Journal of Clinical Monitoring and Computing

https://doi.org/10.1007/s10877-020-00619-3

ORIGINAL RESEARCH

Comparison of the Conox (qCON) and Sedline (PSI) depth

of anaesthesia indices to predict the hypnotic effect during desflurane
general anaesthesia with ketamine
Catherine Christenson1 · Pablo Martinez‑Vazquez2,3 · Max Breidenstein1 · Borzoo Farhang1 · Jackson Mathews1 ·
Umberto Melia2 · Erik Weber Jensen2,4 · Donald Mathews1

Received: 14 February 2020 / Accepted: 9 November 2020

© Springer Nature B.V. 2020

Abstract
Comparison of two depth of anesthesia indices, qCON (Conox) and PSI (Sedline), during desflurane sedation and their
sensitivity to random ketamine boluses in patients undergoing routine surgery. The performance of desflurane and ketamine
on both indices was analyzed for 11 patients, and the ketamine sensitivity was compared with another group of 11 patients
under sevoflurane and propofol.
The MOAA/S was used to determine sedation level and pain. Different boluses of ketamine ranging from 10 to 30 mg where
randomly administered in both groups and the effect on the indexes were measured after 4 min.
The indices were recorded during the whole surgery, and their correlations with the desflurane concentration and the discrimi-
nation between awake and anesthetized states were evaluated with the prediction probability statistic (Pk). The Pk values,
mean (se), discriminating between awake and anesthetized states were 0.974(0.016) for the qCON and 0.962(0.0123) for
the PSI, while the 1-Pk statistic for the qCON and the PSI with respect to the desflurane concentration were 0.927(0.016)
and 0.918(0.018), respectively, with no statistically significant differences.
The agreement between both depth of hypnosis parameters was assessed under the Bland-Altman plot and the Spearman
correlation, rs = 0.57(p < 0.001).
During the sevoflurane-propofol anesthesia, which served as a control group, both indices experienced a similar behavior
with a no significant change of their median values after ketamine. However, during desflurane anesthesia the qCON index
did not change significantly after ketamine administration, qCON (before = 33 (4), after = 30 (17); Wilcoxon, p = 0.89), while
the PSI experienced a significant increase, PSI (before = 31(6), after = 39(16) Wilcoxon, p = 0.013).
This study shows that qCON and PSI have similar performance under desflurane with good discrimination between the awake
and anesthetized states. While both indices exhibited similar behavior under ketamine boluses under a sevoflurane-propofol
anesthesia, the qCON index had a better performance under ketamine during desflurane anesthesia.

Keywords Anesthesia · Depth · EEG · Ketamine · Propofol · Sevoflurane

1 Introduction

Depth of anesthesia (DA) monitors process cortical brain

activity patterns from electroencephalogram (EEG) signals
* Pablo Martinez‑Vazquez
pmvazquez@dpz.eu induced by anesthetics drugs which depress the CNS. The
complexity of anesthetic-induced EEG patterns is summa-
1
University of Vermont Medical Center, Burlington, VT, rized in dimensionless indices reflecting the hypnotic com-
USA ponent of the anesthesia. Over the last few decades, reports
2
Quantium Medical, Mataro, Barcelona, Spain in multiple and diverse surgical scenarios have shown the
3
Deutsches Primaten Zentrum (DPZ)GmbH, Gottingen, benefits of these monitoring technologies when supporting
Germany the anesthesiologist’s practice. Benefits range from reducing
4
Fresenius Kabi GmbH, Bad Homburg, Germany the incidence of awareness [7, 21, 33], to tailoring anesthesia

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 Journal of Clinical Monitoring and Computing

to optimize drug consumption [25, 30, 32], to potentially In this study, we quantified the sensitivity to ketamine
attenuating post-operative adverse effects [5, 16, 17]. Stud- under desflurane for two DA indices, both designed under
ies of anesthesia under propofol and sevoflurane showed different signals processing frameworks but sharing the
that despite these technologies relying on different signal same source of information, the EEG.
processing frameworks, their agreement is strong [3, 12, 20],
mainly because they share a common source of information,
the EEG signal. Unfortunately, due to the lack of a gold 2 Materials and methods
standard on establishing the patient’s real hypnotic state,
DA monitoring systems work on its estimation, which needs 2.1 Patients
to be continuously evaluated on distinct drugs and surgical
scenarios where relative differences in index performances After approval from the University of Vermont IRB and
are shown [11, 24]. informed consent, 22 patients undergoing elective routine
In this study, we evaluate the performance of two DA surgery were enrolled in this study. All patients survived and
indices, the qCON depth of hypnosis index (Conox, Quan- were discharged with no neurological symptoms. Patients
tium Medical, Spain/Fresenius Kabi, Germany) and the who had any history of neurologic, cardiac, pulmonary,
Patient State Index (PSI; Sedline, Massimo, USA), under hepatic, or renal disease, mental disorders or drug addiction,
desflurane and its combination with ketamine during routine and dysfunction of the upper limbs were excluded. A group
surgery. The effects of ketamine on the indices under des- of 11 patients were titrated with desflurane anesthesia while
flurane were compared to a control group under combined a second control group of 11 patients underwent combined
sevoflurane and propofol. sevoflurane-propofol anesthesia.
Desflurane is a highly fluorinated methyl-ethyl ether Patient demographics, preexisting medical problems and
used for induction and/or maintenance in general anesthe- concurrent medication usages were recorded. The patient
sia (GA), and is one of the most commonly used volatile demographics are summarized in Table 1.
anesthetic agents with an excellent safety record. Desflurane In both groups, the sedation was guided by clinical judg-
mainly acts on the lipid matrix of the neuronal membrane ment in combination with the Modified Observer’s Assess-
while enhancing the synaptic activity of the inhibitory neu- ment of Alertness/Sedation (MOAA/S), rather than by one
rotransmitter Gamma-aminobutyric acid ­(GABAA) [22, 23]. of the monitoring devices. Concentrations of anesthetics
Both mechanisms disrupt neuronal transmission in the brain. were recorded and distinct ketamine boluses ranging from
Despite the strong similarities in the induced EEG patterns 10 to 30 mg were administered randomly when both indi-
by desflurane with respect to other GABAergic agents, such ces were lower than 60. Two ketamine boluses given to two
as propofol and sevoflurane, there are some significant dif- patients undergoing desflurane were discarded in the analy-
ferences in the EEG that might have an impact on some DA sis of ketamine effect, since their administration did not ful-
indices, warranting further evaluation. fill the requirement of both indices lower than 60. However,
Ketamine, on the other hand, is a non-GABAergic intra- these two recordings were used for the indices comparisons
venous dissociative anesthetic drug [6, 19] that induces an under desflurane.
EEG pattern quite distinct from other GABAergic drugs.
Ketamine is commonly used in GA, mostly in combina-
tion with other drugs, playing a role in sedation and anal- Table 1  Demographic characteristics of the subjects. Data are
gesia [28], since it is an uncompetitive antagonist of the expressed as mean ± SD. BMI, body mass index; ASA, American
ionotrophic N-methyl-D-aspartic acid (NMDA) receptor Society of Anesthesiologists physical status
involved in excitatory neurotransmission [2]. Ketamine also Patients Males Females
appears to play a role in positive and negative modulation of
the cholinergic, aminergic, and opioid systems. Contrary to n 22 7 15
GABAergic agents, ketamine does not suppress but rather Desflurane 11 3 8
enhances some cortical activity in sensory areas [18, 19], Sevoflurane- 11 4 7
propofol
which might explain why ketamine translates into some
Age (SD) 46.95 ± 17.36 46.00 ± 18.92 47.40 ± 17.26
EEG patterns resembling lower depth of hypnosis, poten-
ASA I 3 1 2
tially biasing some DA indices, depending on the ketamine
II 16 6 10
concentration and the anesthesia context [9, 26, 31]. The
III 3 – 3
ketamine relevant effect localizes on association and higher-
Weight (SD) 87.07 ± 22.38 79.11 ± 21.63
order cortical areas with the disruption of the sensory inputs
Height (SD) 178.86 ± 4.78 163.53 ± 7.81
perception [18, 19]. The effects of ketamine on brain net-
BMI (SD) 27.36 ± 7.75 29.66 ± 8.27
works are nowadays an open issue.

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2.2 EEG recording and replay
The PSI (Sedline) and the qCON (Conox) index were saved
throughout the intraoperative period every second during the
complete procedure as well as the concentrations of desflu-
rane and analgesics. The exact time of the following stages
of the surgery were recorded: start and end of induction, start
and end of intubation/laryngeal mask placement, reporting
any reflexive patient movement following noxious stimula-
tion, start and end of surgery, and emergence from anesthe-
sia. Dosages of anesthetics, analgesics, and local anesthetics
administered during surgery were recorded. Recovery times
from discontinuation of the anesthesia until eye-opening,
following verbal commands, orientation to person, meet-
ing PACU discharge criteria were also saved, as well as the
patient’s analgesic and antiemetic medication requirements.
2.3 Statistical analysis
The correlation measurements on the performance of DA
indices was implemented using the Prediction probability
index (Pk) [29]. For strong positive correlations, Pk values
approaches to 1 (when one variable predicts perfectly the
other variable). Negative correlations produce Pk values
around 0 (when one variable predicts perfectly the other
variable with opposite trend). Pk values around 0.5 indicate
no correlation; no variable can predict the other better than
a 50:50 chance.
Indices where contrasted using the Bland-Altman plot [4],
as well as the Spearman rank correlation.
Fig. 1  Example of the time evolution of qCON and PSI indices. Complementary information provided by the DA monitors: EMG- Electromyo-
gram, BSR-Burst Suppression, SQI- Monitor Signal Quality Index on data signal to noise ratio estimation
The statistical comparisons between two related samples
were performed using Wilcoxon signed-rank test, and the
significance level in this study was set to p < 0.05.
The statistical values will be provided as mean and stand-
ard error, mean(se), or as median and interquartile range,
median(iqr), correspondingly.
3 Results
3.1 Depth of anesthesia indices under desflurane
Figure 1 shows an example of the time evolution of the
two DA systems for a patient’s case. Both DA monitors,
CONOX and Sedline, provide a hypnotic index, qCON
and PSI, as well as the Burst Suppression Ratio (BSR), the
Electromyography (EMG) and a Signal Quality Index (SQI)
measurement. The SQI for the qCON ranges from, where
lower values indicate poorer signal to noise ratio or more
artifacts within signal. The PSI SQI varies in the same range,
but higher values mean lower quality. In the trial depicted
in Fig. 1, the presence of diathermy artifact takes place at
4000 s after induction. In this case, comparing both indices
behaviors, the PSI seems to be significantly affected from
the presence of this artifact, while it is not the case for the
qCON which appears more robust against artifacts.
3.1.1 Indices and patients depth of hypnosis state
The comparison between both indices on the estimation
of the hypnotic state was performed by calculating the Pk
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Table 2  Pk values (mean ± se) for the qCON and PSI indices dis- Table 3 shows the statistical comparison between the
criminating between awake and anesthetized states. Awake state was qCON and PSI indices with respect to the desflurane con-
coded as 0 and anesthetized as 1
centration for the boxplot data shown in Fig. 2. No statistical
Awake vs. qCON PSI Ho: PSI = qCON significance was found between either 1-Pk values.
Anaesthesiated (n = 22 × 1000) (n = 22 × 1000) (Wilcoxon test)
0 1 3.1.3 Depth of hypnosis indices agreement
Pk (m ± se) 0.974 ± 0.016 0.962 ± 0.0123 p = ns
The agreement assessment between both indices was evalu-
ated with the Bland–Altman plot and the scatter plot shown
in Fig. 3. Each monitor provided an index update every sec-
Table 3  1-Pk values (mean ± se) for the qCON and PSI indices cor- ond during the whole intraoperative period for all recordings
relation with the desflurane concentration consisting of n = 76,129 samples. The global agreement was
DA indices vs. qCON PSI (n = 137) Ho: PSI = qCON evaluated on the same data with the Spearman rank correla-
desflurane (n = 137) (Wilcoxon test) tion statisticrs = 0.57(p < 0.001).
1-Pk (m ± se) 0.927 ± 0.016 0.918 ± 0.018 p = ns
3.2 Effect of ketamine on the indices
under Desflurane regime and its comparison
with sevoflurane‑propofol
values between the patient’s behavioral responses to the
anesthesiologist’s evaluation. The values were obtained by The effect of ketamine on qCON and PSI was evaluated by
averaging 1000 times the PK values obtained from 11 pairs comparing their values before and 4 min after different ran-
of data values, one per patient, randomly selected for each dom boluses of ketamine during desflurane anesthesia and
state, and coded as (Anesthesia = 1/Awake = 0), to ensure sevoflurane-propofol anesthesia, with the latter anesthetic
statistical independency. The interval considered for the data regimen as a comparator. Figure 4 shows the index changes
pairs selection was from 2 min before induction until just before and after ketamine, as well as their median and inter-
prior to emergence. quartile range, for 9 ketamine boluses under desflurane and
The Pk for the qCON and PSI for awake and anesthetized 11 boluses of ketamine under sevoflurane-propofol anes-
are shown in Table 2. thesia. The boluses were administered when both indices
reached a stable value less than 60 for 1 min.
3.1.2 Correlation between the indices and the desflurane Under desflurane anesthesia, the qCON index did not
concentration change significantly after ketamine administration, although
there was a negative trend [qCON (before = 33 (4), after = 30
The correlation between indices was computed using the (17); Wilcoxon, p = 0.89)]. The PSI index experienced a
1-Pk statistic, since both dimensionless indices definitions significant increase after ketamine administration [PSI
have a negative trend to the anesthetic agents’ concentra- (before = 31(6), after = 39(16) Wilcoxon, p = 0.013)].
tions. This is done to facilitate the reading of strong cor- Under sevoflurane-propofol anesthesia, neither index
relations to values close to 1, rather than to 0 for the high experienced a significant change after the ketamine
negative correlation that the Pk value provides. boluses, [qCON (before = 43 (7), after = 52 (7.5); Wilcoxon,

Fig. 2  Hypnotic index values respect to the desflurane end-tidal concentrations on the 11 patients. (a) qCON index vs. desflurane concentration.
(b) PSI index vs. desflurane concentration. Boxplots represent the median and interquartile range

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Journal of Clinical Monitoring and Computing
Fig. 3  Agreement assessment between the hypnotic indices qCON and PSI during the whole intra-operative period for the desflurane anesthesia,
76,129 sample pairs of both indices. (a) Bland–Altman plot. (b) Bivariate plot
p = 0.25)] and [PSI (before = 30(11.5), after = 34(9) Wil-
coxon, p = 0.53)].
The overall performance after ketamine under both types
of anesthesia shows a common increment trend of the indi-
ces, around 5, which is significant only for the PSI, [qCON
(before = 40 (12), after = 45 (22); Wilcoxon, p = 0.15)] and
PSI [(before = 31(11), after = 37(17) Wilcoxon, p = 0.027)].
Comparable results were found at 2, 3, and 5 min after the
bolus administration.
4 Discussion
4.1 Indices performance under desflurane
Desflurane partly shares the same receptor action as other
GABAergic drugs, such as propofol [8, 13, 27] and sevoflu-
rane [10, 22], which translates into very similar outcome sig-
natures on the EEG during induced anesthesia, mainly with
increments of slow and alpha wave activities, but with some
small differences, such as the frequency bands domain [14,
15]. While propofol induces alpha activity with an activity
peak located at∼10Hz, under desflurante the alpha activity
center is shifted to lower values∼8Hz.
The strong similarities in the induced EEG activities by
desflurane with respect to other GABAergic agents, is cor-
roborated with the high obtained Pk values of both indi-
ces discriminating between awake and anesthetized state,
with slightly higher PK for the qCON (Table 2). The reason
for the higher Pk for the qCON is likely due to artifactual
increases in the PSI caused by the use of the diathermy
or EMG activity as shown in Fig. 1. The PSI appears to
be more influenced by high frequency activity than does
the qCON. In periods without diathermy the two indices
showed a similar behavior. Globally, there is a high correla-
tion between the indices and the desflurane concentration
(Table 3 and Fig. 2). These performance results indicate
that the differences of the desflurane induced EEG activi-
ties, specifically, the alpha activity shifting to lower values
than other GABAergic drugs, has no observable negative
effect, with comparable performances of both indices to the
ones reported in other studies with propofol and sevoflurane.
Globally, both indices are highly correlated with a trend of
the qCON being slightly more conservative in the assess-
ment of the hypnotic state.
4.2 Sensitivity performance under ketamine
Ketamine induces quite distinct EEG patterns, which can
significantly bias the performance of DA systems [9, 26, 31],
especially due to its dissociative anesthetic characteristic [6,
19], where the sensory inputs may reach cortical receiving
areas, but fail to be perceived in some association areas [19].
Mainly, ketamine enhances slow-delta (0.1 − 4Hz) oscilla-
tions, with coherent theta (4 − 8Hz) and gamma oscillations,
while decreasing the alpha/beta (∼10 − 24Hz) activity. At
higher concentrations, ketamine induces a characteristic
gamma burst pattern in which coherent gamma oscillations
alternate with periods of slow oscillations [1].
An open issue arises when ketamine is used in GA. What
should be the desired behavior of a DA monitor under a keta-
mine bolus? While the analgesic effect of ketamine is clear,
the effect of ketamine on hypnosis is yet not well understood
due to its dissociative effect, which it is not characterized
with a suppression of the sensory inputs at cortical level but
rather a disruption-dissociation of the sensory information
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Fig. 4  Effect of ketamine boluses on the qCON and PSI. Paired boxplots (median and interquartile range) and Wilcoxon signed rank test. (a)
Influence of ketamine boluses during desflurane anesthesia, (b) during sevoflurane-propofol anesthesia, and (c) for both groups

processing at the association areas, at higher-order process- acting on GABA receptors where the sensory inputs are sup-
ing levels. This is a completely different mechanism of pressed. Therefore, the question that comes is, what is the
action for hypnosis than, for instance, propofol or desflurane net effect of ketamine on hypnosis when combined with

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Journal of Clinical Monitoring and Computing
GABA agents? Obviously, the dissociative effect of keta-
mine on sensory processing cannot produce any conscious-
ness arousal, an undesirable bias that DA monitors should
avoid. But, should it lower significantly the hypnosis level?
The answer it seems, is not so evident yet, especially when
ketamine is combined with drugs suppressing the afferent
information on the sensory areas which later pass to the
association areas. In that respect, it is possible that disrup-
tion of sensory information processing might have low or no
significant effect on the hypnosis when sensory information
is not present.
In summary, in principle, at least in combination with
GABA drugs, it is desirable a DA monitor to be robust
against ketamine bias toward high values. However, the net
effect of ketamine might be low or insignificant compared to
the main effect of the GABA agents, a situation that surely is
dose-dependent. Further research is needed to evaluate the
net effect of ketamine on hypnosis.
During GABAergic anesthesia, consisting of a combina-
tion of sevoflurane and propofol, both indices experienced
a similar behavior after ketamine with no significant change
of their median values. However, during a desflurane regime
the qCON index showed better performance under ketamine
compared with the PSI, which showed a significant increase
in their median values.
Overall there is a common trend to increase the indices
after the bolus administration, around 5 units, which is sta-
tistically significant for the PSI. In practice, both indices
show similar performance under ketamine.
5 Conclusions
Both monitoring indices showed similar performance under
desflurane with good discrimination between the awake
and anesthetized states, and correlation with the desflurane
concentration.
While both indices exhibited similar behavior after keta-
mine boluses under sevoflurane-propofol anesthesia, the
qCON index had better performance after ketamine during
desflurane anesthesia.
Compliance with ethical standards
Conflict of interest Catherine Christenson, Max Breidenstein, Borzoo
Farhang, Jackson Mathews and Donald Mathews declare no conflict
of interest. Pablo Martinez-Vazquez, Umberto Melia and Erik Weber
Jensen are employees of Quantium Medical. Quantium Medical is the
commercial developer for the qCON index.
Ethical approval The study was performed after IRB approval (Com-
mittees on Humans Subjects. Serving the University of Vermont and
the UVM Medical Center), code CHRMS 15-618. All the patients have
written informed consent.
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