Seminars in Pediatric Surgery 22 (2013) 5055

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Seminars in Pediatric Surgery

journal homepage: www.elsevier.com/locate/sempedsurg

Anesthesia for fetal surgery

Elaina E. Lin, MDa,b, Kha M. Tran, MDa,b,n
a b

The Center for Fetal Diagnosis and Treatment, Childrens Hospital of Philadelphia, Philadelphia, Pennsylvania Department of Anesthesiology and Critical Care Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania

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Fetal surgery pushes the limits of knowledge and therapy beyond conventional paradigms by treating the developing fetus as a patient. Providing anesthesia for fetal surgery is challenging for many reasons. It requires integration of both obstetric and pediatric anesthesia practice. Two patients must be anesthetized for the benet of one, and there is little margin for error. Many disciplines are involved, and communication must be effective among all of them. Conducting anesthetic research with vulnerable populations, such as the pregnant woman carrying a fetus with a birth defect is difcult, and many questions remain to be answered. Work is needed to study possible neurotoxicity caused by exposure of the developing brain to anesthetic agents. The effects of stress on the developing fetus also must be further delineated. Anesthetic techniques vary by institution, and prospective studies to determine optimal anesthetic regimens are warranted. & 2013 Elsevier Inc. All rights reserved.

Keywords: Fetal therapy Anesthesia Placental circulation Neurotoxicity Stress

Introduction Fetal surgery is a rapidly evolving discipline. The idea of treating the fetus as a patient is not intuitive and has its roots in the 1960s when intraperitoneal blood transfusions were performed for the treatment of erythroblastosis fetalis. Invasive surgical therapies in humans took place in the 1980s after rigorous study in animal models. These operations involved maternal laparotomy and hysterotomy to access and treat fetuses at varying gestational ages. The anesthetic techniques developed to facilitate these invasive procedures are based on the physiology of the pregnant woman and fetus and also on an understanding of the procedure to be performed.

Physiology Maternal physiology The physiologic changes of pregnancy impact anesthetic management. While many organ systems are affected, the most relevant are the neurologic, respiratory, cardiovascular, gastrointestinal, and hematologic systems. Generally, maternal sensitivity to anesthetic agents is increased.1 Minimum alveolar concentration (MAC) for isourane and halothane is lower during pregnancy. Increased dermatomal spread of epidural anesthetics is likely due to increased nerve
n Corresponding author at: Kha M. Tran, MD, Childrens Hospital of Philadelphia, 34th St and Civic Center Boulevard, 9th Floor, Main Hospital, Philadelphia, PA 19104. E-mail address: trank@email.chop.edu (K.M. Tran).

sensitivity, hormonal changes in pregnancy, reduced protein levels, and pH changes in the cerebrospinal uid. Pregnancy also increases sensitivity to nondepolarizing muscle relaxants. Management of the airway of a pregnant woman may be difcult. Engorgement of the airway mucosa has multiple implications. Smaller endotracheal tubes must be used, and nasal intubation may cause epistaxis. The potential for difcult intubation is increased and airway complications are a signicant factor in anesthesia-related morbidity and mortality.25 Oxygen consumption increases and functional residual capacity (FRC) decreases during pregnancy, increasing the risk for hypoxia. Pregnancy is a high cardiac output state. At term cardiac output is increased approximately 50% from nonpregnant values.1 Systemic vascular resistance is decreased by about 20% secondary to vasodilation and the addition of the placenta, a low resistance circuit. Supine hypotension may result from aortocaval compression by the gravid uterus. Plasma volume increases relatively more than red blood cell volume increases, and thus hemoglobin concentrations fall during pregnancy. The pregnant patient is at risk for aspiration of gastric contents due to displacement of the stomach and decreased lower esophageal sphincter tone. Intragastric pressure is highest in the third trimester. Gastric emptying of solids and liquids is slowed during labor.1 The coagulation system is in a state of accelerated, compensated intravascular coagulation. This hypercoagulable state is suggested by an increase in the majority of coagulation factors, a decrease in prothrombin and partial thromboplastin times, and a decrease in antithrombin III. Increased brinolysis is suggested by an increase of brin degradation products. Attention must be paid to thromboprophylaxis.

1055-8586/$ - see front matter & 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1053/j.sempedsurg.2012.10.009

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Fetal physiology Fetal physiology is complex. Neurologic pathways for cortical transmission of noxious stimuli in humans are still developing into the third trimester.6 With both isourane and halothane, anesthetic requirements of fetal lambs are lower than that of a pregnant ewe.7,8 Perception and processing of pain is controversial, but noxious stimuli will elicit a physiologic response in the human fetus, as evidenced by increases in cortisol, b-endorphin, and decreases in the pulsatility index of the fetal middle cerebral artery.9 The placenta acts as the organ of respiration, while a major function of the lung in utero is the production of amniotic uid. Restriction of egress of this uid results in pulmonary hyperplasia, while continuous drainage results in hypoplasia.10 The fetal circulation is notable for being a parallel system prior to transitioning to a serial circulation at birth. The fetal myocardium has a higher proportion of noncontractile elements, and is also stiffer than adult myocardium.11 Increases in preload will provide minimal, if any, incremental increases of stroke volume and cardiac output.12 Variation in heart rate provides a relatively greater contribution to variation in cardiac output compared to stroke volume. A lack of response to preload has been attributed to poor compliance of the myocardium, but may also be due to extrinsic compression of the fetal heart that is relieved with aeration of the lungs and clearance of lung uid after birth.13 The blood volume of a fetus varies over gestation. At 1622 weeks, blood volume of the fetoplacental unit has been estimated at 120162 ml/kg of fetal weight.14,15 It is important to note that about two thirds of the blood volume is contained on the placental side of the fetoplacental unit.16 The coagulation system evolves throughout the fetal and neonatal period. The fetus produces coagulation factors independently of the mother, and these factors do not cross the placenta.17 The plasma concentrations of these proteins increase with advancing gestational age. While in utero, fetal temperature is linked to maternal temperature. A fetus partially removed from the uterus during open surgery needs to increase heat production, but it cannot. Maintenance of normothermia in a fetus exposed during open surgery can be challenging due to the lack of shivering and nonshivering thermogenesis, immature skin barriers, and increased evaporative losses. Fetal pharmacokinetics are not well understood. Historically, the dosing of medications given to the fetus for fetal surgery has been empiric based on data extrapolated from neonatal pharmacokinetic studies. However, a recent study quantifying the serum concentrations of fentanyl after IM injection during ex utero intrapartum therapy (EXIT procedure) at 3437 weeks gestation showed that fetal fentanyl concentrations were higher than expected based on previous neonatal and minimally invasive fetal work and that the concentrations could be quite variable between fetuses.9,18 Some of this variability may be explained by the immaturity of the hepatocytes, bypass of the liver and lungs during fetal circulation, and variations in the fetoplacental blood ow during open fetal surgery. However, further studies are needed to better understand fetal pharmacokinetics. Uteroplacental blood ow The fetus depends on uteroplacental blood ow and patent umbilical vessels for respiration. Uterine blood ow, while a surrogate for fetal oxygen delivery, correlates with fetal umbilical venous PO2.19 Uterine blood ow is directly related to uterine perfusion pressure (the difference between uterine arterial and venous pressure) and inversely related to uterine vascular resistance. For fetal surgical procedures, maternal hypotension,

aortocaval compression, and uterine contractions decrease uterine blood ow. The effects of vasopressors, vasodilators, and anesthetic agents on uterine blood ow are variable because these agents affect uterine arterial pressure and uterine vascular resistance at the same time. Studies comparing ephedrine and phenylephrine for maintenance of blood pressure have shown no dramatic clinical differences in neonatal outcome and lend slightly more support to phenylephrine to support maternal blood pressure.2022 Ephedrine is a logical choice if the maternal heart rate is low, while phenylephrine could be used if the maternal heart rate is high. Neuraxial and general anesthetics have variable effects on uterine blood ow. As long as maternal systemic pressure is maintained, epidural anesthesia does not alter uterine blood ow in elective cesarean sections.23 Pain and stress will decrease uterine blood ow.24 Relief of pain with an epidural may attenuate this reduction. Barring resultant hemodynamic changes, intravenous induction agents, (thiopental, propofol, etomidate, and ketamine) do not affect uterine blood ow dramatically. Volatile anesthetics decrease uterine tone and increase risk of bleeding.25 Light and moderate levels of volatile anesthesia will slightly depress blood pressure, but uterine vasodilation maintains blood ow. In a sheep model of fetal surgery, with deeper levels of volatile anesthesia, uterine vasodilation cannot compensate for the reductions in blood pressure and cardiac output, and fetal acidosis occurs.26 It is important to note, however, that no medications were given to the sheep to support their blood pressure while undergoing general anesthesia with high doses of volatile agent. Maternal hypocapnia or hyperventilation with positive pressure will likely decrease uterine blood ow and fetal oxygen tension. Hypercapnia may increase fetal oxygen tension.27 Simple mechanical factors are important in the maintenance of uteroplacental perfusion and fetal oxygen delivery. Compression of the umbilical cord, either from loss of amniotic uid or from surgical manipulation will cause rapid deterioration in the condition of the fetus. Likewise, integrity of the uteroplacental interface must also be maintained. Separation of the placenta from the uterus (placental abruption) is catastrophic. Placental transport Factors controlling placental drug transfer include size, lipid solubility, protein binding pKa, pH of fetal blood, and blood ow. High lipid solubility allows rapid transfer, but may result in trapping of drug in the placenta. Local anesthetics and opioids have higher acid dissociation constants and may be trapped in ionized form in the fetal circulation if the fetal pH is lower than the drugs pKa. Protein binding has a variable effect depending on the particular drug and protein interaction. While the newer volatile anesthetics, desurane and sevourane have not been studied as thoroughly as halothane and isourane, the low molecular weight and lipid insolubility of these medications should allow rapid transfer with relatively high fetal to maternal (F/M) ratios. Halothane and isourane have a F/M ratio of 0.70.9 and 0.7 respectively.28,29 Nitrous oxide has a F/M ratio of 0.83.30 Thiopental crosses rapidly into the fetal circulation, but F/M ratios range widely, between 0.4 and 1.1.31 Propofol has been studied at both term and midgestation and F/M ratios range between 0.5 and 0.85.31 Propofol infusions may be used for maternal sedation in early pregnancy for minimally invasive operations. Diazepam is a commonly used drug for maternal and fetal sedation. Within minutes of injection the F/M ratio reaches unity and ratios approach two after an hour.31 While midazolam has a F/M ratio of 0.76 at term,31 it is gaining popularity in minimally invasive operations. Morphine is also

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commonly used for maternal and fetal analgesia and sedation. The F/M ratio of fentanyl varied from 0.16 to 1.2 in one small study of maternal intravenous administration.31 Remifentanil is a short acting potent opioid that is nding some use in both obstetric anesthesia and anesthesia for fetal surgery.32 Succinylcholine in large (300 mg) or repeated doses crosses the placenta and affects the fetus. Nondepolarizing muscle relaxants and anticholinesterase agents are large, ionized molecules that do not easily cross the placenta. Vecuronium F/M ratios are 0.060.11. Atropine readily crosses the placenta as opposed to glycopyrrolate which has a mean F/M ratio of 0.22. A case of fetal bradycardia has been attributed to placental passage of neostigmine. Ephedrine crosses the placenta readily with a F/M ratio of 0.7.31

closure, the fetus is replaced in the uterus antibiotics are instilled into the amniotic uid. The uterus is closed and a ap of omentum is sewn over the uterine closure to further seal the hysterotomy closure. EXIT procedure While both types of operations start in a similar fashion, the EXIT procedure has key differences when compared to open fetal surgery operations. Since the fetus will be delivered at the end of the operation, these procedures are performed at or near term to optimize lung maturity. Before the umbilical cord is clamped, surgical intervention is performed that will facilitate successful transition to extra-uterine life.36 This intervention may involve laryngoscopy, rigid bronchoscopy and intubation, tracheostomy, or even resection of cervical masses causing airway obstruction if necessary. Very large lung lesions that would make neonatal resuscitation difcult because of profound mediastinal shift, air trapping, and/or compression of the normal lung are also candidates for the EXIT procedure.37 After completion of the procedure, the newborn is passed to an adjacent room for further resuscitation and then subsequent management in an intensive care unit. It is important in the EXIT that no ventilation of the lungs occurs until the umbilical cord is clamped. Ventilation of the lungs will initiate the cascade of events leading to a transitional/ neonatal circulation, and the benets of operating on placental support are lost.

Surgical issues Minimally invasive interventions Minimally invasive interventions are the most frequently performed fetal surgical procedures. The uterine cavity is accessed percutaneously with needles and small trocar sheaths. Visualization of structures is provided by ultrasound or by a fetoscope inserted through a trocar. Minimally invasive techniques allow for a wide range of therapeutic options via a range of operative techniques. The access may be as minimal as one small gauge radiofrequency probe or may be as involved as multiple trocars for a complex fetoscopic procedure.33 Endoscopes range from 1.0 to 3.8 mm external diameter.34 The timing of minimally invasive procedures is typically in early or midgestation. However, given the varied pathophysiology of the diseases to be treated, and the varied nature of these interventions, it is possible that interventions may be performed at any stage in gestation. Open midgestation surgery Open fetal surgery has been performed to relieve bladder outlet obstruction, resect lung lesions causing signicant mass effect and hydrops, debulk sacrococcygeal teratomas, and repair fetal myelomeningoceles (MMC). The Management of Myelomeningocele Study (MOMS) published in 2011 showed decreased need for ventriculoperitoneal shunting and improved motor function at 30 months in children with prenatally repaired MMCs compared with postnatal repair.35 This was the rst prospective trial to show any signicant benet of a midgestation open surgical procedure; as a result, the number of prenatal myelomeningocele repairs performed has increased. After induction of anesthesia, a maternal laparotomy is performed. The location of this laparotomy incision is usually transverse, and more cephalad than performed for a lower uterine segment cesarean section. Once the uterus is exposed, the placental edges are mapped carefully with sterile ultrasound to plan the hysterotomy. Implantation of the placenta on the anterior or posterior aspect of the uterus will impact surgical approach, and an anterior placenta necessitates exteriorization of the uterus for a posterior or fundal hysterotomy. The fetus is exposed, but only the necessary anatomy is delivered via the hysterotomy. For example, in an MMC closure, the lesion is exposed, while the rest of the fetus remains bathed in amniotic uid in the uterus. Throughout the operation, warmed crystalloid solution is infused to maintain amniotic volume and keep the fetus warm and buoyant. If a fetal thoracotomy is planned, an arm is delivered, and the shoulder and chest are exposed while the rest of the fetus remains in the uterus. After surgery and skin

Anesthetic plan Teamwork/communication Fetal surgery requires teamwork. The disciplines that interact may include pediatric general surgery, obstetrics, pediatric anesthesia, obstetric anesthesia, cardiology, radiology, otolaryngology, neonatology, neonatal nursing, and operating room nursing. At our institution weekly meetings keep team members apprised of new patients and new developments with existing patients. Before open procedures, a multidisciplinary team meeting is held with the family to introduce the team, discuss the details, and address concerns from any of the parties. Minimally invasive procedures also necessitate discussion to communicate special needs. Preoperative preparation Preparation begins with the standard anesthetic history and physical. Specic questions for the mother should evaluate respiratory or circulatory compromise by the gravid uterus, as evidenced by symptoms of shortness of breath or lightheadedness. More severe symptoms of aortocaval compression would call for meticulous left uterine displacement and would raise the level of suspicion in a mother with persistent hypotension after induction of anesthesia. Severity of gastroesophageal reux may change the anesthetic plan in minimally invasive operations where maternal sedation is considered. Maternal imaging and blood work will be guided by the history and physical. A type and screen is reasonable for most minimally invasive operations, while open operations should not proceed without immediately availability of cross-matched blood for the mother and warm type O-negative blood for the fetus. Maternal antibodies to blood antigens can cross the placenta, and the Onegative blood for the fetus can be cross-matched with the maternal sample.

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Specic fetal information is also needed. The location of the placenta affects patient positioning. The estimated fetal weight is used to determine dosage of fetal drugs. The actual disease process and pathophysiology, and the extent of anatomic or physiologic derangement will give the team an idea of the physiologic reserve of the fetus. Fetal studies to elucidate the lesion and extent of physiologic derangement include ultrasound, echocardiography, and fetal magnetic resonance imaging. Serial studies track the changes. Lung lesions may grow or shrink, airway obstruction may worsen or resolve, cardiac outputs may change, hydrops fetalis may ensue, and polyhydramnios may develop. Aspiration prophylaxis in the obstetric population includes oral sodium citrate, histamine receptor blockers or proton pump inhibitors, and prokinetic agents such as metoclopramide. Minimally invasive These operations are the most variable in the need for maternal analgesia and anesthesia, and need for fetal analgesia or immobility. Communication with the surgical team is vital. An anesthetic plan can range from local anesthetic inltration to sedation to neuraxial to general. Medications can be given directly to the mother by the anesthesia team and, thus, indirectly to the fetus by placental transfer. Medications can also be given directly to the fetus by the surgical team. Route of direct administration can be variable, and intramuscular, intravenous, and intracardiac routes have been described.9,38,39 Maternal analgesia can often be accomplished with local anesthetic inltration, while in other cases, a neuraxial technique or general anesthesia may be necessary. Fetal monitoring is typically limited to measurement of the fetal heart rate by the obstetricians with an ultrasound. Echocardiography may be used in cardiac interventions. Instrumentation for treatment of TwinTwin Transfusion Syndrome has shrunk and invasiveness has decreased. Previously, at the authors institution, these procedures were performed with general anesthesia or neuraxial techniques. These procedures are now done with sedation. The current practice at our institution includes maternal fasting, one intravenous (IV) catheter, aspiration prophylaxis, and tocolysis with preoperative indomethacin. Light sedation is administered to the mother to provide maternal comfort and decreased fetal movement. Multiple regimens have been used successfully, including combinations of opioids and other sedatives such as benzodiazepines or propofol. In a randomized double-blind trial comparing diazepam and remifentanil for fetal immobilization in minimally invasive surgery, the remifentanil group (0.1 mcg kg 1 min 1) had signicantly less fetal movement and surgeons reported better operating conditions.40 Initially tocolysis involved preoperative indomethacin, postoperative magnesium infusions, and post-discharge oral nifedipine or subcutaneous terbutaline. Post-discharge tocolysis is now rare. Severe IV uid restriction is no longer routine. Pulmonary edema has been reported after fetoscopic surgery, but this case was more likely due to absorption of irrigation uids through venous channels in the myometrium than a capillary leak phenomenon.41 Since surgical techniques vary, IV uid restriction may be necessary, as well as a close accounting of intrauterine irrigation used during these cases. In contrast to the anesthetic for complicated twin gestations, providing anesthesia for balloon dilation of fetal aortic stenosis and other fetal cardiac procedures involves maternal general endotracheal anesthesia and intramuscular administration of fentanyl, vecuronium, and atropine to the fetus.42 The potential risks of administration of general anesthesia in a pregnant woman are outweighed by the need for a completely immobile

mother and fetus, along with the potential need for fetal analgesia as the catheters and needles are advanced through the fetal chest wall and heart. These two different techniques, both for minimally invasive surgery, illustrate the need for collaboration between the teams to prioritize needs and balance risks and benets to arrive at an optimal anesthetic plan. The location of the placenta inuences the surgical approach, which must avoid trespass of the placenta. Intraoperative ultrasound guides the instruments. If the placenta is implanted on the anterior surface of the uterus, trocars and curved instruments are inserted in the lateral aspect of the uterus if possible, or a laparotomy is made, the uterus exteriorized, and the instruments passed through the posterior uterus. If instruments are to be introduced laterally, positioning the mother may involve bumps for left or right uterine displacement, or even placing the mother in full lateral decubitus position. It is conceivable that some approaches may preclude effective uterine displacement, and in this circumstance, the teams must have a exible plan if supine hypotension from aortocaval compression is clinically signicant. Strategies must be in place for failed procedures or fetal distress. These plans will depend on the gestational age of the fetuses, their projected viability and preoperative discussion with the family. Plans may range from supportive or palliative therapy to emergent cesarean delivery. Open midgestation Open midgestation surgery requires signicant uterine relaxation. General endotracheal anesthesia with high dose volatile (2 MAC) is most often used to achieve uterine relaxation for open surgery. Desurane is the agent chosen at our institution because its low solubility allows for rapid emergence from deep anesthesia. However, a recent retrospective study of patients that presented for mid-gestation open fetal surgery or EXIT procedure showed that desurane anesthesia (1.5 MAC) with supplemental intravenous anesthesia with propofol and remifentanil compared to high dose desurane anesthesia (2.5 MAC) was correlated with less intraoperative left ventricular systolic dysfunction in the fetus and the need for fewer fetal resuscitative measures.43 Further prospective studies should be performed examining the effects of various anesthetic techniques. Nitroglycerin can also be used to relax the uterus. Complete uterine relaxation is mandatory for fetal manipulation and decreases the likelihood of the initiation of labor from uterine surgical manipulation. Relaxation will allow increased uterine blood ow as long as maternal blood pressure is maintained, and nitroglycerin results in less fetal exposure to volatile anesthetic agents. The mother is at risk for hypotension both from the anesthetic agents and from aortocaval compression. The goal systemic blood pressure should be close to baseline. After fasting, placement of a peripheral IV, oral tocolysis, and aspiration prophylaxis, a high lumbar epidural is placed for postoperative analgesia. A test dose of local anesthesia is given, but if volatile anesthesia is used, no other local anesthetic is given until the end of the operation. With standard monitors, left uterine displacement, and preoxygenation, rapid sequence induction and intubation takes place. An orogastric tube and foley catheter are placed. Ventilation should maintain normocapnia. Because of the risk for rapid bleeding, a second large bore peripheral IV is placed. An arterial catheter is placed because small changes in maternal blood pressure may have dramatic effects on fetal perfusion, heart rate and function. Intravenous crystalloid administration is kept to a minimum because of the risk of maternal pulmonary edema after fetal surgery.44 Administration of 500 ml of crystalloid during an operation is typical. Swings in blood pressure are likely

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to be exacerbated by restrictive administration of uids and frequent use of vasopressors. Clinically, the maternal blood pressure improves with exteriorization of the uterus and with surgical manipulation. Phenylephrine and ephedrine should be prepared. Vasopressor infusions allow for smoother blood pressure control. Central venous pressure measurement has guided uid therapy in the past, but has not been used recently. After exposure of the fetus, an intramuscular injection of fentanyl (20 mcg/kg), atropine (20 mcg/kg), and vecuronium (0.2 mg/kg) is given by the surgical team. Amniotic uid is lost through the hysterotomy, but it is replaced with a continuous pressurized infusion of warmed crystalloid. If fetal intravenous access is necessary it is obtained, and IV tubing is handed over the drapes to the anesthesia team. Monitoring of the fetus in these operations includes direct observation, fetal echocardiography, and pulse oximetry.45,46 If a pulse oximeter is placed by the surgical team, the hand is covered with sterile foil to prevent artifact from the operating room lights, and a sterile cable is passed to the anesthesia team. Fetal oxygen saturation ranges from 4070%.47,48 Fetal echocardiography is performed continuously to monitor cardiac lling, contractility, and rate, along with patency of the ductus arteriosus. Umbilical blood gas measurement may be used in selected cases. The anesthesia team must watch closely for fetal bradycardia, maternal or fetal bleeding, and maternal blood pressure changes. Careful observation and understanding of the events occurring in the surgical eld is important. A decrease in fetal oxygen saturation is an indicator of fetal distress.45 In the absence of a decrease in fetal oxygen saturation, a common sign of fetal distress is bradycardia. Blood products should be readily available. Prior to resection of large chest lesions, a transfusion of packed red blood cells may improve fetal hemodynamic stability. With closure of the uterus, tocolysis is begun with a bolus of intravenous magnesium sulfate, the epidural block is initiated, and the volatile anesthetic is reduced. The maternal abdomen is closed, and the mother is extubated awake. Postoperative tocolysis continues with a magnesium infusion which is transitioned to oral nifedipine. EXIT Several key differences for the EXIT procedure are due to the fact that the fetus is to be delivered at the conclusion of the operation. Uterine relaxation is only needed intraoperatively, not postoperatively. Magnesium sulfate is not given, pulmonary edema is less likely, and uid management can be more generous. Another difference is the need for two operating rooms and a resuscitation area for the neonatal team. General endotracheal anesthesia is used at our institution to provide high dose volatile anesthetics, but adequate uterine relaxation with neuraxial anesthetic and nitroglycerin infusion has been reported.49,50 After the patient has been adequately anesthetized, the surgical team passes sterile items off the eld for the anesthesia team. These may include tubing for IV uids, pulse oximeter cables, and oxygen tubing for a sterile Mapleson D circuit. Distinguishing fetal uids and medication from maternal uids and drugs is important to avoid confusion especially in emergent or urgent parts of the procedure. Fetal well-being is monitored with pulse oximetry, heart rate, and echocardiography. Following maternal laparotomy, placental mapping and hysterotomy, the fetal head, arms, and upper torso are delivered while the lower torso and legs remain in the uterus to maintain intrauterine volume. An intramuscular injection is often given depending on the surgical plan (e.g intubation vs. lesion resection). Once the airway is secured or lesion resected, surfactant may be given to the fetus and the lungs are ventilated. Increases in oxygen saturation, the presence of end-tidal CO2, and good chest movement are

indicators of successful intubation. Fiberoptic bronchoscopy can be also used as conrmation. The baby is delivered for care by the neonatal surgical team. Once the umbilical cord is divided, and the placenta is delivered, uterine relaxation must be promptly reversed. Administration of oxytocin and rapidly decreasing the inspired concentration of volatile anesthetic is adequate in most cases, but methylergonovine and prostaglandin F2a should be readily available. After uterine tone is established, the hysterotomy is closed. After maternal hemodynamic stability is ensured, the epidural catheter is dosed to provide postoperative analgesia. The mother is extubated awake. Additional considerations for EXIT procedure include the presence of both a neonatal surgical resuscitation team and a second operating room team. The neonatal surgical team receives the newborn if the EXIT is technically successful, and the operating room team is prepared to take the newborn and complete the surgery (e.g. resection of a cervical teratoma) if the airway access is not stable or if the neonatal surgical procedure needs to be completed. Intraoperative fetal resuscitation Fetal distress may occur during any surgical procedure and may result from cord compression or kinking, placental separation, high uterine tone, maternal hypotension, hypoxia, or anemia. Fetal hypothermia, hypovolemia and anemia are also potential causes of fetal distress. Cardiac dysfunction may result from prolonged exposure to high doses of volatile anesthetic agents. As with any change in vital signs, the cause of the derangement must be sought while therapy begins. Good condition of the mother must be ensured. The umbilical cord must be patent, aortocaval compression should be avoided, and the integrity of the uteroplacental unit must also be conrmed. Fetal distress and new onset maternal hypotension may result from placental abruption which usually manifests as brisk intrauterine bleeding. The surgical team will be able to conrm adequate uterine relaxation, and fetal echocardiography will inform the team about cardiac lling, function and patency of the ductus arteriosus. Measures to resuscitate the fetus will depend on how much access the surgical and anesthesia teams have to the fetus, and may include measures such as ensuring left uterine displacement, and adequate uterine blood ow, administration of maternal vasopressors, or administration of medications or blood directly to the fetus. In open cases, emergency medications such as atropine and epinephrine are handed over in a sterile fashion to the surgical team for intravenous or even intracardiac administration. Fetal cardiac compressions under fetal echocardiographic guidance may be needed.

Pain, stress, and neurotoxicity A study conducted in pregnant sheep demonstrated that fetal sheep have lower anesthetic requirements to achieve a surgical plane of anesthesia than neonatal sheep, which have lower anesthetic requirements than maternal sheep.8 While invasive fetal procedures clearly elicit a stress response,9 there is much debate about the perception of pain in the fetus.20 The long and short term effects of this stress response continue to be studied, as well as the potentially neurotoxic effects of the anesthetics used to block the stress response.51 As procedures and anesthetic techniques evolve, work should be done to quantify human fetal exposure to anesthetic agents and explore the effects of these agents and surgical stress on the fetus.

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Practice points First do no harm, remember maternal safety. The anesthetic plan should be based on understanding of maternal and fetal physiology and the needs of the mother and fetus. Interdisciplinary communication is vital. Minimally invasive operations present the widest range of anesthetic possibilities. Open mid gestation operations require complete intraoperative uterine relaxation and postoperative tocolysis. EXIT procedures require intense intraoperative uterine relaxation and planning for the post-EXIT care of the neonate in the form of neonatology and secondary operating room teams.
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Research agenda Quantication of human fetal exposure to anesthetic agents. Examination of the effects of anesthetics on the developing brain. Examination of the effects of surgical stress on the fetus. Fetal outcome studies with various anesthetic techniques. References

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33. 1. Chang AB. In: Chestnut DH, ed. Physiologic Changes of Pregnancy, Obstetric Anesthesia: Principles and Practice. 3rd ed, Philadelphia: Elsevier-Mosby; 2004. p. 1536. 2. Goldszmidt E. Principles and practices of obstetric airway management. Anesthesiol Clin. 2008;26:109125 [vii]. 3. Munnur U, de Boisblanc B, Suresh MS. Airway problems in pregnancy. Crit Care Med. 2005;33:S259268. 4. Ross BK. ASA closed claims in obstetrics: lessons learned. Anesthesiol Clin North Am. 2003;21:183197. 5. Rudra A, Mondal M, Acharya A, Nayak S, Mukherjee S. Anaesthesia-related maternal mortality. J Indian Med Assoc. 2006;104:312316. 6. Lee SJ, Ralston HJ, Drey EA, Partridge JC, Rosen MA. Fetal pain: a systematic multidisciplinary review of the evidence. JAMA. 2005;294:947954. 7. Bachman CR, Biehl DR, Sitar D, Cumming M, Pucci W. Isourane potency and cardiovascular effects during short exposures in the foetal lamb. Can Anaesth Soc J. 1986;33:4147. 8. Gregory GA, Wade JG, Beihl DR, Ong BY, Sitar DS. Fetal anesthetic requirement (MAC) for halothane. Anesth Analg. 1983;62:914. 9. Fisk NM, Gitau R, Teixeira JM, Giannakoulopoulos X, Cameron AD, Glover VA. Effect of direct fetal opioid analgesia on fetal hormonal and hemodynamic stress response to intrauterine needling. Anesthesiology. 2001;95:828835. 10. Alcorn D, Adamson TM, Lambert TF, Maloney JE, Ritchie BC, Robinson PM. Morphological effects of chronic tracheal ligation and drainage in the fetal lamb lung. J Anat. 1977;123:649660. 11. Rychik J. Fetal cardiovascular physiology. Pediatr Cardiol. 2004;25:201209. 12. Gilbert RD. Control of fetal cardiac output during changes in blood volume. Am J Physiol. 1980;238:H8086. 13. Grant DA, Fauchere JC, Eede KJ, Tyberg JV, Walker AM. Left ventricular stroke volume in the fetal sheep is limited by extracardiac constraint and arterial pressure. J Physiol. 2001;535:231239. 14. Morris JA, Hustead RF, Robinson RG, Haswell GL. Measurement of fetoplacental blood volume in the human previable fetus. Am J Obstet Gynecol. 1974;118:927934. 15. Nicolaides KH, Clewell WH, Rodeck CH. Measurement of human fetoplacental blood volume in erythroblastosis fetalis. Am J Obstet Gynecol. 1987;157:5053. 16. Yao AC, Moinian M, Lind J. Distribution of blood between infant and placenta after birth. Lancet. 1969;2:871873. 17. Cade JF, Hirsh J, Martin M. Placental barrier to coagulation factors: its relevance to the coagulation defect at birth and to haemorrhage in the newborn. Br Med J. 1969;2:281283. 18. Tran KM, Maxwell LG, Cohen DE, et al. Brief report: quantication of serum fentanyl concentrations from umbilical cord blood during ex utero intrapartum therapy. Anesth Analg. 2012;114:12651267. 19. Bilardo CM, Nicolaides KH, Campbell S. Doppler measurements of fetal and uteroplacental circulations: relationship with umbilical venous blood gases measured at cordocentesis. Am J Obstet Gynecol. 1990;162:115120. 20. Lee A, Ngan Kee WD, Gin T. A quantitative, systematic review of randomized controlled trials of ephedrine versus phenylephrine for the management of hypotension during spinal anesthesia for cesarean delivery. Anesth Analg. 2002;94:920926 [table of contents]. 21. Ngan Kee WD, Lee A, Khaw KS, Ng FF, Karmakar MK, Gin T. A randomized double-blinded comparison of phenylephrine and ephedrine infusion

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50.

51.

combinations to maintain blood pressure during spinal anesthesia for cesarean delivery: the effects on fetal acidbase status and hemodynamic control. Anesth Analg. 2008;107:12951302. Thomas DG, Robson SC, Redfern N, Hughes D, Boys RJ. Randomized trial of bolus phenylephrine or ephedrine for maintenance of arterial pressure during spinal anaesthesia for Caesarean section. Br J Anaesth. 1996;76:6165. Alahuhta S, Rasanen J, Jouppila R, Jouppila P, Kangas-Saarela T, Hollmen AI. Uteroplacental and fetal haemodynamics during extradural anaesthesia for caesarean section. Br J Anaesth. 1991;66:319323. Shnider SM, Wright RG, Levinson G, et al. Uterine blood ow and plasma norepinephrine changes during maternal stress in the pregnant ewe. Anesthesiology. 1979;50:524527. Cullen BF, Margolis AJ, Eger EI. 2nd: the effects of anesthesia and pulmonary ventilation on blood loss during elective therapeutic abortion. Anesthesiology. 1970;32:108113. Palahniuk RJ, Shnider SM. Maternal and fetal cardiovascular and acidbase changes during halothane and isourane anesthesia in the pregnant ewe. Anesthesiology. 1974;41:462472. Motoyama EK, Rivard G, Acheson F, Cook CD. The effect of changes in maternal pH and P-CO2 on the P-O2 of fetal lambs. Anesthesiology. 1967;28:891903. Kangas L, Erkkola R, Kanto J, Mansikka M. Halothane anaesthesia in caesarean section. Acta Anaesthesiol Scand. 1976;20:189194. Dwyer R, Fee JP, Moore J. Uptake of halothane and isourane by mother and baby during caesarean section. Br J Anaesth. 1995;74:379383. Polvi HJ, Pirhonen JP, Erkkola RU. Nitrous oxide inhalation: effects on maternal and fetal circulations at term. Obstet Gynecol. 1996;87:10451048. Zakowski MI, Herman NL. In: Chestnut DH, ed. The Placenta: Anatomy, Physiology, and Transfer of Drugs, Obstetric Anesthesia: Principles and Practice. 3rd ed, Philadelphia: Elsevier-Mosby; 2004. p. 4965. Kan RE, Hughes SC, Rosen MA, Kessin C, Preston PG, Lobo EP. Intravenous remifentanil: placental transfer, maternal and neonatal effects. Anesthesiology. 1998;88:14671474. Kohl T, Tchatcheva K, Merz W, et al. Percutaneous fetoscopic patch closure of human spina bida aperta: advances in fetal surgical techniques may obviate the need for early postnatal neurosurgical intervention. Surg Endosc. 2009;23:890895. Klaritsch P, Albert K, Van Mieghem T, et al. Instrumental requirements for minimal invasive fetal surgery. BJOG. 2009;116:188197. Adzick NS, Thom EA, Spong CY, et al. A randomized trial of prenatal versus postnatal repair of myelomeningocele. N Engl J Med. 2011;364:9931004. Mychaliska GB, Bealer JF, Graf JL, Rosen MA, Adzick NS, Harrison MR. Operating on placental support: the ex utero intrapartum treatment procedure. J Pediatr Surg 1997; 32: 227-230 [discussion 230231]. Hedrick HL, Flake AW, Crombleholme TM, et al. The ex utero intrapartum therapy procedure for high-risk fetal lung lesions. J Pediatr Surg. 2005;40: 10381043 [discussion 1044]. Mizrahi-Arnaud A, Tworetzky W, Bulich LA, et al. Pathophysiology, management, and outcomes of fetal hemodynamic instability during prenatal cardiac intervention. Pediatr Res. 2007;62:325330. Deprest J, Jani J, Gratacos E, et al. Fetal intervention for congenital diaphragmatic hernia: the European experience. Semin Perinatol. 2005;29:94103. Van de Velde M, Van Schoubroeck D, Lewi LE, et al. Remifentanil for fetal immobilization and maternal sedation during fetoscopic surgery: a randomized, double-blind comparison with diazepam. Anesth Analg. 2005;101: 251258 [table of contents]. Robinson MB, Crombleholme TM, Kurth CD. Maternal pulmonary edema during fetoscopic surgery. Anesth Analg. 2008;107:19781980. Tworetzky W, Marshall AC. Balloon valvuloplasty for congenital heart disease in the fetus. Clin Perinatol. 2003;30:541550. Boat A, Mahmoud M, Michelfelder EC, et al. Supplementing desurane with intravenous anesthesia reduces fetal cardiac dysfunction during open fetal surgery. Paediatr Anaesth. 2010;20:748756. DiFederico EM, Burlingame JM, Kilpatrick SJ, Harrison M, Matthay MA. Pulmonary edema in obstetric patients is rapidly resolved except in the presence of infection or of nitroglycerin tocolysis after open fetal surgery. Am J Obstet Gynecol. 1998;179:925933. Luks FI, Johnson BD, Papadakis K, Traore M, Piasecki GJ. Predictive value of monitoring parameters in fetal surgery. J Pediatr Surg. 1998;33:12971301. Keswani SG, Crombleholme TM, Rychik J, et al. Impact of continuous intraoperative monitoring on outcomes in open fetal surgery. Fetal Diagn Ther. 2005;20:316320. Helwig JT, Parer JT, Kilpatrick SJ, Laros Jr. RK. Umbilical cord blood acid-base state: what is normal? Am J Obstet Gynecol. 1996;174:18071812 [discussion 18121814]. Johnson N, Johnson VA, Fisher J, Jobbings B, Bannister J, Lilford RJ. Fetal monitoring with pulse oximetry. Br J Obstet Gynaecol. 1991;98:3641. Clark KD, Viscomi CM, Lowell J, Chien EK. Nitroglycerin for relaxation to establish a fetal airway (EXIT procedure). Obstet Gynecol. 2004;103: 11131115. George RB, Melnick AH, Rose EC, Habib AS. Case series: combined spinal epidural anesthesia for Cesarean delivery and ex utero intrapartum treatment procedure. Can J Anaesth. 2007;54:218222. Jevtovic-Todorovic V, Hartman RE, Izumi Y, et al. Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning decits. J Neurosci. 2003;23:876882.