical procedure was evaluated by the attending surgeon based
on a 5-point scale (technically easy = 1, technically
difficult = 5).
Intraoperative
and postoperative
complications
were noted. These included hemodynamic instability
(systolic blood pressure ~85 or >170 mm Hg, heart
rate ~45 or >llO bpm), decreased ventilatory frequency (~8 bpm), pulse oximetric desaturation
(<90%), intraoperative vomiting, and inappropriate
seizures (seizures not associated with ECoG recording
or cortical mapping). The ability to perform appropriately during cortical mapping was also noted. Patient
satisfaction was evaluated using a short questionnaire
completed by each patient in the PACU and on PODS
1 and 5 (Appendix 3).
Nonparametric data (e.g., the incidence of complications) were analyzed using Fisher’s exact test or 2
analysis. The unpaired Student’s t-test was used to
analyze parametric data (e.g., drug dose comparisons
between groups). Satisfaction questionnaire and cognitive function test results were reported in parametric
terms and analyzed using Students t-test. Identical
results were obtained using nonparametric methods
(Mann-Whitney
U-test). Sedation scores were analyzed parametrically using analysis of variance for
repeated measures and the Student-Newman-Keuls
test. To confirm the acceptability of parametric analysis methods, the sedation scores were also subjected to
nonparametric analysis, which yielded identical results. A level of P 5 0.05 was accepted as statistically
significant.
Results
Thirty-seven adult patients scheduled for cortical resection for refractory seizures were studied; 20 received propofol PCS, and 17 received neurolept analgesia. Three additional patients were excluded from
the study because they required general anesthesia.
One patient in the propofol group was converted to
general anesthesia 1.5 h after the commencement of
sedation due to incomplete regional blockade that
could not be remedied during dural opening. Two
patients in the neurolept group were converted to
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Table
NEUROSURGICAL
1. Demographic Data and Surgical Variables
propofol
Fentanyl /
droperidol
30 -c 8
14:6
69 i 13
327 2 48
+ 11
12:5
72 + 12
360 -c 62
PCS
Characteristic
Age W
Sex (M:F)
Weight (kg)
Duration anesthesia
(min)
Surgical site (T/F / C)
Surgical difficulty (l-5)
Local anesthetic scalp
blocks (bupivacaine
0.5% with epinephrine
1/ 200,000)(mL)
Local anesthetic scalp
infiltration (bupivacaine
0.33% with epinephrine
1/ 200,000)(mL)
141214
3 -c 0.7
20 t 1
45
+
22
34
14/l/2
3 k 0.8
20?
1
51 ? 23
Data are presented
as mean + SD or number
of patients.
PCS = patient-controlled
sedation,
T/F/C
= temporal/frontal/central
general anesthesia due to marked anxiety and agitation. For one patient, general anesthesia was induced
prior to sedation; for the other patient, anesthesia was
induced approximately 30 min after the commencement of sedation. In both cases, the patients were
unwilling to continue the procedure awake and requested general anesthesia.
Demographic data for the two groups are shown in
Table 1. The duration of anesthesia and surgery averaged 5-6 h. The majority of patients underwent temporal lobectomy.
Preoperative anticonvulsant medications were similar between groups. Thirty-five percent and 45% of
the patients in the PCS and neurolept groups, respectively, received the usual dose of anticonvulsant
medications on the morning of surgery. The remainder of the patients had anticonvulsant medications
tapered, partially or completely, during preoperative evaluations and received a reduced dose or no
dose of anticonvulsant
medication on the day of
surgery.
All patients received supplemental anesthesiologistadministered fentanyl for discomfort during the cortical resection. The supplemental dose was similar for
the two groups (Table 2). The PCS patients received a
mean propofol dose of 690 + 287 mg, of which 494 2
291 mg (72%) was patient-administered.
Adjustments to predetermined dose regimens (increases in the rate of the fentanyl infusion or increases
in the bolus dose or basal infusion of propofol) were
required for five patients in the neurolept group and
four patients in the PCS group. Three of the patients in
the PCS group had the propofol bolus dose increased
to 0.75-1.0 pg/kg. The fourth PCS patient was converted to a propofol infusion (2-3 mg * kg-’ * h-i) in
response to a request to stop using the PCS device,
ANESTHESIA
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ET AL.
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2. Intraoperative Drug Administration Profile and
Complication Rate
Table
PCS
Characteristic
Total dosefentanyl (Fg / kg)
Supplemental fentanyl
(/-dk)
Total dose droperidol
(mgk)
Total dosepropofol (mg/kg)
Total propofol bolus dose
(mgk)
PCS demand ratio (%)
(successful:totaldemands)
Total dose dimenhydrinate
(mg)
Number of patients given
intraoperative
dimenbydrinate
Intraoperative vomiting
Intraoperative seizures
Transient respiratory rate
depression
Intraoperative tachycardia
propofol
N/A
2.9 ? 2
N/A
Fentanyl /
Droperidol
6.3
2.6
0.04
? 3
? 2
2 0.01
10.2 * 4
N/A
7.2 + 4
N/A
40.3
N/A
13 t
22
22 ? 26
6
9
2
0
5
3
7"
0%
2
6
Data are presented
as mean 2 SD or number
of patients.
PCS = patient-controlled
sedation,
N/A
= not applicable
* P < 0.05 between
groups.
which was prompted by discomfort and fatigue during the terminal stages of the cortical resection. In the
neurolept group, the fentanyl infusion was increased
to 0.9-1.8 pg. kg-i . h-l for five patients. In addition
to an increased fentanyl infusion, one of these patients
also received incremental doses of propofol (lo- to
20-mg boluses, total dose 240 mg over a 1.5-h interval)
at the discretion of the attending anesthesiologist to
manage agitation during the terminal aspects of the
resection and closure. Three patients also received a
single supplemental dose of droperidol ranging from
0.5 to 1.25 mg. Dose adjustments, if needed, typically
reflected a response to restlessness or discomfort, often compounded by nausea, which may accompany
resection of the mesial temporal lobe or basal frontal
lobe. The predetermined sedation protocol, which included the suspension of propofol administration during testing, was not altered in either group during the
preresection period (i.e., prior to or during ECoG
recording).
Sedation Scores
Compared with baseline, sedation scores increased in
a similar fashion in both groups except at the 2-h
assessment, at which point sedation scores in the
propofol group decreased significantly. This assessment coincided with the period during which propofol administration was suspended during intraoperative testing (Figure 1).
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1997;84:1285-91
(Maximum=B)
/
PREOP
1
TIME
Figure 1.
2
FROM
3
PREOP
I
I
4
5
PCS
(Hrs)
sedation
scores assessed intraoperatively
by the
attending
anesthesiologist.
Scoring based on a 5-point scale (Appendix 1). Scores for propofol
PCS (0) and neurolept
analgesia (a) were
assessed at l-h intervals
intraoperatively.
Error bars represent
SEM.
*P < 0.05 between
groups.
Patient
Memory and Cognitive Functioning
Based on recall and recognition tests, memory for
objects was not different between the two groups (Figure 2). Memory encoding and retrieval were not affected substantially by either type of sedation. Cognitive function test results were similar between the two
groups. Free recall of intraoperative events was not
depressed in either group.
NEUROLEPT
PCS
I-HOUR
iIfIUUI
= RECALL
=
= RECOGNITION
Patient satisfaction was similar between groups with
respect to the general level of comfort and willingness
to repeat the procedure using the same sedation technique (Table 3). Satisfaction with the option of selfadministering sedation (assessed only in the PCS
group) was high. Satisfaction with PCS was maintained through the fifth postoperative day.
Complications
Transient decreases in respiratory rate (<8 bpm) after
supplemental doses of fentanyl were more common in
the PCS group (PO.04, Fisher’s exact test) (Table 2).
These episodes were short in duration (<l min) and
did not require intervention. One patient in the neurolept group experienced a brief episode of pulse oximetric desaturation (Spo,89%) associated with the administration
of small doses of propofol during
PCS
NEUROLEPT
POD1
Figure
2. Object recall and recognition
test results at 1 h intraoperatively,
in the postanesthesia
care unit, and on the first postoperative
day (PODl).
Prior to sedation,
patients
were shown
three
objects,
and memory
for these objects was tested 1 h after the
commencement
of sedation.
Patients were then shown three additional objects, and memory
was evaluated
for all six objects in the
postanesthesia
care unit and on PODl. The mean number
of objects
recalled directly
is shown by the height of the vertically
striped area
of each bar. The additional
contribution
of recognition
to the total
number
of objects remembered
is depicted
by the open area of each
bar.
3. Patient Satisfaction Questionnaire Results
Table
Questionnaire score (l-4)
Satisfaction index
Patient Satisfaction
NEUROLEPT
PACU
General level of comfort
PCS
NEUROLEPT
Willingness to use same
technique in future
PCS
NEUROLEPT
Satisfaction with
patient-administration
PCS only
Data
PACU
PACU
POD 1
POD 5
2.7 5 0.8
2.7 +- 0.8
2.7 t 1.1
2.5 -c 0.8
2.9 +- 1.1
2.8 ? 0.9
2.9 -c 0.8
2.7 IL 0.9
3.1 ? 0.9
2.7 +- 0.9
3.0 ? 1.1
2.6 ? 1.2
3.3 i
3.6 -c 0.5
3.6 ? 0.6
are presented as mean +- SD
= postanesthesra
care umt,
patm+controlled
POD
0.7
= postoperatrve
day, PCS =
sedatmn
neurolept analgesia to manage agitation (as discussed
previously).
Intraoperative inappropriate seizures were markedly more common in the neurolept group (P = 0.002,
Fisher’s exact test). Five patients experienced generalized convulsions, and two experienced focal motor
ANESTH
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1997;84:1285-91
seizures. Four of the patients who experienced generalized convulsions received IV thiopental (50- to
75-mg boluses) to terminate the seizures (mean dose
125 mg, range 50-200 mg). Each patient recovered
satisfactorily to complete the procedure under neurolept analgesia. ECoG recordings were satisfactory in
both groups, although a low frequency of ECoG spike
activity noted in one of the patients in the neurolept
group was attributed to the administration of thiopental to terminate a seizure that occurred during the
period preceding ECoG recording. The frequency of
ECoG spike activity did not correlate with the type of
sedation administered, as discussed in detail in the
accompanying article. All patients performed satisfactorily during functional cortical mapping.
Two patients in the PCS group and six patients in
the neurolept group developed tachycardia in excess
of 110 bpm in response to intraoperative discomfort
(P = 0.07, Fisher’s exact test) (Table 2). In all cases,this
response was satisfactorily attenuated with supplemental fentanyl. The incidence of intraoperative vomiting and the administration of antiemetic medication
were similar between the two groups.
Discussion
Sedation during awake craniotomy has traditionally
been provided using a combination of fentanyl and
droperidol. Propofol offers several potential advantages over traditional techniques: its short duration of
action facilitates titration of sedation, it has a wide
spectrum of applications (including conversion to
general anesthesia if clinical circumstances warrant),
and it has been reported to have both antiemetic and
amnestic properties at sedative doses (9-12).
Several studies (5,6,13,14) have endorsed the use of
propofol for sedation during procedures of short duration, both by continuous infusion and via PCA delivery systems. Although the use of propofol sedation
has been reported during epilepsy surgery (3,4), there
is no information available regarding the safety or
efficacy of patient-administered
propofol sedation
during these procedures. PCS offers the opportunity
to combine bolus doses of sedative medication administered by the patient with a continuous basal infusion
controlled by the anesthesiologist. This strategy offers
the patient a sense of control and provides the capacity to administer sedation in response to the individual needs of the patient while enabling the anesthesiologist to determine the background level of sedation.
Our results demonstrate that patient-administered
propofol is just as effective as anesthesiologistadministered neurolept analgesia during these procedures. Patients achieved similar levels of sedation and
were similarly satisfied with both techniques. Patients
using PCS were satisfied with the option of controlling
the administration of sedation.
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Based on our experience, the inclusion of a basal
infusion is advantageous during propofol PCS for
long procedures during which patients often become
restless or fatigued as the procedure progresses (15). A
basal infusion provides a baseline level of sedation
that patients may augment using PCS demands in
response to clinical circumstances. The PCS demand
ratio in this study was 40%. This is consistent with the
results of other investigators (7,16). Although the technique is associated with a relatively high number of
ineffective demands, patients achieved effective levels
of sedation and expressed a high degree of satisfaction
with PCS. These findings probably reflect a favorable
response to the sense of control or participation provided by PCS.
Propofol may exert a positive or euphoric effect on
mood (17-19), which has been postulated to contribute
to the high levels of patient satisfaction reported with
PCS, particularly when assessmentsare conducted intraoperatively or during the early postoperative period (6,14). Our results suggest that patient satisfaction
with propofol PCS is independent of these effects, if
they exist, since satisfaction is maintained well into the
postoperative period, up to POD 5.
Complications associated with the two sedation
techniques were similar. A higher incidence of transient respiratory rate depression was found in the
propofol group after doses of supplemental fentanyl.
However, the fact that these events were not associated with pulse oximetric desaturation emphasizes the
advantage associated with providing supplemental
oxygen during these procedures. Patients receiving
propofol sedation appear to be prone to respiratory
depression associated with the administration of opioids. This observation has also been reported by others (20).
Patients receiving neurolept analgesia experienced a
higher incidence of inappropriate intraoperative seizures compared with the patients who received
propofol. Since the management of anticonvulsant
medications in the preoperative period was similar
between the two groups, these findings suggest that
propofol may suppress seizure activity or that neurolept analgesia may either facilitate seizures or at least
permit normal convulsions. Although its proconvulsant and anticonvulsant profile remains controversial,
propofol has anticonvulsant activity at sedative doses
(21). In contrast, many neuroleptic drugs, including
butyrophenones such as droperidol, have been reported to lower the seizure threshold, and caution has
been advised when administering these drugs to patients with untreated epilepsy (22,23). The facilitation
of seizure activity has not been reported in association
with the administration of droperidol during anesthesia for intractable epilepsy (21). However, comparative studies involving the use of distinctly different
sedation techniques during epilepsy surgery have not
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ET AL
been reported previously.
Further investigations
are
needed to define the basis for the observed difference
in the incidence of seizures.
ECoG recordings were satisfactory
to proceed with
resection in all patients. A comparison
of the ECoG
effects of each of the sedation protocols is addressed in
the accompanying
article.
Propofol reportedly has significant antiemetic properties (9), but the incidence of intraoperative
vomiting
and the administration
of dimenhydrinate
were similar between
our two groups. This may be because
droperidol
also possesses antiemetic properties, or because intraoperative
vomiting was preempted by the
administration
of dimenhydrinate
in response to complaints of nausea. An additional possibility may relate
to the fact that many episodes of vomiting
during
these operations appear to result from discomfort
associated with traction on blood vessels or dura at the
base of the cortical resection. Although propofol and
droperidol
are effective antiemetics for drug-induced
nausea and vomiting mediated by the area posterema,
the mechanisms
for intraoperative
vomiting
during
these procedures
may be less responsive
to therapy.
Cognitive
function
was well preserved
in both
groups, as was memory. Patients in both groups performed well on formal memory testing involving object recall and recognition and demonstrated
little amnesia for intraoperative
events. Although propofol has
been reported to possess amnestic properties at higher
Appendix
sedation doses, our findings, consistent with the results of other investigators,
show that at lower doses,
the amnestic
effects
of propofol
are negligible
(10,12,19).
The results of this study demonstrate
that propofol
PCS provides an effective alternative to neurolept analgesia during craniotomy
performed
under regional
anesthesia.
Our experience regarding
the effect of
propofol
sedation on the quality of intraoperative
ECoG recordings
is described in the accompanying
article.
The authors gratefully
acknowledge
the assistance of Ms. C. Hawke,
Ms. L. Szabo (secretarial
assistance),
and Mr. P. Lok (data analysis)
in the preparation
of this manuscript.
Appendix
1
lntraoperative
Sedation Scale
Score
1
2
3
4
5
Criteria
Fully awake and oriented
Drowsy,
eyes
open
Drowsy, eyes closed, but rousable to command
Drowsy, eyes closed, rousable to mild physical
stimulation
Unrousable
to mild
physical
stimulation
2
Mental Status Questionnaire
1. What is your name?
(3)
2. What is the date today?
Month
Year
Day
3. What is the name of this place?
(3)
Hospital
City
Province
4. What is your address?
5. What is your telephone
6. What is your mother’s
7. Name the next 3 months
8. Subtract
(3)
number?
(1)
first name?
(1)
in a calendar
serial 3’s:
year after the month of August.
I
9. McGill Picture Anomalies Test: Two pictures
peculiar, or out of place in each picture.
Total score =
(3)
120
I
will be shown.
(3)
I
I
Patient is asked to demonstrate
41)
what
is funny,
(2)
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NEUROSURGICAL
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Appendix 3
Patient Satisfaction Questionnaire
Please help us evaluate your anesthetic by completing the following questions. We are interested in your honest
opinion, positive or negative. We also welcome your comments and suggestions.
Circle your answer:
1. How satisfied were you with your pain management and overall level of comfort?
4
3
2
1
very satisfied
mostly satisfied
mildly satisfied
quite dissatisfied
or indifferent
2. If you were to have surgery again, would you opt for the same method of management?
1
2
4
3
no, definitely not
no, I don’t think so
yes, I think so
yes, definitely
3. Did you like the method of self-administration
4
3
yes, definitely
yes, I think so
of sedative medication?
2
no, I don’t think so
References
1. Gignac
E, Manninen
PH, Gelb AW. Comparison
of fentanyl,
sufentanil
and alfentanil
during awake craniotomy
for epilepsy.
Can J Anaesth
1993;40:421-4.
2. Archer
DP, McKenna
JMA, Morin
L, Ravussin
I’. Conscioussedation analgesia during craniotomy
for intractable
epilepsy:
a
review of 354 consecutive
cases. Can J Anaesth
1988;35:338-44.
3. Silbergeld
DL, Mueller
WM, Colley I’S, et al. Use of propofol
(Diprivan)
for awake craniotomies:
technical
note. Surg Neurol
1992;38:271-2.
4. Drummond
JC, Iragui-Madoz
VJ, Alksne JF, Kalkman
CJ. Masking of epileptiform
activity
by propofol
during seizure surgery.
Anesthesiology
1992;76:652-4.
5. Rudkin
GE, Osborne
GA, Curtis
NJ. Intra-operative
patientcontrolled
sedation.
Anaesthesia
1991;46:90-2.
6. Grattidge
I’. Patient-controlled
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