Remifentanil for fetal immobilization and maternal sedation

1. Remifentanil for Fetal Immobilization and Maternal Sedation
During Fetoscopic Surgery: A Randomized, Double-Blind
Comparison with Diazepam
Marc Van de Velde, MD, PhD, Dominique Van Schoubroeck, MD, Liesbeth E. Lewi, MD,
Marco A. E. Marcus, MD, PhD, Jacques C. Jani, MD, Carlo Missant, MD, An Teunkens, MD, and
Jan A. Deprest, MD, PhD
Departments of Anaesthesiology and Obstetrics and Gynaecology, University Hospital Gasthuisberg, Katholieke
Universiteit Leuven, Leuven, Belgium, and the Department of Anaesthesiology, University of Maastricht, The Netherlands
Obstetric endoscopy procedures are routinely performed and Pco2 38.6 4 mm Hg at 40 min of surgery),
at our institution to treat selected complications of mono- whereas diazepam resulted in a more pronounced
chorionic twin gestation. We perform these procedures maternal sedation but no respiratory depression (re-
under combined spinal epidural anesthesia plus maternal spiratory rate 18 3 breaths/min and Pco2 32.7
sedation. In the absence of general anesthesia, fetal immo- 3 mm Hg at 40 min of surgery). Compared with diaz-
bilization is not achieved. We hypothesized that remifen- epam, fetal immobilization with remifentanil oc-
tanil would induce adequate maternal sedation and pro- curred faster and was more pronounced, resulting in
vide fetal immobilization, which is equal or superior to improved surgical conditions; the number of gross
that induced by diazepam. Fifty-four second trimester body and limb movements was 12 4 (diazepam)
pregnant women were included in this randomized, versus 2 1 (remifentanil) at 40 min of surgery. Be-
double-blind trial. After combined spinal epidural anes- cause of this, the mean (range) duration of surgery
thesia, maternal sedation was initiated using either incre- was significantly shorter in the remifentanil-treated
mental doses of diazepam or a continuous infusion of patients, 60 (54 –71) min versus 80 (60 –90) min in the
remifentanil. Maternal sedation, hemodynamics, side ef- diazepam group. We conclude that remifentanil pro-
fects, and fetal hemodynamics and immobilization duces improved fetal immobilization with good ma-
were evaluated before, during, and for 60 min after ternal sedation and only minimal effects on maternal
surgery. Remifentanil produced adequate maternal respiration.
sedation with mild but clinically irrelevant respira-
tory depression (respiratory rate 13 4 breaths/min (Anesth Analg 2005;101:251–8)
A
s a result of advances in high-resolution ultra- revived the interest in fetoscopy and today it has a
sound, an increasing number of fetal conditions distinct place in modern fetal medicine (1,3). Fetal
are diagnosed early in gestation. Some of these surgery includes all types of surgery in which direct
conditions are life threatening or may cause irrevers- interventions on the fetus are performed, but few of
ible organ damage but may benefit from a prenatal them are amenable to treatment by endoscopy. The
intervention (1–3). Miniaturization of endoscopes has term “obstetric endoscopy” was proposed for feto-
scopic procedures on the placenta, the umbilical
cord, and fetal membranes. The technique of laser
Supported, in part, by a 2002 Society of Anesthesia and Reanima-
tion of Belgium (SARB) grant for experimental research, by “Krediet coagulation of the vascular anastomoses on the
aan Navorsers” (nr. 1.5.080.03) granted by the Fund for Scientific monochorionic placenta for twin-to-twin transfu-
Research Flanders (Fonds voor Wetenschappelijk Onderzoek Vlaan- sion syndrome is well established and has recently
deren), and by grants financed by the European Commission (Euro
Twin 2 Twin, QLG1-CT-2002– 01632, to Drs Jani and Lewi). been shown to be superior to amniodrainage in a
Accepted for publication January 7, 2005. randomized controlled trial (4). Therefore, the num-
Address correspondence to: Marc Van de Velde, MD, PhD., ber of these procedures will undoubtedly increase
Director Obstetric Anesthesia and Extra Muros Anesthesia, De-
partment of Anaesthesiology, University Hospitals Gasthuisberg,
(2– 4). Another application of obstetric endoscopy is
Herestraat 49, B - 3000 Leuven, Belgium. Address e-mail to selective feticide by cord occlusion, used in mono-
marc.vandevelde@uz.kuleuven.ac.be. chorionic twin pregnancies complicated by severe
DOI: 10.1213/01.ANE.0000156566.62182.AB discordant anomalies (5,6).
©2005 by the International Anesthesia Research Society
0003-2999/05 Anesth Analg 2005;101:251–8 251

2. 252 OBSTETRIC ANESTHESIA VAN DE VELDE ET AL. ANESTH ANALG
FETAL IMMOBILIZATION WITH REMIFENTANIL DURING FETOSCOPIC SURGERY 2005;101:251–8
These procedures are often performed under local ranitidine 50 mg IV 60 min before initiation of anes-
anesthesia (4). However, we liberally use combined thesia. Mothers were prehydrated using 1000 mL of
spinal epidural anesthesia as a means of maternal lactated Ringer’s solution through an IV catheter in
anesthesia. Combined spinal epidural and local anes- the right forearm. A second IV cannula was positioned
thesia provide neither fetal immobilization nor anes- in the left antecubital vein to infuse maternal sedative
thesia. Based on clinical experience, we believe that drugs. Under local anesthesia, the left radial artery
fetal movements may lead to fetal trauma and may was cannulated to allow continuous arterial blood
hamper surgery, leading to incomplete coagulation of pressure measurements and repetitive blood sam-
vessels, failure of surgery and an increase in the du- pling. Combined spinal epidural anesthesia was per-
ration of the intervention (7). Increasing the duration formed at the L3-4 or L4-5 interspace with the patient
of endoscopic surgery may increase the risk of iatro- sitting. The epidural space was identified using an
genic preterm, prelabor rupture of membranes (8,9). 18-gauge Tuohy needle using the loss of resistance to
Fetal immobilization has been traditionally ob- saline technique. The dura was entered using a 27-
tained by maternal administration of diazepam (DZP), gauge pencil point spinal needle and 8 mg of hyper-
which is associated with maternal sedative effects. baric bupivacaine 0.5% was injected into the spinal
Although it provides maternal sedation, in our expe- space, after which a 20-gauge epidural catheter was
rience DZP produces insufficient fetal immobility. advanced 4 cm into the epidural space. Anesthesia
Remifentanil (REMI) is a novel, short-acting opioid, was maintained by additional epidural top-ups of
which is rapidly hydrolyzed by nonspecific plasma ropivacaine 0.75% at the discretion of the attending
and tissue esterases. It has been used for intraopera- anesthesiologist. If hypotension (defined as a decrease
tive sedation in patients undergoing regional or local in mean arterial blood pressure of 10% from baseline
anesthesia (10 –14). In term pregnant women under- values recorded immediately before anesthesia) oc-
going elective Cesarean delivery under epidural anes- curred, ephedrine or phenylephrine was administered
thesia, it produces excellent maternal sedation without at the discretion of the attending anesthesiologist.
adverse maternal effects (15). Kan et al. (15) demon- The patient was then positioned in the supine posi-
strated that IV REMI, in a dose of 0.1 g · kg 1 · min 1 tion with 15 degrees left lateral tilt to prevent aorto-
and part of a regional anesthetic technique, rapidly caval compression (17). Supplemental oxygen (5
and extensively crosses the placenta (umbilical vein/ L/min) was routinely administered by face mask. Af-
maternal artery ratio, 0.88). An initial dose response ter baseline recordings, maternal IV sedation was
study determined that a dose of 0.1 g · kg 1 · min 1 started. Patients were randomized to 2 groups of 27
of REMI produced excellent fetal immobilization in patients by a computer-generated list. Study drugs
second trimester pregnant patients (16). Based on this were prepared and administered by an anesthesiolo-
dose-response study, we hypothesized that REMI in a gist not involved in further management of the pa-
dose of 0.1 g · kg 1 · min 1 would induce superior tients. Patients, surgeon, and attending anesthesiolo-
fetal immobilization during obstetric endoscopic sur- gist were blinded as to the sedative drugs used. In the
gery as compared with DZP and at the same time DZP group a continuous infusion of saline mimicked
provide appropriate maternal sedation. Therefore, we the REMI infusion. DZP was initiated using a dose of
initiated a randomized, double-blind trial comparing 5 mg IV, followed 10 min later by an additional 5 mg.
the effects of IV DZP versus IV REMI in pregnant Additional 2.5-mg increments of DZP were given
women undergoing obstetric endoscopic surgery un- when maternal sedation was judged inadequate by an
der neuraxial block. We postulated that fetal immobi- observer assessment of alertness/sedation scale
lization and maternal sedation provided by REMI (OAA/S) score of 5 or when fetal immobility was
would be at least as good as, if not superior to, DZP. judged inadequate by the surgeon. In case a top-up
dose of DZP was required, an increase in the “sham”
saline infusion rate was performed simultaneously. As
to the maximum total dose of DZP, no additional
Methods top-ups were given if maternal sedation was profound
After Institutional Ethics Committee approval, 54 (OAA/S score of 3 or less), maternal arterial blood gas
healthy (ASA I–II) women in the second trimester of analysis revealed a pH 7.35 or a Pco2 of 45 mm Hg,
pregnancy (gestational age, 16 –25 wk), carrying a or maternal respiratory rate decreased to 8 breaths
multiple pregnancy and scheduled for either feto- per minute.
scopic laser coagulation or cord occlusion, provided In the REMI group a continuous infusion of REMI
written and informed consent to this randomized, was started at an initial flow rate of 0.1
double-blind trial. g · kg 1 · min 1 (dilution of REMI 50 g/mL) and at
Before anesthesia and surgery, all patients received 0 and 10 min a bolus of normal saline was given to
prophylaxis for acid aspiration using 30 mL oral so- mimic the DZP administration. The initial dose of
dium citrate 0.3 M, metoclopramide 10 mg IV, and REMI was based on a previous dose-response study at

3. ANESTH ANALG OBSTETRIC ANESTHESIA VAN DE VELDE ET AL. 253
2005;101:251–8 FETAL IMMOBILIZATION WITH REMIFENTANIL DURING FETOSCOPIC SURGERY
our institution (16). Sham saline boluses and an in- At the end of the intervention, the surgeon assessed
crease of the REMI infusion rate with 0.025 overall fetal immobility and operating conditions us-
g · kg 1 · min 1 were performed if maternal seda- ing a four-point scale: 1 excellent, 2 good, 3
tion was inadequate (OAA/S score of 5) or if fetal moderate, 4 inadequate or no immobilization. This
immobility was judged to be insufficient by the sur- subjective score represented an overall subjective im-
geon. The REMI or saline infusion was decreased by pression and is further referred to as the surgical
0.025 g · kg 1 · min 1 if maternal sedation was pro- assessment score.
found (OAA/S of 3 or less), maternal blood gas pH Perinatal variables included the number of surviv-
decreased to less than 7.35, the arterial Pco2 increased ing fetuses, gestational age at delivery, and neonatal
to more than 45 mm Hg, or maternal respiratory rate survival and complications.
decreased to 8 breaths per minute. If maternal apnea Data were analyzed using two-way repeated meas-
occurred, cricoid pressure was applied and mask ven- ures analysis of variance followed by Scheffe’s post hoc
tilation was initiated until spontaneous respiration re- testing as required. Categorical data were analyzed
sumed and the REMI infusion would be stopped using 2 analysis and Fisher’s exact test. Data are
immediately. presented as a mean sd, median and interquartile
At the end of surgery the REMI infusion was range, or as percentage of the group total. P 0.05
stopped. The observation period started at the mo- was considered as statistically significant. Our prelim-
ment of first administration of REMI until 60 min after inary experience with DZP sedation demonstrated ad-
the end of surgery. In both groups, all necessary equate fetal immobilization in approximately 30% of
changes in infusion rate and additional boluses of patients; adequate maternal sedation was achieved in
DZP were made by an anesthesiologist not involved in most mothers. In a dose finding study for REMI we
data recording. achieved fetal immobilization in more then 80% of
Before the study, demographic data, medical his- patients using 0.1 g · kg 1 · min 1; maternal seda-
tory, relevant obstetrical data, maternal arterial blood tion was adequate. For sample size calculations, we
pressure as measured invasively, maternal heart and expected a 50% increase in adequate fetal immobility
respiratory rate were recorded. Maternal side effects from 30% to 80% of fetuses when using REMI. We
were noted. Maternal sedation was evaluated by the calculated the number of patients required in each
attending anesthesiologist using the OAA/S (18). We group to demonstrate a statistically significant differ-
targeted the sedation to aim at an ideal OAA/S score ence to be 23 subjects ( 0.05, 0.05).
of 4; a score of 4 was considered profound sedation
and a score 4 was considered insufficient sedation.
Sedation was evaluated at baseline, at 20, 40, and
60 min during surgery, and at 10, 20, 30, and 60 min Results
after completion of surgery. Maternal arterial blood In two patients in each group, fetuses were immobile
gas analysis was performed before the start of seda- before the start of sedation and surgery and therefore
tion, every 20 min during surgery, and at 10, 20, 30, these were excluded. This left 50 patients for analysis,
and 60 min after the end of surgery. 25 in each group. Gestational age at intervention, the
Fetal heart rate was recorded every 15 min using number of laser coagulations, and cord occlusions
ultrasound. Fetal mobility was assessed before, dur- were comparable in the two groups. There was no
ing, and after surgery by taping 5 min ultrasound significant difference in gestational age at delivery and
sequences of fetal movement every 20 min throughout survival rates between the treatment groups, both for
surgery and 10, 20, 30, and 60 min after the end of laser cases and cord occlusions (Table 1). The inci-
surgery. These taped sequences were evaluated off- dence of preterm labor and delivery was not signifi-
line by an experienced ultrasonographer. For that pur- cantly different between the two groups.
pose the video sequences were randomly presented Results related to maternal sedation and fetal im-
with patient identification blinded. The baseline re- mobilization are summarized in Table 2 and Figures 1
cording was presented first for each patient. Two through 6. REMI produced excellent levels of maternal
types of evaluation were performed: a visual analogue sedation in all patients. Only one patient (4%) had
scale score for mobility (0 immobile fetus and 100 an OAA/S score 4 and was therefore considered
baseline mobility) and the number of gross body to be profoundly sedated during surgery (Fig. 4).
movements and limb movements per 5-min period. If The mean REMI infusion rate was 0.115 0.020
fetuses were immobile before the start of sedation, g · kg 1 · min 1. The most rapid REMI infusion
patients were excluded from further analysis. Only the rate was 0.150 g · kg 1 · min 1. In the DZP group,
fetal movements of the non-stuck twin were recorded 11 women (44%) were profoundly sedated (OAA/S
in case of twin-to-twin transfusion syndrome, and score 4). The mean total DZP dose was 14.5
only movements of the normal fetus were recorded in 4.8 mg. Maternal respiratory rate in the REMI group
case of selective feticide. decreased during surgery; it remained stable in the

4. 254 OBSTETRIC ANESTHESIA VAN DE VELDE ET AL. ANESTH ANALG
FETAL IMMOBILIZATION WITH REMIFENTANIL DURING FETOSCOPIC SURGERY 2005;101:251–8
Table 1. Demographic and Obstetrical Data in the Study Population: None of the Differences were Significant
Remifentanil group Diazepam group
Age (yr) 30.2 5.1 29.6 4.8
Weight (kg) 70 11 71 14
Height (cm) 167 5 167 8
Gestational age at procedure (wk) 19.9 2.5 19.6 2.6
Gestational age at delivery (wk) 34 (33–36) 33 (29.5–35)
Coagulation of chorionic vessels for TTTs (%) 84 76
Cord coagulation (%) 16 24
Neonatal survival for TTTS patients (%) 71 63
Survival of non-target fetus in case of cord coagulation (%) 75 67
Data are presented as a mean sd; median and interquartile range or percentage of group total.
TTTS twin to twin transfusion syndrome.
Table 2. Data on maternal sedation, surgeon satisfaction with fetal immobility and surgical conditions, duration of
surgery and the need for ephedrine and phenylephrine in the study population
Remifentanil group Diazepam group P value
Mean remifentanil infusion ( g/kg/min) 0.115 0.020* 0 0.00001
Diazepam dose (mg) 0 14.5 4.8* 0.00001
OAA-score 4 (number of patients) 1 11* 0.001
Satisfaction score 1 or 2 as evaluated by surgeon (n) 23/25 8/25* 0.0001
Duration of surgery (min) 60 (54–71) 80 (60–90)* 0.024
Ephedrine (mg) 21 8 25 11 NS
Phenylephrine ( g) 50 (0–275) 250 (50–500) NS
Epedrine (number of patients) 22 21 NS
Phenylephrine (number of patients) 10 12 NS
Data are presented as a mean sd, median and interquartile range and number of patients.
OAA/S observer assessment of alertness scale; NS not significant.
* P 0.05 versus remifentanil treated patients.
DZP group. As a result of maternal hypoventilation, REMI group, whereas this was good to excellent in
an increase in Pco2 and a decrease in pH was noted only 8 of 25 (32%) in the DZP group. No significant
in the REMI group (Figures 1 through 3). The lowest changes in fetal heart were noted in either group. No
respiratory rate and pH and highest Pco2 in any early or late decelerations or fetal bradycardia were
patient at any stage occurred in one patient treated recorded.
with REMI after 40 min of treatment. Her respira-
tory rate was 7 breaths/min, Pco2 was 48 mm Hg,
and pH was 7.31. REMI infusion was stopped and
the respiratory depression spontaneously resolved Discussion
after several minutes. Maternal hemodynamics re- This randomized double-blind study in patients un-
mained stable throughout the procedure. Similar dergoing obstetrical endoscopic surgery demonstrates
doses and number of top-ups of ephedrine and that REMI induces excellent fetal immobilization and
phenylephrine were needed in both groups. Dura- maternal sedation during surgery, while DZP pro-
tion of surgery was significantly longer in the DZP vides less fetal immobilization and deeper maternal
group, 80 (60 –90) minutes versus 60 (54 –71) min- sedation.
utes in the REMI group. Some in utero conditions are amenable to surgical
REMI induced a significantly higher degree of fetal interventions (1– 4,19). At our institution, obstetric en-
immobilization, whereas DZP had little effect on fetal doscopy procedures are performed regularly. Most
mobility as evaluated by subjective surgical and ob- cases are for treatment of twin-to-twin transfusion
jective ultrasound scores (Figs. 5 and 6). The number syndrome because laser therapy has been proven to be
of fetal gross body and limb movements decreased better then amniodrainage (1,3,4). In addition, selec-
from 18 3 to 2 1 at 40 min of surgery in the REMI tive feticide procedures in selected monochorionic
group; this decrease was much less in the DZP group, twin pregnancies may require in utero endoscopic cord
from 17 4 to 12 4 at 40 min of surgery. The occlusion. These procedures usually do not require
subjective appreciation of fetal immobilization by the maternal general anesthesia (19,20). General anesthe-
surgeon, who was blinded as to the medication, was sia in pregnancy is associated with a more frequent
good to excellent in 23 of 25 patients (92%) in the incidence of maternal mortality and morbidity (21),

5. ANESTH ANALG OBSTETRIC ANESTHESIA VAN DE VELDE ET AL. 255
2005;101:251–8 FETAL IMMOBILIZATION WITH REMIFENTANIL DURING FETOSCOPIC SURGERY
Figure 1. Respiratory rate (breaths per minute) in patients receiving Figure 3. Arterial pH in patients receiving either diazepam (DZP) or
either diazepam (DZP) or remifentanil (REMI) IV sedation. X-axis: remifentanil (REMI) IV sedation. X-axis: BL baseline measure-
BL baseline measurement; 10 – 60 and 10A– 60A measurement ment; 10 – 60 and 10A– 60A measurement 10 – 60 min after start
10 – 60 min after start and, respectively, end (A) of surgery. In the and, respectively, end (A) of surgery. In the REMI group, the REMI
REMI group, the REMI infusion was stopped at the end of surgery. infusion was stopped at the end of surgery. In the DZP group the
In the DZP group the last bolus was given on clinical indication and last bolus was given on clinical indication and no top-ups were
no top-ups were administered after the end of surgery. * P 0.05 administered after the end of surgery. * P 0.05 REMI versus DZP
REMI versus DZP at each time point; ** P 0.05 versus baseline at each time point; ** P 0.05 versus baseline within one group.
within one group.
Figure 4. Observer assessment of alertness (OAA/S) score of 4 in
patients undergoing endoscopic, intrauterine surgery with either
diazepam or remifentanil sedation. BL baseline measurement;
10A measurement 10 min after the end of surgery; 20A meas-
Figure 2. Arterial Pco2 in patients receiving either diazepam (DZP) urement 20 min after the end of surgery; 30A measurement
or remifentanil (REMI) IV sedation. X-axis: BL baseline meas- 30 min after the end of surgery; 60A measurement 60 min after
urement; 10 – 60 and 10A– 60A measurement 10 – 60 min after start the end of surgery. In the remifentanil group, the remifentanil
and, respectively, end (A) of surgery. In the REMI group, the REMI infusion was stopped at the end of surgery. In the diazepam group
infusion was stopped at the end of surgery. In the DZP group the no additional boluses of diazepam were administered after the end
last bolus was given on clinical indication and no top-ups were of surgery.
administered after the end of surgery. * P 0.05 REMI versus DZP
at each time point; ** P 0.05 versus baseline within one group.
of surgery may increase the risk of iatrogenic preterm,
prelabor rupture of membranes (8,9).
mainly as the result of airway problems. Most Euro- To obviate these problems, we initially used IV DZP
pean centers prefer local or regional anesthesia tech- to obtain fetal immobilization. However, the effects on
niques for these cases. However, regional anesthetic fetal mobility of IV maternal DZP were unpredictable
techniques do not provide fetal immobilization or fetal and often disappointing, and maternal sedation was
analgesia. Fetal movements may lead to fetal trauma, profound. In the present trial we confirmed this ob-
may hamper or prolong surgery, or may even result in servation, with only a small percentage of fetuses be-
failure to complete the planned surgery. Prolongation ing adequately immobilized. It has been shown that

6. 256 OBSTETRIC ANESTHESIA VAN DE VELDE ET AL. ANESTH ANALG
FETAL IMMOBILIZATION WITH REMIFENTANIL DURING FETOSCOPIC SURGERY 2005;101:251–8
Figure 5. Visual Analog Scale (VAS) for fetal mobility (0 fetus is
completely immobile; 100 baseline fetal mobility) in patients
receiving either diazepam (DZP) or remifentanil (REMI) IV seda- Figure 6. Number of gross body and limb movements during a
tion. X-axis: BL baseline measurement; 10 – 60 and 10A– 60A 5-min registration period at various time points throughout the
measurement 10 – 60 min after start and, respectively, end (A) of procedure. X-axis: BL baseline measurement; 10 – 60 and 10A–
surgery. In the REMI group, the remifentanil infusion was stopped 60A measurement 10 – 60 min after start and, respectively, end (A)
at the end of surgery. In the DZP group the last bolus was given on of surgery. In the remifentanil (REMI) group, the remifentanil infu-
clinical indication and no top-ups were administered after the end sion was stopped at the end of surgery. In the diazepam (DZP)
of surgery. * P 0.05 REMI versus DZP at each time point; ** P group the last bolus was given on clinical indication and no top-ups
0.05 versus baseline within one group. were administered after the end of surgery. * P 0.05 REMI versus
DZP at each time point.
DZP crosses the placenta rapidly but that the fetal that REMI would provide excellent fetal immobiliza-
capillary blood concentration varies considerably, at tion. REMI rapidly and extensively crosses the pla-
least in term infants (22), and that neonatal effects are centa (umbilical vein/maternal artery ratio, 0.88) in
largely unpredictable. It was also demonstrated that term pregnancies (15). Other opioids have also been
the transfer of DZP across the human placenta is shown to have a rapid and large transplacental pas-
slower in early pregnancy than during labor (23). In sage in early human gestation (29 –31). Although no
addition, there are concerns of DZP being associated pharmacokinetic data on REMI are available at mid-
with neurodevelopmental changes in neonates and gestation and our study similarly does not provide
congenital abnormalities when used chronically (24 – such information, our observations clearly show that
26). Administration of DZP outside the period of or- REMI effectively crosses the placenta and causes fetal
ganogenesis using a single bolus has never been asso- immobilization.
ciated with teratogenic effects. Furthermore, DZP does In contrast to DZP, REMI has the potential, as do
not provide fetal analgesia and fetal and maternal other opioids, to provide effective fetal analgesia after
recovery is slow after DZP administration. accidental direct stimulation (e.g., touching with en-
We decided to use DZP as the control group in the doscopes). Therefore, it has been suggested that pain
present trial despite the possibility of using other more relief has to be provided during in utero interventions
short-acting benzodiazepines. Theoretically, other on the fetus from mid-gestation (20 weeks) on (32–34).
more short-acting benzodiazepines, such as midazo- Direct administration of fentanyl to the human fetus
lam, may yield more consistent and more controllable has been shown to block the fetal stress response
maternal sedation. However, placental passage and during mid-gestational in utero interventions (35). In
thus fetal immobilization remains unpredictable as our trial inadvertent touching of an immobilized fetus
well (27,28). Placental passage of midazolam in preg- resulted in fetal “awakening.” Therefore, when fetal
nant ewes is small, with a fetal/maternal plasma con- analgesia or blunting of the fetal stress response is
centration ratio of 0.15 (27). Also, in term pregnancies required, additional drugs (opioids and nondepolar-
the placental transfer of midazolam is considerably izing muscle relaxants) must be administered directly
less than that of thiopental and REMI (15,28). to the fetus. It must be stressed, however, that fetal
Remifentanil is a novel ultra-short-acting opioid for analgesia is not generally required during in utero
IV use that is clinically proposed for sedation during procedures on the placenta and cord (the procedures
surgical interventions in the nonpregnant and preg- performed in the present trial), as direct fetal trauma
nant population (10 –15). In general, opioids have a should not occur.
large transplacental passage (29,30) and as a conse- Maternal sedation during lengthy or stressful in
quence produce fetal “sleep.” We therefore speculated utero interventions is useful to relieve anxiety and

7. ANESTH ANALG OBSTETRIC ANESTHESIA VAN DE VELDE ET AL. 257
2005;101:251–8 FETAL IMMOBILIZATION WITH REMIFENTANIL DURING FETOSCOPIC SURGERY
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