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  1. Preparation for surgery
    1. Conditions that require emergent surgery in neonates are often accompanied with medical problems. As a result, the care for these critically ill newborns requires careful coordination of medical, surgical, and nursing management. In some cases, surgical procedures might occur at the bedside in the neonatal intensive care unit (NICU). In these instances, before the surgical procedure is initiated, it is important to identify and integrate the key resources and care measures provided by the NICU team into the anesthetic management of the surgical procedure.
    2. Routine standard monitoring for neonates undergoing surgical procedures includes blood pressure monitoring and continuous electrocardiograph, temperature, pulse oximetry, and O2 and CO2 gas measurements. Specialized monitoring for surgical procedures detailed below may also include postductal pulse oximetry, chest piece stethoscopes, and continuous blood pressure monitoring and intermittent blood sampling through arterial and central lines. In infants with umbilical arterial and venous catheters, it is important to confirm the precise location of the tips of the lines and their suitability for fluid and drug infusions and blood sampling.
    3. Nonrebreathing circuits are effective for ventilating and for delivering gaseous anesthetic agents to newborns and infants. The system must have provisions for humidification of the inspired gases to decrease the insensible fluid losses and thereby help maintain the patient’s thermostability. The specialized ventilators used in the NICU (eg, high-frequency oscillator ventilator) and continuous infusions of anesthetics and analgesics are often used for the patient during bedside surgery. A warm environment (85 °F), underbody heaters, radiant warmers, head wraps, and prewarmed IV and surgical fluids are also critical in helping the infant maintain thermoregulation.
    4. A warm neonatal transport isolette complete with monitors, adequate oxygen supply, and emergency airway and drugs is required for moving neonatal patients to and from the intensive care unit and OR.
  2. Respiratory disorders
    1. Differential diagnosis. The following diseases present similarly as pulmonary parenchymal disease and should be considered when evaluating an infant with respiratory distress.
      1. Airway obstruction. Choanal atresia, vocal cord palsy, laryngomalacia, tracheal malacia or stenosis, and compression of the trachea by external masses (eg, cystic hygroma, hemangioma, and vascular ring).
      2. Developmental anomalies. TEF, CDH, congenital lobar emphysema, pulmonary sequestration, bronchogenic cysts and congenital pulmonary airway malformations/congenital cystic adenomatoid malformations.
      3. Nonpulmonary. Cyanotic heart disease, PPHN, congestive heart failure, and metabolic disturbances.
    2. Laboratory studies for an infant in respiratory distress should include an arterial blood gas, pre- and postductal oxygen saturation (determined by pulse oximetry), hemoglobin or hematocrit, 12-lead ECG, and CXR. If these results are abnormal, potential cardiac disease should be evaluated by assessing blood gas tensions while the neonate breathes 100% O2 (hyperoxia test). As indicated, cardiology consultation and an echocardiogram will help evaluate potential congenital heart disease.
    3. Apnea
      1. Etiology and treatments
        1. Central apnea is due to immaturity or depression of the respiratory center (eg, narcotics). It is related to the degree of prematurity and is exacerbated by metabolic disturbances (eg, hypoglycemia, hypocalcemia, hypothermia, hyperthermia, and sepsis). Before 34 weeks of gestational age, central apnea is often treated with methylxanthines such as caffeine citrate.
        2. Obstructive apnea is caused by inconsistent maintenance of a patent airway. It can result from incomplete maturation and poor coordination of upper airway musculature. This form of apnea may respond to changes in head position, insertion of an oral or nasal airway, or placement of the infant in a prone position. Occasionally, administration of continuous positive airway pressure (CPAP) or a high-flow oxygen nasal cannula may be beneficial. These therapies especially may be effective in infants with a large tongue, such as with trisomy 21 or Beckwith-Wiedemann syndrome.
        3. Mixed apnea represents a combination of both central and obstructive apnea.
      2. Postoperative apnea in the neonate
        1. Apnea is associated with anesthesia in infants that are born prematurely. The etiology of postoperative apnea is multifactorial. Risk factors have been identified including postconceptual age less than 60 weeks at time of surgery, anemia, LGA infants, hypothermia, and altered ventilatory response to hypoxemia and hypercarbia induced by general anesthesia.
        2. If it is not possible to delay surgery until the patient is more mature, it is prudent to use postoperative apnea monitoring for 24 hours in neonates who undergo anesthesia at less than 60 weeks postconceptual age. In the previous meta-analysis done by Cotes CJ et al, it was demonstrated that the incidence of apnea following hernia repair remains above 5% until postconceptual age of 48 weeks and the incidence is reduced to less than 1% beyond postconceptual age of 56 weeks. Infants with a history of apnea is at increased risk for postoperative apnea and should be actively monitored.
    4. Respiratory distress syndrome (RDS)
      1. Pathophysiology. RDS results from physiologic surfactant deficiency. This causes decreased lung compliance, alveolar instability, progressive atelectasis, and hypoxemia resulting from intrapulmonary shunting of deoxygenated blood.
      2. Prematurely born infants have an increased incidence of RDS. Newborns at risk for RDS can be identified prenatally by amniocentesis and evaluation of the amniotic fluid phospholipid profile. Lung surfactant maturity in the fetus is associated with a lecithin-to-sphingomyelin ratio greater than 2, saturated phosphatidylcholine level greater than 500 μg/dL, or presence of phosphatidylglycerol in the specimen.
      3. Glucocorticoid (betamethasone) treatment of the mother at least 48 hours prior to delivery decreases the incidence and severity of RDS. Only one full course of a glucocorticoid treatment regimen during a pregnancy is necessary. This is accomplished by giving one dose of glucocorticoid to the pregnant woman per day for 2 days.
      4. Clinical features of RDS include tachypnea, nasal flaring, grunting, and retractions. Cyanosis appears shortly after birth. Because of the intrapulmonary shunt across atelectatic lung units, infants with RDS remain hypoxemic despite breathing at high FIO2.
      5. The CXR will show low lung volumes. A “ground-glass” pattern of the lung fields and air bronchograms may also be evident.
      6. Initial treatment includes warmed, humidified oxygen administered by hood or nasal cannula. The FIO2 should be adjusted to maintain the PaO2 between 50 and 80 mm Hg (SaO2 between 88% and 92%). If an FIO2 greater than 60% is required to keep the patient oxygenated, nasal CPAP should be administered. With more severe disease, or if the nasal CPAP is poorly tolerated, intubation and ventilation with positive end-expiratory pressure may be required. In intubated newborns with RDS, endotracheally administered exogenous surfactant decreases the morbidity and mortality of the disease. In babies with severe RDS, high-frequency oscillatory ventilation (HFOV) decreases the incidence of air leaks and chronic lung disease (CLD).
      7. Broad-spectrum antibiotics are often begun after appropriate cultures are obtained because the clinical signs and CXR of patients with RDS are indistinguishable from pneumonia.
      8. In more mature newborns, RDS may be self-limited. Clinical improvement often occurs after 2 to 3 days and is associated with a spontaneous diuresis. In extremely premature newborns, RDS may progress to CLD.
      9. The morbidity and mortality of patients with RDS are directly related to the degree of prematurity, perinatal resuscitation, and the coexistence of other complications of prematurity (eg, patent ductus arteriosus [PDA], infection, intraventricular hemorrhage). Pneumothoraces, pulmonary interstitial emphysema, and pulmonary hemorrhage may complicate the recovery and can be associated with the evolution to CLD.
    5. Bronchopulmonary dysplasia (BPD)
      1. Etiology. BPD is defined as the continued need for oxygen therapy or mechanical ventilation beyond 36 weeks postconceptual age. BPD is also referred to as CLD of prematurity and is associated with oxygen toxicity, chronic inflammation, and mechanical injury in the lung. BPD can be worsened by the presence of a PDA or infection. However, in some premature infants, BPD occurs in the absence of significant lung injury. Recent studies suggest that BPD is associated with excessive transforming growth factor-beta signaling in the injured developing lung. Preventive strategies include vitamin A or caffeine administration and early initiation of CPAP.
      2. Clinical features include retractions, rales, and areas of lung hyper- and hypoinflation. Because of nonhomogenous ventilation, an intrapulmonary shunt may produce hypoxemia and hypercarbia in patients with BPD. Hypoxia and hypercarbia may also be associated with bronchospasm in many patients with severe BPD. Many patients with severe BPD have growth failure and require high-caloric feeds.
      3. Treatment consists of supportive respiratory care, aggressive nutrition, and diuretic therapy. Because patients with BPD may have lung segments with long time constants, a ventilatory pattern with low respiratory rates and increased inspiratory and expiratory time may decrease gas trapping and improve gas exchange. Permissive hypercapnia is typically utilized to minimize further lung injury. In addition, bronchodilator therapy may be lifesaving in patients with BPD and bronchospasm. Systemic steroids sometimes are used to treat patients with CLD. However, because of adverse long-term neurodevelopmental outcomes observed in infants treated with systemic steroids, this therapy is typically reserved for the most severe cases. In some patients with severe BPD, pulmonary hypertension might be observed. In these cases, pulmonary vasodilators including inhaled NO and type 5 phosphodiesterate inhibitors have been used.
      4. Prognosis of BPD varies with the severity of the disease. Of severely affected infants, 20% die within the first year. Most infants are generally asymptomatic by 2 years of age, but additional morbidities include recurrent respiratory infections, increased pulmonary reactivity and asthma, repeated hospitalizations, pulmonary hypertension, and neurodevelopmental abnormalities.
    6. Pneumothorax
      1. Etiology. Pneumothorax can occur in infants requiring positive pressure or mechanical ventilation. In addition, spontaneous pneumothorax can occur in 1% to 2% of otherwise healthy full-term infants who often remain asymptomatic or mildly symptomatic and require no intervention. The incidence increases up to 5% to 10% of full-term infants with meconium staining or prematurely born infants with RDS.
      2. Clinical features. The diagnosis should be considered in any neonate with an acute deterioration in clinical condition (eg, sudden cyanosis and hypotension). Occasionally, asymmetric chest movement with ventilation and asymmetric breath sounds may be appreciated; however, endobronchial intubation should be ruled out.
      3. Laboratory studies. Transillumination of the chest with a strong light usually will show a hyperlucent hemithorax. If the patient is stable, a CXR may be obtained to confirm the diagnosis.
      4. Treatment
        1. In otherwise stable and well-oxygenated term infants with minimal respiratory distress, a nitrogen washout by breathing a high concentration of oxygen has historically been used to assist with resolution of the pneumothorax. However, the data supporting this mode of therapy are minimal and should be weighed against newer ones, suggesting that hyperoxia is associated with end-organ injury.
        2. In the unstable infant, immediate aspiration of the pleural space with an IV catheter should be performed. Reaccumulation of clinically significant air after aspiration warrants placement of a chest tube.
    7. Meconium aspiration syndrome
      1. Meconium staining of amniotic fluid occurs in 12% of all births and may be associated with fetal distress and perinatal depression.
      2. To decrease the effects of aspiration, it is prudent to intubate and suction the airways of infants with meconium-stained fluid who are born with depressed respirations and poor tone.
      3. Meconium aspiration may produce lung airspace disease by mechanical obstruction of the airways with fecal matter and chemical inflammation and surfactant inactivation causing pneumonitis. Complete obstruction of the airways by meconium results in distal atelectasis. Partial obstruction of the airways may produce overinflation of distal air spaces by a ball-valve effect, leading to pneumothorax. The bile in meconium may cause chemical pneumonitis and airway edema.
      4. Meconium aspiration syndrome is also associated with PPHN (see Section III.C.5).
      5. Chest radiographic findings can include diffuse, patchy intraparenchymal densities with areas of hyper- and hypoinflation.
      6. Respiratory support for meconium aspiration is dependent on the etiology of the poor gas exchange. Obstruction of airways with meconium may require mechanical ventilation with long expiratory times to decrease gas trapping. Pneumothorax is treated by placement of a chest tube. Sometimes HFOV can recruit closed lung segments and improve gas exchange. Alkalosis and inhaled nitric oxide (INO) have been useful to decrease pulmonary vasoconstriction. Exogenous surfactant has also been observed to be beneficial as meconium inhibits endogenous surfactant activity.
    8. Congenital diaphragmatic hernia (CDH)
      1. CDH is a defect of the diaphragm allowing abdominal contents to herniate into the chest. CDH occurs in 1 in 5000 live births and has a high mortality, with 40% not surviving infancy.
      2. Clinical features. CDH is usually detected during a prenatal ultrasound. Eighty-five percent of defects occur in the left posterior lateral region of the diaphragm through the foramen of Bochdalek. The neonate often has a scaphoid abdomen with absent breath sounds on the involved side. Rarely, bowel sounds are heard in the affected hemithorax. The clinical spectrum of CDH may vary and is probably related to the degree of lung hypoplasia and associated pulmonary hypertension and cardiac dysfunction.
      3. The diagnosis is confirmed by CXR. The intestines and stomach are typically observed in the thorax. The liver, spleen, and/or kidneys may also be involved. Approximately 40% of infants with CDH have associated anomalies including cardiac, gastrointestinal, genitourinary, or renal anomalies that significantly increase the risk of mortality.
      4. Treatment is geared toward decreasing pulmonary vascular resistance and facilitating CO2elimination prior to surgical correction. Insufflation of the stomach and intestines is minimized by intubating the patients while they are spontaneously breathing and may often take place in the delivery room. However, if necessary, ventilation with bag and mask should be accomplished with minimal airway pressures. Continuous gastric suction also decreases air insufflation. Conventional ventilation or HFOV is used. Ventilation with INO has been observed to decrease pulmonary vasoconstriction and cyanosis in some patients with CDH. The main causes of mortality are respiratory insufficiency and pulmonary hypertension. Pneumothorax in the unaffected lung can occur and is often the cause of death during resuscitation. Hypotension and shock are frequently seen secondary to prolonged systemic hypoxemia, cardiac impairment caused by shifting of the mediastinal contents by the hernia, and gastrointestinal fluid losses.
      5. Surgical repair involves replacing the abdominal contents and repairing the diaphragm. Current evidence supports first stabilizing the patients with medical therapy and gentle ventilation, using extracorporeal membrane oxygenation (ECMO) as a last resort (see Section III.C.5.d.3). During the stabilization period, pulmonary artery pressures fall, and the patient is subsequently taken to the OR for repair.
      6. Anesthetic considerations: Decompression of the gut with continuous nasogastric suction is helpful. An arterial catheter is indicated for the frequent assessment of acid-base balance, oxygenation, and ventilation. Sodium bicarbonate and hyperventilation are used to treat metabolic and respiratory acidosis, respectively. In addition, alkalosis and INO may decrease pulmonary vasoconstriction. Although spontaneous ventilation may prevent gastric inflation and lung compression, ventilator support is often needed. Using the lowest effective inflating pressures reduces the risk of pneumothorax and ventilator-induced lung injury. Nitrous oxide is avoided because it may distend the gut and compromise lung function. Muscle relaxation, narcotics, and oxygen therapy are often used during anesthesia.
      7. Postoperative morbidities include feeding difficulty, gastroesophageal reflux, hearing loss, neurodevelopmental disability, and potential recurrence of the diaphragmatic hernia, particularly in those infants with a large defect requiring a patch repair.
  3. Cardiovascular disorders
    1. Congenital heart disease should be suspected in the setting of persistent cyanosis, hypotension, respiratory distress, murmur, hypoxemia, poor perfusion, or shock. Congenital heart disease occurs with an overall incidence of 8 per 1000 live births with 2 per 1000 presenting in the first year of life. The most common congenital heart disease lesions include ventricular septal defects, pulmonary stenosis with intact ventricular septum, tetralogy of Fallot, atrial septal defects, or transposition of the great arteries.
    2. Cyanosis
      1. Etiology. There are many causes of cyanosis, including diffusion abnormalities in the lung, intracardiac and extracardiac shunts, and polycythemia. The pulmonary causes of cyanosis are described above.
      2. Cardiac lesions may cause systemic hypoxemia by decreasing pulmonary blood flow or by causing admixture of systemic and pulmonary venous blood via shunts.
      3. Several factors allow the majority of fetuses to tolerate congenital heart lesions in utero. Fetal oxygenation occurs via the placenta, rather than being dependent on pulmonary blood flow. Both the left and right ventricles contribute to systemic blood flow, and mixing occurs at atrial and ductal levels. Furthermore, the fetus has greater oxygen carrying capacity because of fetal hemoglobin and an elevated hemoglobin concentration.
      4. In the newborn, the ductus arteriosus may initially permit pulmonary blood flow in patients with transposition of the great arteries, pulmonic stenosis or atresia, tetralogy of Fallot, or ventricular hypoplasia. Most of these infants become symptomatic as the ductus arteriosus closes at 2 to 3 days of life. If a ductal-dependent cardiac lesion exists, prevention of ductal closure is critical to maintain pulmonary blood flow. This may be accomplished with a prostaglandin E1 infusion. Side effects of prostaglandin treatment include apnea, hypotension, and seizure activity.
      5. Many patients with septal defects are asymptomatic during the fetal and neonatal period. However, with increased pulmonary vascular resistance, right-to-left shunting of deoxygenated blood may produce systemic hypoxemia. Later in life, the normal decrease in pulmonary vascular resistance increases blood flow to the lung and potentially causes pulmonary vascular overcirculation and pulmonary hypertension.
      6. Laboratory studies. In the infant with signs and symptoms of cardiovascular disease, relevant studies include an arterial blood gas, pre- and postductal oxygen saturations, four extremity blood pressures, an ECG, CXR, hemoglobin or hematocrit, and determination of arterial blood gas tension during inhalation of pure oxygen (“hyperoxia test”). A PaO2 that remains below 150 mm Hg while the infant breathes 100% oxygen is suggestive of an intracardiac shunt. Cardiology consultation is indicated, and echocardiography is frequently performed to detect potential structural heart lesions.
    3. Patent ductus arteriosus (PDA)
      1. Clinical features. PDA is commonly encountered in the premature infant and is characterized by a murmur at the left sternal border radiating to the back, bounding pulses, widened pulse pressure, evidence of increased pulmonary blood flow by CXR, respiratory distress, and excessive weight gain. The PDA often can be confirmed by cardiac ultrasound. In some cases, cardiac dysfunction associated with a PDA may decrease systemic blood pressure, peripheral perfusion, and urine output and may be associated with metabolic acidosis.
      2. Although early treatment of a PDA consists of fluid restriction and supportive care, it is important to maintain systemic perfusion. If the degree of shunt through the ductus arteriosus is significant, and renal and platelet function are adequate, pharmacologic closure of the ductus with indomethacin or ibuprofen may be attempted.
      3. Surgical closure of a PDA is indicated in symptomatic infants for whom medical therapy has either failed, is contraindicated, such as those with decreased renal or platelet function, or thought not to be effective.
      4. Anesthetic considerations: Often these infants are critically ill, requiring high levels of oxygen support, ventilator support, and vasopressor therapy. They may have renal dysfunction, because of decreased cardiac output caused by the PDA and fluid restriction, and platelet dysfunction because of medical therapies. Many PDA closures may take place in the NICU to avoid the risk of transporting the infant to the OR. In addition to a preductal pulse oximeter that is used to assess cerebral oxygen delivery, a postductal oximeter can be helpful during the surgical procedure for detecting inadvertent occlusion of the aorta during assessment of the anatomy of the central circulation. An opiate-based anesthetic (eg, fentanyl) with muscle relaxation is a common technique used for infants undergoing PDA ligation. Infants should be monitored closely in the postoperative period for complications including pneumothorax, hypotension, and oliguria.
    4. Dysrhythmias
      1. Supraventricular tachycardia (SVT) is the most frequent dysrhythmia seen in fetuses and neonates. The associated heart rate greater than 250 beats/min is often self-limited and well tolerated. However, if the SVT is associated with hypotension or hemoglobin oxygen desaturation, prompt treatment is required.
      2. SVT treatment consists of vagal maneuvers such as nasopharyngeal stimulation or placement of a cold pack glove or ice-filled glove on the infant’s face. Massage of the eye should be avoided, as this may lead to disruption of the lens in neonates. Adenosine and esophageal pacing are also useful for acute management of symptomatic SVT.
      3. Synchronized electrocardioversion is indicated if the patient is hemodynamically unstable.
    5. Persistent pulmonary hypertension of the newborn (PPHN)
      1. Pathophysiology. PPHN, previously referred to as persistent fetal circulation, is manifested by an increase in lung vascular resistance with resulting pulmonary arterial hypertension, right-to-left shunting across the foramen ovale and the ductus arteriosus, and systemic hypoxemia.
      2. Etiology. It is suspected that many newborns with PPHN have abnormal muscularization of the distal lung vascular bed and reactivity of the pulmonary arteries. Although PPHN is associated with perinatal depression, meconium aspiration, bacterial pneumonia, or sepsis, the exact role of these in the etiology of PPHN is unknown.
      3. Clinical features. Typically, term or near-term newborns with PPHN have severe systemic hypoxemia unrelieved by breathing at high FIO2. They may have shunt evidenced by higher oxygen saturations in the upper versus lower extremities. ECG may reveal right ventricular hypertrophy, and CXR may show decreased pulmonary vascular markings. Echocardiography may demonstrate shunting of blood at the level of the PDA and/or PFO.
      4. Treatment of PPHN
        1. Specific treatments include intubation and mechanical ventilation with high FIO2, induced respiratory or metabolic alkalosis, and INO administration. In nearly 50% of cases, carefully administered inhaled NO gas rapidly vasodilates the pulmonary vasculature, decreases shunt, and increases systemic oxygenation. In babies breathing NO gas, the levels of methemoglobin and inhaled NO oxides need to be measured.
        2. Nonspecific and supportive treatments include aggressive blood pressure support, sedation with narcotics (eg, fentanyl), and occasionally muscle relaxants.
        3. ECMO may be lifesaving for some patients with PPHN refractory to ventilatory and medical therapy.
          1. The ECMO circuit consists of tubing, a reservoir, pump, membrane oxygenator, and heat exchanger. To prevent clotting, the patient is treated with heparin. Because of platelet consumption during ECMO, platelet infusions are often required.
          2. Access. General anesthesia is required for central vascular cannulation during the initiation of ECMO. In neonates with adequate cardiac function, venovenous (VV) ECMO is performed with a single double-lumen catheter placed in the right ventricle via the right internal jugular vein. In neonates with compromised cardiac function and/or congenital heart disease associated with the PPHN, venoarterial (VA) ECMO is facilitated by cannulation of the right common carotid artery and the right internal jugular vein or the femoral artery and vein.
          3. Potential morbidities are associated with ECMO. Heparin treatment can cause intracranial hemorrhage and bleeding from other sites. Right-sided cerebral injuries (focal left-sided seizures, left hemiparesis, and progressive right cerebral atrophy) are thought secondary to cannulation and ligation of the right internal carotid artery.
          4. Because of the potential risks of ECMO, it is reserved for term and late preterm (>34 weeks) infants with a birth weight generally greater than 1800 to 2000 g with severe systemic hypoxemia. Prior to ECMO cannulation, a screening head ultrasound, echocardiogram, and baseline laboratory evaluation should be performed. Most infants with significant intracranial hemorrhage are excluded because of the unacceptable risk of hemorrhage extension while being treated with heparin. Also excluded are infants with multiple congenital anomalies, severe neurologic impairment, or cyanotic congenital heart disease.
  4. Hematologic disorders
    1. Hemolytic disease of the newborn (erythroblastosis fetalis)
      1. Isoimmune hemolytic anemia in the fetus is caused by transplacental passage of maternal IgG antibodies against fetal erythrocytes.
      2. Rh hemolytic disease is usually caused by anti-D antibodies but can also be caused by antibodies to minor antigens including Kell, Duffy, and Kidd. The absence of D antigen makes one Rh negative. A mother can be sensitized to fetal antigens by leakage of fetal blood into the maternal circulation during pregnancy, delivery, abortion, or amniocentesis. To prevent sensitization, an unsensitized Rh-negative mother is given anti-D immune globulin (Rhogam) during pregnancy at 28 weeks of gestation, after any invasive procedure (eg, amniocentesis), and at delivery. Once a mother is sensitized, immune prophylaxis is of no value. Even if treated with immune globulin, a mother can still be sensitized during pregnancy if a large fetomaternal transfusion occurs.
      3. ABO hemolytic disease can occur without maternal sensitization, because a mother with group O blood has naturally occurring anti-A and anti-B antibodies in her circulation. Because these are usually IgM antibodies that cannot cross the placenta, ABO hemolytic disease tends to be milder than Rh disease, with little or no anemia, mild indirect hyperbilirubinemia, and rare need for exchange transfusion.
      4. An indirect Coombs test on maternal blood can detect the presence of IgG antibodies.
      5. A direct Coombs test on the infant’s red blood cells can detect cells already coated with antibody, thus indicating a risk for hemolysis.
      6. Hemolysis occurs when antibodies cross the placenta and attach to the corresponding antigens on fetal erythrocytes. Hepatosplenomegaly results from increased hematopoiesis triggered by hemolysis.
      7. Clinical features. Physical examination may reveal hepatosplenomegaly, edema, pallor, scleral icterus, or jaundice.
      8. Laboratory studies often reveal anemia, thrombocytopenia, a positive direct Coombs test, indirect hyperbilirubinemia, hypoglycemia, hypoalbuminemia, and an elevated reticulocyte count that increases proportionally with the severity of the disease. Serial hematocrit and indirect bilirubin levels should be followed.
      9. First-line treatment consists of phototherapy. Intravenous immunoglobulin (IVIG) administration and/or an exchange transfusion may be required if the total indirect bilirubin level is very high or the rate of rise of bilirubin exceeds 1 mg/dL/h.
    2. Hydrops fetalis
      1. Hydrops fetalis is associated with excessive accumulation of fluid in at least two body compartments of the fetus and can range from mild peripheral edema to massive anasarca with pleural and/or pericardial effusions.
      2. Etiologies. Hydrops fetalis is associated with anemia (eg, hemolytic disease, fetomaternal hemorrhage, donor twin-twin transfusion), cardiac arrhythmias (eg, complete heart block, SVT), congenital heart disease, vascular or lymphatic malformation (eg, hemangioma of the liver, cystic hygroma), and infection (eg, viral, toxoplasmosis, syphilis).
      3. Treatment. The main goals of therapy include prevention of intrauterine or extrauterine death from anemia and hypoxia, restoration of intravascular volume, and avoidance of neurotoxicity from hyperbilirubinemia.
        1. Survival of the unborn fetus may be improved by in utero transfusion via the umbilical vein.
        2. Care of the live born infant with hydrops may include respiratory support with intubation and mechanical ventilation, paracentesis and/or thoracentesis, echocardiogram, placement of central lines, correction of hypovolemia and acidosis, and exchange transfusion. Some of these babies require aggressive and prolonged ventilator support because of pulmonary hypoplasia.
        3. Late complications include anemia, mild graft-versus-host reactions, inspissated bile syndrome (characterized by persistent icterus with elevated direct and indirect bilirubin), and portal vein thrombosis (as a complication of umbilical vein catheterization).
  5. Gastrointestinal disorders
    1. Hyperbilirubinemia
      1. Pathophysiology. Bilirubin is formed from the breakdown of hemoglobin. It is rapidly bound to albumin, transported to the liver (where it is conjugated with glucuronate), and delivered to the intestine in bile. In the intestine, it is either deconjugated by intestinal bacteria and reabsorbed or converted to excretory urobilinogen.
      2. Etiology. Hyperbilirubinemia results from overproduction (eg, hemolysis, absorption of sequestered blood, polycythemia), underconjugation (eg, immature or damaged liver), or underexcretion (eg, biliary atresia). It is often seen in sepsis, asphyxia, and metabolic disorders (eg, hypothyroidism, hypoglycemia, galactosemia) as well as in healthy, typically breast-fed infants.
      3. Toxic effects. Unconjugated (indirect) bilirubin is lipid soluble and is capable of crossing the blood-brain barrier and entering the central nervous system. Toxic levels of bilirubin result in damage of neurons. This process leads to bilirubin encephalopathy or kernicterus and may cause symptoms ranging from mild lethargy and fever to convulsions. Infants with prematurity, respiratory distress, sepsis, metabolic acidosis, hypoglycemia, hypoalbuminemia, or severe hemolytic disease are at risk for kernicterus. Later in life, kernicterus causes neurologic sequelae including diminished cognitive function, mental retardation, sensorineural hearing loss, dental dysplasia, and choreoathetoid cerebral palsy.
      4. Physiologic jaundice results from increased red cell turnover and an immature hepatic conjugation system. It occurs in 60% of term newborns, and peak bilirubin levels occur by day 2 to day 4 of life. Premature infants have an increased incidence (80%) and later bilirubin peak (day 5-day 7 of life).
      5. Breast milk jaundice develops gradually in the second or third week of life. In this disease, bilirubin levels peak at 15 to 25 mg/dL, and the elevated bilirubin levels may persist for 2 days to 3 months. Other causes of hyperbilirubinemia should be excluded before making this diagnosis. Interrupting nursing for a few days and supplementing with formula results in a marked decrease in serum levels, at which time nursing can be restarted. This is a benign type of jaundice without adverse sequelae.
      6. Laboratory studies include total and direct bilirubin, blood type and direct Coombs test, hemoglobin or hematocrit, reticulocyte count, blood smear for red cell morphology, electrolytes, blood urea nitrogen, creatinine, and appropriate cultures if sepsis is suspected. Because hyperbilirubinemia may be the presenting sign of a urinary tract infection, urinalysis and urine cultures should be considered.
      7. Treatment
        1. An elevated bilirubin level in the first 24 hours of life is pathologic and always warrants further investigation.
        2. Management of physiologic or mild hemolytic jaundice consists of monitoring serial bilirubin levels and starting early feeding to reduce enterohepatic cycling of bilirubin.
        3. Phototherapy is used if moderate indirect bilirubin levels or an accelerated rate of rise is noted. Light therapy of 420- to 470-nm wavelength results in photoisomerization of bilirubin, making it water soluble. Eyes must be shielded during phototherapy to prevent retinal damage.
        4. For severe hyperbilirubinemia, IVIG administration and/or exchange transfusion are indicated (eg, indirect bilirubin >25 mg/dL in a full-term infant).
    2. Esophageal atresia (EA) and tracheoesophageal fistula (TEF)
      1. EA is usually associated with TEF. The location of the fistula in patients with TEF is variable, with the most common configuration consisting of a proximal esophageal pouch and a distal TEF. EA/TEF is often accompanied by other congenital abnormalities, particularly cardiac defects.
      2. Pathophysiology. The proximal esophageal pouch has a small capacity, resulting in overflow aspiration. Aspiration leads to the classic clinical triad of coughing, choking, and cyanosis in patients with EA. Occasionally, copious secretions with drooling requiring frequent suctioning may be the only early symptom.
      3. The diagnosis is confirmed by the inability to pass a nasogastric tube into the stomach. A CXR that includes the neck with air- or water-soluble contrast agent will confirm the existence of esophageal atresia.
      4. Medical treatment is directed at reducing aspiration. Neonates should be kept NPO. A nasogastric tube is placed on continuous low suction and the head of the bed is elevated. Aspiration pneumonia should be treated with antibiotics and oxygen as required. Endotracheal intubation and ventilation may be required for severe pneumonia. However, ventilation may be difficult when a TEF exists.
      5. Surgical treatment depends on the stability of the infant. In newborns with severe aspiration pneumonia, surgery may be delayed until the lungs improve. If gastric distention because of air transiting the TEF into the GI tract compromises pulmonary function, a gastrostomy tube may be placed under local anesthesia. After initial stabilization, definitive repair of the esophagus and fistula may occur.
      6. Anesthetic considerations: It is critical, and sometimes difficult, to establish an airway in patients with a TEF. Surgeons should be readily available during the induction should emergent decompression of the stomach be required. The patient should be fully monitored; a precordial chest piece should be placed over the left thorax to aid in the assessment of ventilation. If the patient has a gastrostomy tube, it should be placed to water seal. Spontaneous ventilation during induction, intubation until the time of surgical ligation of the fistula should be maintained. To facilitate placement of the endotracheal tube so that its tip resides between the fistula and the carina, the tube may be placed first into the right mainstem bronchus. The tube then may be withdrawn slowly until breath sounds are heard over the left thorax. Decreased breath sounds and insufflation of the stomach or gas exiting from the gastrostomy tube suggest that the end of the endotracheal tube is above the fistula and that it should be advanced. Once the tube is in a good location, it must be carefully secured and monitored for dislodgement during the surgical procedure.
    3. Duodenal atresia
      1. Clinical features. Duodenal atresia usually presents with bile-stained emesis, abdominal distention, and increased volume of gastric aspirates. It is associated with trisomy 21 and may coexist with other intestinal malformations.
      2. Prenatal ultrasound or a postnatal abdominal x-ray often reveals a “double bubble,” representing air in the stomach and proximal duodenum.
      3. Treatment consists of avoiding oral feeds, use of nasogastric suction, ensuring adequate hydration, and managing electrolytes. Anesthesia consists of an awake or rapid sequence intubation, avoidance of nitrous oxide, and often the use of muscle relaxants.
    4. Pyloric stenosis
      1. Clinical features: Pyloric stenosis usually presents in the third to fifth week of life and is characterized by hypertrophy of the pylorus, which causes gastric outlet obstruction. The patient may present with persistent nonbilious emesis. Although the infant may exhibit hypochloremic, hypokalemic metabolic alkalosis from loss of hydrochloric acid, protracted vomiting may result in metabolic acidosis, intravascular volume depletion, and shock. An abdominal mass consisting of the hypertrophic pylorus or “olive” may be palpable.
      2. An abdominal x-ray usually shows gastric dilatation. The diagnosis is confirmed by abdominal ultrasound. In the past, x-ray examinations with contrast were performed to confirm this disease.
      3. Treatment consists of rehydration, correction of metabolic alkalosis, and nasogastric or orogastric drainage before surgical repair via pyloromyotomy.
      4. Anesthetic considerations: It is critical to empty the stomach before anesthetic induction. Since the patient’s nasogastric tube is often blocked with gastric secretions, it is best replaced just before induction and the patient suctioned while they are positioned supine, lateral, and prone. A rapid-sequence or awake intubation may then be performed. Inhalation anesthetics or muscle relaxants can be used as needed. Opioids often are not necessary, and the patient may be prone to respiratory depression from opioids due to cerebrospinal fluid (CSF) alkalosis. Rectal acetaminophen and local anesthetic infiltration of the surgical incision may be sufficient for analgesia. The neonate should be fully awake and breathing adequately before removing the endotracheal tube.
    5. Omphalocele and gastroschisis
      1. Clinical features. An omphalocele is caused by failure of the migration of the intestine into the abdomen and subsequent closure of the abdominal wall at 6 to 8 weeks of gestation. The viscera remain outside the abdominal cavity and are covered with intact peritoneum. Associated defects are present in 45% to 80% of patients with an omphalocele and can include genetic abnormalities (50%), cardiac defects (28%), exstrophy of the bladder and other genitourinary abnormalities (20%), craniofacial defects (20%), and CDH (12%). Gastroschisis occurs later in fetal life (12-18 weeks of gestation) from interruption of the omphalomesenteric artery. The resulting paraumbilical defect allows exposure of the bowel to the intrauterine environment without peritoneal coverage. Bowel loops are often edematous and covered with an inflammatory exudate. In contrast to omphalocele, gastroschisis is associated with other congenital abnormalities in only 10% to 20% of cases but may be complicated by intestinal atresia/stenosis or midgut volvulus in up to 16% of cases.
      2. Medical stabilization includes nasogastric drainage, IV hydration, and protection of the viscera before surgical repair. If the peritoneal sac is intact, the omphalocele should be covered with sterile, warm, saline-soaked gauze to decrease heat and water loss and the risk of infection. If the sac has ruptured or if the infant has gastroschisis, warm saline-soaked gauze should be used to wrap the exposed viscera or the infant can be placed in a sterile plastic bag with careful ongoing monitoring of intestinal perfusion. The infant should then be wrapped in warm sterile towels before surgical repair.
      3. Anesthetic considerations. In the OR, special measures are directed at compensating for the increased insensible water and heat loss associated with the abdominal surgery. After carefully emptying the stomach, a rapid-sequence induction is performed to minimize gaseous distention of the gastrointestinal tract. Muscle relaxation aids the surgeons in placing the organs into the abdominal wall or silo placement. Special attention is required to maintain ventilation and systemic blood flow after the organs are placed in the abdomen, which can be facilitated by measuring ventilatory pressures, urine output, and lower body blood pressure and oxygen saturation. These data aid in the decision of whether the lesion should be corrected in a single or staged procedure. It is essential to assess ventilation and oxygenation of the patient prior to extubation. The increased intra-abdominal pressures associated with the procedure can compromise the pulmonary function of the patient and perfusion of the abdominal contents.
    6. Necrotizing enterocolitis (NEC)
      1. NEC is an acquired intestinal necrosis that appears in the absence of functional or anatomic lesions. It occurs predominantly in premature infants with an increased incidence at lower gestational ages. It usually develops during the first few weeks of life and almost always after the institution of enteral feedings. Mortality may be as high as 40%.
      2. Pathogenesis is unclear but involves critical stress of an immature gut by ischemic, infectious, or immunologic insults. Enteral feedings seem to potentiate mucosal injury, though feeding with breast milk may be protective.
      3. Clinical features include abdominal distention, feeding intolerance with gastric aspirates or emesis, ileus, abdominal wall erythema, and bloody stool. The infant may demonstrate temperature instability, lethargy, respiratory and circulatory instability, apnea, oliguria, and DIC.
      4. Laboratory studies should include an abdominal x-ray (which may show pneumatosis intestinalis, fixed loops of bowel, portal venous air, or free intraperitoneal air), CBC (revealing leukocytosis, leukopenia, thrombocytopenia), arterial blood gases (demonstrating acidosis), electrolytes (showing hyponatremia or acidosis), stool guaiac (often showing occult blood), and stool Clinitest (showing evidence of carbohydrate malabsorption). Because the differential diagnosis includes sepsis, cultures of blood and urine should also be obtained. If the patient is stable and disseminated intravascular coagulation is not evident, CSF should be obtained by lumbar puncture for Gram stain and culture.
      5. Treatment. When NEC is suspected, enteral feedings are discontinued, and the stomach is decompressed with a nasogastric tube. Oral feeds are withheld for at least 10 to 14 days, and the patient is supported with parenteral nutrition. Broad-spectrum antibiotics (ampicillin, an aminoglycoside and, if perforation is suspected, metronidazole or clindamycin) are administered empirically.
      6. Surgical consultation is indicated, although laparotomy or abdominal drain placement is usually reserved for intestinal perforation, a fixed loop on serial abdominal x-rays, or persistent metabolic acidosis.
      7. Anesthetic concerns include hemodynamic instability due to abdominal sepsis, increasing abdominal girth leading to ventilation challenges, and profound metabolic acidosis, which is associated with severe NEC. It is also important to prevent aspiration of gastric contents and maintaining organ perfusion in the presence of significant third-space fluid losses.
    7. Volvulus
      1. Volvulus may occur as a primary lesion or, more commonly, as the result of intestinal malrotation, which can rapidly compromise blood flow to the intestine causing ischemia. If present in utero, intestinal necrosis may be present at birth, and immediate resection is indicated.
      2. Clinical features may include abdominal distention, bilious emesis, and signs of dehydration, acidosis, sepsis, or shock.
      3. The diagnosis of malrotation is made by upper gastrointestinal and small bowel follow-through examination, which demonstrates an abnormally positioned ligament of Treitz.
      4. Treatment involves volume resuscitation, placement of a nasogastric tube, cessation of feeding, antibiotic administration, and surgical repair.
      5. Anesthetic considerations: After evacuation of the stomach, a rapid sequence induction should be performed and anesthesia maintained with inhalation or IV anesthetics as tolerated. Nitrous oxide should be avoided to prevent further distention of the bowel.
  6. Neurologic disorders
    1. Seizures
      1. Seizures may be generalized, focal, or subclinical.
      2. Etiologies include birth trauma, intracranial hemorrhage, hypoxic ischemic encephalopathy, metabolic disturbances (hypoglycemia or hypocalcemia), drug withdrawal, and infections.
      3. Laboratory evaluation
        1. Initial evaluation includes electrolytes, glucose, calcium, magnesium, and arterial blood gas and pH determination. If a metabolic disease is suspected, serum lactate and ammonia, serum/urine amino acids, and urine for organic acids should be obtained.
        2. CBC with differential, platelet count, and the appropriate cultures, including blood and CSF.
        3. To identify underlying causes of the seizures, neuroimaging is performed, which may include cranial ultrasound, computed tomography (CT) scan, and/or magnetic resonance imaging (MRI) sometimes with T2 diffusion-weighted imaging, and electroencephalograms may be obtained, sometimes during pyridoxine administration.
      4. Treatment includes supportive care. It is critical to ensure that the patient maintains adequate oxygenation. In addition, it is important to correct potential underlying metabolic abnormalities that cause the seizures (eg, hypoglycemia, hypocalcemia). Anticonvulsants are started and, if indicated, a test dose of pyridoxine is administered. In newborns ≥36 weeks of gestational age, if a hypoxic-ischemic event at or near the time of birth is thought to be contributing to the brain injury, and clinical signs suggest that there is moderate-to-severe encephalopathy, then total body or head cooling to 33.5 °C to 34.5 °C is often initiated in the NICU within the first 6 hours of life and employed for 72 hours. In these cases, consultation with experts in neonatal neurology is often sought.
      5. Anticonvulsants
        1. Acute medical treatments include the following:
          1. Phenobarbital, 20 mg/kg IV load over 10 minutes; maintenance dose of 2.5 mg/kg twice daily to maintain a serum level of 20 to 40 μg/mL.
          2. Benzodiazepine (eg, lorazepam 0.1-0.3 mg/kg IV).
          3. Fosphenytoin, 15 to 20 mg/kg IV load over 15 minutes; maintenance dose of 2.5 mg/kg twice daily to maintain a therapeutic level of 15 to 30 μg/mL.
        2. Chronic treatment for neonatal seizures is usually with phenobarbital or levetiracetam.
    2. Intracranial hemorrhage
      1. Intraventricular hemorrhage occurs in more than 30% of infants with birth weights below 1000 g typically within the first 7 days of life. Subdural and subarachnoid hemorrhages are much less common.
      2. Clinical features. Intraventricular hemorrhage is often asymptomatic, although it may present with unexplained lethargy, apnea, or seizures. On examination, the head circumference can be increased, and the fontanelle may be bulging.
      3. Laboratory studies. Laboratory examination may show anemia and acidosis. Screening head ultrasounds are generally performed in infants under 32 weeks of gestational age.
      4. Grading of intraventricular hemorrhage
        1. Grade I. Subependymal or choroid plexus bleeding only.
        2. Grade II. Intraventricular bleeding without dilatation of ventricles.
        3. Grade III. Intraventricular bleeding with dilatation of ventricles.
        4. Grade IV. Intraparenchymal bleeding.
      5. The major complication of intraventricular hemorrhage is CSF obstruction resulting in hydrocephalus. This is followed by measuring daily head circumferences and by serial cranial ultrasounds. Serial lumbar punctures or intraventricular shunting is often required.
      6. Hypertonic agents (eg, 25% dextrose in water) that had previously been advocated in the treatment of hypoglycemia have been implicated in the etiology of intraventricular hemorrhage and should be avoided.
    3. Myelodysplasia
      1. Abnormal neurulation of the embryo can result in failed closure of the posterior neural tube by the fourth week of gestation. A meningocele is caused when the meninges herniate through a bony abnormality in the spine (spina bifida) and form a sac filled with CSF. The spinal cord and nerve roots are generally not involved. A myelomeningocele is the result of spinal cord and meninges herniating through a defect in the spinal canal. Eight percent of myelomeningoceles involve the lumbar spinal region. Hydrocephalus may affect as many as 90% of newborns with myelomeningocele because the cord lesion can displace the cerebellum and interfere with CSF flow.
      2. Myelomeningoceles occur with an incidence of 4 to 10 per 10,000 live births. The incidence has significantly decreased with maternal folic acid supplementation. Women with diabetes or taking certain medications (eg, antiepileptics) are at increased risk of having a child with myelodysplasia.
      3. Postnatal management includes covering the defect with a warm, normal saline-soaked sterile dressing to prevent adhesion of the dressing to the defect. The infant should be kept prone, and latex exposure should be avoided. Preoperatively, the infant should undergo assessment for additional abnormalities (eg, scoliosis, hydrocephalus, Arnold-Chiari malformation), and neuroimaging is recommended. Early surgical repair significantly decreases the risk of infection. Postoperatively, infants must be monitored closely for seizures and hydrocephalus that may require shunt placement. Prognosis ultimately depends on the level of the lesion and the presence of other congenital anomalies.
      4. Anesthetic considerations: During intubation of the patient in a supine position, special care must be taken to pad the exposed neural tissue to prevent injury. In some cases, intubation of the patient in the left lateral decubitus position may be preferred to protect the lesion. Many patients with myelomeningocele may have a short trachea, creating an increased risk for endobronchial intubation. Blood loss tends to be minimal unless extensive subcutaneous tissue dissection is required to mobilize the skin so that it can cover a large lesion. If hydrocephalus is present, the neonate may have a diminished response to hypoxia causing an increased risk of apneic episodes in the postoperative period.
    4. Retinopathy of prematurity (ROP)
      1. Etiologies
        1. The risk of ROP is increased in premature neonates requiring oxygen therapy. ROP is seen in infants with birth weights less than 1500 g and gestational age less than 30 weeks. There is an 80% incidence in infants weighing less than 1000 g. To decrease the incidence of ROP, hyperoxia should be avoided.
        2. Factors other than hyperoxic exposure and prematurity may produce ROP, as it has been demonstrated in full-term infants, infants with cyanotic heart disease, stillborn infants, and infants without hyperoxic exposure. Factors that may increase risk include anemia, infection, intracranial hemorrhage, acidosis, and PDA.
      2. Pathophysiology. ROP begins in the temporal peripheral retina, which is the last part of the retina to vascularize. An elevated ridge demarcating vascularized and nonvascularized retina is initially seen. Fibrovascular proliferation from this border extends posteriorly, and in 90% of patients, gradual resolution occurs from this stage. These patients may develop strabismus, amblyopia, myopia, or peripheral retinal detachment in later life.
      3. In 10% of patients, fibrovascularization extends into the vitreous, resulting in vitreous hemorrhage, peripheral retinal scarring, temporal dragging of the disk and macula, and partial retinal detachment. In severe disease, extensive fibrovascular proliferation can result in a retrolental white mass (leukocoria), complete retinal detachment, and loss of vision.
      4. Infants ≤32 weeks of gestational age, birth weight ≤1500 g, or with additional risk factors should undergo indirect ophthalmoscopy at 34 weeks of corrected gestational age. If ROP is identified, the infant is reexamined at 1- to 2-week intervals until spontaneous resolution occurs. New cases of ROP do not occur after 3 months of age.
      5. Treatment for severe manifestations of ROP has included photocoagulation, diathermy, cryotherapy, vitrectomy, and bevacizumab injection.
  7. Infectious diseases
    1. Environment
      1. Neonates are particularly vulnerable to infection. They have decreased cellular and humoral immune defense systems and are at increased risk for colonization and nosocomial infection.
      2. Prevention. Infectious transmission may be reduced by using separate equipment and isolettes for each infant, by hand washing before and after each contact, and by wearing cover gowns.
    2. Risk factors for infection. Prolonged rupture of membranes is associated with a high incidence of chorioamnionitis and subsequent ascending bacterial and viral infection in the neonate. Maternal fever, maternal leukocytosis, prolonged rupture of membranes, and fetal tachycardia are also associated with neonatal infection.
    3. Laboratory studies include complete blood count with differential and blood cultures. A lumbar puncture for culture and analysis of CSF may be indicated. If appropriate, viral cultures should be obtained.
    4. Neonatal sepsis
      1. Organisms responsible for infections soon after birth are usually acquired in utero or during birth. These can include group B β-hemolytic streptococcus, Escherichia coli, Listeria monocytogenes, and herpes simplex virus. Later-onset infections may be caused by Staphylococcus aureus, Staphylococcus epidermidis, Enterobacter cloacae, Enterococcus, and Pseudomonas aeruginosa.
      2. The clinical features of sepsis include respiratory failure, seizures, and shock. Subtle signs, including respiratory distress, apnea, irritability, and poor feeding, are often seen first and warrant evaluation.
      3. Laboratory studies should include blood, urine, and CSF cultures; CBC with differential; blood glucose; urinalysis; and CXR.
      4. Antibiotic coverage with ampicillin and an aminoglycoside is begun and continued for 48 to 72 hours. If cultures are positive, treatment should continue as indicated by the severity and location of infection. Aminoglycoside serum levels should be monitored and dosages adjusted to prevent toxicity.