Remifentanil for Fetal Immobilization and Maternal SedationDuring Fetoscopic Surgery: A Randomized, Double-BlindComparison...
252   OBSTETRIC ANESTHESIA VAN DE VELDE ET AL.                                                       ANESTH ANALG      FET...
ANESTH ANALG                                                         OBSTETRIC ANESTHESIA  VAN DE VELDE ET AL.   2532005;1...
254   OBSTETRIC ANESTHESIA VAN DE VELDE ET AL.                                                                            ...
ANESTH ANALG                                                                    OBSTETRIC ANESTHESIA  VAN DE VELDE ET AL. ...
256    OBSTETRIC ANESTHESIA VAN DE VELDE ET AL.                                                                           ...
ANESTH ANALG                                                                   OBSTETRIC ANESTHESIA  VAN DE VELDE ET AL.  ...
258    OBSTETRIC ANESTHESIA VAN DE VELDE ET AL.                                                                           ...
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Remifentanil for fetal immobilization and maternal sedation

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Remifentanil for fetal immobilization and maternal sedation

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Transcript of "Remifentanil for fetal immobilization and maternal sedation"

  1. 1. Remifentanil for Fetal Immobilization and Maternal SedationDuring Fetoscopic Surgery: A Randomized, Double-BlindComparison with DiazepamMarc 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, andJan A. Deprest, MD, PhDDepartments of Anaesthesiology and Obstetrics and Gynaecology, University Hospital Gasthuisberg, KatholiekeUniversiteit 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 directconditions are life threatening or may cause irrevers- interventions on the fetus are performed, but few ofible organ damage but may benefit from a prenatal them are amenable to treatment by endoscopy. Theintervention (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 theaan 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 recentlyderen), and by grants financed by the European Commission (EuroTwin 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 increaseDirector Obstetric Anesthesia and Extra Muros Anesthesia, De-partment of Anaesthesiology, University Hospitals Gasthuisberg, (2– 4). Another application of obstetric endoscopy isHerestraat 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 severeDOI: 10.1213/01.ANE.0000156566.62182.AB discordant anomalies (5,6).©2005 by the International Anesthesia Research Society0003-2999/05 Anesth Analg 2005;101:251–8 251
  2. 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 ofspinal epidural anesthesia as a means of maternal lactated Ringer’s solution through an IV catheter inanesthesia. Combined spinal epidural and local anes- the right forearm. A second IV cannula was positionedthesia provide neither fetal immobilization nor anes- in the left antecubital vein to infuse maternal sedativethesia. Based on clinical experience, we believe that drugs. Under local anesthesia, the left radial arteryfetal movements may lead to fetal trauma and may was cannulated to allow continuous arterial bloodhamper 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 patientof endoscopic surgery may increase the risk of iatro- sitting. The epidural space was identified using angenic 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 spinalAlthough it provides maternal sedation, in our expe- space, after which a 20-gauge epidural catheter wasrience DZP produces insufficient fetal immobility. advanced 4 cm into the epidural space. AnesthesiaRemifentanil (REMI) is a novel, short-acting opioid, was maintained by additional epidural top-ups ofwhich is rapidly hydrolyzed by nonspecific plasma ropivacaine 0.75% at the discretion of the attendingand tissue esterases. It has been used for intraopera- anesthesiologist. If hypotension (defined as a decreasetive sedation in patients undergoing regional or local in mean arterial blood pressure of 10% from baselineanesthesia (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 administeredthesia, 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 (5and 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 wasstudy determined that a dose of 0.1 g · kg 1 · min 1 started. Patients were randomized to 2 groups of 27of REMI produced excellent fetal immobilization in patients by a computer-generated list. Study drugssecond 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 thegery as compared with DZP and at the same time DZP group a continuous infusion of saline mimickedprovide appropriate maternal sedation. Therefore, we the REMI infusion. DZP was initiated using a dose ofinitiated 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 givenwomen undergoing obstetric endoscopic surgery un- when maternal sedation was judged inadequate by ander neuraxial block. We postulated that fetal immobi- observer assessment of alertness/sedation scalelization and maternal sedation provided by REMI (OAA/S) score of 5 or when fetal immobility waswould 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 additionalMethods top-ups were given if maternal sedation was profoundAfter Institutional Ethics Committee approval, 54 (OAA/S score of 3 or less), maternal arterial blood gashealthy (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 breathsmultiple pregnancy and scheduled for either feto- per minute.scopic laser coagulation or cord occlusion, provided In the REMI group a continuous infusion of REMIwritten and informed consent to this randomized, was started at an initial flow rate of 0.1double-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 toprophylaxis for acid aspiration using 30 mL oral so- mimic the DZP administration. The initial dose ofdium citrate 0.3 M, metoclopramide 10 mg IV, and REMI was based on a previous dose-response study at
  3. 3. ANESTH ANALG OBSTETRIC ANESTHESIA VAN DE VELDE ET AL. 2532005;101:251–8 FETAL IMMOBILIZATION WITH REMIFENTANIL DURING FETOSCOPIC SURGERYour institution (16). Sham saline boluses and an in- At the end of the intervention, the surgeon assessedcrease 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, 3tion was inadequate (OAA/S score of 5) or if fetal moderate, 4 inadequate or no immobilization. Thisimmobility 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 surgical0.025 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 neonatalto 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 hoctilation was initiated until spontaneous respiration re- testing as required. Categorical data were analyzedsumed and the REMI infusion would be stopped using 2 analysis and Fisher’s exact test. Data areimmediately. 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 0.05stopped. 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% ofchanges in infusion rate and additional boluses of patients; adequate maternal sedation was achieved inDZP were made by an anesthesiologist not involved in most mothers. In a dose finding study for REMI wedata 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, wepressure as measured invasively, maternal heart and expected a 50% increase in adequate fetal immobilityrespiratory rate were recorded. Maternal side effects from 30% to 80% of fetuses when using REMI. Wewere noted. Maternal sedation was evaluated by the calculated the number of patients required in eachattending 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 sedationand a score 4 was considered insufficient sedation.Sedation was evaluated at baseline, at 20, 40, and60 min during surgery, and at 10, 20, 30, and 60 min Resultsafter completion of surgery. Maternal arterial blood In two patients in each group, fetuses were immobilegas analysis was performed before the start of seda- before the start of sedation and surgery and thereforetion, 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 occlusionsultrasound. Fetal mobility was assessed before, dur- were comparable in the two groups. There was noing, and after surgery by taping 5 min ultrasound significant difference in gestational age at delivery andsequences of fetal movement every 20 min throughout survival rates between the treatment groups, both forsurgery 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 1cording was presented first for each patient. Two through 6. REMI produced excellent levels of maternaltypes of evaluation were performed: a visual analogue sedation in all patients. Only one patient (4%) hadscale score for mobility (0 immobile fetus and 100 an OAA/S score 4 and was therefore consideredbaseline 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 0.020fetuses were immobile before the start of sedation, g · kg 1 · min 1. The most rapid REMI infusionpatients 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/Sin case of twin-to-twin transfusion syndrome, and score 4). The mean total DZP dose was 14.5only movements of the normal fetus were recorded in 4.8 mg. Maternal respiratory rate in the REMI groupcase of selective feticide. decreased during surgery; it remained stable in the
  4. 4. 254 OBSTETRIC ANESTHESIA VAN DE VELDE ET AL. ANESTH ANALG FETAL IMMOBILIZATION WITH REMIFENTANIL DURING FETOSCOPIC SURGERY 2005;101:251–8Table 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 ofsurgery 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 inan increase in Pco2 and a decrease in pH was noted only 8 of 25 (32%) in the DZP group. No significantin the REMI group (Figures 1 through 3). The lowest changes in fetal heart were noted in either group. Norespiratory rate and pH and highest Pco2 in any early or late decelerations or fetal bradycardia werepatient 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 andthe respiratory depression spontaneously resolved Discussionafter several minutes. Maternal hemodynamics re- This randomized double-blind study in patients un-mained stable throughout the procedure. Similar dergoing obstetrical endoscopic surgery demonstratesdoses and number of top-ups of ephedrine and that REMI induces excellent fetal immobilization andphenylephrine 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 maternalgroup, 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. Mostmobility as evaluated by subjective surgical and ob- cases are for treatment of twin-to-twin transfusionjective ultrasound scores (Figs. 5 and 6). The number syndrome because laser therapy has been proven to beof 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 monochorionicgroup; this decrease was much less in the DZP group, twin pregnancies may require in utero endoscopic cordfrom 17 4 to 12 4 at 40 min of surgery. The occlusion. These procedures usually do not requiresubjective 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 frequentgood to excellent in 23 of 25 patients (92%) in the incidence of maternal mortality and morbidity (21),
  5. 5. ANESTH ANALG OBSTETRIC ANESTHESIA VAN DE VELDE ET AL. 2552005;101:251–8 FETAL IMMOBILIZATION WITH REMIFENTANIL DURING FETOSCOPIC SURGERYFigure 1. Respiratory rate (breaths per minute) in patients receiving Figure 3. Arterial pH in patients receiving either diazepam (DZP) oreither 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 start10 – 60 min after start and, respectively, end (A) of surgery. In the and, respectively, end (A) of surgery. In the REMI group, the REMIREMI group, the REMI infusion was stopped at the end of surgery. infusion was stopped at the end of surgery. In the DZP group theIn the DZP group the last bolus was given on clinical indication and last bolus was given on clinical indication and no top-ups wereno top-ups were administered after the end of surgery. * P 0.05 administered after the end of surgery. * P 0.05 REMI versus DZPREMI 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 measurementor remifentanil (REMI) IV sedation. X-axis: BL baseline meas- 30 min after the end of surgery; 60A measurement 60 min afterurement; 10 – 60 and 10A– 60A measurement 10 – 60 min after start the end of surgery. In the remifentanil group, the remifentaniland, respectively, end (A) of surgery. In the REMI group, the REMI infusion was stopped at the end of surgery. In the diazepam groupinfusion was stopped at the end of surgery. In the DZP group the no additional boluses of diazepam were administered after the endlast bolus was given on clinical indication and no top-ups were of surgery.administered after the end of surgery. * P 0.05 REMI versus DZPat 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 DZPpean centers prefer local or regional anesthesia tech- to obtain fetal immobilization. However, the effects onniques for these cases. However, regional anesthetic fetal mobility of IV maternal DZP were unpredictabletechniques do not provide fetal immobilization or fetal and often disappointing, and maternal sedation wasanalgesia. 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. 6. 256 OBSTETRIC ANESTHESIA VAN DE VELDE ET AL. ANESTH ANALG FETAL IMMOBILIZATION WITH REMIFENTANIL DURING FETOSCOPIC SURGERY 2005;101:251–8Figure 5. Visual Analog Scale (VAS) for fetal mobility (0 fetus iscompletely immobile; 100 baseline fetal mobility) in patientsreceiving either diazepam (DZP) or remifentanil (REMI) IV seda- Figure 6. Number of gross body and limb movements during ation. X-axis: BL baseline measurement; 10 – 60 and 10A– 60A 5-min registration period at various time points throughout themeasurement 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-ups0.05 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) inlargely unpredictable. It was also demonstrated that term pregnancies (15). Other opioids have also beenthe 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 noaddition, 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 providecongenital abnormalities when used chronically (24 – such information, our observations clearly show that26). Administration of DZP outside the period of or- REMI effectively crosses the placenta and causes fetalganogenesis 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 donot provide fetal analgesia and fetal and maternal other opioids, to provide effective fetal analgesia afterrecovery 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 painpresent trial despite the possibility of using other more relief has to be provided during in utero interventionsshort-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 fetuslam, may yield more consistent and more controllable has been shown to block the fetal stress responsematernal sedation. However, placental passage and during mid-gestational in utero interventions (35). Inthus fetal immobilization remains unpredictable as our trial inadvertent touching of an immobilized fetuswell (27,28). Placental passage of midazolam in preg- resulted in fetal “awakening.” Therefore, when fetalnant ewes is small, with a fetal/maternal plasma con- analgesia or blunting of the fetal stress response iscentration 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 directlyless 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 uteroIV use that is clinically proposed for sedation during procedures on the placenta and cord (the proceduressurgical interventions in the nonpregnant and preg- performed in the present trial), as direct fetal traumanant 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 inquence produce fetal “sleep.” We therefore speculated utero interventions is useful to relieve anxiety and
  7. 7. ANESTH ANALG OBSTETRIC ANESTHESIA VAN DE VELDE ET AL. 2572005;101:251–8 FETAL IMMOBILIZATION WITH REMIFENTANIL DURING FETOSCOPIC SURGERYimprove patient cooperation. Especially in emotion- Referencesally stressful situations, such as selective feticide, 1. Deprest JA, Gratacos E. Obstetrical endoscopy. Curr Opin Ob-effective maternal sedation can be useful from a stet Gynecol 1999;11:195–203.psychological viewpoint. In twin-to-twin transfu- 2. De Lia JE, Cruikshak DP, Keye WR. Fetoscopic neodynium:YAGsion syndrome, the mother usually has serious laser occlusion of placental vessels in severe twin-twin transfu- sion syndrome. Obstet Gynecol 1990;75:1046 –53.discomfort from polyhydramnios, which is only re- 3. Lewi L, Van Schoubroeck D, Gratacos E, et al. Monochorioniclieved at the end of the endoscopic procedure. In the diamniotic twins: complications and management options. Currpresent trial, REMI produced adequate maternal se- Opin Obstet Gynecol 2003;15:177–194.dation, whereas DZP often resulted in sedation that 4. Senat MV, Deprest J, Boulvain M, et al. A randomized trial of endoscopic laser surgery versus serial amnioreduction for se-was considered too deep. Unfortunately, as with vere twin-to-twin transfusion syndrome at midgestation.any opioid, REMI was associated with mild respi- N Engl J Med 2004;351:136 – 44.ratory depression. In our series, this never became 5. Challis D, Gratacos E, Deprest J. Selective termination in mono-clinically relevant, as none of the patients experi- chorionic twins. J Perinat Med 1999;27:327– 8.enced respiratory arrest or signs of severe respira- 6. Deprest J, Evrard V, Van Schoubroeck D. Fetoscopic cord liga- tion. Lancet 1996;384:890 –1.tory acidosis. The sedative and respiratory depres- 7. Rosen MA. Anesthesia for fetal surgery and other intrauterinesant effects of REMI were extremely short-lived. procedures. In: Chestnut DH, ed. Obstetric anesthesia, 3rd ed.This is in line with previous investigations in vol- Philadelphia: Elsevier–Mosby, 2004:96 –109.unteers after bolus or continuous IV infusions or 8. De Lia JE, Kuhlmann RS, Lopez KP. Treating previable twin- twin transfusion syndrome with fetoscopic laser surgery: out-REMI (36,37). When respiratory depression occurs, comes following the learning curve. J Perinat Med 1999;27:61–7.reduction of the REMI infusion or brief cessation 9. Deprest JA, Van Ballaer PP, Evrard VA, et al. Experience withrapidly restores maternal respiration. fetoscopic cord ligation. Eur J Obstet Gynecol Reprod Biol 1998; REMI may be used to induce fetal immobilization in 81:157– 64. 10. Machata AM, Gonano C, Holzer A, et al. Awake nasotrachealother diagnostic or interventional procedures. For exam- fiberoptic intubation: patient comfort, intubating conditions,ple intrauterine transfusion through the umbilical cord and hemodynamic stability during conscious sedation withmay benefit from IV maternal REMI administration to remifentanil. Anesth Analg 2003;97:904 – 8.sedate the mother and immobilize the fetus. In those 11. Sa Rego MM, Inagaki Y, White PF. Remifentanil administration during monitored anesthesia care: are intermittent boluses ancases when perforation of the fetal abdominal wall is effective alternative to a continuous infusion? Anesth Analgrequired for intrahepatic vein transfusion, REMI would 1999;88:518 –22.be insufficient to provide adequate fetal analgesia and 12. Volmanen P, Akural EJ, Raudaskoski T, Alahuhta S. Remifen-immobilization. Direct fetal administration of opi- tanil in obstetric analgesia: a dose-finding study. Anesth Analg 2002;94:913–7.oids and muscle relaxants could be required. 13. Joo HS, Perks WJ, Kataoka MT, et al. A comparison of patient Another application is for fetal magnetic resonance controlled sedation using either remifentanil or remifentanil-imaging studies, when some degree of immobilization propofol for shock wave lithotripsy. Anesth Analg 2001;93:may be helpful. Despite advances in magnetic reso- 1227–32. 14. Lauwers M, Camu F, Breivik H, et al. The safety and effective-nance imaging technology, fetal movements induce ness of remifentanil as an adjunct sedative for regional anesthe-artifacts hampering diagnostic accuracy (38,39). Ben- sia. Anesth Analg 1999;88:134 – 40.zodiazepines have been used for these indications but, 15. Kan RE, Hughes SC, Rosen MA, et al. Intravenous remifentanil:based on the present study, they may produce unre- placental transfer, maternal and neonatal effects. Anesthesiol- ogy 1998;88:1467–74.liable fetal immobilization. In addition, because they 16. Missant C, Van Schoubroeck D, Deprest JA, et al. Remifental forwill result in lengthy maternal sedation, REMI may be foetal immobilisation and maternal sedation during endoscopica better alternative. treatment of twin-to-twin transfusion syndrome: a preliminary An alternative to REMI may be propofol, as it is an dose finding study. Acta Anaesth Belg 2004;55:239 – 44. 17. McLennan CE. Antecubital and femoral venous pressure ineffective, controllable maternal sedative. We decided normal and toxemic pregnancy. Am J Obstet Gynecol 1943;45:not to study propofol because it lacks analgesic prop- 568 –91.erties. Whether it provides similar fetal immobilizing 18. Chernik DA, Gillings D, Laine H, et al. Validity and reliability ofproperties as REMI needs to be established. the observer’s assessment of alertness/sedation scale: study with intravenous midazolam. J Clin Psychopharmacol 1990;10: We conclude that maternally administered REMI is 244 –51.a superior alternative to maternal DZP to induce ma- 19. Sebire NJ, Souka A, Skentou H, et al. Early prediction of severeternal sedation and fetal immobilization. Further stud- twin-to-twin transfusion syndrome. Hum Reprod 2000;15:ies must be conducted to establish long-term effects of 2008 –10. 20. De Lia JE, Kuhlmann RS, Harstad TW, Cruikshank DP. Feto-REMI on the fetus and to establish its place in other scopic laser ablation of placental vessels in severe previablefetal diagnostic and therapeutic interventions. twin-twin transfusion syndrome. Am J Obstet Gynecol 1995;172: 1202–11. 21. Hawkins JL, Koonin LM, Palmer SK, Gibbs CP. AnesthesiaThe authors wish to express their sincere gratitude to the midwifery related deaths during obstetric delivery in the United States,staff of the labor and delivery ward of the UZ Leuven, where these 1979 –1990. Anesthesiology 1997;86:277– 84.procedures are routinely performed. 22. Bakke OM, Haram K. Time course of transplacental passage of diazepam. Clin Pharmacokinetics 1982;7:353– 62.
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