Journal of Clinical Anesthesia (2014) 26, 2535

Original Contribution

Propofol for pediatric tracheal intubation with deep

anesthesia during sevoflurane induction: dosing according
to elapsed time for two age groups
George D. Politis MD, MPH (Associate Professor of Anesthesiology and Pediatrics)a,,
Christopher J. Stemland MD (Associate Professor of Anesthesiology and Pediatrics)a ,
Ravi K. Balireddy MB, BS (Research Associate)a ,
Julie Brockhaus (Research Coordinator)a , Kevin R. Hughes MD (Resident)a ,
Matthew D. Goins MD (Resident)a , Timothy L. McMurry PhD (Statistician)a
a

Department of Anesthesiology, University of Virginia Health System, Charlottesville, VA 22908, USA

Received 14 February 2013; revised 26 July 2013; accepted 3 August 2013

Keywords:
Anesthesia: inhalational
intratracheal, intravenous;
Intubation intratracheal;
Pediatrics

Abstract
Study Objective: To determine, for two different age groups, the effect of duration of sevoflurane
administration on the amount of propofol needed when performing tracheal intubation.
Design: Classic Dixons Up-and-Down sequential method.
Setting: University based operating rooms.
Patients: 106 ASA physical status 1 and 2 patients aged one to 11 years.
Interventions: Patients were allocated to the 16 year ( 12 and b 72 mos) and 611 year ( 72 and
b 132 mos) age groups. Midazolam 0.5 mg/kg was given orally to the 16 year group, and all
patients were induced with 8% dialed sevoflurane and 67% nitrous oxide (N2O), with N2O
discontinued and sevoflurane dialed to 5% after one minute and 1.5 minutes for the younger and
older age groups, respectively. Intravenous access was obtained and propofol was promptly
administered. Propofol dose was determined according to age group and whether propofol was given
24, 46, or 68 minutes after the start of sevoflurane induction, with Dixons Up and Down Method
used separately for each specific age/time group. Tracheal intubation conditions one minute after
propofol were evaluated.
Measurements: Isotonic regression determined propofol ED50 estimates for excellent tracheal
intubation conditions, and linear regression determined the effect of propofol dose on change in
systolic blood pressure (SBP).
Main Results: Estimated propofol ED50 doses for 16 year olds, with 95% confidence intervals (CIs),
were 1.48 mg/kg (0.80, 2.03), 0.00 mg/kg (0.00, 0.38), and 0.07 mg/kg (0.00, 0.68) in the 24, 46,
and 68 minute groups, respectively, with estimated differences between the 24 minute group
versus the 46 and 68 minute groups being 1.47 mg/kg (95% CI = 1.04, 2.06) and 1.41 mg/kg (95%

Supported by the University of Virginia Health System Department of Anesthesiology.

Correspondence: George D. Politis, MD, Department of Anesthesiology, University of Virginia Health System, P.O. Box 800710, Charlottesville, VA
22908, USA.
E-mail address: gdp8a@virginia.edu (G.D. Politisy).

0952-8180/$ see front matter 2014 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.jclinane.2013.08.005

26

G.D. Politis et al.

CI = 0.74, 2.04), respectively. Estimated propofol ED50 doses for 611 year olds, with 95% CIs,
were 2.35 mg/kg (1.97, 2.45) and 2.33 mg/kg (1.59, 2.45) in the 24 and 46 minute groups,
respectively. Diminutions in SBP at one minute and two minutes after propofol administration were
dose dependent for children 16 years of age, decreasing 5.3% and 8.1% for each 1 mg/kg of
propofol, respectively.
Conclusion: The amount of propofol needed to supplement sevoflurane in children 16 years of age
can be expected to decrease after 4 minutes of sevoflurane.
2014 Elsevier Inc. All rights reserved.

1. Introduction
Tracheal intubation of healthy children is frequently
performed during deep anesthesia with no neuromuscular
blockade [1,2]. Sevoflurane alone [35] or in combination
with adjuvants [615] has been used to perform tracheal
intubation during deep anesthesia (TIDA) in pediatric
patients. Propofol supplementation after sevoflurane induction has been deemed one of the most useful techniques for
TIDA [15,16], yet the dose of propofol needed in clinical
scenarios remains unclear because investigations have not
considered the impact of duration of administration of
sevoflurane or patient age (both of which predict intubation
success [5]), have not included children over 8 years of age,
and have not generated results that would apply to
anesthetists who are supervising trainees [1114].
A survey of anesthesiologist members of the Society for
Pediatric Anesthesia published in 1999 found that, for
healthy children 87% of responders induced anesthesia with
inhalation induction, 44% intubated with TIDA, and 78% of
those who used TIDA secured intravenous (IV) access prior
to laryngoscopy [1]. Time to obtain IV access varies
substantially [11], and consequently the effect of time of
administration of sevoflurane on the propofol dose required
for TIDA is particularly important. Our study was planned
with the above practice patterns in mind, and was designed to
independently predict for two separate age cohorts (1272
mos and 72132 mos), using age specific premedication and
induction protocols, the doses of propofol needed for TIDA
after various sevoflurane administration times. The relationship between the dose of propofol used to supplement
sevoflurane for TIDA and alteration of blood pressure (BP)
also was examined.

2. Materials and methods

After receiving approval from the University of Virginia
Health System Institutional Review Board (IRB), we
recruited ASA physical status 1 and 2 patients between one
and 11 years of age, who presented for nonemergent surgery,
in whom tracheal intubation was planned and intraoperative
neuromuscular blockade was not required. The 10-year age
range was divided in the middle to create two age groups, a

16 year age group ( 1 and b 6 yrs) and a 611 year age

group ( 6 and b 11 yrs). Consent was obtained from a legal
guardian of each patient, and each patient who was 7 years
old or older provided patient assent, as per our IRB
requirement. Exclusion criteria were stigmata of a difficult
airway (eg, micrognathia, microstomia, limited neck mobility, limited mouth opening), allergy to propofol, inability to
administer midazolam to patients 16 years old (parents
refused administration or reported a previous adverse
reaction), inability to administer sevoflurane (history of
malignant hyperthermia in pt or first-degree relative), and
weight over 50 kg (to insure a more uniform pt population
with respect to size). Protocol violations resulted in exclusion
from the study.
At least one investigator was present during the induction
and tracheal intubation of each study patient. An instruction
list was given to the anesthesia team participating in the care
of each patient in order to insure familiarity and compliance
with our protocol; directions were given for premedication,
induction, gas flow changes, patient ventilation, intubation,
and evaluation of intubation conditions. The resident
member of the anesthesia team was designated to manage
the airway, including tracheal intubation, providing the
individual had adequate airway management experience;
experienced airway management was ensured by requiring a
minimum of one full rotation through pediatric anesthesia (at
least 4 wks), which also indicated that the resident had a year
or more of clinical anesthesia training. The attending
member of the anesthesia team was designated to manage
the airway when the resident fell short of that requirement.
A diagram of our study protocol is depicted in Fig. 1. The
protocol required all patients in the 16 year age group to
receive oral midazolam elixir 0.5 mg/kg, with a target dosing
time of 1530 minutes prior to the start of induction, while
patients in the older group did not receive midazolam. All
patients received standard ASA monitoring and inhalational
induction with dialed 8% sevoflurane in 4 L/min of nitrous
oxide (N2O) and 2 L/min of oxygen, using primed pediatric
circuits and appropriately sized pediatric masks. Nitrous
oxide was discontinued, O2 was increased to 6 L/min, and
the sevoflurane vaporizer was dialed to 5% at one minute
and at 1.5 minutes from the start of induction for the 16
year and the 611 year age groups, respectively. Sevoflurane was decreased to 5% so as to avoid the greater
diminution of BP associated with longer exposure to 8%

TIDA sevoflurane and propofol

27
Patient Enlistment
(N = 106)

Division by Age
12-72 mo
(N = 72)

Oral Midazolam

72-132 mo
(N = 34)
Wrong dose
(N = 1)

Sevo 8% & N2O 67%

1.0 min
Sevo 5% & 100% O2

Obtain IV Access
& Determine
Timeframe for
Propofol Dose

Wrong
Time

No Premedication

Protocol
Violations
(N = 4)

Sevo 8% & N2O 67%

1.5 min
Sevo 5% & 100% O2

(N = 1)

No IV access
by 8 min
(N = 1)

No IV access
by 8 min
(N = 1)

Obtain IV Access
& Determine
Timeframe for
Propofol Dose

Division by Time to Obtain IV Access

(i.e. duration of sevoflurane at time of
propofol dose)
2-4 min
(N = 19)

4-6 min
(N = 26)

6-8 min
(N = 24)

2-4 min
(N = 15)

4-6 min
(N = 16)

6-8 min
(N = 2)

Administer Propofol ASAP: Dose for 1st Patient in Each Group = 2 mg/kg
Subsequent Dose in Each Group Determined by Result of Previous Patient in Same Group*

Intubation 1 min After Propofol Dose

Fig. 1 Diagram of study protocol showing group divisions by age, then by duration of sevoflurane exposure at the time of propofol
administration. Numbers of patients are given in parentheses. Protocol violations that occurred during the study are shown, including
their numbers. As shown in the image, the experiments for the two age groups were conducted completely independent of one another,
while experiments for all age/time groups were conducted in parallel. Mo=months, N2O=nitrous oxide, IV=intravenous, ASAP=as
soon as possible.

sevoflurane [5]. Spontaneous ventilation was maintained

whenever possible, and whenever controlled ventilation
became necessary, an end-tidal carbon dioxide (ETCO2)
value of 40 mmHg was targeted. An oral airway was inserted
whenever airway obstruction occurred that was not immediately relieved by chin lift or jaw thrust. The presence or absence
of spontaneous ventilation was noted at the time of propofol
administration and at the time of direct laryngoscopy (DL).
The anesthesia team administering the anesthetic obtained
IV access according to their routine without direction from
the research team and without dermal anesthesia, with initial
attempt(s) by the resident member of the anesthesia team.
Once IV access was obtained, propofol was administered by
rapid IV push through a standard unfiltered microbore Tconnector attached directly to the IV, given in a dose

determined by the scheme outlined below, and was

immediately flushed with normal saline to clear the Tconnector of propofol. The physician managing the airway
was blinded to the propofol dose, and initiated laryngoscopy
60 seconds after propofol administration, using the laryngoscope blade of their choice and a styletted endotracheal tube
(ETT) with size dictated by the formula (16 + age)/4 for
uncuffed ETTs (used for all pts in the 16 year group) and
(14 + age)/4 for cuffed ETTs (used for all pts in the 611
year group), rounding to the closest ETT size, and rounding
up if exactly in-between. Laryngoscopy was aborted if
movement occurred and subsequent management was at the
discretion of the anesthesia care team; in such cases,
intubation conditions were labeled as not excellent and
unacceptable. Endotracheal tubes were placed at a distance

28

G.D. Politis et al.

of three times the internal diameter of the ETT in order to

achieve mid-trachea positioning with a reasonable degree of
reliability [17], without stimulating the carina.
End-tidal gas measurements were recorded immediately
before laryngoscopy and immediately after ETT placement.
Gas sampling ports were located in standard 90-degree
elbow connectors placed immediately proximal to facemasks
and ETTs. End-tidal gas sampling at that location may
produce inaccurate values during facemask ventilation due to
large dead space of the facemask and small tidal volumes of
pediatric patients breathing spontaneously using volatile
anesthesia. We administered an assisted or controlled breath
of 1015 mL/kg just prior to intubation in an attempt to
obtain more true end-tidal gas values. We recorded
preintubation and postintubation ETCO2 and sevoflurane
values as a marker of ventilation before laryngoscopy and as
a means to compare with other studies, rather than as a
reliable means of predicting successful intubation.
One attempt at tracheal intubation was allowed. After
intubation the laryngoscopist was asked to score intubation
conditions using a previously established and frequently
used scoring system that evaluates jaw relaxation, vocal cord
position and movement, overall ease of laryngoscopy, limb
movement, and coughing, with each item scored on a 14
point basis (Table 1) [1820]. The laryngoscopist scored all
5 items, but the investigator present at induction could
overrule the laryngoscopists score for movement or
coughing if they disagreed with those two easily visible
criteria. Intubation conditions were defined as excellent
only if all 5 categories received the best possible score of 1;
the intubation was labeled as not excellent whenever any
category had a score of more than 1. In addition, we defined
good conditions as a score of either a 1 or 2 in all
categories, and defined acceptable conditions as having
either good or excellent conditions. After ETT placement,
subsequent care was at the discretion of the anesthesia
care team.
Heart rate (HR) and noninvasive measurements of
systolic blood pressure (SBP), diastolic blood pressure, and
mean arterial pressure were obtained at baseline, which
occurred after midazolam and just before induction in the
operating room for the younger age group, and occurred in
the preoperative area for the older age group. We obtained
further measurements of BP and HR at the time just prior to
propofol administration, and at one and two minutes after
propofol was given.
Table 1

Intubation score

Jaw relaxation
Vocal cords
Laryngoscopy
Coughing
Limb movement

complete
open
easy
none
none

slight
moving
fair
slight
slight

stiff
closing
difficult
moderate
moderate

rigid
closed
impossible
severe
severe

Propofol dosing was determined according to a scheme

that allowed independent dosage determinations for separate
age groups and for different elapsed times from the start of
induction until propofol administration. Elapsed time
depended solely on the time needed to obtain IV access.
Three periods of elapsed time were defined prior to
commencing this study, and were 24 minutes, 46 minutes,
and 68 minutes. The initial propofol dose was 2 mg/kg for
both age groups and all elapsed time periods, but all
subsequent propofol doses were allocated independently
within each separate group using Dixons Up and Down
Method with a standard staircase design [21,22], so that the
propofol dose each patient received was determined by the
dose and the intubation results (excellent or not excellent) of
the immediately preceding patient in the same age group and
elapsed time period. Propofol doses were decreased or
increased by 0.3 mg/kg steps when intubation conditions
were judged to be excellent or not excellent, respectively,
with the increment size of 0.3 mg/kg (15% of our starting
propofol dose) chosen as a mid-range increment size, using
the recommendations of Paul and Fisher [23]. At points
when a 0.3 mg/kg decrease in propofol dose produced a
negative number (ie, when excellent intubation conditions
were found at a dose of 0.2 mg/kg) the propofol dose
decreased to zero, and then increased from zero to 0.2 mg/kg
once conditions were not excellent (allowing use of the same
per kg doses throughout the study). Before each induction,
the propofol dose was determined for each of the three
elapsed time periods so that there would be no delay in
propofol administration after IV cannulation.

2.1. Statistics
The number of patients enrolled in this study was
determined by crossovers (successive pts who differed with
respect to having excellent or not-excellent intubation
conditions, with no pt allowed to be in two separate
crossover pairs) rather than by a power analysis because
our studys primary goal was to estimate the doses of
propofol needed for TIDA; comparison of those estimations
across time groups became a secondary goal of this
investigation. Patient enrollment continued until each
group achieved at least 6 crossover points, which is a wellestablished reasonable number of crossovers [23]. The target
of 6 crossovers was achieved for all groups except the 611
year olds in the 68 minute time frame because IV
cannulation was nearly always achieved before 6 minutes,
and our IRB approval required propofol administration
immediately after IV cannulation. This group was eliminated
due to the inability to enroll patients.
Propofol doses needed to produce 50% excellent
intubation conditions (ED50) were estimated using the
interpolated isotonic regression method of Stylianou and
Flournoy [24]. Our goal was to concentrate the delivered
doses around the ED50, so that we could report the ED50 with
reasonable accuracy, believing that to be a good target

TIDA sevoflurane and propofol

29

10

1.0
0.6

0.8

Raw Estimate
Isotonic Regression

0.4

1.5

Excellent
Not Excellent

1.0

Propofol Dose

2.0

Probabilty of Excellent Intubating Conditions

Ages 1-6 Time 2-4 min

biased coin design, and the former should not be used to find
the ED95 [25]. At each propofol dose level, the proportion of
patients with excellent intubation conditions was estimated.
Those estimates were then adjusted by the isotonic

0.2

because the ED50 for excellent intubation conditions

translated to a high percentage of acceptable conditions in
a previous study [12]. We did not report ED95 values because
we used the classic up and down method, rather than the

15

1.0

1.5

10

15

20

0.9
0.8
0.7

Raw Estimate
Isotonic Regression

0.6

1.0
0.0

0.5

Propofol Dose

1.5

Excellent
Not Excellent

0.5

2.0

Probabilty of Excellent Intubating Conditions

Ages 1-6 Time 4-6 min

25

0.0

0.5

15

2.0

20

0.9
0.8
0.7
0.6
0.5

Raw Estimate
Isotonic Regression

0.4

Probabilty of Excellent Intubating Conditions

2.0
1.0
0.0

0.5

Propofol Dose

1.5

Excellent
Not Excellent

10

1.5

Propofol Dose

Ages 1-6 Time 6-8 min

Patient Number

1.0

1.0

Patient Number

2.0

Propofol Dose

1.0

Patient Number

0.0

0.5

1.0

1.5

2.0

Propofol Dose

Fig. 2 (Left panel) Actual dose and response sequences for each patient group, along with (right panel) the groups' corresponding estimates
of excellent intubating conditions at each propofol dose, shown as raw estimates and estimates after isotonic regression.

G.D. Politis et al.

10

12

0.2

0.4

0.6

0.8

Raw Estimate
Isotonic Regression

0.0

2.2
2.0

Excellent
Not Excellent

1.8

Propofol Dose

2.4

2.6

Probabilty of Excellent Intubating Conditions

Ages 6-11 Time 2-4 min

1.0

30

14

1.8

2.0

2.6

0.8
0.6
0.4
0.2

Excellent
Not Excellent

10

2.4

Raw Estimate
Isotonic Regression

0.0

2.0
1.5

Propofol Dose

2.5

Probabilty of Excellent Intubating Conditions

Ages 6-11 Time 4-6 min

2.2

Propofol Dose

1.0

Patient Number

15

1.5

Patient Number

2.0

2.5

Propofol Dose

Fig. 2

regression method described by Pace and Stylianou [25] to

ensure that the estimated probability of excellent intubation
conditions was nondecreasing with propofol dose.
Finally, the dose corresponding to 50% probability of
excellent intubating conditions was estimated by linear
interpolation of the isotonic regression estimate. Confidence
intervals (CIs) for the ED50 estimates were calculated by the
parametric bootstrap method described by Pace and
Stylianou [25] using R software (R Core Development
Team [26]), as well as additional software in the R language
provided to us by Nathan Pace. Confidence intervals for
differences in ED50 between two groups were constructed by
an extension of Pace and Stylianous technique. On each
bootstrap replication, bootstrap data were generated independently for each group using the methodology of Pace and
Stylianou [25]. The bootstrap ED50 was estimated for each
bootstrap data set, and bootstrap differences were computed
by subtracting the estimated ED50 of one group from another.
The bootstrap differences were then used to construct CIs for
the differences by using the same bias corrected percentile

(continued)

method recommended by Pace and Stylianou [25] and

implemented in the software provided to us by Pace.
The relation between BP change and propofol dose was
assessed using linear regression and Pearsons correlation
coefficients. We compared the proportion of acceptable
intubation conditions in patients with spontaneous ventilation versus those who had become apneic and required
controlled ventilation using a Fishers Exact test with one
degree of freedom and a two-tailed P-value. In all cases, Pvalues less than or equal to 0.05 were considered statistically
significant.

3. Results
One hundred six patients were enrolled in our study. Four
protocol violations occurred, resulting in patient exclusion;
one patient received a higher dose of midazolam than called
for, one had fresh gas adjustments made incorrectly, and two

TIDA sevoflurane and propofol

31

Table 2 Estimated propofol doses producing 50% excellent

intubation conditions
Age
(yrs)

Time to
propofol (min)

Estimated
dose (mg/kg)

95% Confidence
intervals

1-6
1-6
1-6
6-11
6-11

2-4
4-6
6-8
2-4
4-6

1.48
0.00
0.07
2.35
2.33

(0.80, 2.03)
(0.00, 0.38)
(0.00, 0.68)
(1.97, 2.45)
(1.59, 2.45)

had no IV access after 8 minutes from the start of induction.

Our study protocol included a 611 year old group that
received propofol 68 minutes after the start of induction.
However, for that age group IV access was secured outside
the 68 minute time frame in all but two patients;
consequently, there was an inadequate number of patients
to perform analysis for that group. Sixty-nine patients aged
16 years (mean of 3.6 yrs) and 31 patients aged 611 years
(mean of 7.9 yrs), were enlisted by the time 6 crossover pairs
were recruited in all of the 5 study groups. Type of surgery
varied; 30 patients received tonsillectomy and adenoidectomy, 12 had adenoidectomy without tonsil removal, 21
received various urologic procedures, 13 had strabismus
repair, and 24 underwent miscellaneous procedures. Airway
management was performed by senior residents in 95 study
patients and by attending anesthesiologists in 5 patients.
Of the 69 patients aged 16 years, 46 had intubation
conditions that were rated excellent, 18 were rated good, and
5 were rated less than good; 64 (93%) had intubation
conditions that were rated acceptable (either excellent or
good). Of the 31 patients aged 611 years, 17 were rated
excellent, 10 were rated good, and 4 were rated less than
good; 27 (87%) were rated as having acceptable intubation
conditions. Fig. 2 gives the actual dose and response

Table 3

Mean
Mean
Mean
Mean
Mean
Mean
Mean
Mean
Mean
Mean
Mean

sequences for each patient group, along with a panel

showing each groups corresponding estimates of excellent
intubation conditions at each dose level, shown as both the
raw estimates and those estimates after adjustment by
isotonic regression. Estimated propofol doses (mg/kg)
required to produce 50% excellent intubation conditions
(ED50) are summarized in Table 2 according to patient age
and time from the start of anesthetic induction until propofol
administration. The ED50 for the 16 year age group in the
46 minute time window was estimated as 0.00 because all
doses for that group (including 0.00 mg/kg) resulted in at
least 50% excellent conditions. For the 16 year age group,
the estimated differences between the ED50 values for the 2
4 minute group versus the 46 and 68 minute groups were
1.47 mg/kg (95% CI = 1.04, 2.06) and 1.41 mg/kg (95% CI =
0.74, 2.04), respectively, while the ED50 estimates for the 4
6 and the 68 minute groups did not differ from one another
(95% CI for the difference was 1.40, 0.32). For children 6
11 years old, the ED50 estimates did not differ from one
another (95% CI for the difference was 0.49, 0.86).
Spontaneous ventilation was maintained prior to propofol
administration in 53 of 69 (77%) 16 year old patients and
30 of 31 (97%) 611 year old patients. One minute after
propofol administration, 25 of 69 (36%) 16 year olds and 5
of 31 (16%) 611 year olds were breathing spontaneously.
Our data did not find that absence of spontaneous ventilation
at initiation of DL was predictive of acceptable intubation
conditions; unacceptable intubation conditions were present
in only two of 29 patients who had spontaneous ventilation at
DL, which did not differ statistically from the 7 patients
with unacceptable intubations in the group of 71 patients
who had become apneic and received controlled ventilation
at DL (P = 1.0).
For each of the 5 patient groups (with respect to age and
elapsed induction time), mean values for age, weight, end-

Patient data by group (reported as population means)

age (yrs)
weight (kg)
propofol dose (mg/kg)
pre/post-ETT ETCO2 (mmHg)
pre/post-ETT ET Sevo (%)
baseline HR (bpm)
HR at P (bpm)
HR at P + 1 (bpm)
HR at P + 2 (bpm)
baseline SBP (mmHg)
% SBP BL P

1-6 yrs
(24 min)

1-6 yrs
(46 min)

1-6 yrs
(68 min)

6-11 yrs
(24 min)

6-11 yrs
(46 min)

3.8
17.6
1.63
31/40
4.1/4.0
105
121
118
123
100
5.5

3.9
17.4
0.55
30/40
4.3/4.1
110
115
115
129
88
4.7

3.1
16.6
0.71
29/46
4.6/3.6
111
114
118
132
86
8.5

8.3
28.9
2.26
30/39
4.2/3.9
92
111
107
119
102
3.7

7.6
31.6
2.14
28/43
4.3/3.5
90
102
101
129
108
4.9

ETT=endotracheal tube, ETCO2= end-tidal carbon dioxide, Pre/Post-ETT=values measured immediately before and after intubation, ET Sevo=end-tidal
sevoflurane, HR=heart rate, P=time of propofol dosing, P + 1=time one minute after propofol dosing (at time of laryngoscopy), P + 2=time two minutes
after propofol dosing (1 min after laryngoscopy), SBP=systolic blood pressure, % SBP BL P=percent change for each patients SBP from baseline
until time of propofol administration.

32

G.D. Politis et al.

Fig. 3 Scatter plots of individual percent changes in systolic blood pressure (SBP) at one and two minutes after propofol administration
(SBP1 and SBP2, respectively), versus SBP immediately prior to the time propofol was given (SBP.P), shown separately for ages 16 years
and 611 years. Lines of best fit are shown for the younger age group, which showed a correlation between increasing propofol dose and
greater SBP diminution; r-values of 0.44 (P = 0.00015) and 0.35 (P = 0.0097) at one and two minutes, respectively. There was no such
correlation for the older age group.

tidal gas samples prior to and immediately after intubation,

HR, baseline SBP, and individual change in SBP from
baseline until the time when propofol was administered are
summarized in Table 3. Linear regression estimated that for
16 year olds SBP decreased by 3.81% (SE = 1.33%) of
baseline for each minute of induction time prior to propofol
administration; however, the regression intercept was 16.7%
(SE = 7.25%), meaning that those who received early
propofol administration on average experienced an increase
in SBP. For the 16 year group, further decrease in SBP can
be expected after propofol administration; a decrease of SBP
at both one and two minutes after propofol administration
(ie, at the time of intubation and 1 min later, respectively)
were dose-dependent. Pearsons correlation coefficients were

r = 0.44 (P = 0.00015) and r = 0.35 (P = 0.0097) for one

and two minutes, respectively, corresponding to 5.3% (SE =
1.3%) and 8.1% (SE = 3%) decreases in SBP (vs SBP at
the time just prior to propofol administration) for each
1 mg/kg of propofol administered. No correlation was
found in the older age group for propofol dose versus
change in SBP. Fig. 3 shows scatter plots of each
individual patients percent change in SBP at one and
two minutes after propofol dose for both age groups,
compared with SBP at the time of propofol administration,
along with the lines of best fit for the younger age group.
Heart rate increase during sevoflurane induction was seen
in all study groups, with mean HR values at all time points
being higher than at baseline.

TIDA sevoflurane and propofol

During the course of this study, one episode of
laryngospasm and one episode of bronchospasm occurred
in the same patient, a 20 month old who received a dose of
zero mg of propofol. No other complication occurred.

4. Discussion
Propofol is used to supplement anesthetic depth during
TIDA with high concentrations of sevoflurane [1115],
though opioid adjuvants such as remifentanil are equally
effective [15]. Our study examined for the first time the
relationship of propofol dose to duration of sevoflurane
administration. In addition, we not only reported that
relationship for younger children, but also for an older
cohort of children (ages 611 yrs) who had not previously
been included in TIDA studies. We found that the estimated
ED50 of propofol for TIDA for 16 year olds decreased
substantially after 4 minutes of sevoflurane, with ED50
values near zero after that time, but that it did not change for
children 611 years. Finally, our data found that 16 year
olds manifested a propofol-dose dependent decrease in
individual SBP at both one and two minutes after propofol
administration (8.1% decrease at 2 min for each 1 mg/kg of
propofol) compared with SBP immediately prior to propofol.
The novel findings in our study are consistent with a
previous study that demonstrated a predictive relationship
between increasing time of exposure to sevoflurane, lower
age, and increased intubation success during TIDA [5]. Our
ED50 estimate of 1.48 mg/kg for 16 year olds given
propofol 24 minutes after the start of induction is consistent
with a report by Kim et al [14], who found the dose of
propofol producing 50% excellent intubation conditions to
be 1.39 mg/kg when given exactly two minutes after the start
of 5% sevoflurane and 60% N2O in children 37 years of
age. Three other studies have examined propofol added to
sevoflurane for TIDA, including studies by Saddik-Sayyid et
al [13], Lerman et al [11], and Jo et al [12], though
comparison of their data to ours is difficult because none of
them controlled for time of sevoflurane administration.
Saddik-Sayyid et al compared 1 mg/kg and 2 mg/kg of
propofol administered to children 27 years old after IV
access was obtained, which occurred at variable amounts of
time (mean of approximately 4 min) after initiation of 8%
sevoflurane. They found 56% and 92% excellent intubation
conditions in the 1 and 2 mg/kg groups, respectively. Lerman
et al used a dose-ranging protocol in children 28 years of
age, administering either placebo or propofol (0.05., 1.0, 2.0,
and 3.0 mg/kg) immediately after IV cannulation, between
90540 seconds after the start of inhalation induction (mean
of 33.5 min, depending on the group), and found better
intubation scores with 3 mg/kg than with 0.0 or 0.5 mg/kg
while maintaining 70% N2O and 8% sevoflurane until
laryngoscopy. Jo et al reported that the amount of propofol
needed to achieve 50% excellent intubation in children 0.5-

33
5.0 years of age after 7% sevoflurane induction, adjusting the
dialed concentration to achieve either 3.0%, 3.5%, or 4.0%
exhaled sevoflurane target concentrations, was 1.25 mg/kg,
0.76 mg/kg, and 0.47 mg/kg, respectively. In Jo et als study,
the duration of sevoflurane administration varied according
to the time to achieve a steady state, which was defined as
5 breaths with a stable target end-tidal sevoflurane
concentration, and may have varied according to the time
needed to obtain IV access, which was noted to have been
obtained after induction.
Increasing duration of administration of sevoflurane
decreased propofol requirement in our 16 year age group,
and we believe that finding is related to increasing anesthetic
depth from sevoflurane; the interaction of propofol with
sevoflurane appears to be additive for both hypnosis and
immobility in humans [27]. Time of sevoflurane exposure
may do little to change the alveolar-to-inspired fraction of
sevoflurane in the 26 minute window after the start of
induction, which rises rapidly in children; Goldman
demonstrated that the ratio appears constant in that time
frame [28], which is consistent with our end-tidal sevoflurane concentrations reported in Table 3. However, time of
administration of sevoflurane remains relevant because prior
to equilibration, more time at any particular alveolar and
arterial anesthetic partial pressure results in a higher vesselrich group partial pressure. Time constants for the vessel-rich
group range between 1.9 and 3.2 minutes and increase with
age, with equilibration being 63%, 86%, and 95% complete
at one, two, and three time constants, respectively [29].
Accordingly, relatively small changes in sevoflurane central
nervous system (CNS) partial pressure occur after two time
constants (approximately 4 min for the youngest pts), which
was consistent with our younger age groups sustained
decrease in propofol ED50 after 4 minutes. Our older age
group did not manifest any change in propofol requirement
with increasing duration of sevoflurane administration.
Based on the longer vessel-rich group time constant of
older patients, 611 year old patients may manifest a
decrease in propofol ED50 similar to that seen in our younger
age group if given sevoflurane for longer than 6 minutes.
The study design did not permit direct comparison
between age groups with respect to the amount of propofol
required to supplement sevoflurane for TIDA because of
differences in our protocol; only the 16 year olds received
midazolam preoperatively, and 611 year olds received 8%
sevoflurane for 30 seconds longer than the 16 year olds.
Midazolam decreases volatile anesthetic requirement in
adults [30], and one may expect a similar effect for children.
Some data show that younger patients require more propofol
than older patients when propofol is used in settings other
than TIDA [31,32]; however, younger patients might require
less propofol to supplement sevoflurane for TIDA at time
points prior to sevoflurane equilibration because younger
patients have CNS partial pressure increase more rapidly
than older patients. Politis et al found that 14 year olds
required less time when receiving 8% sevoflurane compared

34
with 48 year olds in order to achieve similar intubation
success rates [5], and we suggest that comparison of agerelated propofol requirement, when given as an adjuvant to
sevoflurane for TIDA, should be investigated.
Data from our study imply that larger doses of propofol
may produce negative hemodynamic consequences for
children 16 years; one could expect a mean decrease in
SBP of 16.2% and 24.3% for 2 mg/kg and 3 mg/kg,
respectively, two minutes after propofol administration.
Nonetheless, large BP decreases were rare during our study,
consistent with hemodynamic data from other studies using
propofol for TIDA [11,12,14], and few of our patients
manifested greater than a 25% decrease from their SBP just
prior to propofol (Fig. 3). However, our 16 year group
received mostly small propofol doses, as demonstrated by the
small mean doses reported in Table 3 and by the fact that 42 of
69 patients in that age group received less than or equal to 1
mg/kg, and none received more than 2.3 mg/kg of propofol.
Our data are consistent with those of Siddik-Sayyid et al [13],
who reported that 27 year olds had a lower SBP two minutes
after tracheal intubation (2.75 min after propofol) compared
with baseline values (no numeric values reported).
Our study had limitations worth noting. As mentioned
above, focusing data collection around a 50% success
point does not allow for calculation of a 95% success point
[25]. We hoped to achieve 80% to 100% acceptable
intubation scores rather than a similar percentage of perfect
intubation scores. Such a high percentage of perfect
intubation scores typically has not been the target of
studies that examine intubation conditions for pediatric
TIDA, though a recently published systematic review of
drug combinations used for TIDA in children suggested
that it should be [15]. We used a surrogate target of 50%
excellent conditions because we believed it would lead to
intubation success in our desired range and still allow use
of Dixons Up and Down Method for dose allocation; Jo et
al found 90.5% acceptable conditions using the same target
[12]. In our study, that same target resulted in 93% and
87% acceptable conditions for our younger and older age
groups, respectively. Our study was limited by the use of
age and time groups that were fairly large, and estimates of
propofol requirements could have been more precise if
ages and time frames had been narrower.
We did not use a validated scoring system for evaluation
of tracheal intubation conditions because no such scoring
system exists, which results from the fact that only one
laryngoscopist evaluates all items at a single point in time
(interobserver variability cannot be measured). Some studies
have limited the laryngoscopist to one or to a few
experienced individuals [11,20,33,34], with the hope of
limiting observer variability. We believe that doing so limits
the ability to apply results to broader populations of
anesthetists, and would also render the results useless for
teaching situations. Many studies that have evaluated
adequacy of tracheal intubation have not put limitations on
the number of laryngoscopists [3,57,9,12,19,3537], and in

G.D. Politis et al.

fact that practice was not advocated by Viby-Mogenson et al
in a well-recognized outline of good clinical research
practice [38].
As with all studies, application of our results to clinical
situations requires following our protocol. With that in mind,
we designed a protocol that we believed would be clinically
applicable and easy to reproduce. While our ED50 values
were generated with senior residents managing the airways,
we believe that those same ED50 values could be used
by more experienced airway managers with equally good or
better results.
In conclusion, propofol is one of the most useful adjuncts
for TIDA in the setting of sevoflurane induction [15,16].
High rates of acceptable intubation conditions were achieved
in our patient population when focusing propofol doses
around the ED50 estimates, when administering sevoflurane
and propofol according to our study protocol. Our ED50
results indicate that for children 16 years old, the dose of
propofol chosen to supplement sevoflurane for TIDA may
decrease with increasing time of administration of sevoflurane. Larger propofol doses may lead to greater decreases in
BP when administered to 16 year olds in this setting,
and we believe the effect on BP should be taken
into consideration when choosing propofol doses for that
age group.

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