- Email: [email protected]
Successful diagnostic and therapeutic intrauterine fetal interventions by natural orifice transluminal endoscopic surgery (with videos)
Successful diagnostic and therapeutic intrauterine fetal interventions by natural orifice transluminal endoscopic surgery (with videos) Samuel A. Giday, MD, Jonathan M. Buscaglia, MD, Janyne Althaus, MD, Gianfranco Donatelli, MD, Devi M. Krishnamurty, MD, Xavier Dray, MD, Dawn Ruben, DVM, David Liang, MD, Ronald Wroblewski, RN, Priscilla Magno, MD, Eun Ji Shin, MD, Anthony N. Kalloo, MD Baltimore, Maryland, Washington, DC, USA, Paris, France, Rome, Italy, San Juan, Puerto Rico
Background: Despite advances in the development of fetal surgery, morbidity and mortality are substantial. A natural orifice transluminal endoscopic surgery (NOTES)–guided approach to the gravid uterus may offer a less-invasive technique. Objective: To assess the feasibility of NOTES for diagnostic and therapeutic intrauterine fetal interventions. Setting: Survival and nonsurvival experiments on pregnant sheep. Design and Intervention: Nonsurvival experiments performed in 2 pregnant sheep (80-110 days’ gestation). A third ewe underwent NOTES and survived for 4 weeks. Transgastric (nonsurvival ewes) and transvaginal (1 nonsurvival and the survived ewe) peritoneoscopy was performed after standard needle-knife entry into the peritoneal cavity. Endoscopic access to the gravid uterus was assessed. EUS-guided, transuterine injection of saline solution into the fetal cardiac ventricle and vessels was attempted in all. Main Outcome Measurements: Feasibility of NOTES- and EUS-guided intervention in a pregnant animal model, visibility of fetal parts via EUS compared with transabdominal US. Results: Entry into the peritoneal cavity was achieved in each ewe. Access to and complete visualization of the gravid uterus were successful once within the abdominal cavity. Visualization of the fetal parts and the placental cotyledons by EUS was achieved in all animals. EUS-guided amniocenteses and transuterine intracardiac and intravascular injection of saline were successful. There were no complications or preterm delivery after the procedures. Limitations: Animal model. Conclusions: NOTES is technically feasible in the pregnant ewe. Intraperitoneal EUS via a NOTES approach provides excellent access and visualization of the intrauterine cavity and fetal parts.
Copyright ª 2009 by the American Society for Gastrointestinal Endoscopy 0016-5107/$36.00 doi:10.1016/j.gie.2009.03.022
Currently available approaches to correct these fetal abnormalities that aid in preventing progressive vital organ damage and save the fetus include open and fetoscopic approaches.9,10 The open surgical approach involves the performance of a large abdominal and uterine incision to expose the fetus after which surgical intervention is performed. This approach portends significant morbidity to the mother and the fetus.9 Fetoscopic intrauterine interventions by using laparoscopy provide a less-invasive approach to correct fetal abnormalities. The major limitation of this approach is that the location of the placenta and fetus in relation to the anterior abdominal wall will affect the outcome and limit the number of subjects eligible for this procedure. For instance, an anteriorly positioned placenta or fetal back
www.giejournal.org
Volume 70, No. 2 : 2009 GASTROINTESTINAL ENDOSCOPY 377
The use of high-resolution obstetric US and increased screening programs throughout the world have led to increased detection of fetal abnormalities.1-3 Since the first intrauterine treatment of an anemic fetus by in utero transfusion, the field of intrauterine interventions has taken a tremendous leap and other complex intrauterine procedures are now being performed.4-8 Abbreviations: IVC, inferior vena cava; NOTES, natural orifice transluminal endoscopic surgery. DISCLOSURE: A. N. Kalloo is a member of the Apollo group. All other authors disclosed no financial relationships relevant to this publication.
NOTES-guided intrauterine interventions
make many fetoscopy-based interventions difficult if not impossible.10 Natural orifice transluminal endoscopic surgery (NOTES) may be a minimally invasive option because it does not rely on any abdominal incisions and also because of the fact that the flexible nature of the endoscope may aid in accessing different parts of the uterus. The primary aim of the study was to assess the feasibility of NOTES in performing diagnostic and therapeutic interventions in a pregnant animal model and the fetus. The secondary aims of the study were to assess the safety of NOTES in pregnancy, to assess the utility of EUS in pregnancy, and to compare the ability of NOTES to perform standardized obstetric US examination.
MATERIALS AND METHODS The study was approved by the Johns Hopkins Animal Care Institutional Review Board. NOTES-guided peritoneoscopy and EUS were performed on 3 consecutive pregnant sheep with a gestational age of 80 to 110 days. This gestational age was selected to simulate a uterine size large enough to assess potential complications of NOTES. A later date was not used to allow us to assess survival time.
Animal preparation All feeding was held for 12 hours before the endoscopy. The procedures were performed with the ewes under 1.5% to 2% isoflurane general anesthesia, with 7.0-mm endotracheal intubation (Mallinckrodt Co, C. D. Juarez, Chihuahua, Mexico). Preanesthesia medication consisted of an intramuscular injection of 100 mg/mL tiletamine HCl þ zolazepam HCl (Telazol; Lederle Parenterals, Inc, Carolina, Puerto Rico) reconstituted with 100 mg/mL ketamine HCl and 100 mg/mL xylazine at a total dose of approximately 0.05 mL/kg. An intravenous line was placed in the internal jugular vein, and 1 g thiopental sodium was injected at a dose of 6.6 to 8.8 mg/kg. Continuous monitoring of hemodynamic parameters (heart rate and blood pressure) and exhaled CO2 levels was performed. For the survival experiment, all endoscopes and accessories were disinfected with high-level disinfection solution 0.55% ortho-phthalaldehyde (Cidex OPA; Ethicon Inc, Irvine, Calif) and then gas sterilized with ethylene oxide. The vagina was disinfected with a broad-spectrum topical iodophor microbicide (10% povidone-iodine), and the animal was draped with sterile surgical drapes. Intravenous antibiotic (1 g cefazolin) was then injected in the survived animal. The operator and assistant wore sterile gowns, gloves, and face masks. A sterile endoscope (Olympus GIF-160, Tokyo, Japan) and a linear array echoendoscope (GF-UCT140; Olympus America, Inc, Melville, NY) with the Aloka ProSound SSD 5000 EUS 378 GASTROINTESTINAL ENDOSCOPY Volume 70, No. 2 : 2009
Giday et al
Capsule Summary What is already known on this topic d
Fetoscopic interventions to correct abnormalities in utero have high rates of morbidity and mortality and are limited by the location of the placenta and fetus in relation to the anterior abdominal wall.
What this study adds to our knowledge d
Intraperitoneal EUS via a natural orifice transluminal endoscopic surgery (NOTES) approach provided excellent access and visualization of the intrauterine cavity and fetuses in 3 gravid ewes.
processor were used during the procedure. Vaginal vault puncture was performed by using a needle-knife (Cook Medical Inc, Winston-Salem, NC) and a blended electrocautery setting of 20-J cautery and 30-J cut (Valleylab SSE2L; Tyco Healthcare Group LP, Boulder, Colo). The puncture site was then dilated by using an 18-mm hydrostatic dilation balloon (Cook Medical Inc). The endoscope was advanced into the peritoneal cavity followed by a wireguided exchange to the linear EUS endoscope. In the survived animal, endoscopic closure of the vaginal vault was performed by using a T-bar anchoring system (Cook Medical Inc) and endoscopic clips. The T-bars were deployed on both sides of the vaginotomy and then approximated and cinched together. The nonsurvival animals underwent the same procedures by using nonsterile but chemically (Cidex) disinfected endoscope and accessories without any antiseptic gastric and oral cavity lavage or parenteral antibiotics. One animal was kept alive for a period of 4 weeks. The remaining 2 animals were killed immediately after the procedures. The animal that was kept alive was closely followed daily for any evidence of abortion and signs of infection including fever, changes in appetite, and level of activity. At the end of the observation period, the animal was killed, and immediate necropsy was performed. Close inspection of the uterine wall, placenta, and fetus was performed for any sign of damage.
EUS procedure The American Institute of Ultrasound in Medicine, in conjunction with the American College of Obstetricians and Gynecologists and the American College of Radiology, has defined a set of criteria for a standard obstetric US examination performed in the second or third trimester that is vital for the care of the mother and fetus. Standardized obstetric transabdominal US examination of the fetus was then performed by an experienced obstetrician (J.A.) in all animals and compared with images obtained by EUS subjectively. www.giejournal.org
Giday et al
A linear array echoendoscope (GF-UCT140; Olympus America, Inc, Melville, NY) with the Aloka Prosound SSD 5000 EUS processor was introduced into either the gastric rumen or vagina and advanced into the peritoneal cavity under wire guidance. A standardized obstetric US examination11 was then performed of all 3 fetuses by using a frequency of 7.5 MHz. The fetal heart, hepatic parenchyma, umbilical vessels, amniotic cavity, and intrahepatic portion of the inferior vena cava (IVC) were punctured with a 22-gauge FNA needle (EchoTip; Wilson-Cook Inc). The stylet was withdrawn, and amniotic fluid or blood was aspirated to confirm the proper positioning of the needle. The IVC, cord vessels, and ventricles were injected with agitated saline for use as an US contrast agent. After the completion of the procedure, the FNA needle was removed. The animals were observed for 30 minutes for any sign of bleeding. The animals were then killed, and necropsy was performed. The peritoneal cavity, liver, and other intra-abdominal organs and vessels were closely inspected for any evidence of bleeding or tissue damage.
RESULTS Three animal experiments were successfully completed. Sheep 1 underwent a peritoneoscopy using the transgastric route. Sheep 2 underwent both transvaginal and transgastric peritoneoscopy. Sheep 3 underwent transvaginal peritoneoscopy with no transgastric attempt. The sheep stomach has 4 chambers, and this made the transgastric approach challenging, particularly with regard to achieving a content-free stomach. The most proximal chamber (the rumen) was used because it was the easiest to lavage clear. Identification of intra-abdominal organs was achieved in all animals by both routes. The anterior, posterior, and right lateral and left lateral walls in addition to the fundus and lower poles of the uterus were assessed without any difficulty (Video 1, available at www.giejournal.org). By repositioning the animal, the posterior wall of the uterus was also reached successfully in all animals. No signs of fetal distress (ie, bradycardia) were seen by transabdominal US during peritoneoscopy. Standard obstetric US was performed by using EUS (Table 1). Fetal cardiac activity, the 4-chamber view, and outflow tracts were easily demonstrable from different positions (Video 2, available at www.giejournal.org). In addition, the fetal spine could be followed longitudinally with a clear view of the spinal column (Video 2). Assessment of the placental position and vascular flow could also be seen without any difficulty (Video 2). The umbilical vessels were visualized and followed to their insertion point in the anterior abdominal wall. A color and power Doppler flow scan of the vessels clearly demarcated the umbilical artery and vein (Video 2). These www.giejournal.org
NOTES-guided intrauterine interventions
TABLE 1. Comparison of abdominal obstetric sonography and transluminal EUS Transluminal EUS
Abdominal US
Fetal cardiac activity
Yes
Yes
No. fetuses
Yes
Yes
Presentation
Yes
Yes
Umbilical cord vessels
Yes
Yes
Spine
Yes
Yes
Intra-abdominal organs
Yes
Yes
Chest cavity
Yes
Yes
Extremities
Yes
Yes
4-chamber view of heart
Yes
Yes
vessels could be traced into the intrahepatic segments. The fetal gastric lumen and bladder were seen as anechoic structures in the abdominal cavity in all animals (Video 2). Using 22-gauge EUS FNA needles, we performed puncture of the amniotic cavity and amniocentesis in all animals. The umbilical vein was selectively punctured under EUS guidance with agitated saline solution demonstrating no evidence of leakage. Fetal hepatic parenchyma was traversed by using an EUS FNA needle after which 10 mL of agitated saline solution was injected in the intrahepatic portion of the IVC (Video 3, available at www.giejournal.org). Furthermore, the ventricles of the fetal heart were targeted and successfully injected with saline solution in 2 animals. There were no complications during our experiments. The animals remained stable and displayed no changes in hemodynamic parameters or oxygen saturation during peritoneoscopy, EUS, or EUS-guided fine-needle injection. The animal that survived for 4 weeks remained well with no evidence of infection or bleeding. The animal ate heartily. The fetus survived for 4 weeks with no demonstrable fetal complications. Weekly abdominal sonography revealed no evidence of fetal demise or complications. At the end of the study period, necropsy revealed no evidence of uterine, placental, or fetal damage.
DISCUSSION Surgical interventions during pregnancy pose challenges both to the mother and fetus.12 Maternal complications including preterm labor, postoperative abdominal wound infection, and dehiscence are some of the complications that can be lessened, if not avoided, by using the NOTES approach. Open surgical procedures involve large abdominal and uterine wall incisions followed by exteriorizing of the fetus after Volume 70, No. 2 : 2009 GASTROINTESTINAL ENDOSCOPY 379
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Giday et al
which the required surgical procedure is performed. The procedure, which is available only in few specialized centers in the world, can lead to a significant morbidity in the mother and fetus including infection, bleeding, preterm delivery, and even fetal demise. Fetoscopic intrauterine interventions provide a lessinvasive approach and the opportunity to correct some fetal abnormalities; however, the limitation of this approach is that the placental and fetal position in relation to the anterior abdominal wall affects the outcome by limiting the number of subjects who would qualify for this procedure. For instance, an anteriorly positioned placenta or fetal spine can affect the outcome by increasing the technical difficulty. NOTES provides 360-degree access to the uterine wall, making placental and fetal position irrelevant to degree of difficulty. The approach may provide a postoperative state free of abdominal wound infection or dehiscence and lead to an equal or improved outcome, may avoid the administration of general anesthesia, and lead to an outcome equal to that with laparotomy or laparoscopy. In addition, the potential benefits of a NOTES approach in pregnancy, as opposed to a laparoscopic approach, are the same as in the nonpregnant abdomen, namely, the lack of an abdominal wall incision and potentially less pain. Furthermore, studies have shown that significant differences exist in cardiopulmonary parameters that may favor the NOTES approach over laparoscopy in the pregnant patient.13 None of these have been studied in pregnancy, but we expect that even small changes in cardiopulmonary parameters will more likely to have a significant effect on the pregnant mother and the fetus. Although there is a lack of human data, animal studies have shown that there is a reduced level of inflammatory cytokines, mainly tumor necrosis factor a in NOTES compared with laparoscopic approaches.14 Although laparoscopy has been shown to be safe in pregnancy, the data are based on case series from single institutions. A significant risk of damage to the gravid uterus using Veress needle or trocar insertion, technical difficulty in performing the procedure in the presence of a gravid uterus, concern for the possibility of fetal academia, and decreased maternal venous return secondary to increased intraperitoneal pressure from CO2 insufflation still exist. All these factors can potentially be minimized by using the NOTES approach. The use of EUS will potentially reduce the need to use significant pneumoperitoneum because the procedure is best performed with almost no pneumoperitoneum, with the endoscope adjacent to the uterine wall. Nevertheless, the risk of peritoneal contamination, both from the breach of gut wall and postclosure leakage, should be taken into consideration. In our experiments, we were able to demonstrate that using the transgastric and transvaginal routes into the peritoneal cavity is both feasible and safe.
Successful vascular interventions in the fetus by using US guidance have been reported and have significant potential.15-17 In adults, the use of EUS plays a major role in the diagnosis and management of gastroenterologic and oncologic disorders. In addition to staging GI and pancreaticobiliary malignancies, EUS guidance has been used to perform various less-invasive but effective therapeutic interventions such as celiac nerve block and pancreatic pseudocyst drainage.18-20 Our group has also shown that vascular interventions can be performed safely under the guidance of EUS.21-24 Needle-based interventions provide minimally invasive access to areas where surgical access is difficult or may result in significant morbidity or mortality. In this study, NOTES peritoneoscopy was performed in all animals without any complications. All maternal intraabdominal organs targeted for examination were successfully visualized. Access to the uterus was achievable from all directions. Sites such as the posterior wall of the uterus, usually inaccessible during traditional surgical approaches, were easily accessed by repositioning the animal. In addition, the flexible endoscope was able to reach all poles of the uterus from one entry point. The transgastric access point gave a straight shot trajectory to the uterus, and all maneuvers were able to be completed by using a straight-scope position. The transvaginal access also provided the same straight trajectory to one uterine wall but a retroflexed position had to be used to achieve access to the contralateral wall and uterine fundus. Despite the retroflexed position, all interventions were performed with no significant difficulty. Current advancements in obstetric imaging, including the use of 3- and 4-dimensional US and magnetic resonance imaging, have led to increased diagnostic rates and accuracy of congenital disorders.1,2 Despite these encouraging developments, direct acquisition of fetal tissue samples sometimes remains necessary for accurate diagnosis and therapy. In our study, we were able to demonstrate that access to the fetal cardiovascular system was easily achievable from many angles. Four-chamber cardiac views were obtained easily despite variable fetal positions, with excellent resolution by using the NOTES EUS approach. Furthermore, we were also able to access the fetal cardiac chamber and vascular system with injection of agitated saline solution to show that administration of drugs and other therapeutic agents is technically simple and successful with this approach. All the animals and fetuses survived direct EUS-guided cardiocentesis, cordocentesis, and injection without any complications including hemopericardium. In conclusion, NOTES may provide a minimally invasive alternative to currently available fetal and gestational interventions. Further studies are needed to define its limitations and long-term effects on the fetus and the mother.
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REFERENCES 1. Goncalves LF, Lee W, Espinoza J, et al. Three- and four-dimensional ultrasound in obstetric practice. Does it help? J Ultrasound Med 2005;24:1599-624. 2. Hubbard AM. Ultrafast fetal MRI and prenatal diagnosis. Semin Pediatr Surg 2003;12:143-53. 3. Flood K, Malone FD. Screening for fetal abnormalities with ultrasound. Curr Opin Obstet Gynecol 2008;20:139-45. 4. Bang J, Bock JE, Trolle D. Ultrasound-guided fetal intravenous transfusion for severe rhesus haemolytic disease. Br Med J Clin Res Ed 1982;284:373-4. 5. Rodeck CH, Campbell S. Umbilical-cord insertion as a source of pure fetal blood for prenatal diagnosis. Lancet 1979;1:1244-5. 6. Daffos F, Capella-Pavlovsky M, Foreseier R. A new procedure for fetal blood sampling in utero: preliminary results of fifty-three cases. Am J Obstet Gynecol 1983;146:985-7. 7. Huhta J, Quintero RA, Suh E, et al. Advances in fetal cardiac intervention. Curr Opin Pediatr 2004;16:487-93. 8. Quintero RA, Huhta J, Suh E, et al. In utero cardiac fetal surgery: laser atrial septotomy in the treatment of hypoplastic left heart syndrome with intact atrial septum. Am J Obstet Gynecol 2005;193:1424-8. 9. Cass DL. Fetal surgery for congenital diaphragmatic hernia: the North American experience. Semin Perinatol 2005;29:104-11. 10. Deprest JA, Lerut TE, Vandenberghe K. Operative fetoscopy: new perspective in fetal therapy? Prenat Diagn 1997;17:1247-60. 11. American Institute of Ultrasound in Medicine: AIUM Practice Guideline for the performance of an antepartum obstetric ultrasound examination. J Ultrasound Med 2003;22:1116-25. 12. Lu EJ, Curet MJ, El-Sayed YY, et al. Medical versus surgical management of biliary tract disease in pregnancy. Am J Surg 2004;188: 755-9. 13. Bingener J, Michalek J, Winston J, et al. Randomized blinded trial comparing the cardiopulmonary effects of NOTES with standard laparoscopy in a porcine survival model. Surg Endosc 2008;22:1430-4. 14. McGee MF, Schomisch SJ, Marks JM, et al. Late phase TNF-alpha depression in natural orifice translumenal endoscopic surgery (NOTES) peritoneoscopy. Surgery 2008;143:318-28. 15. Sarno AP, Feinstein SJ, Bell JG, et al. Emergent fetal intracardiac transfusion for thrombocytopenia and acute hypovolemia due to cordocentesis-associated hemorrhage in parvovirus-induced hydrops. Fetal Diagn Ther 2007;22:124-7.
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NOTES-guided intrauterine interventions
16. Quintero RA, Huhta J, Suh E, et al. In utero cardiac fetal surgery: laser atrial septotomy in the treatment of hypoplastic left heart syndrome with intact atrial septum. Am J Obstet Gynecol 2005;193:1424-8. 17. Gardiner HM, Kumar S. Fetal cardiac interventions. Clin Obstet Gynecol 2005;48:956-63. 18. Rosch T. Endosonographic staging of esophageal cancer: a review of literature results. Gastrointest Endosc Clin N Am 1995;5:537-47. 19. Giovannini M, Binmoeller K, Seifert H. Endoscopic ultrasound-guided cystogastrostomy. Endoscopy 2003;35:239-45. 20. Chang KJ. State of the art lecture: endoscopic ultrasound (EUS) and FNA in pancreatico-biliary tumors. Endoscopy 2006;38(Suppl 1):S56-60. 21. Giday SA, Ko CW, Clarke JO, et al. Endoscopic ultrasound (EUS)-guided portal vein catheterization: a novel approach for portal angiography and portal vein pressure measurements. Gastrointest Endosc 2008;67:338-42. 22. Giday SA, Ko CW, Clarke JO, et al. EUS-guided portal vein carbon dioxide angiography: a pilot study in a porcine model. Gastrointest Endosc 2007;66:814-9. 23. Magno P, Ko CW, Buscaglia JM, et al. EUS-guided angiography: a novel approach to diagnostic and therapeutic interventions in the vascular system. Gastrointest Endosc 2007;66:587-91. 24. Buscaglia JM, Shin EJ, Clarke, et al. Endoscopic retrograde cholangiopancreatography, but not esophagogastroduodenoscopy or colonoscopy, significantly increases portal venous pressure: direct portal pressure measurements through endoscopic ultrasound-guided cannulation. Endoscopy 2008;40:670-4.
Received August 29, 2008. Accepted March 11, 2009. Current affiliations: Medicine/Gastroenterology (S.A.G., J.M.B., G.D., D.M.K., X.D., D.L., R.W., P.M., E.J.S., A.N.K.), OB GYN/Maternal Fetal Medicine (J.A.), Comparative Pathology (D.R.), The Johns Hopkins University School of Medicine, Baltimore, Maryland, Howard University College of Medicine (S.A.G.), Washington, DC, Hoˆpital Lariboisiere (X.D.), APHP, Paris 7 University, Paris, France, Department of General Surgery (G.D.), ‘‘P. Stefanini,’’ University of Rome ‘‘La Sapienza,’’ Rome, Italy, Department of Medicine (P.M.), University of Puerto Rico, San Juan, Puerto Rico. Reprint requests: Samuel A. Giday, MD, Division of Gastroenterology, The Johns Hopkins Hospital, 1830 East Monument Street, Room 424, Baltimore, MD 21205. If you want to chat with an author of this article, you may contact him at [email protected].
Volume 70, No. 2 : 2009 GASTROINTESTINAL ENDOSCOPY 381
Background: Despite advances in the development of fetal surgery, morbidity and mortality are substantial. A natural orifice transluminal endoscopic surgery (NOTES)–guided approach to the gravid uterus may offer a less-invasive technique. Objective: To assess the feasibility of NOTES for diagnostic and therapeutic intrauterine fetal interventions. Setting: Survival and nonsurvival experiments on pregnant sheep. Design and Intervention: Nonsurvival experiments performed in 2 pregnant sheep (80-110 days’ gestation). A third ewe underwent NOTES and survived for 4 weeks. Transgastric (nonsurvival ewes) and transvaginal (1 nonsurvival and the survived ewe) peritoneoscopy was performed after standard needle-knife entry into the peritoneal cavity. Endoscopic access to the gravid uterus was assessed. EUS-guided, transuterine injection of saline solution into the fetal cardiac ventricle and vessels was attempted in all. Main Outcome Measurements: Feasibility of NOTES- and EUS-guided intervention in a pregnant animal model, visibility of fetal parts via EUS compared with transabdominal US. Results: Entry into the peritoneal cavity was achieved in each ewe. Access to and complete visualization of the gravid uterus were successful once within the abdominal cavity. Visualization of the fetal parts and the placental cotyledons by EUS was achieved in all animals. EUS-guided amniocenteses and transuterine intracardiac and intravascular injection of saline were successful. There were no complications or preterm delivery after the procedures. Limitations: Animal model. Conclusions: NOTES is technically feasible in the pregnant ewe. Intraperitoneal EUS via a NOTES approach provides excellent access and visualization of the intrauterine cavity and fetal parts.
Copyright ª 2009 by the American Society for Gastrointestinal Endoscopy 0016-5107/$36.00 doi:10.1016/j.gie.2009.03.022
Currently available approaches to correct these fetal abnormalities that aid in preventing progressive vital organ damage and save the fetus include open and fetoscopic approaches.9,10 The open surgical approach involves the performance of a large abdominal and uterine incision to expose the fetus after which surgical intervention is performed. This approach portends significant morbidity to the mother and the fetus.9 Fetoscopic intrauterine interventions by using laparoscopy provide a less-invasive approach to correct fetal abnormalities. The major limitation of this approach is that the location of the placenta and fetus in relation to the anterior abdominal wall will affect the outcome and limit the number of subjects eligible for this procedure. For instance, an anteriorly positioned placenta or fetal back
www.giejournal.org
Volume 70, No. 2 : 2009 GASTROINTESTINAL ENDOSCOPY 377
The use of high-resolution obstetric US and increased screening programs throughout the world have led to increased detection of fetal abnormalities.1-3 Since the first intrauterine treatment of an anemic fetus by in utero transfusion, the field of intrauterine interventions has taken a tremendous leap and other complex intrauterine procedures are now being performed.4-8 Abbreviations: IVC, inferior vena cava; NOTES, natural orifice transluminal endoscopic surgery. DISCLOSURE: A. N. Kalloo is a member of the Apollo group. All other authors disclosed no financial relationships relevant to this publication.
NOTES-guided intrauterine interventions
make many fetoscopy-based interventions difficult if not impossible.10 Natural orifice transluminal endoscopic surgery (NOTES) may be a minimally invasive option because it does not rely on any abdominal incisions and also because of the fact that the flexible nature of the endoscope may aid in accessing different parts of the uterus. The primary aim of the study was to assess the feasibility of NOTES in performing diagnostic and therapeutic interventions in a pregnant animal model and the fetus. The secondary aims of the study were to assess the safety of NOTES in pregnancy, to assess the utility of EUS in pregnancy, and to compare the ability of NOTES to perform standardized obstetric US examination.
MATERIALS AND METHODS The study was approved by the Johns Hopkins Animal Care Institutional Review Board. NOTES-guided peritoneoscopy and EUS were performed on 3 consecutive pregnant sheep with a gestational age of 80 to 110 days. This gestational age was selected to simulate a uterine size large enough to assess potential complications of NOTES. A later date was not used to allow us to assess survival time.
Animal preparation All feeding was held for 12 hours before the endoscopy. The procedures were performed with the ewes under 1.5% to 2% isoflurane general anesthesia, with 7.0-mm endotracheal intubation (Mallinckrodt Co, C. D. Juarez, Chihuahua, Mexico). Preanesthesia medication consisted of an intramuscular injection of 100 mg/mL tiletamine HCl þ zolazepam HCl (Telazol; Lederle Parenterals, Inc, Carolina, Puerto Rico) reconstituted with 100 mg/mL ketamine HCl and 100 mg/mL xylazine at a total dose of approximately 0.05 mL/kg. An intravenous line was placed in the internal jugular vein, and 1 g thiopental sodium was injected at a dose of 6.6 to 8.8 mg/kg. Continuous monitoring of hemodynamic parameters (heart rate and blood pressure) and exhaled CO2 levels was performed. For the survival experiment, all endoscopes and accessories were disinfected with high-level disinfection solution 0.55% ortho-phthalaldehyde (Cidex OPA; Ethicon Inc, Irvine, Calif) and then gas sterilized with ethylene oxide. The vagina was disinfected with a broad-spectrum topical iodophor microbicide (10% povidone-iodine), and the animal was draped with sterile surgical drapes. Intravenous antibiotic (1 g cefazolin) was then injected in the survived animal. The operator and assistant wore sterile gowns, gloves, and face masks. A sterile endoscope (Olympus GIF-160, Tokyo, Japan) and a linear array echoendoscope (GF-UCT140; Olympus America, Inc, Melville, NY) with the Aloka ProSound SSD 5000 EUS 378 GASTROINTESTINAL ENDOSCOPY Volume 70, No. 2 : 2009
Giday et al
Capsule Summary What is already known on this topic d
Fetoscopic interventions to correct abnormalities in utero have high rates of morbidity and mortality and are limited by the location of the placenta and fetus in relation to the anterior abdominal wall.
What this study adds to our knowledge d
Intraperitoneal EUS via a natural orifice transluminal endoscopic surgery (NOTES) approach provided excellent access and visualization of the intrauterine cavity and fetuses in 3 gravid ewes.
processor were used during the procedure. Vaginal vault puncture was performed by using a needle-knife (Cook Medical Inc, Winston-Salem, NC) and a blended electrocautery setting of 20-J cautery and 30-J cut (Valleylab SSE2L; Tyco Healthcare Group LP, Boulder, Colo). The puncture site was then dilated by using an 18-mm hydrostatic dilation balloon (Cook Medical Inc). The endoscope was advanced into the peritoneal cavity followed by a wireguided exchange to the linear EUS endoscope. In the survived animal, endoscopic closure of the vaginal vault was performed by using a T-bar anchoring system (Cook Medical Inc) and endoscopic clips. The T-bars were deployed on both sides of the vaginotomy and then approximated and cinched together. The nonsurvival animals underwent the same procedures by using nonsterile but chemically (Cidex) disinfected endoscope and accessories without any antiseptic gastric and oral cavity lavage or parenteral antibiotics. One animal was kept alive for a period of 4 weeks. The remaining 2 animals were killed immediately after the procedures. The animal that was kept alive was closely followed daily for any evidence of abortion and signs of infection including fever, changes in appetite, and level of activity. At the end of the observation period, the animal was killed, and immediate necropsy was performed. Close inspection of the uterine wall, placenta, and fetus was performed for any sign of damage.
EUS procedure The American Institute of Ultrasound in Medicine, in conjunction with the American College of Obstetricians and Gynecologists and the American College of Radiology, has defined a set of criteria for a standard obstetric US examination performed in the second or third trimester that is vital for the care of the mother and fetus. Standardized obstetric transabdominal US examination of the fetus was then performed by an experienced obstetrician (J.A.) in all animals and compared with images obtained by EUS subjectively. www.giejournal.org
Giday et al
A linear array echoendoscope (GF-UCT140; Olympus America, Inc, Melville, NY) with the Aloka Prosound SSD 5000 EUS processor was introduced into either the gastric rumen or vagina and advanced into the peritoneal cavity under wire guidance. A standardized obstetric US examination11 was then performed of all 3 fetuses by using a frequency of 7.5 MHz. The fetal heart, hepatic parenchyma, umbilical vessels, amniotic cavity, and intrahepatic portion of the inferior vena cava (IVC) were punctured with a 22-gauge FNA needle (EchoTip; Wilson-Cook Inc). The stylet was withdrawn, and amniotic fluid or blood was aspirated to confirm the proper positioning of the needle. The IVC, cord vessels, and ventricles were injected with agitated saline for use as an US contrast agent. After the completion of the procedure, the FNA needle was removed. The animals were observed for 30 minutes for any sign of bleeding. The animals were then killed, and necropsy was performed. The peritoneal cavity, liver, and other intra-abdominal organs and vessels were closely inspected for any evidence of bleeding or tissue damage.
RESULTS Three animal experiments were successfully completed. Sheep 1 underwent a peritoneoscopy using the transgastric route. Sheep 2 underwent both transvaginal and transgastric peritoneoscopy. Sheep 3 underwent transvaginal peritoneoscopy with no transgastric attempt. The sheep stomach has 4 chambers, and this made the transgastric approach challenging, particularly with regard to achieving a content-free stomach. The most proximal chamber (the rumen) was used because it was the easiest to lavage clear. Identification of intra-abdominal organs was achieved in all animals by both routes. The anterior, posterior, and right lateral and left lateral walls in addition to the fundus and lower poles of the uterus were assessed without any difficulty (Video 1, available at www.giejournal.org). By repositioning the animal, the posterior wall of the uterus was also reached successfully in all animals. No signs of fetal distress (ie, bradycardia) were seen by transabdominal US during peritoneoscopy. Standard obstetric US was performed by using EUS (Table 1). Fetal cardiac activity, the 4-chamber view, and outflow tracts were easily demonstrable from different positions (Video 2, available at www.giejournal.org). In addition, the fetal spine could be followed longitudinally with a clear view of the spinal column (Video 2). Assessment of the placental position and vascular flow could also be seen without any difficulty (Video 2). The umbilical vessels were visualized and followed to their insertion point in the anterior abdominal wall. A color and power Doppler flow scan of the vessels clearly demarcated the umbilical artery and vein (Video 2). These www.giejournal.org
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TABLE 1. Comparison of abdominal obstetric sonography and transluminal EUS Transluminal EUS
Abdominal US
Fetal cardiac activity
Yes
Yes
No. fetuses
Yes
Yes
Presentation
Yes
Yes
Umbilical cord vessels
Yes
Yes
Spine
Yes
Yes
Intra-abdominal organs
Yes
Yes
Chest cavity
Yes
Yes
Extremities
Yes
Yes
4-chamber view of heart
Yes
Yes
vessels could be traced into the intrahepatic segments. The fetal gastric lumen and bladder were seen as anechoic structures in the abdominal cavity in all animals (Video 2). Using 22-gauge EUS FNA needles, we performed puncture of the amniotic cavity and amniocentesis in all animals. The umbilical vein was selectively punctured under EUS guidance with agitated saline solution demonstrating no evidence of leakage. Fetal hepatic parenchyma was traversed by using an EUS FNA needle after which 10 mL of agitated saline solution was injected in the intrahepatic portion of the IVC (Video 3, available at www.giejournal.org). Furthermore, the ventricles of the fetal heart were targeted and successfully injected with saline solution in 2 animals. There were no complications during our experiments. The animals remained stable and displayed no changes in hemodynamic parameters or oxygen saturation during peritoneoscopy, EUS, or EUS-guided fine-needle injection. The animal that survived for 4 weeks remained well with no evidence of infection or bleeding. The animal ate heartily. The fetus survived for 4 weeks with no demonstrable fetal complications. Weekly abdominal sonography revealed no evidence of fetal demise or complications. At the end of the study period, necropsy revealed no evidence of uterine, placental, or fetal damage.
DISCUSSION Surgical interventions during pregnancy pose challenges both to the mother and fetus.12 Maternal complications including preterm labor, postoperative abdominal wound infection, and dehiscence are some of the complications that can be lessened, if not avoided, by using the NOTES approach. Open surgical procedures involve large abdominal and uterine wall incisions followed by exteriorizing of the fetus after Volume 70, No. 2 : 2009 GASTROINTESTINAL ENDOSCOPY 379
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which the required surgical procedure is performed. The procedure, which is available only in few specialized centers in the world, can lead to a significant morbidity in the mother and fetus including infection, bleeding, preterm delivery, and even fetal demise. Fetoscopic intrauterine interventions provide a lessinvasive approach and the opportunity to correct some fetal abnormalities; however, the limitation of this approach is that the placental and fetal position in relation to the anterior abdominal wall affects the outcome by limiting the number of subjects who would qualify for this procedure. For instance, an anteriorly positioned placenta or fetal spine can affect the outcome by increasing the technical difficulty. NOTES provides 360-degree access to the uterine wall, making placental and fetal position irrelevant to degree of difficulty. The approach may provide a postoperative state free of abdominal wound infection or dehiscence and lead to an equal or improved outcome, may avoid the administration of general anesthesia, and lead to an outcome equal to that with laparotomy or laparoscopy. In addition, the potential benefits of a NOTES approach in pregnancy, as opposed to a laparoscopic approach, are the same as in the nonpregnant abdomen, namely, the lack of an abdominal wall incision and potentially less pain. Furthermore, studies have shown that significant differences exist in cardiopulmonary parameters that may favor the NOTES approach over laparoscopy in the pregnant patient.13 None of these have been studied in pregnancy, but we expect that even small changes in cardiopulmonary parameters will more likely to have a significant effect on the pregnant mother and the fetus. Although there is a lack of human data, animal studies have shown that there is a reduced level of inflammatory cytokines, mainly tumor necrosis factor a in NOTES compared with laparoscopic approaches.14 Although laparoscopy has been shown to be safe in pregnancy, the data are based on case series from single institutions. A significant risk of damage to the gravid uterus using Veress needle or trocar insertion, technical difficulty in performing the procedure in the presence of a gravid uterus, concern for the possibility of fetal academia, and decreased maternal venous return secondary to increased intraperitoneal pressure from CO2 insufflation still exist. All these factors can potentially be minimized by using the NOTES approach. The use of EUS will potentially reduce the need to use significant pneumoperitoneum because the procedure is best performed with almost no pneumoperitoneum, with the endoscope adjacent to the uterine wall. Nevertheless, the risk of peritoneal contamination, both from the breach of gut wall and postclosure leakage, should be taken into consideration. In our experiments, we were able to demonstrate that using the transgastric and transvaginal routes into the peritoneal cavity is both feasible and safe.
Successful vascular interventions in the fetus by using US guidance have been reported and have significant potential.15-17 In adults, the use of EUS plays a major role in the diagnosis and management of gastroenterologic and oncologic disorders. In addition to staging GI and pancreaticobiliary malignancies, EUS guidance has been used to perform various less-invasive but effective therapeutic interventions such as celiac nerve block and pancreatic pseudocyst drainage.18-20 Our group has also shown that vascular interventions can be performed safely under the guidance of EUS.21-24 Needle-based interventions provide minimally invasive access to areas where surgical access is difficult or may result in significant morbidity or mortality. In this study, NOTES peritoneoscopy was performed in all animals without any complications. All maternal intraabdominal organs targeted for examination were successfully visualized. Access to the uterus was achievable from all directions. Sites such as the posterior wall of the uterus, usually inaccessible during traditional surgical approaches, were easily accessed by repositioning the animal. In addition, the flexible endoscope was able to reach all poles of the uterus from one entry point. The transgastric access point gave a straight shot trajectory to the uterus, and all maneuvers were able to be completed by using a straight-scope position. The transvaginal access also provided the same straight trajectory to one uterine wall but a retroflexed position had to be used to achieve access to the contralateral wall and uterine fundus. Despite the retroflexed position, all interventions were performed with no significant difficulty. Current advancements in obstetric imaging, including the use of 3- and 4-dimensional US and magnetic resonance imaging, have led to increased diagnostic rates and accuracy of congenital disorders.1,2 Despite these encouraging developments, direct acquisition of fetal tissue samples sometimes remains necessary for accurate diagnosis and therapy. In our study, we were able to demonstrate that access to the fetal cardiovascular system was easily achievable from many angles. Four-chamber cardiac views were obtained easily despite variable fetal positions, with excellent resolution by using the NOTES EUS approach. Furthermore, we were also able to access the fetal cardiac chamber and vascular system with injection of agitated saline solution to show that administration of drugs and other therapeutic agents is technically simple and successful with this approach. All the animals and fetuses survived direct EUS-guided cardiocentesis, cordocentesis, and injection without any complications including hemopericardium. In conclusion, NOTES may provide a minimally invasive alternative to currently available fetal and gestational interventions. Further studies are needed to define its limitations and long-term effects on the fetus and the mother.
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16. Quintero RA, Huhta J, Suh E, et al. In utero cardiac fetal surgery: laser atrial septotomy in the treatment of hypoplastic left heart syndrome with intact atrial septum. Am J Obstet Gynecol 2005;193:1424-8. 17. Gardiner HM, Kumar S. Fetal cardiac interventions. Clin Obstet Gynecol 2005;48:956-63. 18. Rosch T. Endosonographic staging of esophageal cancer: a review of literature results. Gastrointest Endosc Clin N Am 1995;5:537-47. 19. Giovannini M, Binmoeller K, Seifert H. Endoscopic ultrasound-guided cystogastrostomy. Endoscopy 2003;35:239-45. 20. Chang KJ. State of the art lecture: endoscopic ultrasound (EUS) and FNA in pancreatico-biliary tumors. Endoscopy 2006;38(Suppl 1):S56-60. 21. Giday SA, Ko CW, Clarke JO, et al. Endoscopic ultrasound (EUS)-guided portal vein catheterization: a novel approach for portal angiography and portal vein pressure measurements. Gastrointest Endosc 2008;67:338-42. 22. Giday SA, Ko CW, Clarke JO, et al. EUS-guided portal vein carbon dioxide angiography: a pilot study in a porcine model. Gastrointest Endosc 2007;66:814-9. 23. Magno P, Ko CW, Buscaglia JM, et al. EUS-guided angiography: a novel approach to diagnostic and therapeutic interventions in the vascular system. Gastrointest Endosc 2007;66:587-91. 24. Buscaglia JM, Shin EJ, Clarke, et al. Endoscopic retrograde cholangiopancreatography, but not esophagogastroduodenoscopy or colonoscopy, significantly increases portal venous pressure: direct portal pressure measurements through endoscopic ultrasound-guided cannulation. Endoscopy 2008;40:670-4.
Received August 29, 2008. Accepted March 11, 2009. Current affiliations: Medicine/Gastroenterology (S.A.G., J.M.B., G.D., D.M.K., X.D., D.L., R.W., P.M., E.J.S., A.N.K.), OB GYN/Maternal Fetal Medicine (J.A.), Comparative Pathology (D.R.), The Johns Hopkins University School of Medicine, Baltimore, Maryland, Howard University College of Medicine (S.A.G.), Washington, DC, Hoˆpital Lariboisiere (X.D.), APHP, Paris 7 University, Paris, France, Department of General Surgery (G.D.), ‘‘P. Stefanini,’’ University of Rome ‘‘La Sapienza,’’ Rome, Italy, Department of Medicine (P.M.), University of Puerto Rico, San Juan, Puerto Rico. Reprint requests: Samuel A. Giday, MD, Division of Gastroenterology, The Johns Hopkins Hospital, 1830 East Monument Street, Room 424, Baltimore, MD 21205. If you want to chat with an author of this article, you may contact him at [email protected].
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