Part F: Gastro-Intestinal

DIAGNOSIS

Omphalocele and gastroschisis represent the 2 most frequently encountered abdominal wall defects requiring neonatal intensive care. As discussed previously in this book, these defects occur in roughly 1–3 per 10,000 live births. Although the incidence of omphalocele has remained constant in recent years, the incidence of gastroschisis has been increasing for unclear reasons.

Clinical Findings

Omphalocele is associated with advanced maternal age and karyotype abnormalities; gastroschisis is associated with maternal age less than 20, smoking, and use of over-the-counter vasoactive drugs and salicylates during pregnancy.^{1, 2, and 3} In addition, illicit drug abuse and smoking may influence the severity of gastroschisis.⁴

Omphalocele is characterized by the failure of the viscera to return to the abdominal cavity following physiologic midgut herniation during the 10th week of gestation. As a result, the omphalocele is contained within a protective membranous sac composed of amniotic epithelium lined by peritoneum, with the intervening space filled by Wharton’s jelly. The stomach, small bowel, colon, and liver are frequently involved. Associated anomalies occur in 50%–70% of infants with omphalocele; cardiac defects are observed in 30%–50%. Karyotype abnormalities occur in 30% of cases, with trisomies 13, 18, and 21 most common.²

Gastroschisis, on the other hand, is characterized by prenatal evisceration through a defect in the anterior abdominal wall, almost always located just to the right of the umbilicus. This right-sided predilection is theorized to be caused by abnormal embryonic regression of the right umbilical vein. Importantly, the eviscerated abdominal contents do not have a protective membrane and are in direct contact with the amniotic fluid. The involved intestine is edematous, sometimes foreshortened, and almost always nonrotated. Of neonates with gastroschisis, 7%–10% will have an associated intestinal atresia. Unlike omphalocele, gastroschisis is not associated with karyotype abnormalities.²

The effective management of both omphalocele and gastroschisis hinges on early diagnosis and the involvement of appropriately trained staff (trained nurses, neonatologist, and pediatric surgeons). The embryologic and anatomic differences, however, lead to the differences in management depicted in the discussion that follows.

Confirmatory (Diagnostic) Tests

Prenatal Imaging

The sensitivity and specificity of prenatal ultrasound in identifying abdominal wall defects are 60%–75% and 95%, respectively.^5,6 Once a fetus with an abdominal wall defect is identified, directed ultrasounds should be performed to look for associated anomalies and malformations. Fetal magnetic resonance imaging is gaining popularity and is now used as a reflex imaging study if initial ultrasound is suspicious for gastroschisis or omphalocele in many centers.

Laboratory Tests

There is a marked elevation of maternal serum α-fetoprotein (AFP) in cases of gastroschisis; omphalocele tends to have a more modest AFP elevation (7–9 multiples of the mean compared to 4 multiples of the mean, respectively).^7,8 As discussed previously in another chapter, a positive ultrasound or a significant elevation of maternal serum AFP should lead to a discussion regarding possible amniocentesis or chorionic villus sampling to identify significant chromosomal abnormalities.

Differential Diagnosis

Umbilical Hernia

Umbilical hernias are differentiated from gastroschisis and omphalocele by the presence of normal skin overlying the defect. They contain easily reducible omentum or intestine. Repair is not undertaken in the neonatal period unless incarceration is present as nearly 90% of these defects close spontaneously by 3 to 4 years of age.⁹

Prune Belly Syndrome

Prune belly (Eagle-Barrett) syndrome consists of deficiency or absence of abdominal wall musculature; a constellation of ureteral, bladder, and urethral anomalies; and bilateral cryptorchidism. Prune belly syndrome is distinguished from other abdominal wall defects by complete containment of the abdominal viscera within a continuous layer of skin with a normal umbilicus. In most cases, the lack of abdominal musculature does not cause significant functional impairment.

Megacystis-Microcolon

Megacystis-microcolon is a rare congenital anomaly resulting in a massively distended, nonobstructed bladder and a secondary microcolon, often with associated hypoperistalsis and small-bowel malrotation.¹⁰ The components of the abdominal wall are present and intact, but the abdomen is massively dilated secondary to the mass effect of the dilated bladder. Diagnosis is typically made by preoperative ultrasound, and initial treatment consists of transurethral bladder drainage. The underlying etiology is poorly understood, and the condition is generally not survivable as a result of the severely dysfunctional and underdeveloped gastrointestinal tract.

PRETREATMENT

Ethical Considerations

Advances in neonatal intensive care and surgical technique have made both gastroschisis in the absence of abdominal catastrophe and isolated omphalocele survivable conditions with little to no long-term morbidity. If however, severe associated anomalies are identified on prenatal imaging or if a significant karyotype abnormality exists, the likelihood of long-term survival is dramatically reduced. A discussion with the parents is necessary to explain the possible outcomes and options, including, if appropriate, pregnancy termination.

Monitoring for Treatment/Procedure/Workup

Serial ultrasounds are necessary to identify any significant comorbidities or fetal compromise.

Sedation/Pain Control Considerations

There are different management options with regard to sedation and analgesia during the reduction of these defects. One option is to intubate the neonate and perform the procedure under general anesthesia along with, most of the time, neuromuscular blockade. In the past few years, there has also been a tendency to perform bedside reductions using oral sucrose solutions for comfort and intravenous narcotics for analgesia. Neuromuscular blockade is not mandatory, and the sedation/analgesia conduct has to be tailored to each particular patient, depending on the size and type of defect, as well as the presence of associated anomalies.

TREATMENT

Prenatal

Early diagnosis and referral to a specialized neonatal center is key to the management of congenital abdominal wall defects. Currently, there is no strong evidence to recommend elective cesarean section vs vaginal delivery, or early vs term delivery in neonates with abdominal wall defects.

Postnatal: Management Algorithm

Both gastroschisis and omphalocele present with varying degrees of severity; nonetheless, the presence of a neonatologist and pediatric surgeon should be considered mandatory in all cases whenever possible. Initial stabilization includes immediate placement of an orogastric tube (OGT) to facilitate visceral decompression, intubation to protect the airway when needed, placement of a urethral catheter in cases of distended bladder to increase the space inside the abdominal cavity, and covering of the exposed viscera with a plastic bag and warm saline. Fluid resuscitation should be aggressive and without delay. The exposed viscera cause significant insensitive fluid loss. Initial resuscitation should include a 20-mL/kg crystalloid bolus followed by two-times maintenance, thereafter. Close blood glucose monitoring is also necessary given the high incidence of Beckwith-Wiedemann syndrome in infants with omphalocele.

After stabilization, the surgeon must assess the viability of the exposed structures. If bowel necrosis is present, the management is much more complicated and the surgical strategy has to be tailored to each particular case. These include emergent resections, creation of stomas, tube diversions, and so on. In the absence of necrosis, the decision on whether to perform a primary vs a delayed reduction depends on the type and size of the defect (omphalocele vs gastroschisis) and the reducibility of the eviscerated structures.

Omphalocele requires postnatal karyotype analysis, echocardiography, renal ultrasound, and detailed physical examination to assess for musculoskeletal defects prior to operative intervention. The definitive intervention depends on the size of the omphalocele. Primary closure of small omphaloceles may be carried out in the immediate neonatal period. Giant omphaloceles, however, are managed by allowing epithelialization of the sac with topical application of silver sulfadiazine, serial reductions with a custom-made splint, and elective repair at 6–24 months (Figures 95-1, 95-2, 95-3, and 95-4). Ruptured omphaloceles have a poor prognosis and require silo placement with delayed primary closure. A complete management algorithm for omphalocele is depicted in Figure 95-5.

Gastroschisis is much less commonly associated with other congenital malformations and does not require as extensive a preoperative assessment. Protection of the eviscerated structures is paramount to the early management of neonates with this defect. Primary or delayed reduction of the eviscerated abdominal organs is still controversial, and there is growing evidence to suggest that a nonoperative reduction may be undertaken with comparable outcomes (Figure 95-6).^{11, 12, and 13} Defects with easily reducible contents are typically repaired primarily with either sutured or sutureless repair (Figure 95-6). Large eviscerations require silo placement with a delayed closure (Figures 95-7, 95-8, 95-9, and 95-10). A complete management algorithm for gastroschisis is depicted in Figure 95-11.

Postreduction: Aftercare

The management of both omphalocele and gastroschisis following reduction focuses on nutritional balance and early recognition of comorbidities. Most surgeons and neonatologists recommend 48 hours of antibiotics following reduction or establishment of silo protection. Parenteral nutrition is established early in all cases of gastroschisis given the near ubiquity of prolonged ileus and is given selectively in omphalocele if ileus is expected. Orogastric feeds are initiated as OGT output decreases and bowel function returns. Given the extent of the ileus in cases of gastroschisis, workup for stricture/atresia is not undertaken until 6 weeks of life. If oral feedings are not tolerated at 6 weeks, an upper gastrointestinal study with small bowel follow through is obtained, and delayed repair of any stricture or atresia is planned (Table 95-1).

CONCLUSION/FOLLOW-UP

Omphalocele and gastroschisis encompass the majority of severe abdominal wall defects encountered in the neonatal period. Prenatal diagnosis, referral to an experienced center, and immediate postnatal intervention are the key factors to effective management of these conditions. The outcomes in gastroschisis without intestinal catastrophe and in omphalocele without associated anomalies are generally good, with little to no long-term morbidity.

REFERENCES

INTRODUCTION

Necrotizing enterocolitis (NEC) continues to be associated with extreme prematurity, resulting in increased morbidity and mortality. Various studies have reported an incidence of NEC of 14% in infants with a birth weight of 501–750 g and an odds ratio for death of 14 for nonsurgical NEC and 25 for surgical NEC. There remains some controversy regarding the diagnosis of perforated NEC vs spontaneous intestinal perforation, and an ongoing multicenter, randomized, controlled trial is attempting to better define the 2 conditions. Regardless of the etiology, severe inflammation and subsequent necrosis, ischemia, perforation, and peritonitis may result in not only death but also severe neurodevelopmental impairment and intestinal failure (IF).

The 2 common surgical interventions for intestinal perforation are exploratory laparotomy and peritoneal drainage. Several case series and observational studies examined the utility and outcome of both operations. To date, only 2 randomized studies compared the 2 operations, with conflicting results concerning mortality. There is a paucity of data regarding the long-term outcomes of either operation.

This chapter focuses on the dilemma of surgical intervention for intestinal perforation/NEC. This discussion includes preoperative, operative, and postoperative management. In addition, the chapter reviews novel therapies designed to prevent the complications associated with surgical NEC.

PREOPERATIVE MANAGEMENT

It is essential first to determine if a patient actually has perforated NEC. Whenever possible, it is strongly recommended to obtain a pediatric surgical consultation when concerned about perforation. Several clinical scenarios of perforation can present to the caregivers. The first is the presence of free abdominal gas within the peritoneal cavity. A patient may demonstrate a large pneumoperitoneum that is easily appreciated on supine abdominal imaging. Radiographic findings include a large gas bubble or gas surrounding the liver, as well as the so-called football sign by which free abdominal gas highlights the falciform ligament. It can be more difficult to detect when there is less free abdominal gas. In these cases, it is imperative to obtain both supine and left lateral decubitus radiographs. The left lateral decubitus image is preferred to a “cross-table” supine study as the former allows free abdominal gas to migrate between the body wall and the liver and not be confused with a gas-filled loop of intestine. In the absence of free abdominal gas, the determination of intestinal perforation is more challenging.

To date, there are no studies designed to confirm perforation by either radiographic or biomarker methods. There are case reports of clinicians utilizing abdominal paracentesis to detect perforation. This technique is associated with significant complications and should be reserved for patients who require therapeutic paracentesis for severe abdominal distension that is having an impact on ventilation. Often, patients with a “gasless” abdomen or with presumed NEC totalis (extensive NEC involving the entire intestinal tract) may require surgical intervention even with no clinical evidence of perforation.

Once the diagnosis of proven or presumed intestinal perforation is made, the patient needs to be quickly moved to a center where pediatric surgical evaluation can be obtained. Regardless of the location, the ABCs of resuscitation need to be applied. Most patients require tracheal intubation and mechanical ventilation. Establishing arterial catheter monitoring of both ventilation and hemodynamics is desirable. The clinician needs to correct any acid-base imbalance and maintain normal age-appropriate arterial blood pressure. Commonly, there is marked fluid loss into the peritoneal spaces, and patients with NEC and sepsis may become markedly edematous. Resuscitation with large amounts of volume may be necessary to support blood pressure and perfusion of the bowel and kidneys. Maintaining adequate urine output has been associated with improved outcome. It is important to remember that patients with perforated NEC will often deteriorate after their operation, so establishing secure vascular access before the surgery will avoid the potential need for subsequent surgically obtained venous catheters.

Although only 25% of patients with NEC have culture-proven bacteremia, broad-spectrum antibiotics need to be administered. Common initial choices are vancomycin, gram-negative coverage such as an aminoglycoside or piperacillin/tazobactam, and metronidazole as an aerobic bacterial antibiotic. As mentioned, many of these patients have extensive abdominal distention, so placing a large-diameter sump-type orogastric tube with adequate continuous suction will assist in decompression and improve mesenteric perfusion and diaphragmatic excursion.

By developing a long-standing and collegial relationship with pediatric surgeons, the preoperative period can be streamlined. Two major impediments to timely surgical intervention are the availability of an operating room/team and blood products for operation. Many institutions have developed protocols permitting both peritoneal drainage and exploratory laparotomy at the bedside in the neonatal intensive care unit (NICU), thus eliminating the need for an operating room and the time and risk involved in moving the patient. It is important for the nonsurgical clinician to remember that performing a laparotomy requires an entire surgical team and often a pediatric anesthesiologist. Thus, consulting a surgeon early will avoid delays. Last, regardless of surgical procedure choice, cross-matched blood products need to be available prior to any operation.

OPERATIVE MANAGEMENT

Once the decision has been to proceed with surgical intervention, the next step is to determine what type of operation would result in the best outcome. The debate over the preferred operation has a long history and even now is a subject of ongoing clinical research. Prior to 1978, the standard surgical approach for premature infants with perforated NEC was an exploratory laparotomy with resection of diseased intestine. That year, Ein et al reported their experience with a novel surgical intervention in which 5 premature infants underwent peritoneal drainage as a temporizing therapy. The decision to delay laparotomy and default to peritoneal drainage was based on the surgeons’ assessment that the patients were too medically unstable to tolerate a definitive operation. In this case series, 3 patients survived and did not require a subsequent laparotomy. The other 2 infants died but were found to have intact intestines at autopsy.

Over the next 20 years, myriad case studies were published comparing primary peritoneal drainage (PPD) to standard laparotomy. Moss et al published a meta-analysis of these studies in 2001. The results of that study demonstrated marked bias in operation choice based on patient birth weight and gestational age, thus making it impossible to determine the best surgical approach. This study was the basis of the first multicenter, randomized, controlled trial comparing patient survival between PPD and laparotomy. The mortality rate in both groups was approximately 35%; thus, the conclusion of the trial was neither operation was superior to the other. A similar study by Rees et al in Europe published in 2008 had similar results, although the authors suggested laparotomy might result in better survival.

At the time of writing, a third multicenter trial funded by the National Institutes of Health was under way, comparing PPD to laparotomy with regard to not only survival but also long-term complications (ie, neurodevelopment and the development of IF).

If the decision is PPD, this operation is usually not performed in the operating room. After adequate sedation, the surgeon surgically places a Penrose drain in the right lower abdominal quadrant through a small incision and secures the drain with a suture. The advantage of PPD is that it avoids a long operation and patient transport. The disadvantages are that the abdomen is not visualized and diseased tissue not resected.

When undergoing laparotomy, the patient receives general anesthesia in the operating room. Once the abdominal cavity is exposed, the surgeon inspects the intestine to determine the site or sites of perforation as well as the extent of necrotic intestine. In some cases, the surgeon is able to resect the affected intestine and perform a primary anastomosis. More often, an enterostomy is created using the proximal portion of the intestine. In some cases, the distal portion of the intestine is used to create a mucous fistula. The fistula promotes drainage and decompression of the distal intestinal tract and can be used for “refeeding” (see postoperative management). If a mucous fistula is not established, the distal intestine is surgically sutured to create a blind pouch. The advantages of a laparotomy are that the surgeon sees the extent of NEC and perforation and any ischemic bowel is removed.

The disadvantages include not only the inherent stress from a large operation but also the quandary about how much intestine to remove. Some patients have obvious demarcation between healthy and diseased intestine, but in others, the line between dead and inflamed/ischemic intestine is unclear. The surgeon can also be presented with a situation where there the entire intestinal tract is necrotic. Historically, in this case no resection is attempted and the patient’s abdomen is closed with the anticipation that the infant will receive comfort care and expire. With the advent of novel interventions that are mentioned further in the chapter, some surgeons will resect extensive amounts of intestine in the hope that intestinal rehabilitation or multivisceral transplantation may be possible.

POSTOPERATIVE MANAGEMENT

The postoperative management, both short term and long term, is unique for both surgical approaches. That stated, all patients receive a long course of broad-spectrum antimicrobial therapy. As in the preoperative period, the patients may require escalated ventilator assistance, correction of acidosis (both metabolic and respiratory), multiple transfusions of various blood products, pressor support to maintain adequate hemodynamics, and pain control.

Patients undergoing PPD are closely monitored for worsening clinical parameters. As mentioned, PPD was initially designed as a temporizing operation that evolved into definitive surgical management. Some surgeons will perform a so-called salvage laparotomy soon after PPD if they feel the patient’s clinical presentation warrants. More often, the infant is managed with only medical intervention. Most surgeons will wait at least 6 weeks after PPD to assess intestinal integrity. If the patient’s abdominal examination normalizes and defecation has resumed, a trial of trophic feedings may be initiated without further intestinal imaging. If, however, there are concerns for an intestinal stricture or other post-NEC complications, contrast imaging is required. The standard decision is to have the patient undergo a contrast enema first as most NEC-associated strictures occur in the distal bowel. Following passage of the contrast material, the proximal bowel is studied using fluoroscopy to investigate the stomach and duodenum, followed by serial supine radiographs to detect normal passage of contrast material. If there is concern for post-NEC complications, the patient is taken to the operating room for an exploratory laparotomy.

Patients undergoing initial laparotomy have a different postoperative course. The enterostomy is kept moist and observed for signs of necrosis. Once there is passage of intestinal content, an ostomy bag is placed. The nature and volume of ostomy output need to be closely monitored. The mucous fistula, if present, is maintained in a similar manner. Once intestinal function has returned, enteral feedings can be resumed. The location of the enterostomy will dictate enteral feedings based on the volume of output. The surgical teaching for normal output is less than 50 mL/kg/d or 2 mL/kg/h. If there is a proximal enterostomy, there may be a large amount of ostomy output when feedings are resumed. It may be necessary to utilize continuous gavage feedings to prevent “dumping.” Human breast milk is the preferred feeding substrate, but patients with a proximal enterostomy or extensive short-bowel may need an elemental formula to allow adequate absorption.

As mentioned, some patients may have a mucous fistula. The fistula can be used to allow enteral feeding advancement. In this technique, the distal intestine is examined using either antegrade or retrograde contrast imaging. If no strictures are present, the contents from the proximal ostomy can be collected into a syringe and infused using a catheter into the distal mucous fistula. This practice has several advantages. By refeeding, the clinician essentially provides a conduit that approximates bowel integrity. Thus, feeding advancement is not limited by the volume of proximal ostomy output but rather by rectal stooling pattern. If the mucous fistula includes a portion of small intestine, it also provides additional absorption of enteral nutrition. In addition, refeeding the distal small intestine promotes the normal enterohepatic circulation and thus prevents cholestasis. Refeeding promotes small intestinal adaptation, which is essential when large amounts of intestine were resected. Last, this technique “primes” the colon for eventual surgical anastomosis by establishing water absorption and a more normal microbiome.

Once the patient is clinically stable and enteral feedings are tolerated, the next decision is when to the patient should undergo intestinal anastomosis. As with PPD, a 6-week waiting period is commonly used before any subsequent operation is performed. Following an anastomosis and return of bowel function, enteral feedings can be resumed.

INTESTINAL REHABILITATION AND INTESTINAL FAILURE-ASSOCIATED LIVER DISEASE

Often, infants who require surgical intervention for perforated NEC develop IF. The current definition of IF is the inability to establish enteral nutrition adequate for reasonable growth without the need for at least some parenteral nutrition. IF is associated with intestinal motility dysfunction, small-bowel bacterial overgrowth, and intestinal failure-associated liver disease (IFALD). Patients with IF may require medications that alter motility, not only to promote normal peristalsis but also to prevent extensive defecation. Some patients with proven or presumed small intestinal bacterial overgrowth respond to a short course of enteral antibiotics followed by a similar course of probiotic therapy.

The etiology of IFALD is likely multifactorial. Ongoing intestinal inflammation and bacterial translocation, lack of enteral feeding with associated cholestasis, and parenteral nutrition have all been thought to contribute to ongoing liver disease. Recently, the amount and composition of the lipid component of parenteral nutrition has been shown to be a major cause of IFALD. One technique to avoid IFALD is lipid restriction. Restricting to 1 g/kg/d or less of a standard omega-6 lipid emulsion has been associated with resolution of IFALD. Even more recently, several centers have reported using a similar dose of reduced omega-3 lipids with even better results. To date, no randomized, controlled trial has compared the 2 lipid preparations for efficacy and safety.

As mentioned, there is often concern regarding the ethical nature of extensive intestinal resection. Although the patient may survive in the short term, the long-term course of patients with short bowel can be difficult. It is important that the clinician understand this when counseling parents about therapeutic options. There are, however, novel therapies that may provide some promise with regard to patients with ultrashort bowel. Many centers have established dedicated multidisciplinary intestinal rehabilitation teams that have been shown to have better outcomes than more traditional caregivers. Bowel-lengthening operations are becoming less complicated and have better results. One such operation is the serial transverse enteroplasty (STEP). This is a simpler operation and can double the length of dilated intestine. Last, the outcomes of multivisceral transplantation have improved over since the mid-2000s, with some centers reporting a 5-year survival of 70%. All of these modalities may provide a degree of hope for parents and caregivers in the face of perforated NEC and extensive necrosis.

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INDICATION

Reduction of elevated or increasing unconjugated (indirect) bilirubin levels, measured as total plasma bilirubin (TB) or transcutaneous bilirubin (TcB), is key to the prevention of bilirubin toxicity. Preterm and sick infants are at increased risk for hyperbilirubinemia and its sequelae. Factors that place these populations at risk for hyperbilirubinemia include impaired bilirubin-albumin binding, decreased enteral intake, and decreased gastrointestinal activity, resulting in increased enterohepatic circulation. As a result of biological conditions such as vulnerability of the blood-brain barrier, asphyxia, acidosis, and hypoalbuminemia, neurotoxicity may occur at lower bilirubin levels than for term and healthy infants.

Clinical

Levels of Hyperbilirubinemia

1. Newborns 35 weeks’ gestational age (GA) or older

   • Significant hyperbilirubinemia: greater than 95th percentile for age hours

   • Severe hyperbilirubinemia: hour-specific value at which phototherapy is recommended

   • Extreme hyperbilirubinemia: TB greater than 25 mg/dL

2. Newborns less than 35 weeks’ GA

   • Significant hyperbilirubinemia: greater than 5 mg/dL (possibly: no consensus opinion)

   • Severe hyperbilirubinemia: hour-specific value at which phototherapy is recommended

   • Extreme hyperbilirubinemia: TB greater than 20 mg/dL (possibly: no consensus opinion)

Clinical Risk Factors

1. TB greater than 95th percentile for age in hours (≥35 weeks’ GA)

2. Neonatal hemolysis (intravascular, extravascular)

3. Male gender

4. Asian race

5. Prematurity (each week)

6. Glucose-6-phosphate dehydrogenase (G-6-PD) deficiency (race/ethnicity: African Americans with jaundice, East Asians, Middle Eastern, and Mediterranean)

7. Maternal diabetes mellitus

8. Suboptimal breast milk intake

9. Early discharge (before age 72 hours)

10. Family history (of jaundice or its treatment)

Clinical Manifestations

Jaundice can be detected by blanching the skin with digital pressure to reveal the underlying skin and subcutaneous tissue color at the forehead, sternum, iliac crest, patella, and malleolus. Jaundice should be assessed whenever the infant’s vital signs are measured, but no less than every 8 to 12 hours. The assessment of jaundice must be done in a well-lit room or, preferably, in daylight with ambient sunlight. There is usually a cephalocaudal progression, and sometimes it can fade in and out like a tan. Color varies from lemon yellow to bright orange and sienna. Assessment may be limited by skin pigmentation, plethora, decreased ambient light, and exposure to sun or phototherapy. Absence of jaundice is not an indication of the absence of hyperbilirubinemia; estimating the degree of hyperbilirubinemia can lead to errors, and the absence or severity of jaundice is not predictive of subsequent severe hyperbilirubinemia.

1. Onset of jaundice in the first 24 hours of life should be considered a sign of excessive rate of bilirubin rise and indication for emergency bilirubin testing and further evaluation.

2. Progression of jaundice is usually seen, with appearance first in the face and progressing caudally to the trunk and extremities, but sometimes it appears and fades similar to a tan.

Testing

1. TB is measured in plasma to objectively assess the severity of jaundice. In term and late-preterm infants, this level is plotted on an hour-specific nomogram that identifies risk zones or assessment of clinical risk factors. The hour-specific nomogram provides a more appropriate understanding of the magnitude of hyperbilirubinemia and its projected rate of rise in the contexts of postnatal age in hours and the percentile level as defined for healthy infants.

2. TcB testing is a noninvasive alternative to TB measurement. TcB devices are useful screening tools and provide a valid estimate of the TB level, although data are limited.

   1. Measurements in newborns using the new TcB devices are within 2–3 mg/dL of the TB and are useful to screen for or trend TB levels less than 12 mg/dL.

   2. The use of TcB measurements in sick and preterm infants as well as those undergoing phototherapy has not yet been validated.

   3. Confounding effects of skin melanin content among different races and manufacturing consistency among devices are additional limitations.

Differential Diagnosis

Table 97-1 shows the basis for the differential diagnosis.

EVALUATION

Table 97-2 provides information on the clinical evaluation of the jaundiced infant at 35 weeks’ gestation and older.

TREATMENT STRATEGIES FOR BILIRUBIN REDUCTION

Strategies to rapidly reduce the bilirubin load are described in the 2004 American Academy of Pediatrics Practice Parameters, a recent Technical Report, and an Expert Commentary. Be alert to nonspecific signs of acute bilirubin encephalopathy (ABE), especially in preterm infants. Severely jaundiced babies and symptomatic babies should be admitted directly to the neonatal intensive care unit (NICU).

Interventions for Bilirubin Reduction

Table 97-3 provides the possible interventions for bilirubin reduction.

Effective Phototherapy

Background Information

The optimal light source is blue-green light with a narrow-range wavelength (such as that provided by light-emitting diodes [LEDs]) that is distributed evenly to 1 plane of the body (and can be increased to both ventral and dorsal planes or even circumferentially) at an irradiance of more than 30 to less than 65 μW/cm² surface area. The effect of light on bilirubin is almost immediate and may not be reflected by measured TB value. The absorption of light by the normal form of bilirubin (4Z,15Z bilirubin), at a peak wavelength of 460 nm, generates transient excited-state bilirubin molecules. These fleeting intermediates can react with oxygen to produce colorless, lower molecular weight products, or they can undergo rearrangement to become structural isomers (lumirubins) or isomers in which the configuration of at least 1 of the 2 Z-configuration double bonds has changed to an E configuration. The plasma from an infant undergoing phototherapy contains several photoisomers, including the predominant 4Z,15E isomer. The photoisomers are less lipophilic than the natural 4Z,15Z form of bilirubin and can be excreted unchanged in the bile without undergoing glucuronidation. Once in bile, the configurational isomers revert spontaneously to the natural bilirubin. Most lumirubins and some photooxidation products are excreted in the urine. Bilirubin photoisomer by-products may confound the total bilirubin assay and have an impact on bilirubin’s ability to bind to albumin.

Blue lights in the 425- to 475-nm range (Phillips F-20 T12/BB or NeoBlue™) should be easily and rapidly accessible and periodically inspected and maintained to ensure proper functioning. These light sources may be complemented with white halogen lights to cover a wider surface area. Avoid shadows with multiple lights and other interferences for optimal light exposure. Avoid exposure to ultraviolet lights.

Practice Considerations for Optimal Administration of Effective Phototherapy

Table 97-4 discusses practice considerations for the optimal administration of effective phototherapy.

Figure 97-1 provides guidelines for intensive phototherapy in infants older than 35 weeks.

• Use total bilirubin. Do not subtract direct-reacting or conjugated bilirubin.

• Neurotoxicity risk factors are isoimmune hemolytic disease, G-6-PD deficiency, asphyxia, significant lethargy, temperature instability, sepsis, acidosis, or albumin less than 3.0 g/dL (if measured).

• For well infants at 35 to 37 + 6/7 weeks, TB levels can be adjusted for intervention around the medium risk line. It is an option to intervene at lower TB levels for infants closer to 35 weeks and at higher TB levels for those closer to 37 + 6/7 weeks.

• It is an option to provide conventional phototherapy in the hospital or at home at TB levels 2–3 mg/dL (35–50 mmol/L) below those shown, but home phototherapy should not be used in any infant with risk factors.

“Crash-Cart” Approach for an Infant Readmitted for Severe Hyperbilirubinemia

1. Assess for ABE (neurologic signs) regardless of the TB level.

2. Check TB/TcB and send labs (stat).

3. Conduct procedures while the infant is under phototherapy lights.

4. Prepare for an exchange transfusion (look for line placement sites).

5. Evaluate for concurrent dehydration (such as hypernatremia): Intravenous infusions will not lower TB levels.

6. Continue enteral feedings to decrease enterohepatic circulation of bilirubin. Breast-feeding can occur with infant (and mother) under phototherapy lights. The baby is unwrapped for skin exposure, and heat lamps may be needed to maintain temperature.

Table 97-5 provides considerations for the crash-cart approach.

Management of Hyperbilirubinemia in Sick and Preterm Infants

The primary strategy of clinical management for sick and preterm infants is prevention. Jaundice should be monitored along with other vital signs. Bilirubin testing should be conducted every 8–12 hours; testing can be decreased to every 12–24 hours during phototherapy, when bilirubin levels are decreasing, or when the infant is beyond 1 week of age. Sick and preterm infants may be at increased risk for an acute rise of bilirubin with concurrent infection or illness, when not receiving anything orally, or as a result of a transfusion or acute hemolysis. Table 97-6 provides operational thresholds for management of hyperbilirubinemia in preterm infants (<35 weeks’ GA).

SEQUELAE AND PROGRESSION OF CLINICAL SIGNS OF ABE

Table 97-7 gives the sequelae and progression of clinical signs of ABE.

RESCUE INTERVENTION: EXCHANGE TRANSFUSION

Figure 97-2 provides guidelines for exchange transfusion in infants older than 35 weeks.

POSTDISCHARGE MANAGEMENT

Initial Follow-up

Care for initial follow-up is individualized to assess for rebound hyperbilirubinemia and prolonged unconjugated hyperbilirubinemia (TB > 14 mg/dL) and is based on postnatal age, GA, hemolysis, and etiology of jaundice. Follow-up should include the following

1. Neurologic and neurodevelopmental evaluation at discharge and within 3 months

2. Neuroimaging with magnetic resonance imaging (MRI) at discharge

3. Auditory evoked brainstem responses (ABRs) at discharge and within 3 months.

Long-Term Follow-up

Infants with TB levels greater than 25 mg/dL and those who receive an exchange transfusion should have developmental follow-up through infancy until school age for awkwardness, gait abnormality, failure of fine stereognosis, gaze abnormalities, hearing loss, poor coordination, and exaggerated extrapyramidal reflexes. They may be at risk of subtle posticteric sequelae during infancy and childhood.

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INDICATION

Jaundice that persists or recurs during the second week of life requires inquiry. Frequently, such jaundice is caused by elevation of the unconjugated, or indirect, bilirubin and is often the result of a benign process. More concerning is jaundice caused by elevation of the conjugated bilirubin fraction. Neonatal cholestasis is caused by an accumulation of biliary substances, such as bilirubin and bile acids, because of impaired canalicular bile flow. Manifestations of conjugated hyperbilirubinemia must be differentiated from unconjugated hyperbilirubinemia because it is more often associated with a specific disease process (Figure 98-1). The medical management of cholestasis is largely supportive because the underlying disease is often untreatable medically. Such treatment addresses complications of chronic cholestasis rather than the underlying cause. These complications include malabsorption, nutritional deficiencies, and pruritus.

Clinical

Levels of Hyperbilirubinemia

1. Direct bilirubin greater than 10% of total bilirubin (TB; < 5 mg/dL)

2. Conjugated bilirubin greater than 1 mg/dL (TB < 5 mg/dL)

3. Direct bilirubin greater than 20% of TB (TB > 5 mg/dL)

4. Conjugated bilirubin greater than 2 mg/dL (TB > 5 mg/dL)

Clinical Risk Factors for Hyperbilirubinemia

The Cholestasis Guideline Committee recommended that any infant noted to be jaundiced at 2 weeks of age be evaluated for cholestasis with measurement of total and direct serum bilirubin.

Clinical Manifestations

1. Onset of jaundice after the first weeks of age should be considered abnormal.

2. Persistence of jaundice after 2 weeks of age should be considered abnormal.

3. Association of pale stools or dark urine should be an alert for cholestasis.

Testing

The most commonly used laboratory determination (the diazo or van den Bergh method) does not specifically measure conjugated bilirubin but reports direct bilirubin. For methodological reasons, the higher the total bilirubin (even if it is all unconjugated) value, the higher the reported direct bilirubin will be. Measurements of direct bilirubin may vary significantly both within and between laboratories.

DIFFERENTIAL DIAGNOSIS

Table 98-1 provides information on the differential diagnosis of conjugated hyperbilirubinemia.

IMMEDIATE ACTION

If total parenteral nutrition (TPN) is prescribed, either wean or discontinue intravenous lipid infusion, especially in preterm infants, until a nutrition plan is developed and individualized.

EVALUATION

Table 98-2 delineates the steps in the evaluation process.

BILIRUBIN FOLLOW-UP

1. Serial TB/direct bilirubin assay for progression of hyperbilirubinemia until levels decline

   1. Newborns 35 weeks or older gestational age (GA)

      • For onset of jaundice: check immediately

      • Persistence: check every 1–2 days until levels plateau or decline

      • Aggressively investigate for etiology

   2. Newborns less than 35 weeks’ GA

      • All infants: check levels every day initially

      • Serial follow-up until TB declines: 1–2/week based on rate of TB rise/decline

      • After significant decline: may track clinical resolution of jaundice

2. Serial TB/direct bilirubin assay to track decline of hyperbilirubinemia to levels <1 mg/dL.

MANAGEMENT

Nutritional Goal

The nutritional goal is to discontinue parenteral feedings and transition to full enteral feedings. In infants who are not tolerating full enteral feedings, management includes trophic enteral feedings, making changes to TPN substrates (eg, limiting glucose intake to 15 g/kg/d), supplementation with taurine and glutamine, limiting intake of lipid emulsions, and cycling of the TPN to 12 hours/day.

Medications

Pharmacologic management (see Table 98-3) includes ursodeoxycholic acid to increase bile acid excretion. Cholecystokinin-octapetide and the cholecystokinin analogue ceruletide may prevent cholelithiasis or liver disease in patients receiving TPN by stimulating gallbladder contraction.

Growth Parameters and Nutrition

Growth parameter and nutrition assessment, such as height and weight for age and weight for height, should be closely followed by tracking growth velocity, percentile track, and signs of malabsorption of fats.

Nutrient Choice

Long-chain fatty acids are not well absorbed; this leads to malnutrition and fat-soluble vitamin deficiency. Medium-chain triglycerides (MCTs) are more readily absorbed and are a better source of fat calories. These infants should be started on a formula containing MCTs such as Enfaport, Pregestimil, or Alimentum. If oral intake is not sufficient, patients may be started on nocturnal enteral feedings. Because of steatorrhea and increased energy expenditure, the caloric intake goal should be 125% of recommended dietary allowance based on ideal body weight.

Vitamins

The intestinal absorption of fat-soluble vitamins (A, D, E, and K) requires the presence of bile acids. Doses of at least 2–4 times the recommended daily allowance are given. Vitamin supplementation (Table 98-4) should continue for 3 months after resolution of jaundice.

Neonatal Phototherapy in Cholestasis

The bronze infant syndrome is the dark, grayish-brown discoloration of skin as a complication of phototherapy and may be caused by accumulation of porphyrins and other metabolites. This is generally benign; if there is an urgent need for phototherapy for excessive unconjugated bilirubinemia, direct hyperbilirubinemia should not be an absolute contraindication. However, the products of phototherapy are excreted in bile, and cholestasis can reduce the effectiveness of phototherapy or may impair bilirubin-albumin binding. Furthermore, the potential neurotoxicity of the isomers attributed to conjugated bilirubin and the “bronze pigment” or porphyrins has not been excluded. Importantly, the direct serum bilirubin should not be subtracted from the total serum bilirubin concentration when making decisions about exchange transfusions.

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