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Remifentanil for Fetal Immobilization and Maternal Sedation During Fetoscopic Surgery: A Randomized, Double-Blind Comparison with Diazepam

Van de Velde, Marc MD, PhD; Van Schoubroeck, Dominique MD; Lewi, Liesbeth E. MD; Marcus, Marco A.E. MD, PhD; Jani, Jacques C. MD; Missant, Carlo MD; Teunkens, An MD; Deprest, Jan A. MD, PhD

doi: 10.1213/01.ANE.0000156566.62182.AB
Obstetric Anesthesia: Research Report

Obstetric endoscopy procedures are routinely performed at our institution to treat selected complications of monochorionic twin gestation. We perform these procedures under combined spinal epidural anesthesia plus maternal sedation. In the absence of general anesthesia, fetal immobilization is not achieved. We hypothesized that remifentanil would induce adequate maternal sedation and provide fetal immobilization, which is equal or superior to that induced by diazepam. Fifty-four second trimester pregnant women were included in this randomized, double-blind trial. After combined spinal epidural anesthesia, maternal sedation was initiated using either incremental doses of diazepam or a continuous infusion of remifentanil. Maternal sedation, hemodynamics, side effects, and fetal hemodynamics and immobilization were evaluated before, during, and for 60 min after surgery. Remifentanil produced adequate maternal sedation with mild but clinically irrelevant respiratory depression (respiratory rate 13 ± 4 breaths/min and Pco2 38.6 ± 4 mm Hg at 40 min of surgery), whereas diazepam resulted in a more pronounced maternal sedation but no respiratory depression (respiratory rate 18 ± 3 breaths/min and Pco2 32.7 ± 3 mm Hg at 40 min of surgery). Compared with diazepam, fetal immobilization with remifentanil occurred faster and was more pronounced, resulting in improved surgical conditions; the number of gross body and limb movements was 12 ± 4 (diazepam) versus 2 ± 1 (remifentanil) at 40 min of surgery. Because of this, the mean (range) duration of surgery was significantly shorter in the remifentanil-treated patients, 60 (54–71) min versus 80 (60–90) min in the diazepam group. We conclude that remifentanil produces improved fetal immobilization with good maternal sedation and only minimal effects on maternal respiration.

IMPLICATIONS: This trial tested the use of remifentanil for maternal sedation and fetal immobilization during endoscopic intrauterine surgery on the cord and placenta. Remifentanil was superior to diazepam for inducing adequate sedation and fetal immobilization and also facilitated faster surgery.

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

Supported, in part, by a 2002 Society of Anesthesia and Reanimation of Belgium (SARB) grant for experimental research, by “Krediet aan Navorsers” (nr. 1.5.080.03) granted by the Fund for Scientific Research Flanders (Fonds voor Wetenschappelijk Onderzoek Vlaanderen), and by grants financed by the European Commission (Euro Twin 2 Twin, QLG1-CT-2002–01632, to Drs Jani and Lewi).

Accepted for publication January 7, 2005.

Address correspondence to: Marc Van de Velde, MD, PhD., Director Obstetric Anesthesia and Extra Muros Anesthesia, Department of Anaesthesiology, University Hospitals Gasthuisberg, Herestraat 49, B - 3000 Leuven, Belgium. Address e-mail to marc.vandevelde@uz.kuleuven.ac.be.

As a result of advances in high-resolution ultrasound, an increasing number of fetal conditions are diagnosed early in gestation. Some of these conditions are life threatening or may cause irreversible organ damage but may benefit from a prenatal intervention (1–3). Miniaturization of endoscopes has revived the interest in fetoscopy and today it has a distinct place in modern fetal medicine (1,3). Fetal surgery includes all types of surgery in which direct interventions on the fetus are performed, but few of them are amenable to treatment by endoscopy. The term “obstetric endoscopy” was proposed for fetoscopic procedures on the placenta, the umbilical cord, and fetal membranes. The technique of laser coagulation of the vascular anastomoses on the monochorionic placenta for twin-to-twin transfusion syndrome is well established and has recently been shown to be superior to amniodrainage in a randomized controlled trial (4). Therefore, the number of these procedures will undoubtedly increase (2–4). Another application of obstetric endoscopy is selective feticide by cord occlusion, used in monochorionic twin pregnancies complicated by severe discordant anomalies (5,6).

These procedures are often performed under local anesthesia (4). However, we liberally use combined spinal epidural anesthesia as a means of maternal anesthesia. Combined spinal epidural and local anesthesia provide neither fetal immobilization nor anesthesia. Based on clinical experience, we believe that fetal movements may lead to fetal trauma and may hamper surgery, leading to incomplete coagulation of vessels, failure of surgery and an increase in the duration of the intervention (7). Increasing the duration of endoscopic surgery may increase the risk of iatrogenic preterm, prelabor rupture of membranes (8,9).

Fetal immobilization has been traditionally obtained by maternal administration of diazepam (DZP), which is associated with maternal sedative effects. Although it provides maternal sedation, in our experience DZP produces insufficient fetal immobility. Remifentanil (REMI) is a novel, short-acting opioid, which is rapidly hydrolyzed by nonspecific plasma and tissue esterases. It has been used for intraoperative sedation in patients undergoing regional or local anesthesia (10–14). In term pregnant women undergoing elective Cesarean delivery under epidural anesthesia, it produces excellent maternal sedation without adverse maternal effects (15). Kan et al. (15) demonstrated that IV REMI, in a dose of 0.1 μg · kg1 · min−1 and part of a regional anesthetic technique, rapidly and extensively crosses the placenta (umbilical vein/maternal artery ratio, 0.88). An initial dose response study determined that a dose of 0.1 μg · kg1 · min−1 of REMI produced excellent fetal immobilization in second trimester pregnant patients (16). Based on this dose-response study, we hypothesized that REMI in a dose of 0.1 μg · kg1 · min−1 would induce superior fetal immobilization during obstetric endoscopic surgery as compared with DZP and at the same time provide appropriate maternal sedation. Therefore, we initiated a randomized, double-blind trial comparing the effects of IV DZP versus IV REMI in pregnant women undergoing obstetric endoscopic surgery under neuraxial block. We postulated that fetal immobilization and maternal sedation provided by REMI would be at least as good as, if not superior to, DZP.

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Methods

After Institutional Ethics Committee approval, 54 healthy (ASA I–II) women in the second trimester of pregnancy (gestational age, 16–25 wk), carrying a multiple pregnancy and scheduled for either fetoscopic laser coagulation or cord occlusion, provided written and informed consent to this randomized, double-blind trial.

Before anesthesia and surgery, all patients received prophylaxis for acid aspiration using 30 mL oral sodium citrate 0.3 M, metoclopramide 10 mg IV, and ranitidine 50 mg IV 60 min before initiation of anesthesia. Mothers were prehydrated using 1000 mL of lactated Ringer’s solution through an IV catheter in the right forearm. A second IV cannula was positioned in the left antecubital vein to infuse maternal sedative drugs. Under local anesthesia, the left radial artery was cannulated to allow continuous arterial blood pressure measurements and repetitive blood sampling. Combined spinal epidural anesthesia was performed at the L3-4 or L4-5 interspace with the patient sitting. The epidural space was identified using an 18-gauge Tuohy needle using the loss of resistance to saline technique. The dura was entered using a 27-gauge pencil point spinal needle and 8 mg of hyperbaric bupivacaine 0.5% was injected into the spinal space, after which a 20-gauge epidural catheter was advanced 4 cm into the epidural space. Anesthesia was maintained by additional epidural top-ups of ropivacaine 0.75% at the discretion of the attending anesthesiologist. If hypotension (defined as a decrease in mean arterial blood pressure of >10% from baseline values recorded immediately before anesthesia) occurred, ephedrine or phenylephrine was administered at the discretion of the attending anesthesiologist.

The patient was then positioned in the supine position with 15 degrees left lateral tilt to prevent aortocaval compression (17). Supplemental oxygen (5 L/min) was routinely administered by face mask. After baseline recordings, maternal IV sedation was started. Patients were randomized to 2 groups of 27 patients by a computer-generated list. Study drugs were prepared and administered by an anesthesiologist not involved in further management of the patients. Patients, surgeon, and attending anesthesiologist were blinded as to the sedative drugs used. In the DZP group a continuous infusion of saline mimicked the REMI infusion. DZP was initiated using a dose of 5 mg IV, followed 10 min later by an additional 5 mg. Additional 2.5-mg increments of DZP were given when maternal sedation was judged inadequate by an observer assessment of alertness/sedation scale (OAA/S) score of 5 or when fetal immobility was 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 top-ups were given if maternal sedation was profound (OAA/S score of 3 or less), maternal arterial blood gas analysis revealed a pH <7.35 or a Pco2 of >45 mm Hg, or maternal respiratory rate decreased to <8 breaths per minute.

In the REMI group a continuous infusion of REMI was started at an initial flow rate of 0.1 μg · kg1 · min−1 (dilution of REMI 50 μg/mL) and at 0 and 10 min a bolus of normal saline was given to mimic the DZP administration. The initial dose of REMI was based on a previous dose-response study at our institution (16). Sham saline boluses and an increase of the REMI infusion rate with 0.025 μg · kg1 · min−1 were performed if maternal sedation was inadequate (OAA/S score of 5) or if fetal immobility was judged to be insufficient by the surgeon. The REMI or saline infusion was decreased by 0.025 μg · kg1 · min−1 if maternal sedation was profound (OAA/S of 3 or less), maternal blood gas pH decreased to less than 7.35, the arterial Pco2 increased to more than 45 mm Hg, or maternal respiratory rate decreased to <8 breaths per minute. If maternal apnea occurred, cricoid pressure was applied and mask ventilation was initiated until spontaneous respiration resumed and the REMI infusion would be stopped immediately.

At the end of surgery the REMI infusion was stopped. The observation period started at the moment of first administration of REMI until 60 min after the end of surgery. In both groups, all necessary changes in infusion rate and additional boluses of DZP were made by an anesthesiologist not involved in data recording.

Before the study, demographic data, medical history, relevant obstetrical data, maternal arterial blood pressure as measured invasively, maternal heart and respiratory rate were recorded. Maternal side effects were noted. Maternal sedation was evaluated by the attending anesthesiologist using the OAA/S (18). We targeted the sedation to aim at an ideal OAA/S score 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 after completion of surgery. Maternal arterial blood gas analysis was performed before the start of sedation, every 20 min during surgery, and at 10, 20, 30, and 60 min after the end of surgery.

Fetal heart rate was recorded every 15 min using ultrasound. Fetal mobility was assessed before, during, and after surgery by taping 5 min ultrasound sequences of fetal movement every 20 min throughout surgery and 10, 20, 30, and 60 min after the end of surgery. These taped sequences were evaluated off-line by an experienced ultrasonographer. For that purpose the video sequences were randomly presented with patient identification blinded. The baseline recording was presented first for each patient. Two types of evaluation were performed: a visual analogue scale score for mobility (0 = immobile fetus and 100 = baseline mobility) and the number of gross body movements and limb movements per 5-min period. If fetuses were immobile before the start of sedation, patients were excluded from further analysis. Only the fetal movements of the non-stuck twin were recorded in case of twin-to-twin transfusion syndrome, and only movements of the normal fetus were recorded in case of selective feticide.

At the end of the intervention, the surgeon assessed overall fetal immobility and operating conditions using a four-point scale: 1 = excellent, 2 = good, 3 = moderate, 4 = inadequate or no immobilization. This subjective score represented an overall subjective impression and is further referred to as the surgical assessment score.

Perinatal variables included the number of surviving fetuses, gestational age at delivery, and neonatal survival and complications.

Data were analyzed using two-way repeated measures analysis of variance followed by Scheffe’s post hoc testing as required. Categorical data were analyzed using χ2 analysis and Fisher’s exact test. Data are presented as a mean ± sd, median and interquartile range, or as percentage of the group total. P < 0.05 was considered as statistically significant. Our preliminary experience with DZP sedation demonstrated adequate fetal immobilization in approximately 30% of patients; adequate maternal sedation was achieved in most mothers. In a dose finding study for REMI we achieved fetal immobilization in more then 80% of patients using 0.1 μg · kg1 · min−1; maternal sedation was adequate. For sample size calculations, we expected a 50% increase in adequate fetal immobility from 30% to 80% of fetuses when using REMI. We calculated the number of patients required in each group to demonstrate a statistically significant difference to be 23 subjects (α = 0.05, β = 0.05).

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Results

In two patients in each group, fetuses were immobile before the start of sedation and surgery and therefore these were excluded. This left 50 patients for analysis, 25 in each group. Gestational age at intervention, the number of laser coagulations, and cord occlusions were comparable in the two groups. There was no significant difference in gestational age at delivery and survival rates between the treatment groups, both for laser cases and cord occlusions (Table 1). The incidence of preterm labor and delivery was not significantly different between the two groups.

Table 1

Table 1

Results related to maternal sedation and fetal immobilization are summarized in Table 2 and Figures 1 through 6. REMI produced excellent levels of maternal sedation in all patients. Only one patient (4%) had an OAA/S score <4 and was therefore considered to be profoundly sedated during surgery (Fig. 4). The mean REMI infusion rate was 0.115 ± 0.020 μg · kg−1 · min−1. The most rapid REMI infusion rate was 0.150 μg · kg−1 · min−1. In the DZP group, 11 women (44%) were profoundly sedated (OAA/S score <4). The mean total DZP dose was 14.5 ± 4.8 mg. Maternal respiratory rate in the REMI group decreased during surgery; it remained stable in the DZP group. As a result of maternal hypoventilation, an increase in Pco2 and a decrease in pH was noted in the REMI group (Figures 1 through 3). The lowest respiratory rate and pH and highest Pco2 in any patient at any stage occurred in one patient treated with REMI after 40 min of treatment. Her respiratory 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 after several minutes. Maternal hemodynamics remained stable throughout the procedure. Similar doses and number of top-ups of ephedrine and phenylephrine were needed in both groups. Duration of surgery was significantly longer in the DZP group, 80 (60–90) minutes versus 60 (54–71) minutes in the REMI group.

Table 2

Table 2

Figure 1

Figure 1

Figure 2

Figure 2

Figure 3

Figure 3

Figure 4

Figure 4

Figure 5

Figure 5

Figure 6

Figure 6

REMI induced a significantly higher degree of fetal immobilization, whereas DZP had little effect on fetal mobility as evaluated by subjective surgical and objective ultrasound scores (Figs. 5 and 6). The number of fetal gross body and limb movements decreased from 18 ± 3 to 2 ± 1 at 40 min of surgery in the REMI group; this decrease was much less in the DZP group, from 17 ± 4 to 12 ± 4 at 40 min of surgery. The subjective appreciation of fetal immobilization by the surgeon, who was blinded as to the medication, was good to excellent in 23 of 25 patients (92%) in the REMI group, whereas this was good to excellent in only 8 of 25 (32%) in the DZP group. No significant changes in fetal heart were noted in either group. No early or late decelerations or fetal bradycardia were recorded.

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Discussion

This randomized double-blind study in patients undergoing obstetrical endoscopic surgery demonstrates that REMI induces excellent fetal immobilization and maternal sedation during surgery, while DZP provides less fetal immobilization and deeper maternal sedation.

Some in utero conditions are amenable to surgical interventions (1–4,19). At our institution, obstetric endoscopy procedures are performed regularly. Most cases are for treatment of twin-to-twin transfusion syndrome because laser therapy has been proven to be better then amniodrainage (1,3,4). In addition, selective feticide procedures in selected monochorionic twin pregnancies may require in utero endoscopic cord occlusion. These procedures usually do not require maternal general anesthesia (19,20). General anesthesia in pregnancy is associated with a more frequent incidence of maternal mortality and morbidity (21), mainly as the result of airway problems. Most European centers prefer local or regional anesthesia techniques for these cases. However, regional anesthetic techniques do not provide fetal immobilization or fetal analgesia. Fetal movements may lead to fetal trauma, may hamper or prolong surgery, or may even result in failure to complete the planned surgery. Prolongation of surgery may increase the risk of iatrogenic preterm, prelabor rupture of membranes (8,9).

To obviate these problems, we initially used IV DZP to obtain fetal immobilization. However, the effects on fetal mobility of IV maternal DZP were unpredictable and often disappointing, and maternal sedation was profound. In the present trial we confirmed this observation, with only a small percentage of fetuses being adequately immobilized. It has been shown that DZP crosses the placenta rapidly but that the fetal capillary blood concentration varies considerably, at least in term infants (22), and that neonatal effects are largely unpredictable. It was also demonstrated that the transfer of DZP across the human placenta is slower in early pregnancy than during labor (23). In addition, there are concerns of DZP being associated with neurodevelopmental changes in neonates and congenital abnormalities when used chronically (24–26). Administration of DZP outside the period of organogenesis using a single bolus has never been associated with teratogenic effects. Furthermore, DZP does not provide fetal analgesia and fetal and maternal recovery is slow after DZP administration.

We decided to use DZP as the control group in the present trial despite the possibility of using other more short-acting benzodiazepines. Theoretically, other more short-acting benzodiazepines, such as midazolam, may yield more consistent and more controllable maternal sedation. However, placental passage and thus fetal immobilization remains unpredictable as well (27,28). Placental passage of midazolam in pregnant ewes is small, with a fetal/maternal plasma concentration ratio of 0.15 (27). Also, in term pregnancies the placental transfer of midazolam is considerably less than that of thiopental and REMI (15,28).

Remifentanil is a novel ultra-short-acting opioid for IV use that is clinically proposed for sedation during surgical interventions in the nonpregnant and pregnant population (10–15). In general, opioids have a large transplacental passage (29,30) and as a consequence produce fetal “sleep.” We therefore speculated that REMI would provide excellent fetal immobilization. REMI rapidly and extensively crosses the placenta (umbilical vein/maternal artery ratio, 0.88) in term pregnancies (15). Other opioids have also been shown to have a rapid and large transplacental passage in early human gestation (29–31). Although no pharmacokinetic data on REMI are available at mid-gestation and our study similarly does not provide such information, our observations clearly show that REMI effectively crosses the placenta and causes fetal immobilization.

In contrast to DZP, REMI has the potential, as do other opioids, to provide effective fetal analgesia after accidental direct stimulation (e.g., touching with endoscopes). Therefore, it has been suggested that pain relief has to be provided during in utero interventions on the fetus from mid-gestation (20 weeks) on (32–34). Direct administration of fentanyl to the human fetus has been shown to block the fetal stress response during mid-gestational in utero interventions (35). In our trial inadvertent touching of an immobilized fetus resulted in fetal “awakening.” Therefore, when fetal analgesia or blunting of the fetal stress response is required, additional drugs (opioids and nondepolarizing muscle relaxants) must be administered directly to the fetus. It must be stressed, however, that fetal analgesia is not generally required during in utero procedures on the placenta and cord (the procedures performed in the present trial), as direct fetal trauma should not occur.

Maternal sedation during lengthy or stressful in utero interventions is useful to relieve anxiety and improve patient cooperation. Especially in emotionally stressful situations, such as selective feticide, effective maternal sedation can be useful from a psychological viewpoint. In twin-to-twin transfusion syndrome, the mother usually has serious discomfort from polyhydramnios, which is only relieved at the end of the endoscopic procedure. In the present trial, REMI produced adequate maternal sedation, whereas DZP often resulted in sedation that was considered too deep. Unfortunately, as with any opioid, REMI was associated with mild respiratory depression. In our series, this never became clinically relevant, as none of the patients experienced respiratory arrest or signs of severe respiratory acidosis. The sedative and respiratory depressant effects of REMI were extremely short-lived. This is in line with previous investigations in volunteers after bolus or continuous IV infusions or REMI (36,37). When respiratory depression occurs, reduction of the REMI infusion or brief cessation rapidly restores maternal respiration.

REMI may be used to induce fetal immobilization in other diagnostic or interventional procedures. For example intrauterine transfusion through the umbilical cord may benefit from IV maternal REMI administration to sedate the mother and immobilize the fetus. In those cases when perforation of the fetal abdominal wall is required for intrahepatic vein transfusion, REMI would be insufficient to provide adequate fetal analgesia and immobilization. Direct fetal administration of opioids and muscle relaxants could be required.

Another application is for fetal magnetic resonance imaging studies, when some degree of immobilization may be helpful. Despite advances in magnetic resonance imaging technology, fetal movements induce artifacts hampering diagnostic accuracy (38,39). Benzodiazepines have been used for these indications but, based on the present study, they may produce unreliable fetal immobilization. In addition, because they will result in lengthy maternal sedation, REMI may be a better alternative.

An alternative to REMI may be propofol, as it is an effective, controllable maternal sedative. We decided not to study propofol because it lacks analgesic properties. Whether it provides similar fetal immobilizing properties as REMI needs to be established.

We conclude that maternally administered REMI is a superior alternative to maternal DZP to induce maternal sedation and fetal immobilization. Further studies must be conducted to establish long-term effects of REMI on the fetus and to establish its place in other fetal diagnostic and therapeutic interventions.

The authors wish to express their sincere gratitude to the midwifery staff of the labor and delivery ward of the UZ Leuven, where these procedures are routinely performed.

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References

1. Deprest JA, Gratacos E. Obstetrical endoscopy. Curr Opin Obstet Gynecol 1999;11:195–203.
2. De Lia JE, Cruikshak DP, Keye WR. Fetoscopic neodynium:YAG laser occlusion of placental vessels in severe twin-twin transfusion syndrome. Obstet Gynecol 1990;75:1046–53.
3. Lewi L, Van Schoubroeck D, Gratacos E, et al. Monochorionic diamniotic twins: complications and management options. Curr Opin Obstet Gynecol 2003;15:177–194.
4. Senat MV, Deprest J, Boulvain M, et al. A randomized trial of endoscopic laser surgery versus serial amnioreduction for severe twin-to-twin transfusion syndrome at midgestation. N Engl J Med 2004;351:136–44.
5. Challis D, Gratacos E, Deprest J. Selective termination in monochorionic twins. J Perinat Med 1999;27:327–8.
6. Deprest J, Evrard V, Van Schoubroeck D. Fetoscopic cord ligation. Lancet 1996;384:890–1.
7. Rosen MA. Anesthesia for fetal surgery and other intrauterine procedures. In: Chestnut DH, ed. Obstetric anesthesia, 3rd ed. Philadelphia: Elsevier–Mosby, 2004:96–109.
8. De Lia JE, Kuhlmann RS, Lopez KP. Treating previable twin-twin transfusion syndrome with fetoscopic laser surgery: outcomes following the learning curve. J Perinat Med 1999;27:61–7.
9. Deprest JA, Van Ballaer PP, Evrard VA, et al. Experience with fetoscopic cord ligation. Eur J Obstet Gynecol Reprod Biol 1998;81:157–64.
10. Machata AM, Gonano C, Holzer A, et al. Awake nasotracheal fiberoptic intubation: patient comfort, intubating conditions, and hemodynamic stability during conscious sedation with remifentanil. Anesth Analg 2003;97:904–8.
11. Sa Rego MM, Inagaki Y, White PF. Remifentanil administration during monitored anesthesia care: are intermittent boluses an effective alternative to a continuous infusion? Anesth Analg 1999;88:518–22.
12. Volmanen P, Akural EJ, Raudaskoski T, Alahuhta S. Remifentanil in obstetric analgesia: a dose-finding study. Anesth Analg 2002;94:913–7.
13. Joo HS, Perks WJ, Kataoka MT, et al. A comparison of patient controlled sedation using either remifentanil or remifentanil-propofol for shock wave lithotripsy. Anesth Analg 2001;93:1227–32.
14. Lauwers M, Camu F, Breivik H, et al. The safety and effectiveness of remifentanil as an adjunct sedative for regional anesthesia. Anesth Analg 1999;88:134–40.
15. Kan RE, Hughes SC, Rosen MA, et al. Intravenous remifentanil: placental transfer, maternal and neonatal effects. Anesthesiology 1998;88:1467–74.
16. Missant C, Van Schoubroeck D, Deprest JA, et al. Remifental for foetal immobilisation and maternal sedation during endoscopic treatment of twin-to-twin transfusion syndrome: a preliminary dose finding study. Acta Anaesth Belg 2004;55:239–44.
17. McLennan CE. Antecubital and femoral venous pressure in normal and toxemic pregnancy. Am J Obstet Gynecol 1943;45:568–91.
18. Chernik DA, Gillings D, Laine H, et al. Validity and reliability of the observer’s assessment of alertness/sedation scale: study with intravenous midazolam. J Clin Psychopharmacol 1990;10:244–51.
19. Sebire NJ, Souka A, Skentou H, et al. Early prediction of severe twin-to-twin transfusion syndrome. Hum Reprod 2000;15:2008–10.
20. De Lia JE, Kuhlmann RS, Harstad TW, Cruikshank DP. Fetoscopic laser ablation of placental vessels in severe previable twin-twin transfusion syndrome. Am J Obstet Gynecol 1995;172:1202–11.
21. Hawkins JL, Koonin LM, Palmer SK, Gibbs CP. Anesthesia related deaths during obstetric delivery in the United States, 1979–1990. Anesthesiology 1997;86:277–84.
22. Bakke OM, Haram K. Time course of transplacental passage of diazepam. Clin Pharmacokinetics 1982;7:353–62.
23. Kanto J, Erkkola R. The feto-maternal distribution of diazepam in early human pregnancy. Ann Chir Gynaecol Fenniae 1974;63:489–91.
24. Saxen I, Saxen L. Association between maternal intake of diazepam and oral clefts. Lancet 1975;2:498.
25. Mehanny SZ, Abdel-Rahman MS, Ahmed YY. Teratogenic effect of cocaine and diazepam in CF1 mice. Teratology 1991;43:11–7.
26. Kellog CK. Benzodiazepines: influence on the developing brain. Prog Brain Res 1988;73:207–28.
27. Vree TB, Reekers-Keeting JJ, Fragen RJ, Arts TH. Placental transfer of midazolam and its metabolite 1-hydroxymethylmidazolam in the pregnant ewe. Anesth Analg 1984;63:31–4.
28. Bach V, Carl P, Ravlo O, et al. A randomised comparison between midazolam and thiopental for elective cesarean section anesthesia: III. Placental transfer and elimination in neonates. Anesth Analg 1989;68:238–42.
29. Shannon C, Jauniaux E, Gulbis B, et al. Placental transfer of fentanyl in early human pregnancy. Hum Reprod 1998;13:2317–20.
30. Cooper J, Jauniaux E, Gulbis B, et al. Placental transfer of fentanyl in early human pregnancy and its detection in fetal brain. Br J Anaesth 1999;82:929–31.
31. Krishna BR, Zakowski MI, Grant GJ. Sufentanil transfer in the human placenta during in vitro perfusion. Can J Anaesth 1997;44:996–1001.
32. Giannakoulopoulos X, Sepulveda W, Kourtis P, et al. Fetal plasma cortisol and beta endorphin response to intrauterine needling. Lancet 1994;344:77–81.
33. Giannakopoulos X, Teixeira J, Fisk N, Glover V. Human fetal and maternal noradrenaline responses to invasive procedures. Ped Res 1999;45:494–9.
34. Anand KJS, Maze M. Fetuses, fentanyl, and the stress response. Anesthesiology 2001;95:823–5.
35. Fisk NM, Gitau R, Teixeira JM, et al. Effect of direct fetal opioid analgesia on fetal hormonal and hemodynamic stress response to intrauterine needling. Anesthesiology 2001;95:828–35.
36. Babenco HD, Conard PF, Gross JB. The pharmacodynamic effect of a remifentanil bolus on ventilatory control. Anesthesiology 2000;92:393–8.
37. Nieuwenhuijs DJF, Olofsen E, Romberg RR, et al. Response surface modeling of remifentanil-propofol interaction on cardiorespiratory control and bispectral index. Anesthesiology 2003;98:312–22.
38. Levine D, Stroustrup Smith A, McKenzie C. Tips and tricks of fetal MR imaging. Radiol Clin N Am 2003;41:729–45.
39. Luks FI, Carr SR, Ponte B, et al. Preoperative planning with magnetic resonance imaging and computerized volume rendering in twin-to-twin transfusion syndrome. Am J Obstet Gynecol 2001;185:216–9.
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