Full text of DOI:10.1007/BF03017905

1070
OBSTETRICAL AND PEDIATRIC ANESTHESIA
Fentanyl is more effective than remifentanil at
preventing increases in cerebral blood flow
velocity during intubation in children
[Le fentanyl est plus efficace que le rémifentanil à prévenir des augmentations de
la vitesse circulatoire cérébrale pendant l’intubation chez les enfants]
Claude Abdallah MD FRCPC, Cengiz Karsli BSc MD FRCPC, Bruno Bissonnette BSc MD FRCPC
Purpose: Controlling the cerebral and systemic hemodynamic
responses to laryngoscopy and tracheal intubation may play a role
in determining clinical outcome in pediatric neurosurgical patients.
This study compared the effects of remifentanil and fentanyl on
cerebral blood flow velocity (CBFV) and hemodynamic profile dur-
ing laryngoscopy and tracheal intubation in children under sevoflu-
rane anesthesia.
Objectif : Le contrôle des réponses hémodynamiques cérébrale et
générale à la laryngoscopie et à l’intubation trachéale peut influencer
de façon déterminante l’évolution clinique des enfants de neu-
rochirurgie. La présente étude a comparé les effets du rémifentanil et
du fentanyl sur la vitesse du flux sanguin cérébral (VFSC) et sur le pro-
fil hémodynamique pendant la laryngoscopie et l’intubation trachéale
chez des enfants soumis à une anesthésie au sévoflurane.
Methods: Sixty healthy children aged two to six years undergoing
dental surgery under general anesthesia were enrolled. Each child
was randomly assigned to receive a remifentanil or fentanyl infu-
sion, at a rate of 0.75, 1.0, or 1.5 µg·kg–1·min–1 after induction of
anesthesia with 2% sevoflurane. Middle cerebral artery blood flow
velocity was measured by transcranial Doppler (TCD) sonography.
Once a baseline set of hemodynamic variables and TCD measure-
ments were recorded, the opioid infusion was started.
Measurements were taken at two-minute intervals, starting four
minutes prior to laryngoscopy until four minutes following naso-tra-
cheal intubation.
Méthode : Soixante enfants en bonne santé devant subir une inter-
vention dentaire sous anesthésie générale ont été choisis pour l’étude.
Chaque enfant a été assigné au hasard pour recevoir une perfusion de
rémifentanil ou de fentanyl selon une vitesse de 0,75, 1,0 ou 1,5
µg·kg–1·min–1, après l’induction de l’anesthésie avec du sévoflurane à
2 %. La vitesse circulatoire de l’artère cérébrale moyenne a été
mesurée par Doppler transcrânien (DTC). La perfusion a commencé
après la réalisation des mesures de base des variables hémody-
namiques et du DTC. Les mesures ont été prises aux deux minutes,
en commençant quatre minutes avant la laryngoscopie jusqu’à quatre
minutes après l’intubation nasotrachéale.
Results: Remifentanil caused a more significant decrease in mean
arterial pressure and CBFV prior to tracheal intubation than did fen-
tanyl (P < 0.001). During laryngoscopy and for two minutes fol-
lowing tracheal intubation, CBFV increased in all remifentanil groups
(P < 0.05), whereas it remained stable in all fentanyl groups.
Conclusion: This study suggests that fentanyl was more effective
than remifentanil at preventing increases in CBFV during and imme-
diately following laryngoscopy and tracheal intubation in children
undergoing sevoflurane anesthesia. Fentanyl also seemed to pro-
vide a more stable hemodynamic profile prior to laryngoscopy and
tracheal intubation when compared to remifentanil.
Résultats : Avant l’intubation trachéale, le rémifentanil, comparé au
fentanyl, a causé une baisse plus importante de la pression de l’artère
moyenne et de la VFSC (P < 0,001). Pendant la laryngoscopie et pen-
dant deux minutes après l’intubation trachéale, la VFSC a augmenté
avec le rémifentanil (P < 0,05) alors qu’elle est demeurée stable avec
le fentanyl.
Conclusion : Cette étude montre que le fentanyl a été plus efficace
que le rémifentanil à prévenir des hausses de la VFSC pendant et
immédiatement après la laryngoscopie et l’intubation trachéale chez
des enfants sous anesthésie avec du sévoflurane. Le fentanyl, compa-
rativement au rémifentanil, semble fournir aussi un profil hémody-
namique plus stable avant la laryngoscopie et l’intubation trachéale.
From the Department of Anaesthesia, The Hospital for Sick Children and the University of Toronto, Toronto, Ontario, Canada.
Address correspondence to: Dr. B. Bissonnette, Department of Anaesthesia, The Hospital for Sick Children, 555 University Avenue,
Toronto, Ontario M5G 1X8, Canada. Phone: 416-813-7445, Fax: 416-813-7543; E-mail: bruno@anaes.sickkids.on.ca
Presented in part at the Annual Meeting of the American Society of Anesthesiologists in New Orleans, October 2001.
Accepted for publication July 10, 2002.
Revision accepted August 26, 2002.
CAN J ANESTH 2002 / 49: 10 / pp 1070–1075

Abdallah et al.: OPIOIDS AND CBFV IN CHILDREN
1071
ARYNGOSCOPY and tracheal intubation
may cause significant cerebral and systemic
hemodynamic responses, including tachy-
L
cardia, hypertension and increased intracra-
nial pressure.1–3 Controlling these responses on
induction of anesthesia may be an important factor in
improving outcome in pediatric neurosurgical
patients. Remifentanil is a µ-opioid receptor agonist,
rapidly metabolized by nonspecific esterases through-
out the blood and tissues. The elimination half-life of
remifentanil is less than ten minutes, compared to 219
min for fentanyl.4–6 It does not accumulate after pro-
longed continuous infusion and the blood brain equi-
libration time is rapid.5,7 Its use is characterized by
rapid and complete offset of opioid effects within min-
utes of infusion discontinuation.4 These distinctive
pharmacokinetic and pharmacodynamic characteristics
make remifentanil a potentially attractive opioid for
use in pediatric anesthesia. Comparative data assessing
cerebral blood flow velocity (CBFV) on induction and
tracheal intubation with remifentanil and fentanyl has
not been documented in the pediatric population.
The aim of this study was to compare the effects of
remifentanil and fentanyl on CBFV and hemodynam-
ic profile during laryngoscopy and tracheal intubation
in children under sevoflurane anesthesia.
Methods
FIGURE 1 Changes in cerebral blood flow velocity (CBFV) and
With Regional Ethics Board approval and written
parental consent, 60 unpremedicated children aged two
to six years, ASA I or II, undergoing dental surgical
procedures requiring general anesthesia were enrolled.
Exclusion criteria included emergency surgery, central
nervous system or cardiovascular disease. Using a ran-
domization table, patients were prospectively assigned
to receive either a remifentanil or fentanyl infusion, at a
rate of 0.75, 1.0 or 1.5 µg·kg–1·min–1. In each child,
anesthesia was induced with sevoflurane in oxygen, with
the inspired sevoflurane concentration being kept at 2%
upon loss of consciousness. A peripheral iv catheter was
then inserted. Monitoring of the patient included the
standard anesthesia monitors. A transcranial Doppler
(TCD) probe with a 2-mHz emitted ultrasonic fre-
quency was placed appropriately to measure middle
cerebral artery (MCA) blood flow velocity (Vmca) at
the M1 segment. A custom designed head frame was
used to prevent the probe from moving during the
study period.8 Once a baseline set of variables [heart
rate (HR), respiratory rate, oxygen saturation, peak air-
way pressure, non invasive blood pressure, axillary tem-
perature, end-tidal CO2 concentration and Vmca] was
recorded, the opioid infusion was started. These vari-
ables were recorded at two-minute intervals, starting
ETCO2 over time comparing fentanyl and remifentanil infusions. *
represents a decrease in CBFV with remifentanil 1.0 and 1.5 when
compared to baseline (P < 0.001). † indicates an increase in CBFV
after laryngoscopy and tracheal intubation with remifentanil 1.0 and
1.5 (P < 0.05). ‡ denotes a decrease in CBFV with fentanyl 1.5
when compared to baseline (P < 0.001). ** indicates an increase in
ETCO2 in all groups when compared to baseline (P < 0.001).
four minutes prior to laryngoscopy, until four minutes
post naso-tracheal intubation, at which point the infu-
sion was discontinued. Manual face-mask ventilation
was instituted to maintain normocapnea in those
patients who became apneic prior to tracheal intuba-
tion. All patients were horizontal and supine through-
out the study.
Demographic data are expressed as mean stan-
dard deviation. The number of patients needed to
demonstrate a direct effect on CBFV was calculated
with the assumption that a 20% change would be clin-
ically relevant. Based on a statistical power of 0.8, an
α2 = 0.05 and a ß = 0.2, six patients per group was
suggested. A total of ten patients per group was stud-
ied to account for methodological difficulties that

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CANADIAN JOURNAL OF ANESTHESIA
groups. The TCD measurements were completed in all
children and there were no complications that resulted
from this study. Changes in CBFV and PETCO2 are
shown in Figure 1. Hemodynamic responses to induc-
tion and tracheal intubation are shown in Figure 2.
When compared to baseline, there was a significant
decrease in Vmca in the remifentanil 1.0 and 1.5
µg·kg–1·min–1 groups both at four and two minutes
prior to tracheal intubation (P < 0.001), despite a con-
current increase in PETCO2 (Figure 1). A decrease in
Vmca was also seen in the fentanyl 1.5 µg·kg–1·min–1
group (P < 0.001), but only at two minutes pre-intu-
bation. Remifentanil caused a more important decrease
in mean arterial pressure (MAP) at two minutes prior to
intubation than did fentanyl (P < 0.001; Figure 2). The
MAP two minutes before intubation was lower in all
remifentanil groups than any of the fentanyl groups (P
< 0.05). There was a decrease in HR two minutes prior
to intubation in the R1.0, R1.5 and F1.5 groups when
compared to baseline (P < 0.001).
During laryngoscopy and for two minutes follow-
ing tracheal intubation, Vmca increased in all remifen-
tanil groups (P < 0.05), whereas it remained stable in
all fentanyl groups during that same period (Figure 1).
There were no significant changes in HR or MAP in
any of the groups following tracheal intubation, and
changes in PETCO2 were similar in both the fentanyl
and remifentanil groups. Except for the F0.75 group,
in which only 50% of patients became apneic, greater
than 80% of patients in all other groups including the
R0.75 group became apneic prior to tracheal intuba-
tion. There was no difference in the incidence of
apnea between the F and R groups at both 1.0 and 1.5
µg·kg–1·min–1. Face-mask ventilation immediately
prior to tracheal intubation was scored as easy in all
children, and intubating conditions were excellent
(jaw relaxed, vocal cords open, no coughing) in all
patients. Peripheral oxygen saturation remained above
95% in all children throughout the study.
FIGURE 2 Changes in heart rate (HR) and mean arterial pres-
sure (MAP) over time comparing fentanyl and remifentanil infu-
sions. * represents a decrease in MAP for all remifentanil doses (P
< 0.05).
could have led to exclusion from the study.
Differences within groups in Vmca, HR, blood pres-
sure and end-tidal CO2 (PETCO2) were analyzed with
repeated measures ANOVA and the Student-
Newman-Keuls test for multiple comparisons.
Between groups statistical analysis was achieved using
ANOVA and the Tukey test for multiple comparisons.
Non-parametric data (apnea, score of intubation)
were analyzed using the Kruskall-Wallis test. The
analysis of each set of TCD measurements was carried
out by an investigator unaware of the drug and the
concentration administered. All patients were used as
their own control. A P value less than 0.05 was accept-
ed for statistical significance.
Discussion
CBFV decreased early and significantly in the medium
and high dose remifentanil groups prior to tracheal
intubation, despite a concurrent increase in end-tidal
CO2. Furthermore, remifentanil was significantly less
effective than fentanyl at preventing increases in
CBFV during and immediately following laryn-
goscopy and tracheal intubation. Human adult and
animal studies designed to assess the effects of differ-
ent opioids on cerebral hemodynamics have yielded
conflicting results. Narcotic infusions have been
shown to increase,9 decrease,10 or cause no change11
in CBFV. In the present study, end-tidal carbon diox-
Results
Sixty patients were studied, with an average age and
weight of 4.2 1.3 yr and 17.6 4.2 kg, respectively.
There were no demographic differences between the

Abdallah et al.: OPIOIDS AND CBFV IN CHILDREN
1073
ide levels increased equally in all groups prior to tra-
cheal intubation, and since cerebrovascular reactivity
to CO2 is preserved with both remifentanil and fen-
tanyl,12 an increase in CBFV might have been expect-
ed, rather than the noted decrease. In clinical pediatric
neuroanesthetic practice manual ventilation is often
used during anesthetic induction to avoid hypercarbia.
One may speculate then that in neurosurgical patients
with intracranial hypertension, the decrease in CBFV
and cerebral perfusion induced by remifentanil might
be even more clinically relevant if ETCO2 is kept
lower. Opioid-induced decreases in CBFV have been
theorized to be due to i) decreased cerebral metabol-
ic rate for oxygen (CMRO2),13 ii) loss of cerebral pres-
sure autoregulation, or iii) direct cerebral
vasoconstriction.14 Sufentanil has been shown in ani-
mal and adult human studies to decrease CMRO2,15,16
however the effect of remifentanil on CMRO2 in chil-
dren is unknown.
In the present study, remifentanil caused a more
pronounced decrease in MAP prior to tracheal intuba-
tion than did fentanyl. In fact, there was a 30% drop
in MAP prior to laryngoscopy in the high-dose
remifentanil group. These findings are in agreement
with adult studies, which demonstrated significant
decreases in MAP when higher doses of remifentanil
were used either as a bolus or continuous infusion.17,18
The decrease in CBFV prior to tracheal intubation
seemed to coincide with a decrease in MAP in the pre-
sent study, suggesting that remifentanil may be associ-
ated with impaired cerebral blood pressure
autoregulation. Alternatively, remifentanil may have
decreased MAP to pressures below the lower limit of
cerebral autoregulation. Establishing a cause-and-
effect relationship between MAP and CBFV would
require a demonstration that CBFV was maintained
only when MAP was kept constant with the use of a
vasopressor during the narcotic infusion period.
In adults, fentanyl 5–8 µg·kg–1 iv given before
induction of anesthesia is effective in suppressing the
cardiovascular responses to laryngoscopy and tracheal
intubation.19 In the present study fentanyl provided a
more stable blood pressure profile prior to tracheal
intubation than did remifentanil. Both agents were
equally successful in maintaining stable hemodynamic
parameters after tracheal intubation. In addition, both
remifentanil and fentanyl offered equally good intu-
bating conditions.
Sevoflurane has been shown to effectively preserve
cerebral blood pressure autoregulation21 and cere-
brovascular CO2 reactivity.22 In addition, induction
and maintenance of anesthesia for children with
sevoflurane represents common pediatric practice.
In order to properly compare the effects of
remifentanil and fentanyl on cerebral and systemic
hemodynamics, it was essential that they be adminis-
tered at equipotent doses. Although opinions vary
regarding remifentanil’s relative potency, most studies
have found that it is 15–40 times more potent than
alfentanil.23,24 Electro-encephalographic studies esti-
mate that remifentanil is 30 times more potent than
alfentanil,24 which puts it very close to fentanyl.25,26
Although the elimination half-life of fentanyl is longer
than that of remifentanil, in the context of a very brief
infusion period (eight minutes in this case), the differ-
ence in terms of postoperative duration of action may
be clinically insignificant. Postoperative discharge
times were not delayed in any of the patients in the
current study.
A full explanation of TCD methodology in children
has been presented in a previous article.8 TCD valida-
tion studies have found that changes in CBFV as mea-
sured by TCD sonography can accurately reflect
changes in cerebral blood flow.27,28 Nevertheless,
some methodological limitations to TCD sonography
interpretation deserve mention. Doppler flow mea-
surements at the middle cerebral artery may not
reflect changes in CBFV if the probe is positioned
inappropriately, or if the probe angle or MCA diame-
ter change during the study.29 In order to minimize
some of these pitfalls, an experienced operator applied
the probe, which was then fixed in position,8 ensuring
that the patient’s head position did not change
throughout the study period. Studies have demon-
strated that the caliber of the proximal cerebral arter-
ies (such as the MCA) remains constant despite
variations in blood pressure and end-tidal CO2,30 and
that it is the more distal arterial branches that change
in diameter during pressure changes.31
Understanding the possible limitations of using
TCD sonography as a measure of cerebral blood flow,
it can be concluded that in children undergoing
sevoflurane anesthesia, remifentanil was associated
with a more pronounced decrease in MAP prior to
laryngoscopy and tracheal intubation when compared
to fentanyl. In addition, remifentanil was less effective
than fentanyl at preventing further increases in CBFV
during and immediately following tracheal intubation.
Therefore, we speculate that the potential benefits of
using the ultra short-acting opioid remifentanil on
induction of anesthesia in pediatric neurosurgical
Sevoflurane was chosen as the background anes-
thetic agent in this study for several reasons. Like all
other volatile agents, sevoflurane causes dose-depen-
dent cerebral vasodilatation,20 however this effect is
not as pronounced as it is with isoflurane.16

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CANADIAN JOURNAL OF ANESTHESIA
13 Stephan H, Groger P, Weyland A, Hoeft A, Sonntag H.
The effect of sufentanil on cerebral blood flow, cerebral
metabolism and the CO2 reactivity of the cerebral ves-
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14 Sandor P, De Jong W, De Wied D. Endorphinergic
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Brain Res 1986; 386: 122–9.
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ous changes in cerebral and systemic hemodynamics
preceding tracheal intubation.
Acknowledgements
The authors would like to thank their colleagues from
the Department of Dentistry and Operating Room
nurses for their assistance with this study.
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