Surg Endosc (2003) 17: 1454–1460 DOI: 10.1007/s00464-002-9191-1 Ó Springer-Verlag New York Inc. 2003

Percutaneous fetoscopic tracheal balloon occlusion in sheep A minimally invasive approach to reduce maternal injury during fetal surgery for diaphragmatic hernia T. Kohl,1,2 M. G. Hartlage,3 D. Kienitz,2 M. Westphal,3 A. Brentrup,4 S. Aryee,2 S. Achenbach,2 T. Buller,2 G. I. Bizjak,1 R. Stressig,1 H. Van Aken,3 U. Gembruch1 1 2 3 4

Department Department Department Department

of of of of

Obstetrics and Prenatal Medicine, University of Bonn, Sigmund Freud Str 25, 53105 Bonn, Germany Pediatric Cardiology, University Children’s Hospital Mu¨nster, 48149 Monster, Germany Anesthesiology, University Hospital Mu¨nster, 48149 Mu¨nster, Germany Neurosurgery, University Hospital Mu¨nster, 48149 Mu¨nster, Germany

Received: 22 August 2002/Accepted: 21 November 2002/Online publication: 17 June 2003

Abstract Background: In order to minimize maternal trauma from current techniques for temporary fetoscopic tracheal occlusion, we tried to develop a percutaneous fetoscopic technique in sheep. Methods: In nine ewes between 77 and 128 days of gestation, the amniotic cavity was entered percutaneously. Each fetus was positioned and the feasibility of fetal laryngoscopy and percutaneous fetoscopic tracheal balloon occlusion was assessed. Results: Percutaneous intraamniotic access, fetal positioning, oropharyngeal sheath insertion, and fetoscopic laryngoscopy were achieved in all nine fetal sheep. Following some technical modifications to the working channel of the fetoscope, percutaneous fetoscopic tracheal balloon occlusion was successfully achieved in the last seven sheep. Conclusion: Percutaneous fetoscopic balloon occlusion of the fetal trachea can effectively and safely be achieved in sheep. Because intraamniotic spatial relationships, fetal position, and umbilical cord length are technically less favorable in sheep, our operative techniques might be feasible in humans even if difficult intraamniotic conditions are encountered. Key words: Fetoscopy — Fetal surgery — Diaphragmatic hernia — Tracheal balloon occlusion — Sheep

Temporary tracheal occlusion by open and fetoscopic operative approaches has improved outcome in selected human fetuses with life-threatening diaphragmatic Correspondence to: T. Kohl

hernias by stimulating the growth of their hypoplastic lungs [3, 7, 9]. The open operative approach in humans requires maternal laparotomy, hysterotomy, and partial fetal exteriorization followed by tracheal dissection and occlusion with external clips [7]. A fetoscopic approach by Harrison and colleagues [9, 18] also employs maternal laparotomy but avoids hysterotomy by direct placement of endoscopic ports through the uterine wall into the amniotic cavity. Fetoscopic tracheal occlusion is then achieved by tracheal dissection and external clip application using endoscopic instruments or, recently, by intraluminal balloon insertion [8, 9, 18]. Alternatively, an ultrasound-guided technique for fetal tracheal occlusion that requires maternal laparotomy has been developed in sheep [6]. Laparotomy and hysterotomy required for the open operative approach for tracheal occlusion in human fetuses with diaphragmatic hernia cause significant maternal injury. Despite the promise of improved outcomes, the maternal trauma of the fetoscopic and ultrasound-guided approaches at tracheal occlusion remains considerable if maternal laparotomy is preferred or required. However, the degree of maternal injury, not only impacts perioperative management, neonatal outcome, and procedural costs but also, most important, maternal consent and ethical approval by society for these procedures. These important concerns have prompted efforts to assess the feasibility of a fully percutaneous fetoscopic technique for fetal tracheal occlusion. Because only one of these procedures has been published to date [16], the purpose of this study is to present a fully percutaneous fetoscopic technique developed in sheep that, even if difficult intraoperative conditions are encountered, permits reliable and reproducible access to the fetal trachea. Relevant differences between sheep and humans are discussed.

1455 Table 1. Balloon occlusion in sheep Skin-to-skin time of successful procedures (min)

Head suspension required

Successful laryngoscopy

Successful tracheal balloon occlusion

+ +

+ +

) )

A A

+

+

+

A

90

)

+ + + + ) )

+ + + + + +

+ + + + + +

C A C C C C

80 110 70 55 65 90

) ) ) ) ) )

Study

Maternal complications ) )

Fetal trauma (other than from stay suture)

Pulmonary hyperplasia in chronic studies

Tracheal balloon dislodgment in chronic studies

— — Skin laceration at fetal neck Oropharyngeal laceration — — — — —

+

)

+ + + +

+ + ) +

A, acute; C, chronic

Materials and methods We employed the technique for percutaneous fetoscopic tracheal balloon occlusion in nine pregnant ewes between 77 and 128 days of gestation (term, 145 days). The study protocol was approved by the local committee on animal research and was performed according to institutional guidelines and guidelines for the provision of standard care to laboratory animals. Each ewe was positioned supine, intubated, and ventilated with 0.5–1.5% isoflurane in 100% oxygen. Placental transfer of the anesthetic gas provided fetal anesthesia. After surgical draping, we performed a detailed transabdominal ultrasound study to determine fetal number and position, amniotic fluid volume, as well as the fetal abdominal insertion site and placental origin of the umbilical cord. The tracheal diameter of each fetus was recorded by maternal transabdominal ultrasound in order to determine the volume required for silicone balloon insufflation as noted by Chiba et al. [2]. We then entered the amniotic cavity by a percutaneous approach with a commercially available 11-Fr arterial sheath (Radiofocus II, Terumo Deutschland GmbH, Frankfurt, Germany) and one or two trocars with an external diameter of 3.8 mm (Karl Storz GmbH, Tuttlingen, Germany). The number of trocars needed during the operation in addition to the 11-Fr sheath was dictated by the complexity of fetal lie and intraamniotic spatial relationships. In the first four studies, partial amniotic fluid removal and lowpressure (7–12 mmHg) insufflation of the amniotic cavity with filtered air were carried out in order to improve fetal visualization. In the last five studies, only amniotic fluid exchange was carried out in order to improve fetal visualization, and the fetuses were kept submerged throughout the entire procedure. Each fetus was postured supine, the head was stabilized in seven fetuses with a stay suture around the lower mandible, and the 11-Fr catheter sheath was percutaneously inserted into the fetal oropharynx. In two fetuses, the head remained in a stable position such that no additional stay suture was required. Following percutaneous intraamniotic access and fetal posturing, we assessed the feasibility of percutaneous fetal laryngoscopy and percutaneous fetoscopic tracheal occlusion with a commercially available three-component introducer system for a low-detachment silicone balloon (Order Nos. M0037715510, M0014301700, and M0011031410; Boston Scientific–Target, Ratingen, Germany). The balloon delivery was visualized by a 1.9- to 2.1-mm, 0° rod lens endoscope housed in a modified sheath with enlarged working channel (Karl Storz). If intratracheal balloon deployment was achieved, the balloon was filled with a defined amount of sterile saline according to Chiba and colleagues [2] and detached from its infusion catheter, effectively occluding the trachea but avoiding ischemic pressure necrosis. In the fetuses, the skin-to-skin time of the entire procedure was recorded. Following the fetoscopic operations, four of the nine ewes were terminated and, together with their operated fetuses, studied for untoward acute effects from the procedure. Five ewes were recovered from surgery in order to verify correct placement of the balloon by assessment of postoperative lung growth. Subsequently, fetal delivery

by the EXIT procedure [14] was scheduled following 2 or 3 weeks of percutaneous fetoscopic tracheal balloon occlusion in order to assess the efficacy of this approach. In these fetuses, fetal transesophageal ultrasound monitoring using a multimodal intravascular ultrasound system (Acuson Aspen Imagegate & AcuNav, Acuson-A-Siemens Company, Nu¨rnberg, Germany) was performed throughout the procedure to assess any detrimental effects of the percutaneous fetoscopic approach and of acute tracheal distension by the balloon on fetal heart rate and fetoplacental hemodynamics [12].

Results Percutaneous intraamniotic access, fetal posturing, oropharyngeal catheter sheath insertion, and fetoscopic laryngoscopy were achieved in all nine sheep fetuses studied (Table 1). In the first two fetuses, difficulties advancing the silicone balloon through the working channel of the custom-made fetoscope shaft resulted in premature balloon detachment from its infusion catheter. Following technical modifications to the working channel of the endoscope shaft, percutaneous fetoscopic balloon occlusion of the fetal trachea was achieved in the next seven fetuses within 55–110 min (Table 1; Fig. 1). Correct intratracheal balloon deployment and adequate filling were confirmed by fetoscopy and ultrasound imaging or at autopsy (Fig. 2). In five fetuses that were recovered from surgery, fetal transesophageal ultrasound monitoring confirmed normal heart rates and fetoplacental hemodynamics throughout the procedure. These animals subsequently underwent the EXIT procedure within 2 or 3 weeks after tracheal balloon occlusion (Fig. 3). The lungs of all tracheal occlusion fetuses were markedly distended. Operative trauma Apart from the small openings inside the maternal abdominal wall and uterus from trocar and sheath insertion, no further maternal injury was observed following percutaneous fetoscopic tracheal occlusion. Apart from the stay suture around the fetal mandible, minor hematomas from posturing, and a perioral laceration in one fetus, no further fetal injury resulted from fetal

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Fig. 1. Percutaneous fetoscopic balloon occlusion of the trachea in a fetal sheep at 91 days of gestation. (Top, left) Maternal transabdominal ultrasound imaging is performed prior to intraamniotic access for assessment of fetal tracheal diameter (T). The inflation volume for the silicone balloon can then be determined by the method described by Chiba et al. [2]. (Right) Percutaneous intraamniotic access and posturing from an unfavorable position required two trocars with an external diameter of 4-mm and one 11-Fr arterial sheath. (Second row, left) The fetal head is suspended by a chin stitch and the shaft of the 11Fr arterial sheath is inserted into the fetal oropharynx. (Right) Fetoscopic visualization of the epiglottis (E) and vocal cords (VC) by the 1.9- to 2.1-mm, 0° rod lens endoscope. (Third row, left) The detachable silicone balloon (SB) has an external diameter of 1.5 mm; the maximum filling volume is 0.5 ml. (Right) During intratracheal balloon insertion via the working canal of the endoscope shaft, an external holder holds the endoscope shaft firmly in position. (Bottom, left) The silicone balloon (SB) can be seen just passing the vocal cords. In this study, slight fetal bleeding from mucosal injury by a ragged sheath shaftresulted in impaired visualization of this critical step. (Right) Following intratracheal detachment of the balloon from its infusion catheter (IC), the catheter is withdrawn. Upon completion of these steps, amniotic fluid is replaced by warmed sterile saline, all trocars are removed, and their abdominal insertion sites are closed.

posturing and head suspension (Fig. 2). In one study, the distal end the 11-Fr sheath became slightly ragged during percutaneous intraamniotic insertion. Subsequently, the defective sheath end was responsible for a tiny mucosal bleed inside the fetal oropharynx, slightly impairing the visualization of intratracheal silicone balloon deployment (Fig. 1). In the five medium-term survivors, the minor lesions from head suspension and posturing healed completely. Apart from minor epithelial changes, no further tracheal damage from balloon obstruction was macroscopically observed in these fetuses. Particularly, all tracheal rings at the balloon sites were intact.

Discussion Our study demonstrates that percutaneous fetoscopic balloon occlusion of the fetal trachea can be achieved effectively and safely in sheep. Because intraamniotic spatial relationships, fetal position, and umbilical cord length are technically less favorable in sheep, our operative techniques might be feasible in humans even under difficult intraamniotic conditions. Despite the fully percutaneous fetoscopic approach, the skin-to-skin time of less than 2 h compares favorably with that of most currently performed open and fetoscopic approaches in the human. In contrast to these

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Fig. 2. Percutaneous fetoscopic balloon occlusion of the trachea in a fetal sheep at 91 days of gestation. (Top, left) Following tracheal balloon occlusion the endoscope is withdrawn and a 10Fr intravascular ultrasound catheter is inserted into the fetal esophagus. Multimodal imaging confirms normal fetal heart rate and fetoplacental blood flow following the fetoscopic approach and acute tracheal distension by the balloon UA, umbilical artery; UV, umbilical vein; DV, ductus venosus. (Middle) Upon completion of percutaneous fetoscopic balloon occlusion of the fetal trachea, the correct intratracheal position of the silicone balloon (SB) can be demonstrated by maternal transabdominal ultrasound imagingor by fetoscopy (bottom, left). (Bottom, middle) Apart from the stay suture required for fetal head suspension, fetal posturing did not result in further fetal injury. (Bottom, right) Following transsection of the fetal trachea, the silicone balloon (arrow) can be seen emerging from the trachea, Note that all images in the bottom row were obtained from a different study fetus in which percutaneous fetoscopic tracheal balloon occlusion was achieved at 98 days of gestation.

approaches and to a recently proposed ultrasoundguided technique in sheep [6], a fully percutaneous technique promises a substantial reduction of maternal trauma from fetal tracheal occlusion since neither laparotomy nor hysterotomy is required. As a consequence, more pregnant women carrying fetuses affected by life-threatening diaphragmatic hernias might consent to this truly minimally invasive approach. Percutaneous intraamniotic access is rapidly and safely achieved by our combined ultrasound and fetoscopic techniques, which were originally developed for fetal cardiac interventions [10, 11, 13]. Although the

3.8-mm trocars and the 11-Fr sheath are slightly larger than those usually employed during other fetoscopic procedures, the one to three openings in the uterine wall required by our procedure had a similar size than one produced by a 2.5-mm device inserted directly because we employed a modified Seldinger technique for trocar insertion. Because these trocars allow for the insertion of a 3.4-mm rod lens endoscope, visualization of intraamniotic contents is greatly improved. In addition, instruments with thicker shafts can be inserted that do not bend if larger fetuses need to be postured from even an unfavorable position. Hence, satisfactory fetal posturing

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Fig. 3. EXIT procedure in a fetal sheep at 103 days of gestation demonstrating effective percutaneous fetoscopic tracheal balloon occlusion over a 12-day period. (Top, left) The uterus was exteriorized by a midline laparotomy. A uterine cutting/ stapling device provides simultaneous hysterotomy and closure of the wound edges. (Middle) The fetal head sits between the hysterotomy edges. (Right) A 1.9- to 2.1-mm rod lens endoscope is advanced into the trachea. (Second row, left) Visualization of adequate wall contact of the inflated silicone balloon (SB) has been improved by staining of the balloon infusion fluid. At the time of removal, transillumination of the stained balloon by the intratracheal light source facilitates localization of its exact intratracheal position for percutaneous puncture. (Right) Only minor epithelial damage (arrow) is apparent following balloon removal (Third row) Posterior lung aspects. The lung of the tracheal occlusion fetus (left) was markedly distended and weighed twice as much as the lung of its similar-sized unoperated twin sibling (right; 150 vs 75 g). Apart from minor epithelial changes, no further tracheal damage wasobserved. (Bottom, left and middle) Corresponding external and internal tracheal images demonstrating the previous balloon occlusion site. (Right) Anterior aspect demonstrating the spatial heart–lung relationships following fetal tracheal occlusion.

was attained in all our studies regardless of fetal lie, origin of the short ovine umbilical cord, or the presence of additional siblings. These results are very encouraging with regard to the application of our percutaneous operative approach to human singletons in whom intraamniotic spatial relationships, fetal lie, and umbilical cord length are technically more favorable than in sheep. Because the small graspers of the endoscopic instruments are either ineffective or too traumatic for positioning the fetus, we preferred to position the fetus with the instrument shafts and, if necessary, stabilize the head position by placing a stay suture around the fetal

mandible. Based on our experience of more than 50 chronic percutaneous fetoscopic fetal cardiac procedures in sheep, these positioning techniques are very effective and result only in minor acute trauma to the fetus that heals completely until delivery. Once the fetal head is stabilized and the oral sheath inserted, the endoscope sheath containing the 1.9- to 2.1-mm rod lens fetoscope can be advanced into the fetal oropharynx. In order to become accustomed to the highly magnified two-dimensional video images of this anatomical region, in a previous pilot study on exteriorized fetuses we studied the fetoscopic visualization of

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the fetal airway anatomy. Based on these simulations, percutaneous fetoscopic fetal laryngoscopy as the most important operative step before intratracheal silicone balloon deployment could effectively and safely be achieved in all fetuses in the current study. In order to achieve successful percutaneous balloon insertion, the entire length of the working canal of the endoscope must be large and smooth enough to permit unhindered passage of the balloon. In our first two studies, tiny welding edges inside the working channel caused premature balloon dislodgment during the percutaneous approach. Dislodgment occurred despite the fact that in both studies the balloon had passed through the channel during a preoperative simulation. This emphasizes the need for selecting well-tested equipment before this approach is undertaken in humans. Following adequate modifications to our straight rigid fetoscope sheath, percutaneous fetoscopic tracheal balloon occlusion was subsequently achieved in the last seven studies. Effective tracheal occlusion was confirmed in two of these fetuses following acute studies (Fig. 2) and in the remaining five fetuses by the degree of pulmonary hyperplasia observed following an EXIT training procedure after approximately 2 or 3 weeks of tracheal occlusion (Fig. 3). This survival period was arbitrarily selected because the trachea in sheep fetuses grows larger than that in human fetuses. Therefore, an effective obstruction until term would have been unlikely by the particular balloon employed in our study, a fact that was demonstrated by balloon dislodgment in three of the five fetuses of our chronic group. Closure of the uterine trocar insertion sites was not required in our study. Due to the introduction of the trocars by a modified Seldinger approach, we did not observe any significant postoperative intraabdominal or transvaginal amniotic fluid leakage. In contrast, following human procedures closure of the trocar insertion sites may be performed to decrease the risk or postpone the occurrence of preterm premature rupture of membranes.

Study limitations Studying the modification of fetal tracheal occlusion from open fetal surgery or fetoscopic or ultrasoundguided approaches that require laparotomy to a percutaneous approach may only partially be applicable to the clinical situation because the sheep is a ruminant, has a very thin abdominal wall, and may have different interposition of bowel/stomach from that in humans. For this reason, we chose a large variation of gestational ages, which results in greatly different intraamniotic access conditions and fetal sizes. We believe that although the abdominal and uterine walls in humans are generally thicker and the uterus is more vascularized than in sheep, the risk for bleeding complications during percutaneous trocar insertion in humans can be minimized by careful Doppler color ultrasound scanning with low Nyquist limits employing a high-frequency linear transducer and by modified Seldinger insertion techniques for intraamniotic trocar placement.

In addition, the chorioamniotic membranes, the mobility of the ovine fetus, and the presence of additional siblings are not comparable to the situation in humans. The operative goal of our study, therefore, seems more difficult to achieve in sheep than in human fetuses, in whom intraamniotic spatial relationships, fetal position, and umbilical cord length are technically more favorable. These more favorable conditions are reflected by the early clinical experience of other investigators, who have recently achieved percutaneous fetoscopic tracheal balloon obstruction in some human fetuses via one or two trocars only [16] (J. Deprest, personal communication, 2002). However, to perform percutaneous fetoscopic balloon occlusion in humans, the placenta must be located posteriorly. In case of an anteriorly positioned placenta, laparotomy and transuterine placement of the silicone balloon guided by fetoscopy or by ultrasound [6, 8] may be required to achieve the operative goal. Although percutaneous fetoscopic tracheal balloon occlusion can be achieved if the fetus remains submerged, gas insufflation of the amniotic cavity greatly improves fetal visualization and manipulation. Throughout our experimental procedures, gas insufflation of the amniotic cavity did not result in any untoward maternal or fetal complications. Bruner and colleagues [1] were the first to demonstrate the feasibility of amniotic gas insufflation during fetoscopic myelomeningocele repair in humans. The amniotic insufflation times and pressures in the described human cases were similar to those required in our percutaneous approach. However, due to the marked anatomical differences of ovine and human placentae, further safety studies in primates are required before amnion insufflation can become a standard technique for human fetoscopic surgery. Based on the studies of previous investigators who provided abundant data on the physiologic and pathohistologic effects of tracheal balloon occlusion on the fetal trachea and lungs, different operative approaches, and characteristics of the silicone balloon [3–5, 7–9, 15, 17–19], our study was intentionally limited to the technical aspects of the procedure to focus on technically relevant differences between sheep and humans. Because intraamniotic spatial relationships, fetal position, and umbilical cord length are technically less favorable in sheep, our operative techniques might be helpful during percutaneous human procedures if difficult intraamniotic conditions are encountered. Acknowledgments. We thank Stefan Brodner and our animal care staff for expert technical assistance. We are indebted to Karl Ruck, Josef Boes, and Axel Zscheile from the Department of Biomechanics at Mu¨nster University for providing numerous technical modifications to our equipment. This study was partially supported by a research grant Ko 1484/3-2 from the Deutsche Forschungsgemeinschaft (DFG), Bonn, Germany. We thank Sybill Storz for providing all fetoscopic equipment. We thank Ethicon (Norderstedt, Germany) for providing suture material and Ross Product Division, Abbot Laboratories (Columbus, OH, USA) for providing T-fasteners. Furthermore, we acknowledge the support of Allegiance Healthcare (Kleve, Germany) and Mo¨lnlycke Health Care (Go¨teburg, Sweden) for providing sterile surgical drapings and gowns.

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