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Ketofol (mixture of Ketamine and Propofol) administration in

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Anaesth Intensive Care 2012; 40: 305-310

Ketofol (mixture of ketamine and propofol) administration

in electroconvulsive therapy
G. ERDOGAN KAYHAN*, A. YUCEL*, Y. Z. COLAK†, U. OZGUL*, S. YOLOGLU‡, R. KARLIDAG§,
M. O. ERSOY**
Department of Anaesthesiology and Reanimation, Inonu University Medical Faculty, Malatya, Turkey

SUMMARY
The aim of this study was to evaluate the effect of a ketamine:propofol combination (‘ketofol’) for
electroconvulsive therapy on seizure activity, haemodynamic response and recovery parameters, and to
compare with these with the effects of propofol alone. Twenty-four patients underwent a total of 144 electro-
convulsive therapy sessions, allocated in this prospective, double-blind, crossover study. Patients were
randomly assigned to receive 1 mg/kg ketofol (0.5 mg/kg propofol plus 0.5 mg/kg ketamine) or 1 mg/kg propofol
1% for anaesthesia induction. Seizure duration and quality, haemodynamic data, recovery parameters and
side-effects were recorded and analysed between groups. Both motor and electroencephalography seizure
durations in the ketofol group (29±17 and 41±17 seconds, respectively) were similar to that in the propofol
group (28±13 and 38±16 seconds, respectively). Postictal suppression index was higher in the ketofol group
(89.63±7.88) than in the propofol group (79.74±14.6) (P <0.05). In the ketofol group, heart rate after the
seizure ended and mean arterial pressures, recorded at 0 and 5 minutes after the seizure ended, were higher
than in the propofol group. Time to obeying commands was longer in the ketofol group (P <0.05). There
were no untoward psychological reactions following ketofol. Although no superiority to propofol in terms of
seizure duration, haemodynamic or recovery parameters was found, the ketofol mixture selected in our
study provided better seizure quality than propofol. We conclude that ketofol can be an alternative strategy
to enhance the seizure quality and clinical efficiency of electroconvulsive therapy.
Key Words: ketamine, propofol, electroconvulsive therapy

Electroconvulsive therapy (ECT) is a common
treatment method used in severe depression and
other psychiatric diseases. Currently, most ECT
procedures are carried out with muscle paralysis
under general anaesthesia. The anticonvulsant
properties of sedative and hypnotic drugs used
during general anaesthesia may reduce the efficacy
of ECT. It is important to establish an accurate
balance between adequate anaesthesia depth and
optimal seizure duration. Moreover, the electrical
current applied during the ECT stimulates the
autonomic nervous system and leads to haemo-
dynamic changes in both systemic and cerebral
circulations1. As anaesthetists play a critical role in
* MD, Assistant Professor.
† MD, Assistant Doctor.
‡ PhD, Professor, Department of Biostatistics.
§ MD, Asssociate Professor, Department of Psychiatry.
**MD, Professor.
Address for correspondence: Assistant Professor G. Erdogan Kayhan,
Turgut Özal Mah. Fahri Kayahan Bulvarı, Nazar 2 Daire 15, Malatya,
Turkey. Email: drgulayer@yahoo.com
Accepted for publication on November 25, 2011.
Anaesthesia and Intensive Care, Vol. 40, No. 2, March 2012
this procedure, there is an ongoing investigation for
improving the efficacy and reliability of the method
by trying different anaesthetic drugs and procedures.
Although the cerebral and systemic haemodynamic
response is known to be relatively stable under
propofol anaesthesia, the seizure duration tends to
be shorter due to its strong anticonvulsant effect1,2.
Ketamine has been a less preferred anaesthetic
agent because of concerns about the risk of excessive
cardiovascular system response, elevated intracranial
pressure and untoward psychological reactions2.
However, it is noted that ketamine has a lesser
anticonvulsant effect and prolongs seizure duration
in cases with an inadequate seizure period3. More-
over, an increasing number of studies suggest that
it provides an earlier recovery after ECT, and has
the potential to reduce retrograde amnesia and
accelerate the clinical response to ECT due to its
antidepressive action3-8.
The opposing effects of ketamine and propofol on
the haemodynamic and respiratory systems are well
known. Their side-effects on these systems could be
reduced by administering a combination of them at a
lower dose. Thus, a ketamine:propofol combination
306 G. ErdoGan Kayhan, a. yucEl Et al
in the same syringe (called ‘ketofol’) has been
shown to be a reliable and effective combination
in shorter emergency procedures, paediatric cases
and regional anaesthesia9-11. Ketamine and propofol
have been observed to form no particles within
the same injector at 23°C for one hour and they
have been determined to be suitable for combined
use12.
In the literature, we could find no study on the
use of ketofol in ECT. We thought that by using
subanaesthetic ketamine and low-dose propofol
we could increase the seizure duration, provide
haemodynamic stability and earlier recovery
compared with the use of a full dose of propofol
alone. Therefore, the present study was designed
to test the hypothesis that ketofol would be a good
alternative anaesthetic agent and better than
propofol in ECT procedures.
MATERIALS AND METHODS
Our prospective, randomised, double-blind, cross-
over study included 25 patients with American
Society of Anesthesiologists physical status I to II
who were referred to our clinic for ECT. The age
range was 18 to 65 years. Prior to the study, approval
of the Inonu University Local Ethics Committee
(acceptance number 2010/162) and written informed
consent of each patient and/or their relatives
was obtained. Six consecutive ECT sessions were
included in the assessment. Patients with pregnancy,
cerebrovascular disease, epilepsy, myocardial
infarction within the past six months, as well as
those using anticonvulsant drugs, were excluded.
One of the patients was excluded during the study
due to severe hypertension during ECT after four
sessions.
The patients were taken into the operating room
without any premedication and they were subjected
to routine monitoring. Thereafter, patients were
randomly assigned into two groups by computer-
generated random numbers to receive either ketofol
or propofol for the initial ECT. In the following
ECT sessions the groups were crossed over to the
other agent, respectively (3:3). Ketofol was prepared
as a 1:1 mixture of ketamine 10 mg/ml and propofol
10 mg/ml whereas propofol was prepared as
propofol 1% solution. Study drugs were drawn up in
20 ml syringes. Determination of the study groups
and preparation of the drugs were carried out by
an anaesthetist not present in the operating room
during ECT sessions. Anaesthesia induction was
achieved with 1 mg/kg ketofol (0.5 mg/kg propofol
plus 0.5 mg/kg ketamine) or by 1 mg/kg propofol
1% and both were delivered within 30 to 60 seconds.
Consciousness was evaluated by the absence of
response to verbal commands and loss of eyelash
reflex. If needed, additional doses were administered
from the drug remaining in the same syringe and
recorded.
After loss of consciousness an isolated forearm
technique was performed by inflating the tourniquet
that had been applied on the right arm and an
electrode was placed on the right hand
for electromyography recording. Thereafter, a
succinylcholine 0.5 mg/kg bolus was administered
intravenously from the contralateral arm. The
patients were ventilated with 100% O2 at 20 breaths
per minute. Then a psychiatrist blinded to the
study groups administered electrical stimuli through
bifrontotemporal electrodes (Thymatron System
IV, Somatics Inc., Lake Bluff, IL, USA). In the first
session, the patients received ECT with 30 to 50%
of the maximum output stimulus depending on
the psychiatrist’s choice. After the first session, the
same psychiatrist organised the stimulus amplitudes
according to each patient’s clinical outcomes.
Motor seizure duration, electroencephalogram
(EEG) seizure duration, and postictal suppression
index (PSI) were recorded from the EEG and
electromyography traces obtained during the seizure.
Systolic blood pressure (SBP), diastolic blood
pressure (DBP), mean blood pressure (MAP), heart
rate (HR) and peripheral oxygen saturation values
were recorded before the seizure (Tbaseline), after
the seizure (T0), and following the ECT session
at one (T1), three (T3), five (T5), and 10 (T10)
minutes.
The time from the end of succinylcholine
administration to recovery of spontaneous breathing,
eye-opening and time to obey to verbal commands
were recorded separately. Presence of complications
such as arrhythmia, laryngospasm and agitation
were recorded. The patients were checked for
nausea/vomiting and the presence of untoward
psychological reactions in the recovery room and
on the following day.
A difference of at least six seconds of seizure
duration between two groups was considered
clinically significant as observed in a previous study13.
For a power of 0.8 and α=0.05, a sample size of
11 patients in each group was required. Statistical
analysis was performed using SPSS for Windows
version 13.0 program. All data were reported as
mean±SD. Normality for continued variables in
groups was confirmed by a Shapiro Wilk test. Un-
paired t-test and paired t-test were used. P <0.05
was considered statistically significant.
Anaesthesia and Intensive Care, Vol. 40, No. 2, March 2012
 KEtofol in Ect thErapy 307

RESULTS tablE 1
The mean age for the 13 women and 11 men Seizure, recovery parameters and supplemental doses with
ketamine:propofol combination (ketofol) or propofol
included in the study was 26 years (range 19 to
46 years) and their mean weight was 70 kg (range 50 Ketofol, n=72 Propofol, n=72
to 93 kg). Patients received a total of 144 ECTs in
Seizure parameters
six sessions within a three-days-per-week program.
The clinical diagnoses of the patients were Motor seizure duration(s) 29±17 28±13
schizophrenia in 12, bipolar affective disorder EEG seizure duration(s) 41±17 38±16
in eight, major depression in two, postpartum PSI, % 89.63±7.88* 79.74±14.6
psychosis in one and conversion disorder in one Recovery parameters(s)
patient.
Spontaneous breathing 163±73 171±77
There was no statistically significant difference
between ketofol (29±17 seconds) and propofol Open eyes 321±81 304±95
(28±13 seconds) with regard to motor seizure Obey commands 484±120** 424±100
duration. Although EEG seizure duration was Supplemental doses, mg 27.88±13 30.78±22.86
longer with ketofol than propofol (ketofol 41±17 EEG=electroencephalogram, PSI=postictal suppression index.
seconds, propofol 38±16 seconds), the difference Values are mean±SD. * P <0.001, ** P=0.006

180
Propofol
160
Ketofol
140
Heart rate (bpm)

120

100

80

60

40
Tbaseline T0 T1 T3 T5 T10
Time
fiGurE 1: Heart rate values using the ketamine:propofol combination (ketofol) and propofol. Tbaseline=before the seizure;
T0=after the seizure; T1, T3, T5 and T10=following the ECT session at 1, 3, 5 and 10 minutes repectively. * P <0.05 between groups.

200 Propofol

180 Ketofol

160
SBP (mmHg)

140

120

100

80

60
Tbaseline T0 T1 T3 T5 T10
Time
fiGurE 2: Systolic blood pressure values using the ketamine:propofol combination (ketofol) and propofol. Tbaseline=before the seizure;
T0=after the seizure; T1, T3, T5 and T10=following the ECT session at 1, 3, 5 and 10 minutes respectively. * P <0.05 between groups.
Anaesthesia and Intensive Care, Vol. 40, No. 2, March 2012
308 G. ErdoGan Kayhan, a. yucEl Et al
was not statistically significant or clinically relevant.
EEG seizure duration was below 25 seconds in eight
sessions with ketofol and 14 sessions with propofol.
The PSI value was higher with ketofol (89.63±7.88)
than with propofol (79.74±14.6). Motor seizure
duration, EEG seizure duration and PSI value are
shown in Table 1.
The HR at T0 was higher than the baseline value
with ketofol, but significantly lower than the baseline
value at T1 (P=0.001, P=0.034 respectively). With
propofol, HR was significantly higher at T0 and T5
compared with the baseline (P=0.001, P=0.034
respectively). There was a significant difference
between the ketofol and propofol in terms of HR
at T0 and ketofol led to higher HRs (P=0.03).
The SBP, DBP and MAP values were significantly
higher at all timepoints in the ketofol group
compared with the baseline values (P=0.001). In
the propofol group, while SBP was observed to be
significantly higher at all timepoints (P <0.004),
DBP and MAP values were determined to be
higher at T0, T1, T3, and T5 compared with the
baseline (DBP P <0.029; MAP P <0.001). The
comparison of the two groups revealed differences
in SBP at T0 and T1 (P=0.018, P=0.034); in
DBP at T0, T1, T3, and T5 (P=0.001, P=0.002,
P=0.011, P=0.007); and in MAP at T0 and T5
(P=0.001, P=0.033). Ketofol was found to cause
significantly higher increases at all those timepoints
compared with the propofol. HR and SBP data
are shown in Figures 1 and 2.
No differences were observed between ketofol
and propofol regarding recovery of spontaneous
breathing (163±73 and 171±77 seconds, respectively)
and eye-opening (321±81 and 304±95 seconds,
respectively). Time to obeying commands was
significantly longer in the ketofol group (ketofol
484±120 seconds; propofol 424±100 seconds;
P=0.006) (Table 1).
While an additional dose was required after 53
ECT procedures in the ketofol group and only
32 ECT procedures in the propofol group, the
difference was not statistically significant (Table 1).
During recovery, laryngospasm was observed in
one case in each group. Moreover, we encountered
agitation in one patient during one session, nausea/
vomiting in one patient in one session and atrial
arrhythmia in one patient in one session with
ketofol. We did not encounter untoward psycho-
logical reactions with ketofol.
DISCUSSION
To our knowledge, this is the first reported use
of a ketamine:propofol combination (ketofol) for
ECT anaesthesia. We compared this to the use of
propofol which we previously used routinely in our
clinical practice. According to our observations the
seizure quality was better with ketofol in comparison
to the propofol group. However, we found no
statistically significant difference between the
ketofol and the propofol groups with regard to
motor seizure duration and EEG seizure duration.
Seizure duration has been shown to be prolonged
by decreasing the propofol dose and by adding
short-acting opioids as adjuvants14,15. In our study, we
followed the same principle; the propofol dose was
reduced by combination with low-dose ketamine.
However, at the doses we used, no significant
prolongation was found in the seizure durations.
Previous reports suggest that ketamine provides
longer seizure durations than other anaesthetics1,3,16.
Krystal et al3 retrospectively investigated cases in
which ECTs with methohexitone produced seizures
lasting shorter than 25 seconds, despite maximal
stimulation, and reported that the addition of
ketamine at a mean dose of 1.31 (0.7 to 2.8) mg/kg
increased seizure duration in 30 of 36 cases. On the
other hand, there are also studies suggesting that
ketamine does not prolong seizure duration during
ECT procedures17,18. Rasmussen et al17 used ketamine
during ECT in 10 patients with no extension of
motor and EEG seizure length. They used ketamine
at higher doses (1.04 to 3.12 mg/kg) and later in the
course they noted that these factors were possible
explanations for why ketamine seizures were not
longer. In our study, despite the use of lower dose
ketamine and propofol, no extension of seizure
duration was observed.
However, some investigators have reported that
multiple-lead EEGs recorded during ketamine
seizures revealed greater ictal power, suggesting that
there might be qualitative differences in the seizure
between ketamine and methohexitone17.
It has been suggested that seizure duration and
seizure quality have no relationship19-21. Moreover,
studies underline the importance of seizure quality
in terms of the clinical efficacy of ECT3,20,21. It has
been suggested that clinical efficacy is primarily
correlated with more intense seizure activity with
higher amplitudes on EEG and more pronounced
PSI20. The PSI reflects how quickly the EEG
amplitude decrease ‘flattens’ just after the end of
seizure and is more directly related to the intensity
or generalisation of seizure than to its duration19.
Under that circumstance we believe that ketofol can
be more suitable for enhancing seizure quality and
clinical effectiveness of ECT. However, the clinical
efficacy and therapeutic response of study drugs
Anaesthesia and Intensive Care, Vol. 40, No. 2, March 2012
 KEtofol in Ect thErapy
could not be evaluated in this study because of the
crossover design.
In relation to haemodynamic parameters, propofol
appeared to provide better management of the
cardiovascular response to ECT. Studies comparing
ketofol and propofol have shown that ketofol
provides better haemodynamic stability9,10. In some
studies, drugs were delivered during regional
anaesthesia for achievement of adequate deep
sedation. Therefore, ketofol may be more
advantageous than propofol in preventing hypo-
tension or maintaining stable haemodynamics
after anaesthesia induction. In our study, we did
not evaluate the haemodynamic parameters after
anaesthesia induction. However, ketofol was
observed to be less effective than propofol in
managing the cardiovascular sympathetic response
during seizure activity. Krystal et al3 were able to
perform haemodynamic evaluations in only 12 of
36 cases in which ketamine was used. They found
no difference between ketamine and methohexitone
in relation to peak HR and SBP, whereas DBP
was found to be higher among patients receiving
ketamine. Rasmussen et al13 found that blood
pressurewas higher in the ketamine group than in
the methohexitone group. Ketofol may provide a
better haemodynamic stability compared with the
ketamine alone. However, we cannot comment on
this because our study did not include a ketamine
group.
While there was no difference between the groups
in terms of early recovery criteria including time to
spontaneous breathing and eye-opening, time
to obeying verbal commands was more prolonged
in the ketofol group. In a study by Andolfatto et
al10, recovery time was 14 minutes in the emergency
cases that had received ketofol in the 0.2 to
2.7 mg/kg range. In their study there was no
propofol group and unlike our study, recovery
criteria were assessed by a modified Aldrete Scale.
Singh et al22 used regional anaesthesia on paediatric
patients and infused a mixture of propofol and
ketamine for sedation. They utilised a modified
Aldrete Scale as the recovery criteria and found
no difference. The conflicting results between our
study and the abovementioned studies may be
due to the different age group and different
procedures.
Krystal et al3 found side-effects in three of 36
cases with ketamine. Two patients exhibited agitation
during recovery from anaesthesia and one developed
hallucinations lasting until the next day. This case
was an alcoholic patient who had received high-
dose ketamine (2.8 mg/kg). Ketamine is known to
Anaesthesia and Intensive Care, Vol. 40, No. 2, March 2012
309
cause untoward psychological reactions such as
hallucinations in a dose-dependent way. Therefore
some authors believe that this side-effect can be
prevented by using an adjuvant at a subanaesthetic
dose7. Nagato et al found that propofol could inhibit
psychomimetic activity associated with ketamine
by inducing γ-aminobutyric acid type A receptor
activation in animal studies23,24. Although some of
our patients were suffering from schizophrenia,
an untoward reaction was not encountered during
ketofol administration in any of the sessions. Only
one patient, who had a bipolar affective disorder,
exhibited agitation for a brief period after the
procedure. Thus ketofol use may be a safer
strategy for prevention of untoward psychological
reactions.
In the current study, we prepared ketofol mixture
at 1:1 ratio as in previous studies10,11,25. The initial dose
was 1 mg/kg in both groups, but the requirement
for additional doses was more frequent in the
ketofol group. Daabiss et al compared two different
mixtures of propofol and ketamine and found that
while the sedation scores were the same, side-effects
were reduced and recovery was shortened with a
lower dose of ketamine26. Therefore, we believe that
varying ketamine and propofol rates can be tested
in order to improve requirement for additional
dose, haemodynamics, recovery and side-effects.
We evaluated patients’ various clinical diagnoses
in our study. Ketofol may have different effects
on distinct clinical diagnoses like schizophrenia or
major depression. In some studies investigators
have observed rapid and strong antidepressant
effects at subanaesthetic doses of ketamine in
medical and ECT treatment-resistant depression
patients27,28. Zarate et al used a single dose of
intravenous ketamine (0.5 mg/kg in 40 minutes)
and observed improvement in depression starting
between 110 minutes and seven days27. Okamoto
et al compared ketamine and propofol in ECT
anaesthesia for treatment-resistant depression
patients. They observed an earlier recovery in
patients who received ketamine5. Therefore it is
possible that a subanaesthetic dose of ketamine,
such as that used in our study, may cause more rapid
recovery in major depression patients. However,
future studies are required on this issue.
In summary, ketofol used at a 1 mg/kg dose for
ECT procedures yielded similar seizure durations
as propofol, but produced a better seizure quality.
Accordingly, we conclude that ketofol can be an
alternative agent to enhance the seizure quality
and possibly clinical efficiency of ECT. However,
future studies are required to evaluate the effects of
310 G. ErdoGan Kayhan, a. yucEl Et al
ketofol with different concentrations and in
different clinical diagnostic groups.
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