Anesthetic Management of Ex Utero Intrapartum Treatment (EXIT) and Fetal Surgery

Function

Maternal-fetal surgeries are challenging and complex; they demand a ready availability of multidisciplinary teams, including anesthesia, obstetrician, fetal surgeon, radiologist, cardiologist, neonatologist, feto-maternal medicine, nurses, and ancillary staff. Fetal operating suites usually consist of two adjacent operating rooms with multidisciplinary teams ready to resuscitate and carry out neonatal intervention if needed. Anesthesia for fetal surgery is unique and meticulous. It is directed to two patients: first, the parturient who has altered physiology related to pregnancy, and second the fetus needs to be anesthetized and maintained on placental circulation. In recent years because of a better understanding of the maternal and fetal pathophysiology and promising results from the fetal surgeries, it has been expanding in terms of indications and numbers. Broadly it can be divided into:

1. Minimally Invasive Fetal Surgery: These are the fetal surgeries done with the help of the fetoscope through the abdominal wall under ultrasound guidance. They are carried out either late into the second trimester or third trimester. These are usually done.
1. To place stents/shunts: Thoraco-amniotic shunt placement, vesico-amniotic shunt
2. To coagulate vascular structures or the umbilical cord. Twin-twin transfusion syndrome (TTTS), Selective fetal laser procedure, Twin Reverse Arterial Perfusion (TRAP) Syndrome, Radiofrequency ablation of the acardiac/acephalic twin.
3. For Mid-gestation Fetoscopic Procedures: Fetoscopic MMC repair, fetoscopic endoluminal tracheal occlusion (FETO) for Congenital Diaphragmatic Hernia, Ballon valvuloplasty or septoplasty for aortic/pulmonary stenosis     
2. Mid-gestation Open Procedures: Surgery on the fetus through hysterotomy, part of the fetus is exposed, operated on placental circulation, and replaced in the uterus for the remainder of the pregnancy.
   1. Myelomeningocele repair
   2. Resection of congenital cystic adenomatoid malformation (CCAM)
   3. Resection of other intrathoracic masses compromising heart and lung development
   4. Congenital diaphragmatic hernia
   5. Sacrococcygeal tumor resection 
3. EXIT (Ex-Utero Intrapartum Treatment): This is indicated for the high-risk deliveries, which are not lethal in utero and can wait until term without hampering significant growth of organs but may not be compatible with life immediately after birth. The fetus is delivered through a cesarean section, the fetal airway and circulation are ensured before discontinuing the fetoplacental circulation. This is also called operation on placental support (OOPS).
   1. Laryngoscopy and intubation +/- bronchoscopy for a cervical neck mass
   2. ECMO (extracorporeal membrane oxygenation) cannulation for severe lung hypoplasia 
   3. Congenital high airway obstruction (CHAOS)
   4. Second stage FETO procedure

Issues of Concern

Although the anesthetic plan differs according to the type of fetal procedure and timing of surgery, length, and complexity of the surgery, some common features apply to nearly all the anesthetics for fetal surgeries.  

1. Altered maternal physiology and maternal anesthesia
2. Maintenance of placental blood flow
3. Tocolysis
4. Fetal anesthetic aspects of fetal surgery

1. Altered Maternal Physiology and Maternal Anesthesia

The parturient coming for fetal surgery usually undergo extensive testing and counseling before the procedure and are usually healthy, fall under ASA I or II physical status. However, altered physiology related to pregnancy affects anesthetic management and may pose specific risks. The risks are briefly summarized in the table below. 

The parturient should be counseled on the benefits and risks of various anesthetic techniques in conjunction with the surgical procedures. Informed consent should be obtained. Regional anesthesia is usually considered superior to general anesthesia in parturients because of reduced need for airway management, lower incidence of aspiration, improved pain control, and greater overall maternal safety.[1] The fetal drug exposure is also minimized with regional anesthesia administration. However, lengthy procedures, uncomfortable operating positions, the complexity of the cases, and maternal preference may mandate general anesthesia. Most general anesthetic drugs can cross the placenta and provide analgesia, anesthesia, immobility to the fetus and blunt the stress response to the surgery, which is desirable. In addition, volatile anesthetics also provide excellent titratable tocolysis to the gravid uterus. 

Regardless of the anesthetic plan, the parturient is kept nil per oral for the procedure. They receive Metoclopramide and Sodium citrate for aspiration prophylaxis. Some sedation with midazolam and fentanyl may be helpful to relieve maternal anxiety and to facilitate epidural placement. Left lateral uterine displacement is employed to decrease the risk of supine hypotension syndrome from aortocaval compression. Maintenance of maternal blood pressure is important to maintain placental blood flow and fetal perfusion. Fluids and vasopressors can be used. However, fluids should be cautiously used because of the risk of pulmonary edema from absorption of a larger amount on the irrigation fluid from the surgical site and some procedures from amnioinfusion.[2] The choice of vasopressors can be ephedrine or phenylephrine, as they have been found safe and do not cause clinically significant compromise in the placental flow and fetal acidosis.[3] Perioperative pain management decreases the risk of premature uterine contraction and premature labor and improves maternal satisfaction. So multimodal analgesia is usually offered to them, including the epidural. 

2. Maintenance of Placental Blood Flow 

The placental blood flow is dependent on maternal blood pressure, as placental vessels cannot autoregulate flow. So, the most important factor for adequate fetal perfusion is to maintain maternal blood pressure. Left uterine displacement, preloading/co-loading, vasopressors help to restore maternal blood pressure. Maternal hypercarbia may cause fetal acidosis, and hypocarbia may result in uteroplacental vasoconstriction, so end-tidal CO2 of 30-35 is targeted, and maternal overventilation is avoided. The conditions such as retroplacental hemorrhage or clot, placental separation, and compression or kinking of the umbilical cord can limit the placental blood flow. Close monitoring of uterine tone is essential as it can lead to early detection of the conditions so that and appropriate intervention can be instituted timely.  

3. Uterine Relaxation

Tocolysis is the cornerstone of fetal surgery. Surgical manipulations or uterine incisions may initiate uterine contractions. These contractions can compress the umbilical vessels, compromise the placental blood flow, and even lead to placental abruption from the endometrium, leading to complete disruption of fetal blood flow, necessitating emergent fetal delivery. They may also result in premature labor. So, it is an integral component of fetal surgery. It is often needed for a prolonged period, usually for days, as in midgestational fetal surgeries. However, for EXIT procedures, short-acting tocolytics are preferred as adequate uterine contraction is desired immediately after profound relaxation to minimize the bleeding from the hysterotomy site. The choice and dose of tocolytic agents should be discussed with the feto-maternal team and obstetrician. Commonly used tocolytic agents are described below. 

• Volatile anesthetic agent: Most of the volatile anesthetics depress the amplitude and frequency of the uterine contraction in a dose-dependent manner (Desflurane> sevoflurane> halothane> isoflurane).[4] Desflurane and sevoflurane have low blood-gas partition coefficients resulting in rapid onset and offset of action and are commonly used for tocolysis for fetal surgeries, especially when an adequate uterine tone is desired immediately after profound atony during the procedure. High minimum alveolar concentration (MAC) such as 2 to 2.5 of MAC of volatile anesthetics can give adequate tocolysis but at the expense of maternal hypotension, decreased fetal blood flow, fetal acidosis, and vasopressor requirements. The higher fetal concentration of these anesthetic agents is also associated with impaired systolic function and fetal cardiac depression.[5][6] A lower concentration of gas (1 to 1.5 MAC) can be used with adequate relaxation when supplemented with IV anesthetics like propofol and remifentanil or when used with other tocolytics.[7] If deemed inadequate, nitroglycerine bolus or infusion may be added to achieve adequate uterine atony. The downside of using volatile anesthetic as tocolytic is the need for general anesthesia for its delivery, while many of these procedures can be carried out safely under regional anesthesia.

• Nitroglycerine: A rapidly acting tocolytic agent that is rapidly metabolized by the placenta and has minimal fetal hemodynamic changes.[8] When given through the intravenous route, it relaxes the uterine muscle in 30 to 60 seconds, and the relaxation typically lasts around 4 to 8 minutes. Usually, 25 to 100 to mcg loading dose with an infusion of 0.5 to 10 mcg/kg/min is used for tocolysis. Co-administration of vasopressors can counteract the fall in maternal blood pressure.

• Terbutaline, Nifedipine, magnesium sulfate, indomethacin, and atosiban are other tocolytic agents used in practice. They are often used in midgestational procedures as an adjunct to volatile anesthetics or nitroglycerine infusion to maintain long-term uterine relaxation. Indomethacin, a prostaglandin synthesis inhibitor, decreases the decidual inflammation, which is more pronounced before 30 weeks of pregnancy. However, when it is used after 32 weeks of gestation, it is associated with decreased fetal renal blood flow, oligohydramnios, and premature closure of the ductus arteriosus.[9]

 4. Fetal Anesthesia

Fetuses have fully developed neuroanatomical structures needed for pain perception by midgestation. They also show humoral response, behavioral response, and hemodynamic response to noxious stimuli comparable to older infants and adults after 26 weeks of gestational age.[10] Despite these facts, whether they feel pain is still controversial. Whether they feel pain or not, analgesia and anesthesia are indicated in the fetus for immobilization, better uterine atony, and also for prevention of neuroendocrine stress response, which can be detrimental to the fetus.11 It can be achieved indirectly through the mother via placental transfer of the anesthetic drugs. 

However, depending upon the type of surgery and age of the fetus, it can also be given directly to the fetus via intravascular or intramuscular injection or indirectly from the intraamniotic infusion. 

Anesthetic doses of commonly used drugs such as volatile anesthetics, induction agents, benzodiazepines, and muscle relaxants, have not been associated with teratogenicity.[11] There are animal studies that have shown an association of anesthesia with neurodevelopment, memory and learning problems, and neuroapoptosis of the fetus. However, human data to show a detrimental effect on fetal neurodevelopment are still lacking.[12][13]

Clinical Significance

Minimally Invasive Fetal Surgery

 They are usually carried out around 20 to 24 weeks of gestation, either under local or regional anesthesia. If the placenta is posterior, straight scopes can be passed from the anterior abdominal wall. They are often well tolerated with skin and peritoneal infiltration of local anesthetics by the surgeons. When the placenta is anterior, access is usually from the lateral abdominal wall with curved scopes, which necessitates almost a lateral position of the parturient. They often need regional anesthesia. Usually, a lumbar epidural or combined spinal-epidural is offered. Intravenous sedation is helpful to decrease maternal discomfort and can be given according to patient preference. Propofol, dexmedetomidine, and remifentanil are commonly used for sedation either alone or in combination. General anesthesia may be needed as a backup if the operating conditions are suboptimal from maternal discomfort due to positioning or a failed regional technique.

Because of the minimally invasive nature of the surgery, Standard ASA monitoring together with uterine tone assessment is usually sufficient. They usually do not require an arterial line. Uterine relaxation is usually provided using a bolus dose of magnesium sulfate during incision, and then an infusion is continued through the intraoperative and postoperative period. Other uterine relaxants may be supplemented as needed. Fetoscope is placed using ultrasound guidance, and trocars are inserted into the amniotic sac through the mother’s abdominal wall. Very rarely, hysterotomy is needed. Large amounts of irrigating fluid may be absorbed from the amniotic membrane, so IV fluids are often restricted to 500 to 750 ml for the entire procedure to minimize the risk of pulmonary edema. Fentanyl 20 mcg/kg may be given to the fetus with a spinal needle by the surgeon in the event of a rise in heart rate response from the operative stimuli. Very rarely they need the fetal cocktail. Apart from the usual anesthesia complications, other complications specific to minimally invasive surgeries include preterm labor, chorio-amniotic separation, infection, hemorrhage, pulmonary edema, etc.

Midgestational Open Surgeries

In midgestational open fetal surgeries, part of the fetus is exposed through a hysterotomy, operated on placental circulation, and replaced in the uterus for the remainder of the pregnancy. Technically, it can be done either under regional or general anesthesia. With a posterior placenta, hysterotomy can be done on the anterior uterine wall, and the fetus could be easily exposed. It can be done under regional anesthesia. But when the placenta is anterior, hysterotomy is usually done on the lateral or posterior uterine wall, which needs exteriorization of the uterus. Exteriorization is usually not tolerated well by the mother, so they are usually carried out under general anesthesia. General anesthesia with volatile anesthetics gives excellent uterine relaxation and provides analgesia and anesthesia to the fetus, which is desirable. So general anesthesia is usually preferred over regional anesthesia for midgestational open procedures. 

Because of the invasiveness of the surgery, they often require invasive blood pressure monitoring apart from ASA standards of monitoring to ensure adequate placental circulation. They also require extensive fetal monitoring and additional preparation for fetal anesthesia and possible fetal resuscitation.   

Fetal Monitoring and Anesthesia

To ensure fetal wellbeing, maternal blood pressure is closely monitored. The uterus is continuously monitored for any contraction, retroplacental bleed/hematoma, and placental abruption using an ultrasonogram. Continuous echocardiography monitoring of the fetus is started even before the uterine incision by the fetal cardiologist. They monitor the fetal heart rate, cardiac filling, cardiac contractility, and patency of the ductus arteriosus. After delivery of the fetal hand, a pulse oximeter is connected to monitor fetal oxygenation status, which is usually between 55 to 70% on placental circulation. Usually, 15 to 20 ml/kg of O negative blood is reserved for the fetus. A tray of sterile fetal anesthesia medications and resuscitation equipment is prepared, which contains:

Medications: 

Fetal cocktail medication: fentanyl 10 to 20 mcg/kg, vecuronium 10 to 20 mcg/kg and atropine 10 to 20 mcg/kg

Resuscitation medication: syringes containing unit dose of: atropine 0.1 mg, epinephrine 1 mcg/kg, calcium gluconate 30 mg/kg

Resuscitation equipment: Self-inflating bag connecting to the oxygen source, end-tidal monitor

Others: pulse oximetry, intravenous cannula, and IV fluids

Profound uterine atony is achieved by volatile anesthetics at 1 to 1.5 MAC with a bolus of 4 to 6 g of magnesium sulfate just during skin incision followed by 2-4 gm/hr continuous infusion. Nitroglycerine may be supplemented if more relaxation is required. When the fetus is exposed, fetal anesthesia and analgesia are achieved using a combination of fentanyl 10 to 20 mcg/kg, vecuronium 10- 20 mcg/kg, and atropine 10- 20 mcg/kg as an intramuscular injection, often referred to as the ‘fetal cocktail.’ A fetal pulse oximeter is attached, and continuous fetal echocardiography is performed. The uterus is filled with warm saline to avoid any uterine contraction, which is constantly monitored by the obstetrician.

At the end of the procedure, the fetus is returned to the uterine cavity, and amniotic fluid is replaced. Tocolytic therapy is continued to prevent premature labor, which is a major concern during these procedures. The total fluid intake for the mother should be minimized to 1 to 1.5 L as volume overload and pulmonary edema may develop especially when magnesium sulfate is used as a tocolytic.[14] Given the use of muscle relaxants with magnesium sulfate or calcium channel blockers, prolonged skeletal muscle relaxation can happen.

EXIT Procedures

Because of their complexity and need for reversible profound tocolysis, general anesthesia is often considered for EXIT procedures, although regional anesthesia is also an option. Depending on the procedure, the adjacent operating room is usually reserved with a separate team if the fetus needs any further intervention after delivery from EXIT.

EXIT procedures are like midgestational procedures except that the umbilical cord is clamped, and the fetus is delivered at the end of the procedure. So, they need profound uterine relaxation during the procedure but needs adequate uterine tone immediately after clamping the umbilical cord to minimize postpartum hemorrhage. Lengthy hysterotomy and profound uterine relaxation may put the mother at significant risk of bleeding. These procedures are associated with a higher incidence of transfusion compared to a conventional cesarean section (6% vs. 2% to 4%).[15] So adequate uterine relaxation is provided with short-acting uterine relaxants such as volatile anesthetics and nitroglycerine while minimizing the use of longer-acting tocolytics. After clamping the cord, Oxytocin is usually initiated as a bolus and continued as an infusion. Methylergometrine and Carboprost may be needed to gain adequate uterine tone. Fetus monitoring, analgesia, and anesthesia are similar to mid gestational open procedures.

Other Issues

The maternal and fetal complications occur more with open surgeries as compared to minimally invasive surgeries. The incidence of premature rupture of membranes, placental abruption, postoperative vaginal bleeding, preterm delivery, pulmonary edema is similar in endoscopic and open procedures.[16] EXIT procedures have a significantly higher risk of bleeding than other fetal surgeries and are associated with a higher incidence of transfusion.[17]

Enhancing Healthcare Team Outcomes

Fetal surgeries are challenging endeavors, requiring collaboration between multiple teams, including but not limited to surgeons, otolaryngologists, obstetricians, neonatologists, feto-maternal physicians, anesthesiologists, nursing, and other ancillary staff. An inter-disciplinary discussion should be held in advance to create an elaborate plan. Shared decision-making should also involve the parturient to set expectations. These procedures are physically and emotionally taxing for the mother and could be associated with multiple complications for both the mother and the child. Thorough, closed-loop communication is monumental. The team should ensure a seamless continuation of care from the antenatal period into preoperative optimization and care in the operating room and care in the NICU to optimize maternal and fetal outcomes.