Full text of DOI:10.1007/BF03017452

718
CARDIOTHORACIC ANESTHESIA, RESPIRATION AND AIRWAY
Alfentanil does not increase resistance of the respi-
ratory system in ASA I patients ventilated
mechanically during general anesthesia
[L’alfentanil n’augmente pas la résistance du système respiratoire chez des patients
d’état physique ASA I ventilés mécaniquement pendant l’anesthésie générale]
Giorgio Conti MD, Germano De Cosmo MD, Maria Grazia Bocci MD, Massimo Antonelli MD,
Giorgia Ferro MD, Roberta Costa MD, Geremia Zito MD, Rodolfo Proietti MD
Purpose: Several experimental and clinical studies have demon-
strated a direct bronchoconstrictor effect of opioids on smooth
bronchial musculature following iv administration.
The aim of this study was to evaluate the effects of alfentanil on res-
piratory system mechanics in a group of ASA I patients ventilated
mechanically during general anesthesia.
Objectif : De nombreuses études expérimentales et cliniques ont
démontré un effet bronchoconstricteur direct des opioïdes intraveineux
sur la musculature lisse bronchique. Le but de notre étude était d’é-
valuer les effets de l’alfentanil sur la mécanique du système respira-
toire chez un groupe de patients ASA I ventilés mécaniquement
pendant une anesthésie générale.
Éléments cliniques : Vingt patients consécutifs ASA I ont été
étudiés (dix hommes) pendant une intervention de chirurgie générale
(âge moyen 45,4 ± 9,9 ans, poids moyen 61,9 ± 6,7 kg). Les
critères d’exclusion étaient : un historique de bronchite chronique
obstructive, asthme ou autres maladies pulmonaires, allergies, taba-
gisme, sibilances à l’auscultation pulmonaire et un âge inférieur à 18
ans. Les sujets ont été randomisés en deux groupes : Groupe A, rece-
vant 15 µg·kg–1 d’alfentanil et Groupe B recevant 30 µg·kg–1 d’alfen-
tanil. Les variables de la mécanique respiratoire ont été mesurés au
départ (T0) et après trois, dix et 15 min (T1, T2 et T3, respective-
ment). Les données de base ont été comparées avec les données
mesurées après chaque intervalle de temps, les valeurs de P < 0,05
ont été jugées statistiquement significatives.
Clinical features: Twenty consecutive ASA I patients (ten men and
ten women) scheduled for general surgery interventions were
studied (mean age 45.4 ± 9.9 yr, mean weight 61.9 ± 6.7 kg).
Exclusion criteria were a history of chronic obstructive pulmonary
disease, asthma or other pulmonary disease, atopy, wheezes,
smoking and age below 18 yr. Subjects were randomly divided in
two groups: Group A, receiving alfentanil at a 15 µg·kg–1 dose and
Group B receiving alfentanil at a 30 µg·kg–1 dose. Respiratory
mechanic variables were acquired at baseline (T0) and after three,
ten and 15 min (T1, T2 and T3, respectively). We compared the
basal values to the values measured at each time interval; basal val-
ues, prior to drug administration, served as control for each patient.
P values < 0.05 were considered statistically significant.
Résultats : Aucune différence significative entre les variables de
mécanique respiratoire n’a été observée après l’administration d’alfen-
tanil, aussi bien après une dose de 15 que de 30 µg·kg–1. En partic-
ulier, la compliance du système respiratoire et les différentes variables
des composantes des résistances du système respiratoire (les résis-
tances maximale, minimale et delta du système respiratoire) se si-
tuaient dans des limites normales et n’ont pas montré de variations
significatives après alfentanil.
Results: We did not observe significant differences in respiratory
mechanic variables after the administration of alfentanil, 15 and 30
µg·kg–1. More specifically, respiratory system compliance and the dif-
ferent subcomponents of respiratory system resistances (i.e., maxi-
mum, minimum and delta resistance of respiratory system) were
within normal limits and did not vary after alfentanil administration.
Conclusion: No respiratory adverse effect was reported after
alfentanil iv administration.
Conclusion : Aucun effet secondaire sur la mécanique respiratoire
n’a été remarqué après l’administration iv d’alfentanil.
From the Department of Anesthesia, University of Cattolica del Sacro Cuore di Roma, Policlinico Universitario “A. Gemelli”, Rome, Italy.
Address correspondence to: Dr. Giorgio Conti, Istituto di Anestesia e Rianimazione dell’, Università Cattolica del “Sacro Cuore” di
Roma, Largo F. Vito 1, 00168 Rome, Italy. Phone: +39 06 30154386; Fax: +39 06 3013450; E-mail: g.conti @rm.unicatt.it
Accepted for publication January 28, 2002.
Revision accepted May 13, 2002.
CAN J ANESTH 2002 / 49: 7 / pp 718–723

Conti et al.: ALFENTANIL AND RRS
719
ing alfentanil 15 µg·kg–1, and Group B receiving alfen-
tanil 30 µg·kg–1.
Alfentanil was administered as an iv bolus, after the
induction of general anesthesia. All measurements
were performed before surgical manipulations.
PIOIDS are widely used in clinical anes-
thesia, both to reduce the requirements
of inhalation agents, and to provide
intra- and postoperative analgesia.
O
However, opioid administration may have significant
repercussions on respiratory function.
Beside respiratory depression, several experimental
and clinical studies demonstrated a direct bron-
chocostrictor effect of opioids on smooth bronchial
musculature following iv administration.1,2 The conse-
quent increase in bronchial tone could be particularly
harmful during general anesthesia, when it can cause
an increase in airway pressure, and increase the risk of
ventilation-induced barotrauma.3,4
Experimental protocol
After preoxygenation for five minutes via face mask
(FIO2 = 1), anesthesia was induced with sodium thiopen-
tal (8 mg·kg–1) and maintained for a few minutes with a
continuous infusion of sodium thiopental at the dose of
8 mg·kg–1·min–1. Cis-atracurium 0.2 mg·kg–1, was
administered to facilitate endotracheal intubation, after
the disappearance of the T1 response of the train-of-four
(TOF) stimulation, as measured by acceleromyography
with the TOF Guard (Organon Teknika, The
Netherlands). Cis-atracurium was chosen for its lack of
histamine release properties at clinical doses.11
Alfentanil is a central analgesic, belonging to the 4-
amydo pirydines; it is active predominantly on mu-
receptors and its analgesic effect is 70-fold higher than
that of morphine, and does not cause histamine
release.5 The maximal analgesic effect appears within
one minute after bolus iv administration. The rapid
onset and the rapid offset of its pharmacological action
make alfentanil suitable during balanced anesthesia, to
control the neuroendocrine response to surgical stress.
The administration of alfentanil (5–50 µg·kg–1) signifi-
cantly reduces hemodynamic responses to laryn-
goscopy, endotracheal intubation and surgical incision.6
In spite of the great number of studies dedicated to
the use of opioids during anesthesia, few data are avail-
able regarding the effects of last generation opioids on
Standard monitoring included noninvasive arterial
pressure, heart rate, SpO2, end-tidal CO2. Patients were
ventilated in intemittent pressure positive ventilation
mode with a Siemens Servo Ventilator 900C/ Siemens-
Elema, Sweden12 with the following setting: tidal volume
10 mL·kg–1, FIO2
= 0.5, respiratory rate 10
breaths·min–1, zero end expiratory pressure, I:E ratio 1–2.
The ventilatory circuit included standard tubing, and the
endotracheal tube (internal diameter from 7–8 mm).
Respiratory mechanics measurements
respiratory mechanics under general anesthesia.7–9
A
Under general anesthesia with paralysis and constant
flow controlled mechanical ventilation, a three second
end- inspiratory airway occlusion, performed by press-
ing the dedicated ventilator button,13,14 causes a
biphasic decay of the pressure in the respiratory system,
from a maximum value (Pmax) to a value of pressure
called P1. Minimal resistance of the respiratory system
(RRSmin), mainly representing airway resistance, can
be calculated as the difference between Pmax and P1
divided by the inspiratory flow (Figure 1).15,16
A further, slower decay of the pressure in the air-
ways, from P1 to a plateau value P2 is then observed,
reflecting the forces resulting from the elastic recoil of
the respiratory system, at the end of the inspiratory
phase. The total RRSmax can be calculated by divid-
ing Pmax - P2 by the inspiratory flow. Finally, by sub-
tracting RRSmin from RRSmax it is possible to
calculate deltaRRS, mainly representing the visco-elas-
tic resistance of the respiratory system.17,18
previous study has evaluated the effects on respiratory
mechanics of high-dose alfentanil administration in
patients undergoing cardiac surgery.10
The aim of this study was to evaluate the effects of
alfentanil administration on respiratory system mechan-
ics in a group of ASA I patients mechanically ventilated
during general anesthesia for general surgery.
Methods
Patients
After approval of our Institutional Ethics Committee
and informed consent, 20 consecutive ASA I patients
(ten men and ten women) scheduled for general
surgery (mean age 45.4 9.9 yr, mean weight 61.9
6.7 kg) were enrolled. This sample size was chosen in
accordance to the Neto et al. study.10
Exclusion criteria were a history of chronic obstruc-
tive pulmonary disease, asthma or other pulmonary
disease, atopy, wheezes, smoking of tobacco and age
below 18 yr. All patients presenting an expected risk of
difficult intubation were excluded from the study.
Subjects were randomly divided (computer gener-
ated randomization) in two groups: Group A, receiv-
Airway pressure signal is measured at the level of
the carina with an air-filled non-compliant catheter
(1.2 mm internal diameter), provided with multiple
side holes and an occluded terminal lumen, placed
inside the endotracheal tube.19

720
CANADIAN JOURNAL OF ANESTHESIA
FIGURE 2 Modification of respiratory system (RS) compliance
during the study. Empty columns = Group A (alfentanil 15
µg·kg–1); Hatched columns = Group B (alfentanil 30 µg·kg–1). All
data as mean SD.
FIGURE 1 Schematic representation of an airflow and airway
pressure tracing for assessment of resistances (see text for details).
The analysis of respiratory system mechanics is then
completed by calculating respiratory system compliance
(Crs), that is obtained by dividing the tidal volume
(TV) by the difference between P2 and the tele-expira-
tory pressure (P3), after checking for the absence of
auto-positive end-expiratory pressure (Figure 1).
Respiratory mechanics variables were acquired using a
Bicore pulmonary system CP-100 (Irvine, CA, USA)
connected to the endotracheal tube at the Y piece.20
Data were recorded using a channel for airway pressure,
a channel for air flow, and a third channel for TV; volume
was obtained by electronic integration of flow signal over
time; airway pressure was evaluated at the carinal level,19
to eliminate a bias secondary to the possible modification
of tube resistance (by kinking, secretions or displace-
ment); this was not done in the previous study published
by Neto et al.,10 where airway pressure was measured
inside the ventilator expiratory line.
The pulmonary monitor was connected to an Intel
based personal computer using a RS232 standard ser-
ial connection. Acquisition was performed with a soft-
ware Bicore CP-100 version 2.0 (Bicore Monitoring
Systems 2 Faraday Irvine, CA, USA).20 Collected data
were then converted into ASCII format for further
analysis. Analysis of collected data was performed
using Anadat™ version 5.1 by RHT-InfoDat Inc.
(Montréal, Québec, Canada).
were acquired after three, ten and 15 min (T1, T2 and
T3 respectively). This short time of observation was
chosen to minimize the risk of a type II error due to
the progressive decrease in functional residual capaci-
ty observed over time in supine patients ventilated
mechanically during general anesthesia.15 All measure-
ments were performed in triplicate.
Statistical analysis
Mean values and standard deviation of Crs, RRSmin,
RRSmax and deltaRRS, in the two groups of patients,
were calculated for each time interval (T0, T1, T2, T3).
Statistical analysis was performed using one-way
repeated measure Anova. Post hoc comparison was
performed using paired t test. We compared the basal
values to the values measured at each time interval; P
values < 0.05 were considered statistically significant.
Results
The results of the study are presented in Tables I, II
and in Figure 2, expressed as mean SD. We did not
observe any statistically significant differences in respi-
ratory mechanics variables after the administration of
alfentanil 15 and 30 µg·kg–1.
More specifically, the values of Crs (Figure 2) and of
the different components of respiratory system resis-
tances (i.e., RRSmax, RRSmin and deltaRRS) were
within standard limits for intubated patients and did not
show variations after alfentanil administration.18
After obtaining basal measurements (T0), alfentanil
was administered. Respiratory mechanics variables

Conti et al.: ALFENTANIL AND RRS
721
TABLE I RRS in patients receiving alfentanil
RRSmin
RRSmax
DeltaRRS
(cm H2O·L–1·sec–1)
(cm H2O·L–1·sec–1)
(cm H2O·L–1·sec–1)
Group A
Group B
Group A
Group B
Group A
Group B
T0 (basal)
T1 (3 min)
T2 (10 min)
T3 (15 min)
ANOVA
4.0 1.0
3.7 2.4
5.3 2.5
4.9 2.7
NS
3.7 2.3
3.4 1.9
4.5 3.0
4.8 3.4
NS
6.3 1.8
6.2 1.9
8.3 3.3
7.9 3.6
NS
5.2 2.8
5.4 2.2
6.1 3.1
6.8 3.5
NS
2.5 1.3
2.1 0.6
2.9 0.9
3.2 2.2
NS
1.5 0.8
2.0 0.7
1.5 0.5
1.8 0.4
NS
Group A (n = 10): 15 µg·kg–1; Group B (n = 10): 30 µg·kg–1; RRSmin = minimal resistance of the respiration system; RRSmax = total
resistance of the respiratory system; DeltaRRS = delta resistance of the respiratory system. All data mean standard deviation; NS = not
significant.
TABLE II Hemodynamic variables in patients receiving alfentanil
Systolic blood pressure
(mmHg)
Diastolic blood pressure
(mmHg)
Heart rate
(beats·min–1)
Group A
Group B
Group A
Group B
Group A
Group B
Post-ETI
Incision
ANOVA
123 10.2
116.8 6.7
NS
124 9.3
125.3 11.2
NS
76.3 5.8
76.3 6.7
NS
77.7 8.1
74.7 8.1
NS
67.8 8.2
68.3 8.3
NS
67.6 9.8
69.9 11.8
NS
Group A (n = 10): 15 µg·kg–1; Group B (n = 10): 30 µg·kg–1. All data mean standard deviation. ETI = endotracheal intubation;
NS = not significant.
No other respiratory or hemodynamic side-effect
was recorded during the study and during the surgical
procedure.
respectively); however, the alfentanil doses we used are
those commonly suggested6 in clinical anesthesia for
procedures lasting less than two hours.
An increase of airway resistance after opioid admin-
istration has been reported in several studies, suggesting
a possible role played both by histamine release and by
an increase in cholinergic tone.21,22 A significant hista-
mine release was reported by Flacke et al.21 after the
administration of morphine and pethidine, but has not
been reported after alfentanil, sufentanil, fentanyl and
remifentanil administration.22,23 An increase in cholin-
ergic tone, with a consequent vagomimetic effect, has
been demonstrated in experimental animals after fen-
tanyl administration1 and could be related to a dramat-
ic reduction in the amount of circulating
catecholamines, causing the predominance of choliner-
gic effects on bronchomotor tone.
Discussion
The main result of this study was the absence of effect
of alfentanil on respiratory system mechanics in two
groups of ASA I patients undergoing general surgery
procedures.
This result is in apparent contrast with the results
reported by Ruiz Neto et al. in a study conducted in a
group of ten patients in which the effects of alfentanil
on the resistance and elastance of the respiratory sys-
tem, thoracic wall and lungs were assessed.10
Respiratory mechanics were assessed by the end-infla-
tion occlusion method, as in the present study.
Measurements were performed before drug administra-
tion and after two, five and ten minutes, in patients
undergoing coronary artery bypass grafting. The
authors reported an increase of respiratory system resis-
tance two, five and ten minutes after alfentanil adminis-
tration, together with a parallel increase in respiratory
system elastance (the reciprocal of compliance). The
authors also evaluated the effects of fentanyl (30
µg·kg–1) on respiratory system mechanics and observed
similar effects. Comparing our results with those
reported by Neto,10 some differences can be explained
by the different doses (120 µg·kg–1 vs 15 or 30 µg·kg–1
Bibault et al.24 evaluated the effects of general anes-
thesia with propofol and alfentanil on airway resistance
in two groups of patients: nine subjects were free from
pulmonary disease, while eight had bronchial hyperre-
activity, with a clinical diagnosis of asthma. In all
patients, airway resistance was evaluated with the
patients breathing spontaneously before surgery, during
induction of general anesthesia and after extubation.
No significant modification in bronchial tone was
reported in both subgroups of patients. The authors
concluded that the association of propofol and alfen-

722
CANADIAN JOURNAL OF ANESTHESIA
endothelial cells. Anesthesiology 2000; 93: 825–31.
9 de Wet C, Moss J. Metabolic functions of the lung.
Anesthesiol Clin North Am 1998; 16: 181–99.
10 Ruiz Neto PP, Auler JOC Jr. Respiratory mechanical
properties during fentanyl and alfentanil anaesthesia.
Can J Anaesth 1992; 39: 458–65.
11 Bryson HM, Faulds D. Cisatracurium besilate. A review
of its pharmacology and clinical potential in anaesthetic
practice. Drugs 1997; 53: 848–66.
12 Sly PD, Bates JH, Milic-Emili J. Measurement of respi-
ratory mechanics using the Siemens Servo Ventilator
900 C. Pediatr Pulmonol 1987; 3: 400–5.
13 Bates JH, Hunter IW, Sly PD, Okubo S, Filiatrault S,
Milic-Emili J. Effect of valve closure time on the deter-
mination of respiratory resistance by flow interruption.
Med Biol Eng Comput 1987; 25: 136–40.
14 Similowski T, Levy P, Corbeil C, et al. Viscoelastic
behavior of lung and chest wall in dogs determined by
flow interruption. J Appl Physiol 1989; 67: 2219–29.
15 D’Angelo E, Calderini E, Torri G, Robatto FM, Bono D,
Milic-Emili J. Respiratory mechanics in anesthetized-
paralyzed humans: effect of flow, volume, and time. J
Appl Physiol 1989; 67: 2556–64.
16 Milic-Emili J, Robatto FM, Bates JHT. Respiratory
mechanics in anaesthesia. Br J Anaesth 1990; 65: 4–12.
17 Johnson A, Bengtsson M. Comparison of anaesthesia
ventilators using a lung model. Acta Anaesthesiol
Scand 1990; 34: 222–6.
tanil is safe in patients with bronchial hyperreactivity;
the use of propofol, considered to be the agent of
choice for the induction of anesthesia in asthmatic
patients for its possible bronchodilator effect,25,26 could
have influenced the effects of alfentanil. We used sodi-
um thiopental and cis- atracurium for the maintenance
of anesthesia, as both drugs are free from effects on
bronchomotor tone, thus minimizing the risks of phar-
macologic interferences.27,28 For this reason we avoided
the administration of any volatile agent.
When long-term measurements are required (i.e.,
assessment of modifications over several hours) airway
pressure must be measured at the carinal level,19 to
eliminate possible and progressive modifications of
tube resistance (by kinking, secretions or displace-
ment). Our measurements of RRSmin and RRSmax,
therefore, do not include the intrinsic resistance of the
tube and are technically reliable. The level of anesthe-
sia, muscle relaxation and ventilator settings were kept
constant, so any observed modification of respiratory
system mechanics should be attributable to the admin-
istration of alfentanil.
In conclusion, we have shown that alfentanil
(15–30 µg·kg–1) has no effect on respiratory system
mechanics and airway resistance of ASA I patients ven-
tilated mechanically during general anesthesia.
References
18 D’Angelo E, Robatto FM, Calderini E, et al. Pulmonary
and chest wall mechanics in anesthetized paralyzed
humans. J Appl Physiol 1991; 70: 2602–10.
1 Gentil B, Macquin-Mavier I, Harf A. Fentanyl-induced
airway hyperreactivity in the guinea pig. Eur J
Pharmacol 1989; 159: 181–5.
19 Conti G, De Blasi RA, Lappa A, et al. Evaluation of
respiratory system resistance in mechanically ventilated
patients: the role of the endotracheal tube. Intensive
Care Med 1994; 20: 421–4.
2 Cohendy R, Lefrant JY, Laracine M, Rebiere T, Eledjam
JJ. Effect of fentanyl on ventilatory resistances during
barbiturate general anaesthesia. Br J Anaesth 1992; 69:
595–8.
20 Petros AJ, Lamond CT, Bennett D. The Bicore pul-
monary monitor. A device to assess the work of breath-
ing while weaning from mechanical ventilation.
Anaesthesia 1993; 48: 985–8.
3 Yasuda I, Hirano T, Yusa T, Satoh M. Tracheal con-
striction by morphine and by fentanyl in man.
Anesthesiology 1978; 49: 117–9.
4 Cigarini I, Bonnet F, Lorino AM, Harf A, Desmonts
JM. Comparison of the effects of fentanyl on respirato-
ry mechanics under propofol or thiopental anaesthesia.
Acta Anaesth Scand 1990; 34: 253–6.
5 Levy JH, Brister NW, Shearin A, et al. Wheal and flare
responses to opioids in humans. Anesthesiology 1989;
70: 756–60.
6 Baley PL, Egan TD, Stanley TH. Intravenous opioid
anesthetics. In: Miller RD (Ed.). Anesthesia, 5th ed.
2000; 1: 314–5; 333–4.
21 Flacke JW, Flacke WE, Bloor BC, Van Etten AP, Kripke
BJ. Histamine release by four narcotics: a double- blind
study in humans. Anesth Analg 1987; 66: 723–30.
22 Bowdle TA. Adverse effects of opioid agonists and agonist
-antagonists in anaesthesia. Drug saf 1998; 19: 173–89.
23 Lien CA, Belmont MR, Abalos A, et al. The cardiovas-
cular effects and histamine-releasing properties of
51W89 in patients receiving nitrous oxide/opioid/bar-
biturate anesthesia. Anesthesiology 1995; 82: 1131–8.
24 Bilbault P, Boisson-Bertrand D, Duvivier C, Peslin R,
Laxenaire MC. Influence de l’association propofol-
alfentanil sur les resistances bronchiques du sujet asth-
matique (French). Ann Fr Anesth Reanim 1991; 10:
264–8.
7 Taeger K, Weninger E, Schmelzer F, Adt M, Franke N,
Peter K. Pulmonary kinetics of fentanyl and alfentanil
in surgical patients. Br J Anaesth 1988; 61: 425–34.
8 Waters CM, Krejcie TC, Avram MJ. Facilitated uptake
of fentanyl, but not alfentanil, by human pulmonary

Conti et al.: ALFENTANIL AND RRS
723
25 Bremerich DH. Anesthesia in bronchial asthma
(German). Anasthesiol Intensivmed Notfallmed
Schmerzther 2000; 35: 545–58.
26 Hirota K, Sato T, Hashimoto Y, et al. Relaxant effect of
propofol on the airway in dogs. Br J Anaesth 1999;
83: 292–5.
27 Mustafa S, Thulesius L, Thulesius O. The contractile
response of thiopental in large and small ovine airways.
Acta Anaesthesiol Scand 1994; 38: 499–504.
28 Wu RSC, Wu KC, Sum DCW, Bishop MJ. Comparative
effects of thiopentone and propofol on respiratory
resistance after tracheal intubation. Br J Anaesth 1996;
77: 735–8.