Module 3. Neonatology. Lesson 8. Topics:
Theme 1. The peculiarities of premature newborns adaptation. Medical care for premature newborns.
Premature babies. Etiological factors of prematurity. Anatomic physiological features. Degree of morphological and neuro-functional maturity of premature babies. Adaptation features of preterm and disadaptative syndromes. Differential diagnosis of hyperbilirubinemia in premature babies. Intrauterine growth retardation (IUGR): causes, diagnosis, treatment, nursing profilaktika.Printsipy premature babies in the hospital and in the second phase of nursing. Features of feeding preterm infants. Urgent help with basic emergency conditions in premature novonarod-fiance: respiratory failure, intestinal paresis, hyperbilirubinemia, hypoglycemia.
Theme 2. Respiratory distress-syndrome iewborns. Etiology. Pathogenesis. Clinic. Diagnostics. Differential diagnosis. Treatment. Prevention. Outlook.
1. Premature newborns.
Every newborn is classified at birth as one of the following: premature (less than 37 weeks gestation, tabl. 1), full-term (37 to 42 weeks gestation), or postmature (was born after 42 weeks gestation). Preterm infant (Premature infant; Preemie) – any infant born before 37 weeks of estimated gestational age.
Tabl. 1. Classification of prematuriry.
|
The grade of the prematurity |
Term of the gestation |
Weight, gr |
|
I |
35 – 37 weeks |
2001 – 2500 |
|
II |
32 – 34 weeks |
1501 – 2000 |
|
III |
29 – 31 weeks |
1001 – 1500 |
|
IV |
Under 29 weeks |
Less than 1000 |
Extremely low birth weight (ELBW) is defined as a birth weight less than
Often, the cause of premature labor, or premature rupture of the membranes followed by premature labor, is unknown.
Risk factors
2. Abnormalities of the uterus or cervical incompetence
4. Untreated disease or infection (such as urinary tract infection or infection of the amniotic membranes)
5. Multiple pregnancy (the presence of more than one fetus in the uterus) accounts for 15% of all premature births.
6. Premature rupture of the membranes or placenta previa
7. Preeclampsia
8. kidney disease,
9. diabetes,
10. heart disease.
Risk factors that may contribute to preterm labor include lack of prenatal care, poor nutrition, adolescent pregnancy (mothers less than 18 years old), and substance abuse.
1. low birth weight – less than
2. thin, smooth, shiny, almost translucent skin
3. veins are easily seen through the skin (transparent skin)
4. wrinkled features
5. soft, flexible ear cartilage
6. body hair called lanugo
7. irregular breathing pattern
8. weak cry
9. usually inactive, may be unusually active immediately after birth
10. ineffective suck and swallow (poor feeding)
11. enlarged clitoris (female infant)
12. small scrotum, smooth without ridges (male infant)
The preterm infant faces a variety of physiological handicaps:
1. The ability to suck, swallow and breathe in a coordinated fashion is not achieved until 34-36 weeks of gestation.
2. Decreased ability to maintain body temperature.
3. Pulmonary immaturity – surfactant deficiency.
4. Immature control of respiration, leading to apnea and bradypnea, bradycardia.
5. Persistent potency of the ductus arteriosus, leading to further compromise of pulmonary gas exchange because of overperfusion of the lungs.
6. Immature cerebral vasculature, predisposing to subependymal or intraventricular hemorrhage and periventricular leucomalacia.
7. Impaired substrate absorption by the gastrointestinal tract, compromising nutritional management.
8. Immature renal function, complicating fluid and electrolyte management.
9. Increased susceptibility to infection.
10. Immature of metabolic processes, predisposing to hypoglycemia and hypocalcemia.
Fig. Premature Infant. Note how small he is compared to hand.
The peculiarities of transitory states:
1. Physiological jaundice extends to 3 – weeks, high bilirubin level, encephalopathy may occur even the bilirubin level is not only high, needs treatment.
2. Physiological erythema extends to 2 weeks.
3. Physiological weight loss is 9-14%; body weight became the same as after birth in 2-3 weeks.
4. Toxic erythema, hormonal crisis, transitory hyperthermia are absent.
Signs and tests Common tests on a premature infant include:
· chest X-ray to determine lung maturity and onset of respiratory distress syndrome
· blood gas analysis
· serum bilirubin
Thermoregulation As a result of a high body surface area–to–body weight ratio, decreased brown fat stores, and decreased glycogen supply, ELBW infants are particularly susceptible to heat loss immediately after birth. Hypothermia may result in hypoglycemia, apnea, and metabolic acidosis. ELBW infants can lose heat in 4 ways, namely, via radiation, conduction, convection, and evaporation. Radiation occurs when the infant loses heat to a colder object, conduction occurs when the infant loses heat through contact with a surface, convection occurs when the infant loses heat to the surrounding air, and evaporation occurs when heat is lost through water dissipation.
Temperature control is paramount to survival and typically is achieved with use of radiant warmers or double-walled incubators. Immediately after birth, the infant should be dried and placed on a radiant warmer and a hat or another covering should be placed on its head. Hypothermia (<
During transport from the delivery room to the neonatal intensive care unit, care should be taken to cover the baby, either with warmed blankets or with cellophane wrap, to help the infant retain body heat. The infant should be placed in a double-walled heated incubator during transport. The delivery room and the neonatal intensive care unit also should be kept warm to prevent hypothermia in the infant. Future architectural designs should facilitate adjacent location of delivery rooms and neonatal intensive care units or at least provide separately heated resuscitation rooms.
Hypoglycemia Fetal euglycemia is maintained during pregnancy by the mother via the placenta. However, ELBW infants have difficulty maintaining glucose levels within reference range after birth, at which time the maternal source of glucose is lost. In addition, ELBW infants are usually under stress and have insufficient levels of glycogen stores. In the preterm infant, hypoglycemia usually is diagnosed when whole blood glucose levels are lower than 20-40 mg/dL. In a recent review, Cornblath et al also recommended that a glucose concentration of less than 45 mg/dL be used as a screening or treating level in preterms infants. Symptoms may be present but may not be as obvious as those in a more mature infant (seizures, jitteriness, lethargy, apnea, poor feeding).
Thus, hypoglycemia often may be discovered only after routine serum dextrose sampling. One form of accepted treatment consists of an immediate intravenous glucose infusion of 2 mL/kg of 10% dextrose-in-water solution (200 mg/kg) followed by a continuous infusion of dextrose at 6-8 mg/kg/min to maintain a constant supply of glucose for metabolic needs and to avoid hypoglycemia.
Hyperbilirubinemia Most ELBW infants develop clinically significant typically unconjugated or indirect hyperbilirubinemia requiring treatment. Hyperbilirubinemia develops as a result of increased red blood cell turnover and destruction, an immature liver that is impaired during conjugation and elimination of bilirubin, and reduced bowel motility, which delays elimination of bilirubin-containing meconium. These manifestations of extreme prematurity in addition to typical conditions that cause jaundice (eg, ABO incompatibility, Rh disease, sepsis, inherited diseases) place these infants at higher risk for kernicterus at levels of bilirubin far below those in more mature infants. Kernicterus occurs when unconjugated bilirubin crosses the blood-brain barrier and stains the basal ganglia, pons, and cerebellum. Infants with kernicterus who do not die may have sequelae such as deafness, mental retardation, and cerebral palsy.
Phototherapy is used to decrease bilirubin levels to prevent the elevation of unconjugated bilirubin to levels that cause kernicterus. Phototherapy, which uses special blue lamps with wavelengths of 420-475 nm, breaks down unconjugated bilirubin to a more water-soluble product via photoisomerization and photooxidation through the skin. Then, this product can be eliminated in bile and urine. The fluorescent bulbs are positioned at
While phototherapy is initiated at birth of ELBW infants at some institutions, others start phototherapy when the bilirubin value approaches 50% of the birth weight value (eg, 4 mg/dL in an 800-g infant). If the level of bilirubin does not decrease satisfactorily with phototherapy, exchange transfusion is another option. If the level of bilirubin approaches 10 mg/dL (or 10 mg/dL/kg), exchange transfusion can begin to be considered in ELBW infants. In otherwise healthy term infants, exchange transfusion is not considered until the bilirubin level approaches 25 mg/dL.
In exchange transfusions, almost 90% of the infant’s blood is replaced with donor blood, and the bilirubin level falls to 50-60% of the preexchange level. Complications include electrolyte abnormalities (hypocalcemia, hyperkalemia), acidosis, thrombosis, sepsis, and bleeding.
Apnea Periodic breathing is defined as apnea that lasts only five to 10 seconds. This occurs in 40 to 50 percent of premature infants and is thought to be benign. Some infants with apnea benefit from theophylline therapy. The usual dosage is 3 to 5 mg per kg every eight to 12 hours to maintain a serum theophylline level of 8 to 12 µg per mL.
Respiratory distress syndrome An early complication of extreme prematurity is respiratory distress syndrome (RDS), which is caused by surfactant deficiency. Clinical signs include tachypnea (>60 breaths/min), cyanosis, chest retractions, nasal flaring, and grunting. Untreated RDS results in increased difficulty in breathing and an increased oxygen requirement over the first 24-72 hours of life. Chest radiographs reveal a uniform reticulogranular pattern with air bronchograms. Since the incidence of RDS correlates with the degree of prematurity, most ELBW infants are affected. As a result of surfactant deficiency, the alveoli collapse, causing a worsening of atelectasis, edema, and decreased total lung capacity. Surfactants decrease the surface tension of the smaller airways so that the alveoli or the terminal air sacs do not collapse, which results in less need for supplemental oxygen and ventilatory support.
Common complications include air leak syndromes, CLD, and retinopathy of prematurity (ROP). Surfactant agents may be administered as prevention or prophylactic treatment or as rescue intervention after hyaline membrane disease (HMD) is established. Synthetic surfactants lack the proteins found in animal-derived surfactants and may not be as effective as the latter.
Available evidence based on cost analysis and clinical outcome suggests that surfactants should be administered routinely as prophylaxis in infants younger than 30 weeks’ gestation. When used as prophylactic treatment, surfactants should be administered as soon after birth as possible. When administered as rescue treatment, a reasonable guideline is to administer surfactants when the infant reaches an arterial-to-alveolar (a/A) oxygen ratio of 0.22 or less. Typically, this is seen in an infant who requires greater than 35% oxygen to maintain a PaO2 of 50-
A major morbidity of premature birth is CLD, which is defined as receiving supplemental oxygen at 36 weeks’ postmenstrual age, which has become more frequently accepted than the former definition of oxygen dependence beyond age of 28 days. BPD is included in the spectrum of CLD and was originally described by Northway et al in 1967 as the clinical sequelae of prolonged ventilation associated with radiographic and pathologic findings.
Lemons et al looked at the outcomes of 4438 infants in the National Institutes of Child Health and Human Development Neonatal Research Network (NICHD) registry with birth weights between 501-
Apnea of prematurity (AOP) is common in ELBW infants and is defined as cessation of breathing, typically lasting 15-20 seconds, with or without bradycardia or cyanosis. The incidence is inversely correlated with gestational age and weight. As many as 90% of infants weighing less than
In addition, apnea can be caused by hypoxia, sepsis, hypoglycemia, neurologic lesions, seizures, and temperature irregularities. Apnea is diagnosed clinically and can be detected via use of cardiorespiratory monitors and pulse oximetry. A pneumogram can be used to illustrate the number and severity of the apneic episodes, with or without bradycardia, in conjunction with a continuous electrocardiogram reading. Treatment of AOP includes nasal continuous positive airway pressure (CPAP) and use of pharmacologic agents, such as theophylline and caffeine citrate. Caffeine appears to be more effective in stimulating the central nervous system and has a wider therapeutic range than theophylline, and caffeine causes less tachycardia than theophylline. Theophylline is more efficacious than caffeine as a bronchodilator and diuretic.
Premature infants who are believed to have AOP at the time of discharge may be sent home with an apnea monitor. In one study, as many as 40% of babies born weighing less than
Patent ductus arteriosus In the fetus, the ductus arteriosus is a conduit between the left pulmonary artery and the aorta that results in shunting of blood past the lungs. In full-term newborns, the PDA typically closes within 48 hours of birth because of oxygen-induced prostaglandin production, which constricts the ductus. However, as many as 80% of ELBW infants have a clinically significant PDA, resulting in a left-to-right shunt that causes a variety of symptoms, including a loud systolic murmur, widened pulse pressures, bounding pulses, hyperactive precordium, increased effort to breathe, and, because of a net decrease in systemic cardiac output due to left-to-right shunting, decreased urine output, feeding intolerance, and hypotension. Diagnosis typically is confirmed using echocardiography, and treatment includes decrease of fluid intake, indomethacin administration, and surgical ligation, if necessary.
Indomethacin is used prophylactically at some institutions and is administered in the first 24 hours of life to close a PDA in anticipation of the deleterious effects of a continued PDA in an ELBW infant. Some evidence suggests that prophylactic use of indomethacin has led to decreased symptomatic PDAs and PDA ligations in ELBW infants. Concerns regarding indomethacin and its effects on cerebral and renal blood flow have led to the investigation of the role of intravenous ibuprofen as an agent to close a PDA in preterm infants.
Infection Infection remains a major contributing factor to the morbidity and mortality of ELBW infants and can present at any point in the clinical course. Early infection that occurs during the first 3-4 days of life is believed to result from maternal factors, particularly if chorioamnionitis was diagnosed prenatally. Late nosocomial infections typically occur after the first week of life and result from endogenous hospital flora. Signs of infection are myriad, may be nonspecific, and include temperature instability (hypothermia or hyperthermia), tachycardia, decreased activity, poor perfusion, apnea, bradycardia, feeding intolerance, increased need for oxygen or higher ventilatory settings, and metabolic acidosis. Laboratory studies may include complete blood count with differential, blood culture, cerebrospinal fluid culture, urine culture, and cultures from indwelling foreign bodies, such as central lines or endotracheal tubes.
The most common causes of early sepsis in the immediate newborn period are group B streptococci (GBS), Escherichia coli, and Listeria monocytogenes. Nosocomial sources of infection include coagulase-negative staphylococci (CoNS), and Klebsiella and Pseudomonas species, which may necessitate a different antibiotic regimen than antibiotics typically started after birth for suspected sepsis. CoNS and fungi, most commonly Candida albicans, are causes of late-onset sepsis and may manifest with the above-mentioned symptoms and with thrombocytopenia. Importantly, fulminant late-onset clinical sepsis rarely is caused by CoNS and is more commonly secondary to gram-negative organisms. Late-onset sepsis is especially common in ELBW infants who have indwelling catheters, and it may occur in as many as 40% of these infants.
In most institutions, first-line therapy in infants with early sepsis is with ampicillin and gentamicin or a third-generation cephalosporin. Vancomycin should be reserved for proven CoNS infections and organisms resistant to other agents to prevent the emergence of resistant organisms. Vancomycin and a third-generation cephalosporin often are used to treat late-onset sepsis. Therapy with amphotericin commonly is initiated in infants with fungal infections. Cultures should dictate antibiotic management whenever possible.
Necrotizing enterocolitis NEC is a disease of the premature gastrointestinal tract that represents injury to the intestinal mucosa and vasculature. Incidence of NEC is associated with decreasing gestational age, and it is a dreaded complication of premature birth. NEC accounts for 7.5% of all neonatal deaths. Risk factors include asphyxia or any ischemic insult to the gastrointestinal blood supply. The role of enteral feeding is controversial. Breast milk may have a protective effect but has not been shown to prevent NEC.
Presenting symptoms may be vague and include apnea, bradycardia, and abdominal distention. These symptoms can quickly progress to indicators of increasing sepsis, such as large gastric residuals, metabolic acidosis, and lethargy. Radiographic findings include stacked bowel loops, pneumatosis intestinalis (presence of gas in the bowel wall), portal venous gas, and free air, which indicates perforation of the bowel and is an ominous sign of impending deterioration. NEC usually presents close to the time that the infant is taking full enteral feedings, usually between the second and third weeks of life.
NEC is commonly managed with antibiotics, elimination of oral intake, gastric decompression by nasogastric tube, and supportive measures to correct complications such as metabolic acidosis, thrombocytopenia, and hypotension. Surgical intervention may be necessary if evidence of perforation exists (presence of free air on radiographs) or medical treatment fails. Long-term complications include those related to bowel resection (short gut syndrome), bowel strictures, and risk of abdominal adhesions.
Spontaneous bowel perforation often occurs in the first week of life, presenting earlier than a typical case of NEC. Stark et al showed a strong interaction between postnatal use of dexamethasone and indomethacin on incidence of perforation (19%) in ELBW infants in a trial designed to determine if a 10-day course of postnatal dexamethasone would reduce the risk of CLD or death.
Intraventricular hemorrhage A hemorrhage in the brain that begins in the periventricular subependymal germinal matrix can progress into the ventricular system. Both incidence and severity of IVH are inversely related to gestational age. ELBW babies are at particular risk for IVH because development of the germinal matrix typically is incomplete. Any event that results in disruption of vascular autoregulation can cause IVH, including hypoxia, ischemia, rapid fluid changes, and pneumothorax. Presentation can be asymptomatic or catastrophic, depending on the degree of the hemorrhage. Symptoms include apnea, hypertension or hypotension, sudden anemia, acidosis, changes in muscular tone, and seizures. One commonly used system classifies IVH into 4 grades, as follows:
· Grade I – Germinal matrix hemorrhage
· Grade II – IVH without ventricular dilatation
· Grade III – IVH with ventricular dilatation
· Grade IV – IVH with extension into the parenchyma
IVH is diagnosed using cranial ultrasound, which usually is performed on ELBW infants during the first week after birth, since most IVHs occur within 72 hours of delivery. Use of antenatal steroids decreases incidence of IVH, and treatment consists of supportive care. Early administration of indomethacin also reduces the risk of IVH when used prophylactically in ELBW infants but may affect urine output and platelet function adversely. Prognosis is correlated with the grade of IVH. The outcome in infants with grades I and II is good; as many as 40% of infants with grade III IVH have significant cognitive impairment, and as many as 90% of infants with grade IV IVH have major neurologic sequelae.
The recent Trial of Indomethacin Prophylaxis in Prematurity (TIPP) demonstrated a decrease in the incidence of severe grades of IVH but no difference ieurodevelopmental outcomes at age 18-24 months. Thus, the question of using such an approach remains unanswered. The use of antenatal steroids has been associated with a decreased incidence of IVH in ELBW infants.
Periventricular leukomalacia Periventricular leukomalacia (PVL) is defined as damage to white matter that results in severe motor and cognitive deficits in ELBW infants who survive. PVL occurs most often at the site of the occipital radiation at the trigone of the lateral ventricles and around the foramen of Monro. The origin of PVL is believed to be multifactorial; the injury possibly results from episodes of fluctuating cerebral blood flow, which are caused by prolonged episodes of systemic hypertension or hypotension. PVL has been linked to periods of hypocarbic alkalosis. Recently, PVL also has been associated with chorioamnionitis. PVL is diagnosed using brain ultrasound in patients aged 4-6 weeks, and it occurs in 10-15% of ELBW infants. The presence of PVL, particularly cystic PVL, is associated with an increased risk of cerebral palsy; spastic diplegia is the most common outcome.
Anemia Factors that lead to anemia in premature infants include the following:
1. lower iron
2. stores than those in term infants,
3. lower erythropoietin production compared with that in term infants and
4. frequent blood sampling, which can reduce an infant’s blood volume by up to 10 percent within a few days of frequent sampling.
Anemia usually reaches its nadir at one to three months of age, when hemoglobin values of
During office visits, signs and symptoms such as tachycardia, tachypnea, pallor, lethargy, poor feeding, poor weight gain and apnea with bradycardia may indicate the presence of anemia. If these signs and symptoms develop, the blood count should be checked. Routine hemoglobin determinations may be considered for infants with hemolytic disease, such as ABO or Rh incompatibility. Although hematocrit levels below 25 percent are often poorly tolerated, the need for transfusion should be based on the patient’s signs and symptoms rather than on a specific hematocrit level. Infants with large left-to-right shunts usually benefit from a hematocrit level of greater than 40 percent.
Iron supplementation reduces the level and duration of anemia. Starting between two weeks and two months of age, iron supplementation in a dosage of 2 to 4 mg per kg per day for 12 to 15 months is recommended. Ferrous sulfate drops contain 25 mg of elemental iron per mL, and the usual 0.6-mL dose contains 15 mg.
Although it has been postulated that vitamin E reduces hemolysis and is frequently diminished in premature infants, vitamin E supplementation does not affect hemoglobin concentration, reticulocyte count or red blood cell morphology. Although erythropoietin is used in some neonatal intensive care units (NICU) in the treatment of anemia of prematurity, it is not routinely recommended.
Gastroesophageal Reflux Gastroesophageal reflux is common in premature infants and usually presents as regurgitation. There is widespread concern about gastroesophageal reflux (GER) in preterm infants. This article reviews the evidence for this concern. GER is common in infants, which is related to their large fluid intake (corresponding to 14 L/day in an adult) and supine body position, resulting in the gastroesophageal junction’s being constantly “under water.” pH monitoring, the standard for reflux detection, is of limited use in preterm infants whose gastric pH is >4 for 90% of the time.
New methods such as the multiple intraluminal impedance technique and micromanometric catheters may be promising alternatives but require careful evaluation before applying them to clinical practice.
A critical review of the evidence for potential sequelae of GER in preterm infants shows that 1) apnea is unrelated to GER in most infants,
2) failure to thrive practically does not occur with GER, and
3) a relationship between GER and chronic airway problems has not yet been confirmed in preterm infants.
Thus, there is currently insufficient evidence to justify the apparently widespread practice of treating GER in infants with symptoms such as recurrent apnea or regurgitation or of prolonging their hospital stay, unless there is unequivocal evidence of complications, eg, recurrent aspiration or cyanosis during vomiting. Objective criteria that help to identify those presumably few infants who do require treatment for GER disease are urgently needed.
PATHOGENESIS OF GER IN INFANTS
Reflux may occur when the lower esophageal sphincter relaxes. In an upright adult, gas will exit the stomach during these transient lower esophageal sphincter relaxations (TLESRs), causing belching. In a subject lying supine, however, the gastroesophageal junction is constantly under water, and liquid instead of gas will enter the esophagus. The quantity of the reflux depends on the fluid volume inside the stomach. The volume of fluid given to an infant (180 mL/kg per day) would correspond to a daily intake of ∼14 L/day in an adult. GER in an otherwise healthy infant may simply serve as a pop-off valve to cope with this high volume.Thus, GER may be a completely normal phenomenon in infants, and its frequent occurrence in this age group may be merely a result of their age-specific body position and high fluid intake. Whether GER will become clinically relevant will then depend on the quality (eg, pH) and the quantity of the refluxate.
These theoretical considerations were recently confirmed in preterm infants.Using a micromanometric transducer device also incorporating a pH catheter and a feeding tube, Omari et al studied TLESR in 36 preterm infants, 14 of whom had symptomatic GER, ie, GER disease (GERD). They found that both symptomatic and asymptomatic infants had 92% and 94%, respectively, of their reflux episodes associated with TLESR. The latter were triggered by gastric distension (eg, feeding) and abdominothoracic straining (eg, during motion). TLESRs were equally common in infants with and without GERD, the only group difference being a higher proportion of acid GER (16.5% vs 5.9%) in symptomatic infants. Acid GER was reduced by low-volume feeds and shorter feeding intervals. The authors concluded that infants with GERD do not have more TLESRs but some anatomic or sensory variation that increases the likelihood for liquid and/or acid reflux to occur during TLESR.
One factor that increases this likelihood is a feeding tube. Using the multiple intraluminal impedance technique, a pH-independent method for reflux detection (see below), we studied the frequency of GER with and without an 8-French nasogastric tube passing through the lower esophageal sphincter. We found that the frequency of GER almost doubled when the tube ended inside the stomach instead of the esophagus, ie, when lower esophageal sphincter competence was likely impaired.
A traditional view has been that infants with GERD have delayed gastric emptying, allowing more time for reflux to occur after a meal. Recently, however, both Omari et aland Ewer et alshowed that gastric emptying was not delayed in infants with GERD. This finding has practical consequences as it questions the rationale for prokinetics in the treatment of GERD. After the recent withdrawal of cisapride, there is now increasing interest in the use of erythromycin, which binds to neural motilin receptors and stimulates antral contractions and, in lower doses, induces antral migrating motor complexes, which are important for gastric emptying.Although 2 recent randomized, controlled trials reported a more rapid achievement of full oral feeds in infants who were treated with erythromycin (10–12 mg/kg per day),9 there remain several concerns with this practice, including the potential to induce cardiac arrhythmias, pyloric stenosis, or septicemia from multiresistant organisms. Also, a recent developmental study on the effects of erythromycin on migrating motor complexes showed that these were induced only in infants with gestational ages of 32 weeks or older. Delayed feeding advancements resulting in prolonged parenteral nutrition, however, are a problem mainly in infants who are born well before 32 weeks’ gestation. Thus, the role of delayed gastric emptying in promoting GER and the potential usefulness of erythromycin in treating the physiologically slow gastrointestinal motility in this age group remain at present unclear.
METHODS FOR REFLUX DETECTION
Reflux detection requires continuous measurements; that 1 or 2 reflux episodes occur during a 10-minute radiologic, scintigraphic, or sonographic investigation does not allow any conclusion as to whether a patient has GERD. For this reason, pH monitoring has become the “gold standard” for reflux detection. With the introduction of antimony pH electrodes, this technique has become easy to use and also allows measurements at multiple sites, eg, in both the stomach and the esophagus, or above the lower esophageal sphincter and at the pharyngeal level. The main disadvantage of pH monitoring is that it relies on gastric acidity: GER cannot be detected when gastric pH is >4. This is relevant in infants, particularly those who are born preterm, who may have gastric pH values >4 for >90% of the time, making it almost impossible to detect GER by this technique.
A potential solution to this dilemma is the multiple intraluminal impedance (MII) technique, which has recently become commercially available. This technique is based on the intraluminal measurement of electrical impedance between a number of closely arranged electrodes during a bolus passage. Electrical impedance is defined as the ratio between voltage and current and is inversely proportional to electrical conductivity.
CMA AS A DIFFERENTIAL DIAGNOSIS
That recurrent vomiting in a preterm infant can be a symptom of an underlying anatomic, metabolic, infectious, or central nervous disorder is widely known; an extensive review of these underlying conditions is beyond the focus of this article. In addition, vomiting, feeding problems, failure to thrive, and irritability, the leading symptoms of GERD, are characteristic of CMA. This disorder affects between 0.3% and 7.5% of term infants, usually within the first 4 months of life. Recently, it has also been described in preterm infants, who shared the same symptoms and also had the eosinophilic inflammation of the antral mucosa characteristic of CMA in older infants. Although the incidence of CMA at this age is yet unknown, the authors suggested that CMA should be considered in preterm infants with recurrent vomiting and irritability. Confirmation of this diagnosis (and treatment) consists of a trial of cow milk protein–free formula. It has to be kept in mind, however, that some infants are also allergic to hydrolysate and will respond only to an amino acid–based formula. More data on the relevance of this potential underlying diagnosis in preterm infants with recurrent vomiting are required.
POTENTIAL CLINICAL PROBLEMS RESULTING FROM GER
Apnea
Problems that are frequently cited in conjunction with GER are apnea, failure to thrive, and airway problems such as recurrent aspiration or wheezing. Preterm infants often exhibit both apnea and GER, and the belief that the latter is an underlying cause of apnea of prematurity (AOP) is evident from the fact that it was the most frequent indication for the widespread use of cisapride in preterm newborns (see above). The evidence for this proposed relationship, however, is largely circumstantial and includes the observation that AOP occurs frequently in the immediate postprandial period, ie, when GER is most likely to occur. It also includes data from animal studies that show that apnea can be induced by the instillation of small amounts of liquid into the larynx, resulting in stimulation of laryngeal chemoreceptors, and the observation that apneas are more likely to occur after episodes of regurgitation. The latter observation is supported further by anecdotal reports of apneic spells occurring immediately after a reflux episode. Most studies that attempted to document a temporal relationship between apnea and GER, however, failed to do so.
We recently addressed this issue by performing simultaneous recordings of MII and cardiorespiratory signals in 19 preterm infants with AOP. The frequency of apnea occurring within 20 seconds of a reflux episode was not significantly different from that during reflux-free epochs (0.19 vs 0.25/min). The same was true for desaturations and bradycardias, which are often considered more likely than central apneas to be associated with GER. Only 9 (4.8%) desaturations were associated with a reflux episode, and the frequency of desaturation occurring with GER was agaiot significantly different from that occurring during reflux-free epochs. Also, only 1 of 44 bradycardias occurred within ±20 seconds of a reflux episode. Thus, both cardiorespiratory events and GER were common in these infants but were not temporally related.1
Similarly, Page and Jeffery observed that preterm infants who were studied at term-equivalent age responded to the pharyngeal infusion of small volumes of 0.9% saline or water during sleep with a volume-dependent increase in swallowing frequency but not with an increased apnea rate. These authors suggested that apnea and bradycardia are predominantly evoked when the larynx rather than the pharynx is stimulated, which does not usually occur during regurgitation of small amounts of liquid. Finally, treatment with cisapride or metoclopramide had no effect on AOP. Infants in these studies, however, were not selected because they had symptoms suggestive of GER-related apnea. Thus, there may be the occasional infant with such symptoms, as also reported in case studies. In the majority of infants with AOP, however, the latter seems to be unrelated to GER and therefore does not justify provision of anti-reflux treatment.
Failure to Thrive
Failure to thrive, a symptom frequently reported in older infants with GER, seems rare in preterm infants who exhibit this disorder. Khalaf et al, in a cohort study of 150 neonatal intensive care unit (NICU) residents evaluated by a pH study, did not find a significant difference in body weight between infants with and without GER. A recent case-control study from another NICU confirmed these findings. Specifically, weekly weight gain and caloric intake were similar between groups. Nonetheless, infants with GER had a significantly longer hospital stay than those without (99 vs 70 days; P < .002). Thus, it seems that the close attention given to weight gain in NICU residents seems to protect against the failure to thrive often seen in older infants with GERD but that physicians are still sufficiently concerned by GER to keep these infants in the hospital for longer periods of time. Whether this concern is justified remains to be proved.
Airway Problems
GER may undoubtedly cause pulmonary aspiration, but this is usually a dramatic event that is clinically and radiologically apparent. The more controversial issue is whether chronic airway problems may be caused by clinically inapparent or “silent” GER. In one of the first studies that addressed this issue in infants, midesophageal pH, exhaled CO2, and breathing movements were measured in six 2- to 12-month-old infants with stridor; 5 of these also had some clinical suspicion of GER. Within 5 to 20 minutes after onset of acid reflux, retractions and stridor were observed in all infants. Stridor improved with medical management (bethanechol, positioning, feed thickeners) in all 5 infants in whom this was attempted. More recent, Bibi et al studied 116 children, aged 3 to 28 months, with flexible bronchoscopy including bronchoalveolar lavage and chest radiography; 54 of these had tracheo- and/or bronchomalacia. Patients with recurrent vomiting and/or feeding-related or unexplained cough (
Treatment Current use of a nasogastric tube for feedings appears to increase the incidence of reflux.Theophylline reduces lower esophageal sphincter tone and may worsen reflux symptoms. Placing the infant in an infant seat after feeding has not been shown to reduce reflux. Metoclopramide (Reglan), in a dosage of 0.1 mg per kg four times a day, and cisapride (Propulsid), in a dosage of 0.2 mg per kg three or four times a day, are often used in the treatment of reflux, but there are conflicting studies on the effectiveness of these agents in infants. In addition, metoclopramide carries the small risk of tardive dyskinesia. Surgery may be required in severe cases.
Vision Retinopathy of prematurity (ROP) is a disease of a premature retina that has not yet fully vascularized. Changes in oxygen exposure have been postulated to cause a disruption in the natural course of vascularization and may result in abnormal growth of blood vessels, which can result in retinal detachment and blindness. All infants with birth weights less than
If ROP is present, its stage and location dictate management, which can range from repeat examinations 1 week later to laser surgery or cryotherapy. The presence of plus disease, or tortuosity of the retinal vessels, is a poor prognostic sign and requires immediate treatment. Infants with ROP are also at greater risk for sequelae, such as myopia, strabismus, and amblyopia. ELBW infants without ROP should have a follow-up eye examination at age 6 months.
Hearing All infants should undergo hearing examinations prior to discharge, using either evoked otoacoustic emissions or brainstem auditory evoked potentials. ELBW infants are at higher risk for hearing impairment because of their low birth weights. Other risk factors include meningitis, asphyxia, exchange transfusions, and administration of ototoxic drugs such as gentamicin. In addition, ELBW infants should undergo repeat hearing examinations at age 6 months.
Fluids and electrolytes Fluid and electrolyte management must be closely controlled because disturbances may result in or exacerbate morbidities, such as patent ductus arteriosus (PDA), intraventricular hemorrhage (IVH), and chronic lung disease (CLD) or bronchopulmonary dysplasia (BPD). Compared to full-term newborns, ELBW infants have proportionally more fluid in the extracellular fluid compartment than the intracellular compartment. They also have a larger proportion of total body weight composed of water. During the early days after birth, diuresis may result in a 10-20% weight loss, which can be exacerbated by iatrogenic causes, such as radiant warmers and phototherapy.
ELBW infants also have compromised renal function stemming from a decreased glomerular filtration rate; a decreased ability to reabsorb bicarbonate, secrete potassium, and other ions; and a relative inability to concentrate urine. In addition, they reabsorb creatinine via the tubules following birth and, thus, serum creatinine levels are elevated for at least the first 48 hours of life, especially in ELBW infants, and do not reflect renal function for the first few days following birth. Fluid status is commonly monitored with daily (or sometimes twice daily) body weights and strict recording of fluid intake and output.
Electrolytes are monitored frequently to maintain homeostasis. ELBW infants are prone to nonoliguric hyperkalemia, defined as a serum potassium level greater than 6.5 mmol/L, which has been associated with cardiac arrhythmias and death. Omar et al concluded that prenatal administration of steroids prevented nonoliguric hyperkalemia in ELBW infants, and they speculated that prenatal use of steroids induced up-regulation of cell membrane sodium-potassium-ATP activity in the fetus.
Nutrition Initiating and maintaining growth of ELBW infants is a continuing challenge. Infants commonly are weighed daily, and body length and head circumference usually are measured weekly to track growth. The growth rate often lags because of complications such as hypoxia and sepsis. Concern that early feeding may be a risk factor for necrotizing enterocolitis (NEC) often deters initiation of enteral feeding. Parenteral nutrition may provide the greater source of energy in ELBW infants in the first few weeks after birth.
ELBW infants have high energy requirements because of their greater growth rate. Heat loss from the skin also raises energy needs. ELBW infants expend 60-75 kcal/kg/d and need at least 120 kcal/kg/d to achieve the desired growth rate of 15 g/kg/d. Current common practice in the early days after birth calls for most energy to be provided in the form of parenteral glucose and lipids. ELBW infants may tolerate a glucose infusion rate of 6-8 mg/kg/min, but hyperglycemia may be a common and serious complication early after birth.
Lipid intake may vary from 1-4 g/kg/d of 20% lipid emulsion, as tolerated. Since ELBW infants lose at least 1.2 g/kg/d of endogenous protein, they require at least that amount of amino acids and 30 kcal/kg/d to maintain protein homeostasis. They also need such essential amino acids as cysteine and may require glutamine, found in human breast milk but not always present in parenteral nutrition mixtures. Trace minerals, such as iron, iodine, zinc, copper, selenium, and fluorine, are beneficial as well. Early evidence suggests that chromium, molybdenum, manganese, and cobalt may need to be added to the nutritional regimen, especially in ELBW infants who require long-term parenteral nutrition.
Enteral feeding often is begun when the infant is medically stable, using small-volume trophic feeding (approximately 10 mL/kg/d) to stimulate the gastrointestinal tract and prevent mucosal atrophy. Prolonged use of parenteral nutrition may result in cholestasis and elevated triglyceride levels. To reduce these complications, weekly laboratory tests usually are obtained to evaluate liver function, alkaline phosphatase, and triglyceride levels. Bolus feedings every 2-4 hours may begin as early as day 1. If tolerated, as evidenced by minimal gastric residuals and clinical stability, feeding may increase to 10-20 mL/kg/d, although feeding practices vary widely. Although bolus feeding may appear to be more physiologically appropriate, infants who do not tolerate the volume of the bolus may be fed continuously.
Breast milk is considered by some to be the best choice for enteral feeding and has been suggested to have protective effects against NEC. Breast milk must be fortified with calcium and phosphorus to promote proper bone growth. Low birth weight infants have a high need for macronutrients and micronutrients that approaches intrauterine needs; at the same time, the functionally immature gastrointestinal tract precludes adequate enteral intake. Despite its many immunologic and nutritional advantages, an exclusive diet of unsupplemented breast milk may provide insufficient quantities of energy, protein, calcium, and phosphorous to support the goals of intrauterine bone mineralization and growth rates in small premature infants.
Human milk may be supplemented by adding liquid or powder commercially available fortifiers, premature infant formulas, modular supplements, or vitamin/mineral supplements. Commercially available multinutrient fortifiers include Enfamil Human Milk Fortifier (Mead Johnson Nutritionals; Evansville, Indiana) or Similac Human Milk Fortifier (Ross Products, Abbott Laboratories; Columbus, Ohio), both of which are powders. Similac Natural Care Liquid Fortifier (Ross Products), which is a liquid, is also available.
Comparisons of the nutrient content and source of macronutrients of these fortifiers have been published. Potential complications of human milk fortifiers include nutrient imbalance, increased osmolarity, and bacterial contamination. A number of specially formulated preterm formulas are available that have been shown to promote proper growth, as well. Caloric density usually is increased when a full feeding volume is achieved and the infant is no longer on intravenous supplementation.
Vitamins and Minerals Vitamins D, E and K, and folic acid are especially important for low-birth-weight infants. Except for vitamin D deficiency, vitamin deficiencies are unlikely to occur after discharge from a neonatal intensive care center.
Although vitamin deficiencies are rare, all breast-fed infants should probably receive vitamin supplementation during the first year of life. One quart of formula or a standard dose of infant vitamins that provides 400 IU of vitamin D per day is advised for both premature and term infants. If the infant is bottle-fed with a standard formula, supplemental vitamins are advised until the infant is ingesting
Supplemental iron is advised, either as iron-fortified formula or as a liquid, given in a dosage of 2 to 4 mg per kg per day in breast-fed infants or infants receiving low-iron formulas. Iron supplementation should be started two weeks to two months after birth and continued for 12 to 15 months. An iron supplement in suspension form, such as Fer-in-Sol, provides 15 mg of iron per 0.6 mL.
The infant should receive 0.25 mg of fluoride supplementation daily if the water in the household is not fluoridated. Many dental problems, including enamel hypoplasia, dental caries and delayed dental development, are reported to be more common in preterm infants than in term infants.
Although rare, deficiencies of zinc and copper have been reported in premature infants at three to six months of age. Zinc deficiency occurs in breast-fed infants whose mothers have a rare metabolic deficiency that prevents the secretion of zinc into their breast milk.
Follow-up CARE Nearly all ELBW infants require neurodevelopmental follow-up monitoring to track their progress and to identify disorders that were not apparent during the hospital stay. These infants typically have complicated medical courses and often go home with multiple treatments and medications. In addition to monitoring their immediate medical needs upon discharge, evaluation of cognitive development, vision and hearing ability, and neurodevelopmental progress is important.
As many as 48% of ELBW infants have some type of major neurosensory or neurodevelopmental impairment. Infants with grade III or IV IVH or infants with PVL (cysts in brain parenchyma, typically seen on routine brain ultrasound images in infants aged 4-6 wk) are at the greatest risk for mental retardation. Other risk factors for developmental disabilities include meningitis, asphyxia, delayed head growth, and CLD.
Other therapy For problems with cognitive and neurodevelopmental development, physical and occupational therapy and early intervention development programs should be some of the options available. Such programs should be coordinated with the infant’s pediatrician and with the follow-up care clinic. As an increasing number of babies are born and continue to survive with birth weights less than
Immunizations The timing of immunizations in the physician’s office should be based on the infant’s chronologic age, not the gestational age. The only exception is hepatitis B vaccination. The American Academy of Pediatrics Committee on Infectious Diseases has issued a statement indicating that it may be advisable to delay administration of hepatitis B vaccine until the infant weighs
The full dose of all immunizations should be given. As with term infants, premature infants should be given the acellullar pertussis vaccine when it is available. The acellular pertussis vaccine is preferred over the whole-cell pertussis vaccine in infants with neurologic problems.
The medical record should be reviewed to determine if any immunizations were given in the NICU. Influenza vaccine should be given to infants over six months of age with chronic medical problems, especially lung disease. In all premature infants, consideration should also be given to administering influenza vaccine before the influenza season to parents and other frequent visitors in the home. Administration of the pneumococcal vaccine at two years of age may be beneficial in infants with chronic problems such as lung disease.
RSV Immune Globulin Respiratory syncytial virus immune globulin intravenous (RSV-IGIV) prevents severe RSV infection when it is administered monthly during the RSV season. In two clinical trials, infants who received RSV-IGIV had a 41 percent reduction and a 65 percent reduction in the rate of hospitalization compared with the rate of hospitalization in infants who did not receive the agent. RSV-IGIV should be considered for use in infants under 24 months of age with bronchopulmonary dysplasia who required oxygen therapy in the preceding six months and in infants of a gestational age of 32 weeks or less. Once an RSV infection has developed, RSV-IGIV will not help. Because antibodies from RSV-IGIV block immunity to measles vaccine, measles-containing vaccines should not administered for nine months after the last dose of RSV-IGIV.31 No changes are necessary for other routine immunizations.
Prevention One of the most important steps to preventing prematurity is to begin prenatal care as early as possible and to continue prenatal care throughout the pregnancy. This cannot be stressed enough.
Statistics clearly show that early and good prenatal care reduces the chance of a premature birth, having a small baby, and related deaths during delivery and the neonatal period.
Premature labor can sometimes be treated or delayed by a medication that inhibits uterine contractions. Many times, however, attempts to inhibit premature labor are not successful and thus a “cure” for prematurity remains elusive.
Prognosis Approximately 85 percent of infants with a birth weight under
2. Respiratory distress-syndrome.
Respiratory distress syndrome (RDS), also known as hyaline membrane disease (HMD), occurs almost exclusively in premature infants. RDS has been reported in all races worldwide, occurring more often in premature infants of Caucasian ancestry. Although reduced, the incidence and severity of complications of RDS continue to present significant morbidities.
Pathophysiology:
– Surfactant is a complex lipoprotein comprised of 6 phospholipids and 4 apoproteins. Functionally, lecithin is the principle phospholipid. It along with apoproteins or with the addition of other substances lowers the surface tension at the alveolar air-fluid interface in vivo.
– The components of pulmonary surfactant are synthesized in the Golgi apparatus of the endoplasmic reticulum of the type II alveolar cell.
– Hypoxia, acidosis, hypothermia, and hypotension may impair surfactant production and/or secretion of surfactant.
– A relative deficiency of surfactant, which leads to decrease in lung compliance and functional residual capacity with increased dead space, causes RDS. The resulting large ventilation-perfusion mismatch and right-to-left shunt may involve as much as 80% of cardiac output. Macroscopically, the lungs appear airless and ruddy (ie, liverlike). Thus, the lungs of these infants require a higher critical opening pressure to inflate. Diffuse atelectasis of distal airspaces along with distension of some distal airways and perilymphatic areas are observed microscopically. With progressive atelectasis along with barotrauma or volutrauma and oxygen toxicity, endothelial and epithelial cells lining these distal airways are damaged, resulting in exudation of fibrinous matrix derived from blood.
– Hyaline membranes that line the alveoli are formed within one half hour after birth. At 36-72 hours after birth, the epithelium begins to heal and surfactant synthesis begins.
Fig. 1. Pathogenesis of respiratory distress syndrome is a vicious cycle
Clinical History: RDS frequently occurs in the following individuals:
· Male infants
· Infants born to mothers with diabetes
· Infants delivered via cesarean without maternal labor
· Second-born twins
· Infants with a family history of RDS
In contrast, the incidence of RDS decreases with the following:
· Use of antenatal steroids
· Pregnancy-induced or chronic maternal hypertension
· Prolonged rupture of membranes
· Maternal narcotic addiction
Secondary surfactant deficiency may occur in infants with the following:
· Intrapartum asphyxia
· Pulmonary infections
· Pulmonary hemorrhage
· Meconium aspiration pneumonia
· Oxygen toxicity along with barotrauma or volutrauma to the lungs
Physical: Physical findings are consistent with the infant’s maturity assessed by Dubowitz examination or its modification by Ballard. Progressive signs of respiratory distress are noted soon after birth and include the following:
· Tachypnea
· Expiratory grunting (from partial closure of glottis)
· Subcostal and intercostal retractions
· Cyanosis
· Nasal flaring
· Extremely immature infants may develop apnea and/or hypothermia.
Differential diagnosis: Several diagnoses may coexist and further complicate the course of RDS including the following:
1. Pneumonia often is secondary to group B beta hemolytic streptococci (GBBS) and often coexists with RDS.
2. Metabolic problems (eg, hypothermia, hypoglycemia) may occur.
3. Hematologic problems (eg, anemia, polycythemia) may occur.
4. Transient tachypnea of the newborn usually occurs in term or near-term infants, usually after cesarean delivery. The chest x-ray of an infant with transient tachypnea exhibits good lung expansion and, often, fluid in the horizontal fissure.
5. Aspiration syndromes may result from aspiration of amniotic fluid, blood, or meconium. Aspiration syndrome also is observed in more mature infants and is differentiated by obtaining a history and by viewing the chest x-ray findings.
6. Pulmonary air leaks (eg, pneumothorax, interstitial emphysema, pneumomediastinum, pneumopericardium) may occur. In premature infants, these complications may occur from excessive positive pressure ventilation, or they may be spontaneous.
7. Congenital anomalies of the lungs (eg, diaphragmatic hernia, chylothorax, congenital cystic adenomatoid malformation of the lung, lobar emphysema, bronchogenic cyst, and pulmonary sequestration) and heart (eg, cardiac anomalies) are rare in premature infants.
These entities can be diagnosed based on chest x-ray or ultrasound examination findings and, on rare occasion, may coexist with RDS.
Lab Studies: Blood gases usually are obtained as clinically indicated from either an indwelling arterial (umbilical) catheter or an arterial puncture. Blood gases exhibit respiratory and metabolic acidosis along with hypoxia.
· Respiratory acidosis occurs because of alveolar atelectasis and/or overdistension of terminal airways.
· Metabolic acidosis is primarily lactic acidosis, which results from poor tissue perfusion and anaerobic metabolism.
· Hypoxia occurs from right-to-left shunting of blood through the pulmonary vessels, PDA, and/or foramen ovale. Pulse oximetry is used as a noninvasive tool to monitor oxygen saturation, which should be maintained at 90-95%.
Imaging Studies: Chest x-rays of an infant with RDS exhibit bilateral diffuse reticular granular or ground glass appearance, air bronchograms, and poor lung expansion (fig. 2,3).
· The prominent air bronchograms represent aerated bronchioles superimposed on a background of collapsed alveoli.
· The cardiac silhouette may be normal or enlarged. Cardiomegaly may be the result of prenatal asphyxia, maternal diabetes, PDA, an associated congenital heart anomaly, or simply poor lung expansion.
· These findings may be altered with either early surfactant therapy or indomethacin treatment with mechanical ventilation.
· The radiologic findings of RDS cannot be differentiated reliably from those of pneumonia, which is caused most commonly by GBBS.
Fig. 2,3. X-ray of newborns with HMD.
Medical Care:
· Prenatal prevention and prediction of RDS: Obstetricians with experience in fetal medicine should care for mothers whose infants are at an increased risk for developing RDS. Strategies to prevent premature birth (eg, bed rest, tocolytics, appropriate antibiotics) and the prudent use of antenatal steroids to mature fetal lungs may decrease the incidence and severity of RDS. Fetal lung maturity can be predicted by estimating the lecithin-to-sphingomyelin ratio and the presence of phosphatidylglycerol in the amniotic fluid obtained via amniocentesis.
· Delivery and resuscitation: A neonatologist experienced in the resuscitation and care of premature infants should attend deliveries of fetuses when younger than 28 weeks’ gestation. They are at a high risk of maladaptation, which further inhibits surfactant production.
· Surfactant replacement therapy: Mortality of RDS has decreased 50% during the last decade with the advent of surfactant therapy.
- Infants diagnosed with RDS who require assisted ventilation with more than 0.40 fraction of inspiratory oxygen (FIO2) should receive intratracheal surfactant as soon as possible, preferably within 2 hours after birth.
- Because surfactant is protective of delicate lungs, several investigators have recommended prophylactic use following resuscitation in extremely premature infants (<27 weeks’ gestation). However, prophylactic surfactant is expensive and unnecessary in most instances because 40-60% of premature infants do not have surfactant deficiency and, thus, are intubated with its inherent risks.
- Premature infants with surfactant deficiency and RDS have an alveolar pool size of approximately 5 mg/kg. Full-term animal models have pool sizes with a range of 50-100 mg/kg. The recommended dose of the clinically available surfactant preparations has a range of 50-200 mg/kg, which is an approximation of the surfactant pool of term newborn lungs. Most infants require 2 doses; however, as many as 4 doses at 6- to 12-hour intervals have been used in several clinical trials. If the infant improves rapidly after only 1 dose, the infant most likely does not have RDS. Conversely, in infants who respond poorly or are nonresponders to surfactant, exclude PDA, pneumonia, and complications of ventilation (air leak), especially prior to using third and subsequent doses.
· Oxygen and continuous positive airway pressure: In 1971, continuous positive airway pressure (CPAP) was introduced as the primary therapeutic modality when Gregory et al demonstrated a marked reduction in RDS mortality. Oxygen was the primary therapeutic modality prior to the introduction of CPAP.
o The goal of therapy for patients with RDS is to maintain a pH of 7.25-7.4, an arterial oxygen (PaO2) of 50-
· Assisted ventilation further decreased RDS-related mortality; however, earlier ventilators were associated with complications, such as air leaks, airway damage, and intraventricular hemorrhage.
· Consider ventilation as a necessary physiologic support while the infant recovers from RDS. Several investigators have suggested that permissive hypercapnia with arterial carbon dioxide (PaCO2) with a range of 45-
Supportive therapy includes the following:
· Temperature regulation: Hypothermia increases oxygen consumption.
· Fluids, metabolism, and nutrition: In infants with RDS, initially administer 5% or 10% dextrose intravenously at 60-80 mL/kg/d. Closely monitor blood glucose (Dextrostix), electrolytes, calcium, phosphorous, renal function, and hydration (determined by body weight and urine output) to prevent any imbalance. Add calcium at birth to the initial intravenous fluid. Start electrolytes as soon as the infant voids and as indicated by electrolytes. Gradually increase the intake of fluid to 120-140 mL/kg/d. Extremely premature infants occasionally may require fluid intake of as much as 200-300 mL/kg or more because of insensible water loss occurring from their large body surfaces.
Once the infant is stable, add intravenous nutrition with amino acids and lipid. After the respiratory status is stable, initiate a small volume of gastric feeds (preferably breast milk) via a tube to initially stimulate gut development and, thereafter, provide nutrition as intravenous nutritional support is being decreased.
· Correction of circulation and anemia.
· Antibiotic administration: Start antibiotics in all infants who present with respiratory distress at birth after obtaining blood cultures and discontinue antibiotics after 3-5 days if blood cultures are negative.
Fig. 4. Chest radiographs in a premature infant with respiratory distress syndrome before and after surfactant treatment. Left, Initial radiograph shows poor lung expansion, air bronchogram, and reticular granular appearance. Right, Repeat chest radiograph obtained when the neonate is aged 3 hours and after surfactant therapy demonstrates marked improvement.
MEDICATION
|
Drug Name |
Beractant (Survanta, Alveofact) |
|
Pediatric Dose |
ET: 4 mL/kg (100 mg/kg) divided in 4 aliquots administered at least 6 h apart for 1-4 doses |
|
Drug Name |
Calfactant (Infasurf |
|
Pediatric Dose |
ET: 3 mL/kg (105 mg/kg) q6-12h for 1-4 doses |
|
Drug Name |
Poractant (Curosurf) |
|
Pediatric Dose |
ET: 2.5 mL/kg (200 mg/kg); then 1.25 mL/kg (100 mg/kg) at 12-h intervals prn in 2 subsequent doses |
|
Drug Name |
Colfosceril (Exosurf Neonatal) |
|
Pediatric Dose |
ET: 5 mL/kg (67.5 mg/kg) q12h for 1-4 doses |
Complications:
Acute complications include the following:
· Chronic lung disease
· Prolonged need for respiratory support
· Childhood otitis media
· Reactive airway disease
· Complications attendant to these conditions
· Alveolar rupture.
· Infections
· Intracranial hemorrhage and periventricular leucomalacia.
· Patent ductus arteriosus (PDA) with increasing left-to-right shunt, especially in infants weaned rapidly after surfactant therapy.
· Occurrence of pulmonary hemorrhage increases in tiny premature infants, especially following surfactant therapy.
· Suspect necrotizing enterocolitis and/or gastrointestinal perforation in any infant with abnormal abdominal findings on physical examination.
· Apnea of prematurity is common in immature infants, and its incidence has increased with surfactant therapy, possibly due to early extubation.
Chronic complications include the following:
· Bronchopulmonary dysplasia: BPD is a chronic lung disease and is defined as oxygen requirement at a corrected gestational age of 36 weeks. BPD is related directly to high volume and/or pressures that are used in mechanical ventilation, infections, inflammation, and vitamin A deficiency. BPD increases with decreasing gestational age. The postnatal use of surfactant therapy, gentler ventilation, vitamin A, and steroids reduces the severity of BPD.
· Retinopathy of prematurity (ROP): Infants with RDS and PaO2 greater than
· Neurologic impairment: Hearing and visual handicaps further may compromise the development of these infants. They may develop a specific learning disability and aberrant behavior.
· Familial psychopathology: Infants with RDS are at a greater risk of child abuse and failure to thrive.
Besides, RDS can occure (like clinical syndrome) in the following pathological conditions:
– neonatal pneumonia (congenital and postnatal)
– meconium aspiration syndrome
– pulmonary interstitial emphysema
Congenital Pneumonia: Pneumonia is an inflammatory pulmonary process that may originate in the lung or be a manifestation of a systemic process. Pneumonia occurs frequently iewborn infants, although reported rates vary considerably depending on the diagnostic criteria used and the characteristics of the population under study. Most reports cite frequencies in the range of 5-50 per 1000 live births, with higher rates in the settings of maternal chorioamnionitis, prematurity, and meconium in the amniotic fluid.
Transmission of congenital pneumonia usually occurs via 1 of 3 routes:
1. Hematogenous transmission: If the mother has a bloodstream infection.
2. Ascending transmission: Ascending infection from the birth canal and aspiration of infected or inflamed amniotic fluid.
3. Transmission via aspiration.
Pathogenesis Ieonatal pneumonia, pulmonary and extrapulmonary injuries are caused directly and indirectly by the invading microorganisms or foreign material and by poorly targeted or inappropriate responses by the host defense system that damage healthy host tissues as badly or worse than the invading agent.
The activated inflammatory response often results in targeted migration of phagocytes, with the release of toxic substances from granules and other microbicidal packages and the initiation of poorly regulated cascades (eg, complement, coagulation, cytokines). These cascades may directly injure host tissues and adversely alter endothelial and epithelial integrity, vasomotor tone, intravascular thrombi and thrombolysis, and the activation state of fixed and migratory phagocytes at the inflammatory focus.
Alveolar diffusion barriers may increase, intrapulmonary shunts may worsen, and ventilation-perfusion mismatch may further impair gas exchange despite endogenous homeostatic attempts to improve matching by regional vasoconstriction or bronchoconstriction. Since the myocardium has to work harder to overcome the alterations in pulmonary vascular resistance that accompany the above changes of pneumonia, the lungs may be less able to add oxygen and remove carbon dioxide from mixed venous blood for delivery to end organs. The spread of infection or inflammatory response, either systemically or to other focal sites, further exacerbates the situation.
Newborns pneumonias classification:
A. Intrauterine and postnatal.
B. Clinical forms: bronchopneumonia, – interstitial pneumonia.
|
C. Hardness:
D. Duration: |
a) Mild (no complicated) form; b) Moderate form; c) Severe form (breath insufficiency II–III stages, cardiac and vascular syndromes, neurotoxicosis, acidic and alkaline disbalances). a) Acute; b) Subacute; c) Prolonged. |
CLINICAL: risk factors for congenital pneumonia include the following:
1. Unexplained preterm labor
2. Rupture of membranes before the onset of labor
3. Membrane rupture more than 18 hours before delivery
4. Maternal fever (>38°C/100.4°F)
5. Uterine tenderness
6. Foul-smelling amniotic fluid
7. Infection of the maternal genitourinary tract
8. Previous infant with neonatal infection
9. Nonreassuring fetal well-being test results
10. Fetal tachycardia
11. Meconium in the amniotic fluid
12. Recurrent maternal urinary tract infection
13. Gestational history of illness consistent with an organism known to have transplacental pathogenic potential
Review antenatal screening tests for infection, such as serologic tests for syphilis and birth canal tests for Neisseria gonorrhea, Chlamydia species, or group B Streptococcus, as well as any treatment courses and testing for cure.
Intrapartum antibiotic therapy reduces the risk of postpartum maternal infection and infection of the infant in the presence of some of these risk factors, but it does not eliminate the risk.
Absence of these risk factors does not exclude pneumonia.
Physical: Physical findings may be pulmonary, systemic, or localized.
Pulmonary findings
· Tachypnea (respiratory rate >60/min) may be present.
· Expiratory grunting may occur.
· Accessory respiratory muscle recruitment, such as nasal flaring and retractions at subcostal, intercostal, or suprasternal sites, may occur.
· Airway secretions may vary substantially in quality and quantity but are most often profuse and progress from serosanguinous to a more purulent appearance. White, yellow, green, or hemorrhagic colors and creamy or chunky textures are not infrequent.
· If aspiration of meconium, blood, or other proinflammatory fluid is suspected, other colors and textures reflective of the aspirated material are seen.
· Rales, rhonchi, and cough are all observed much less frequently in infants with pneumonia than in older individuals. If appreciated, they may be caused by noninflammatory processes, such as congestive heart failure, condensation from humidified gas administered during mechanical ventilation, or endotracheal tube displacement. Although alternative explanations are possible, these findings should prompt careful consideration of pneumonia in the differential diagnosis.
· Cyanosis of central tissues, such as the trunk, implies a deoxyhemoglobin concentration of approximately 5 g/dL or more and is consistent with severe derangement of gas exchange from severe pulmonary dysfunction as in pneumonia, although congenital structural heart disease, hemoglobinopathy, polycythemia, and pulmonary hypertension (with or without other associated parenchymal lung disease) must be considered.
· Infants may have external staining or discoloration of skin, hair, and nails when meconium, blood, or other implicated materials are aspirated. The oral, nasal, and, especially, tracheal presence of such substances is particularly suggestive.
· In infants requiring respiratory support, such as increased oxygen concentration, positive pressure ventilation, or continuous positive airway pressure, increased respiratory support requirements are common before recovery begins.
· Infants with pneumonia may manifest asymmetry of breath sounds and chest excursions, which suggest air leak or emphysematous changes secondary to partial airway obstruction.
Systemic findings – Often mirror manifestations seen with sepsis or other severe infections
· Temperature instability
· Skin rash
· Jaundice at birth
· Tachycardia
· Glucose intolerance
· Abdominal distention
· Hypoperfusion
· Oliguria
Localized findings
· Conjunctivitis
· Vesicles or other focal skin lesions
· Unusual nasal secretions
· Erythema, swelling, growth, unusual drainage, or asymmetry of other structures suggestive of inflammation
Other findings
· Adenopathy suggests long-standing infection and should suggest a more chronic causative agent.
· Hepatomegaly from infection may result from the presence of some chronic causative agents, cardiac impairment, or increased intravascular volume. Apparent hepatomegaly may result if therapeutic airway pressures result in generous lung inflation and downward displacement of a normal liver.
Causes: Pneumonia that becomes clinically evident within 24 hours of birth may originate at 3 different times. Overlap often exists among the 3 types, and assigning a particular pneumonic episode to one of these categories may be difficult. The 3 categories of congenital pneumonia are (1) true congenital pneumonia, (2) intrapartum pneumonia, and (3) postnatal pneumonia. Not all pneumonia diagnosed in the first 24 hours of life is infectious; nonetheless, many cases are infectious and benefit from targeted antimicrobial therapy.
True congenital pneumonia is already established at birth.
· True congenital pneumonia may be established long before birth or relatively shortly before birth.
· The infant has clinical signs of pneumonia almost immediately after birth. Further deterioration is frequent as the process progresses and the infant is confronted with the exigencies of adapting to extrauterine existence.
· If the infant tolerated labor poorly or has been exposed to agents that depress respiratory effort, the infant may initially be apneic, with no ability to manifest signs of respiratory distress.
Intrapartum pneumonia is acquired during passage through the birth canal.
· Intrapartum pneumonia may be acquired via hematogenous or ascending transmission, or it may result from aspiration of infected or contaminated maternal fluids or from mechanical or ischemic disruption of a mucosal surface that has been freshly colonized with a maternal organism of appropriate invasive potential and virulence.
· Infants who aspirate proinflammatory foreign material, such as meconium or blood, may manifest pulmonary signs immediately after or very shortly after birth.
· Infectious processes often have a honeymoon period of a few hours before sufficient invasion, replication, and inflammatory response have occurred to cause clinical signs.
Postnatal pneumonia in the first 24 hours of life originates after the infant has left the birth canal.
· Postnatal pneumonia may result from some of the same processes as the other forms, but infection occurs after the birth process.
· Colonization of a mucoepithelial surface with an appropriate pathogen from a maternal or environmental source and subsequent disruption allows the organism to enter the bloodstream, lymphatics, or deep parenchymal structures.
· The pressure to use antibiotics encountered in many neonatal intensive care units (NICUs) often results in an infant predisposition to colonization by resistant organisms of unusual pathogenicity. Invasive therapies typically required in these infants often allow microbes accelerated entry into deep structures that ordinarily are not easily accessible.
· Enteral feedings may result in aspiration events of significant inflammatory potential. Indwelling feeding tubes may further predispose infants to gastroesophageal reflux and other aspiration events. These infants are often relatively asymptomatic at birth or manifest noninflammatory pulmonary disease consistent with gestational age, but they develop signs that progress well after 24 hours.
Differential diagnosis. Consider any other diseases that may present with respiratory dysfunction in the first 24 hours of life. Consider that any of the conditions listed above may have superimposed pneumonia as well.
Lab Studies: The most useful tests for congenital pneumonia facilitate identification of the infective microorganism. Results can be used for therapeutic decisions and prognostic and infection control considerations.
· Cell culture (the foul smell of amniotic fluid)
· Blood culture
· Culture of specimens from lumbar puncture. Spinal fluid may yield a pathogen when blood does not (especially following maternal antibiotic pretreatment), or the presence of the pathogen in spinal fluid may indicate the need for alteration in the selection, dosage, and duration of antibiotic therapy even if cultures from other sites yield the same organism.
· Culture of specimens from endotracheal aspiration
· Culture from extrapulmonary sites (abscesses, conjunctivitis, skin lesions, and vesicles). Detection of microorganisms at inflamed extrapulmonary sites may be helpful, since concurrent involvement of the lungs is likely.
Serologic tests have limited use but may offer some insights.
Markers of inflammation: Various indices derived from differential leukocyte counts have been used most widely for this purpose, although noninfectious causes of such abnormal results are numerous, and many reports have been published regarding infants with proven infection who initially had neutrophil indices within reference ranges.
Quantitative measurements of C-reactive protein, cytokines tests may be useful in assessing the resolution of an inflammatory process, including infection, but they are not sufficiently precise to establish a diagnosis without additional supporting information.
Imaging Studies:
1. Radiography: A well-centered, appropriately penetrated, anteroposterior chest radiograph is often helpful. When considering pneumonia, devote particular attention to the following (fig. 6,7):
§ Costophrenic angles
§ Pleural surfaces
§ Diaphragmatic margins
§ Cardiothymic silhouette
§ Pulmonary vasculature
§ Right major fissure
§ Air bronchograms overlying the cardiac shadow
§ Lung expansion
§ Patterns of aeration
Fig. 6,7. X-ray of newborns with pneumonia.
2. Sonography: Ultrasound may be helpful in selected circumstances. Sonograms are particularly useful for identifying and localizing fluid in the pleural and pericardial spaces.
3. CT or MRI may be helpful for excluding tumors, aberrant vessels, sequestered lobes, or other primary pulmonary anomalies and for establishing the presence of an infiltrate.
Procedures:
1. Thoracentesis: If significant pleural fluid is detected radiographically or sonographically, consider thoracentesis for Gram staining, culturing, and biochemical testing.
2. Bronchoscopy: The rigid technique of direct bronchoscopy is used in larger infants; fiberoptic technique is used in smaller infants or infants in whom the site is not easily reached using the rigid technique.
3. Aspiration: If a prominent infiltrate can be adequately localized in multiple planes, direct aspiration of the infected lung may be performed for culturing or biopsy analysis.
Complications:
1. Restrictive pleural effusion
2. Infected pleural effusion
3. Empyema
4. Systemic infection with metastatic foci
5. Pulmonary Hypertension, Persistent-newborn
6. Air leak syndrome, including pneumothorax, pneumomediastinum, pneumopericardium, and pulmonary interstitial emphysema
7. Airway injury
8. Obstructive airway secretions
9. Hypoperfusion
10. Chronic lung disease
11. Hypoxic-ischemic and cytokine-mediated end-organ injury
TREATMENT: Therapy in infants with neonatal pneumonia is multifaceted. The goals of therapy are to eradicate infection and provide adequate support of gas exchange to ensure the survival and eventual well being of the infant.
Antimicrobial therapy
1. Initial empiric antibiotics are selected according to the susceptibility pattern of the likely pathogens, based on experience at the institution and tempered by knowledge of delivery of that agent to the suspected infected sites within the lung. At most institutions, initial empiric therapy consists of ampicillin and either gentamicin or cefotaxime. Dosage regimens vary according to gestational and postnatal age, as well as renal function.
2. Since congenital pneumonia frequently results from bloodstream infection attaining an adequate plasma concentration of the antimicrobial agent via a parenteral route is essential.
3. Isolation of a specific pathogen from a normally sterile site in the infant allows revision of therapy to the drug that is least toxic, has the narrowest spectrum, and is most effective. Dosing intervals for ampicillin, cefotaxime, gentamicin, and other antimicrobial agents typically require readjustment once the infant is older than 7 days, if the infant still requires antimicrobial therapy.
4. The duration of antimicrobial therapy for neonatal pneumonia has not been rigorously assessed in comparative trials. Most clinicians treat infants for 7-10 days if clinical signs resolve rapidly. If positive results on culturing were found at a normally sterile site, treatment for 7-10 days following sterilization is prudent. Longer periods of therapy may be warranted if a sequestered focus is seen, such as empyema or abscess, or if metastatic infection develops.
5. Continue to perform careful serial examinations for evidence of complications that may warrant a change in therapy or dosing regimen, surgical drainage, or other intervention.
Respiratory support: Criteria for institution and weaning of supplemental oxygen and mechanical support are similar to those for other neonatal respiratory diseases.
Hemodynamic support
1. Red blood cells should be administered to ensure a hemoglobin concentration of 14-16 g/dL in the acutely ill infant.
2. Delivery of adequate amounts of glucose and maintenance of thermoregulation, electrolyte balance, and other aspects of neonatal supportive care also are warranted.
Nutritional support: Attempts at enteral feeding usually are withheld in favor of parenteral nutritional support until respiratory and hemodynamic status is sufficiently stable.
MEDICATION
|
Drug Name |
Ampicillin (Omnipen, Polycillin, Principen) — offers antimicrobial efficacy against group B Streptococcus, many types of other streptococci, L monocytogenes, and some strains of E coli, enterococci, and untypable H influenzae. |
|
Pediatric Dose |
Birth weight <2000 g: 50 mg/kg IV/IM q12h in first 24 h after birth |
|
Drug Name |
Cefotaxime (Claforan) — offers antimicrobial efficacy against many gram-negative pathogens |
|
Pediatric Dose |
Newborn infants of all birth weights: 50 mg/kg IV/IM q12h |
|
Drug Name |
Gentamicin (Garamycin) — offers antimicrobial efficacy against many gram-negative pathogens, including E coli, untypable H influenzae, Klebsiella species, and other enteric organisms. Also variably effective against some strains of certain gram-positive organisms, including S aureus, enterococci, and L monocytogenes. |
|
Pediatric Dose |
In first days of life, 4 mg/kg IM/IV may be administered as single daily dose in full-term well-perfused infants who are believed to have normal renal function |
Deterrence/Prevention:
1. Consider intrapartum antibiotic chemoprophylaxis with penicillin or another appropriate antimicrobial agent in mothers with the following risk factors for early-onset group B streptococcal disease:
o Premature delivery
o Membrane rupture more than 18 hours before delivery
o Intrapartum fever
o Group B streptococcal bacteriuria
o History of previous infant with early-onset neonatal group B streptococcal infection
o Known colonization of birth canal by group B Streptococcus
2. Prevention strategies may include antepartum and intrapartum broad-spectrum antibiotic treatment in mothers with preterm rupture of membranes or in whom chorioamnionitis is suspected.
4. The cost-versus-benefit balance of immunoprophylaxis against respiratory syncytial virus is controversial.
Prognosis: Although quantitation of risk is difficult and strongly influenced by gestational age, congenital anomalies, and coexisting cardiovascular disease, there is a consensus that congenital pneumonia increases the following:
Meconium Aspiration Syndrome Meconium-stained amniotic fluid may be aspirated during labor and delivery, causing neonatal respiratory distress. Because meconium rarely is found in the amniotic fluid prior to 34 weeks’ gestation, meconium aspiration chiefly affects infants at term and postterm. In developing countries with less availability of prenatal care and where home births are common, incidence of MAS is thought to be higher and is associated with a greater mortality rate. The mortality rate for MAS resulting from severe parenchymal pulmonary disease and pulmonary hypertension is as high as 20%.
Pathophysiology: meconium passage results from neural stimulation of a mature GI tract. As the fetus approaches term, the GI tract matures, and vagal stimulation from head or cord compression may cause peristalsis and relaxation of the rectal sphincter leading to meconium passage.
Although the etiology is not well understood, effects of meconium are well documented. Meconium directly alters the amniotic fluid, reducing antibacterial activity and subsequently increasing the risk of perinatal bacterial infection. Additionally, meconium is irritating to fetal skin, thus increasing the incidence of erythema toxicum. However, the most severe complication of meconium passage in utero is aspiration of stained amniotic fluid before, during, and after birth. Aspiration induces 3 major pulmonary effects, which are airway obstruction, surfactant dysfunction, and chemical pneumonitis.
Airway obstruction Complete obstruction of the airways results in atelectasis. Partial obstruction causes air trapping and hyperdistention of the alveoli. Hyperdistention of the alveoli occurs from airway expansion during inhalation and airway collapse around inspissated meconium in the airway, causing increased resistance during exhalation. The gas that is trapped, hyperinflating the lung, may rupture into the pleura (pneumothorax), mediastinum (pneumomediastinum), or pericardium (pneumopericardium).
Surfactant dysfunction Several constituents of meconium, especially the free fatty acids (eg, palmitic, stearic, oleic), have a higher minimal surface tension than surfactant and strip it from the alveolar surface, resulting in diffuse atelectasis.
Chemical pneumonitis Enzymes, bile salts, and fats in meconium irritate the airways and parenchyma, causing a diffuse pneumonia that may begin within a few hours of aspiration.
All of these pulmonary effects can produce gross ventilation-perfusion (V-Q) mismatch. To complicate matters further, many infants with meconium aspiration syndrome (MAS) have primary or secondary persistent pulmonary hypertension of the newborn (PPHN) as a result of chronic in utero stress and thickening of the pulmonary vessels. Finally, though meconium is sterile, its presence in the air passages can predispose the infant to pulmonary infection.
Causes: Factors that promote the passage of meconium in utero include the following:
· Placental insufficiency
· Maternal hypertension
· Preeclampsia
· Oligohydramnios
· Maternal drug abuse, especially of tobacco and cocaine
CLINICAL History: Severe respiratory distress may be present. Symptoms include the following:
· Cyanosis
· End-expiratory grunting
· Alar flaring
· Intercostal retractions
· Tachypnea
· Barrel chest in the presence of air trapping
Green urine may be observed iewborns with meconium aspiration syndrome (MAS) less than 24 hours after birth. Meconium pigments can be absorbed by the lung and excreted in urine.
Physical: Presence of meconium in amniotic fluid is essential to the initiation of the pathogenesis.
Lab Studies:
· Metabolic acidosis from perinatal stress is complicated by respiratory acidosis from parenchymal disease and PPHN.
· Arterial blood gases that measure pH, partial pressure of carbon dioxide (pCO2), partial pressure of oxygen (pO2), and continuous measurement of oxygenation by pulse oximetry are necessary for appropriate management.
Serum electrolytes: Obtain sodium, potassium, and calcium concentrations when the infant with MAS is aged 24 hours because the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and acute renal failure are frequent complications of perinatal stress.
CBC Hemoglobin and hematocrit levels must be sufficient to ensure adequate oxygen-carrying capacity. Thrombocytopenia increases the risk for neonatal hemorrhage. Neutropenia or neutrophilia with left shift of the differential may indicate perinatal bacterial infection.
Imaging Studies:
A chest radiograph is essential to do the following (fig. 8):
· Determine the extent of intrathoracic pathology
· Identify areas of atelectasis and air block syndromes
· Assure appropriate positioning of an endotracheal tube and umbilical arterial catheter
Fig. 8. X-ray of newborn with MAS.
Later in the course of MAS when the infant is stable, imaging procedures of the brain, such as MRI, CT scan, or cranial ultrasound, are indicated if findings of the infant’s neurologic examination are abnormal.
Medical Care:
Prevention
· Obstetricians should monitor fetal status in an attempt to prevent and assuage fetal stress.
· When meconium is detected, administering amnioinfusion with warm sterile saline may be beneficial. This procedure dilutes meconium in the amniotic fluid; therefore, the severity of aspiration may be minimized.
· Upon delivery of the head of the baby, careful suctioning of the posterior pharynx decreases the potential for aspiration of meconium. When aspiration occurs, intubation and immediate suctioning of the airway can remove much of the aspirated meconium.
· No clinical trials justify suctioning based on the consistency of meconium. Do not perform the following harmful techniques to prevent aspiration of meconium-stained amniotic fluid:
1. Squeezing the chest of the baby
2. Inserting a finger into the mouth of the baby
3. Externally occluding the airway of the baby
The American Academy of Pediatrics Neonatal Resuscitation Program Steering Committee has promulgated the following guidelines for management of the baby exposed to meconium:
1. If the baby is not vigorous (Apgar 1-3): Suction the trachea soon after delivery (ie, before many respirations have occurred). Suction for no longer than 5 seconds. If no meconium is retrieved, do not repeat intubation and suction. If meconium is retrieved and no bradycardia is present, reintubate and suction. If the heart rate is low, administer positive pressure ventilation and consider suctioning again later.
2. If the baby is vigorous (Apgar >5): Clear secretions and meconium from the mouth and nose with a bulb syringe or a large-bore suction catheter. In either case, the remainder of the initial resuscitation steps should ensue: dry, stimulate, reposition, and administer oxygen as necessary.
Intervention
· Maintain an optimal thermal environment and minimal handling because these infants are agitated easily and quickly become hypoxemic and acidotic.
· Continue respiratory care. Oxygen therapy via hood or positive pressure is crucial in maintaining adequate arterial oxygenation. If mechanical ventilation is required, make concerted efforts to minimize the mean airway pressure and to use as short an inspiratory time as possible. Use of surfactant has not yet been proven to be efficacious in this setting and is under investigation.
· Although conventional ventilation commonly is used initially, oscillatory, high-frequency, and jet ventilation are alternative effective therapies. Hyperventilation to induce hypocapnia and respiratory alkalosis is used as primary therapy for pulmonary hypertension. Inhaled nitric oxide has displaced the use of most intravenous pulmonary vasodilators.
· Pay careful attention to systemic blood volume and blood pressure (BP). Volume expansion, transfusion therapy, and systemic vasopressors are critical in maintaining systemic BP greater than pulmonary BP, thereby decreasing the right-to-left shunt through the patent ductus arteriosus.
· Extracorporeal membrane oxygenation (ECMO) is employed if all other therapeutic options have been exhausted.
Surgical Care: Although primary management of air block syndromes is achieved by thoracic drainage tubes inserted by a neonatologist, a pediatric surgical consultation may be necessary in severe cases.
Diet: Perinatal distress and severe respiratory distress preclude feeding. Intravenous fluid therapy begins with adequate dextrose infusion to prevent hypoglycemia. Progressively add electrolytes, protein, lipids, and vitamins to ensure adequate nutrition and prevent essential amino acid and essential fatty acid deficiencies.
MEDICATION Drug Category: Pulmonary vasodilating agents — Decreases pulmonary vascular resistance. Administer directly into the main pulmonary artery because the major complication is systemic hypotension without significant effects on pulmonary hypertension. Because of the severe systemic hypotensive effects of tolazoline and nitroprusside, inhaled nitric oxide is used more commonly.
|
Drug Name |
Tolazoline (Priscoline) |
|
Pediatric Dose |
1-2 mg/kg IV infused over 10 min into a vein that drains via the superior vena cava; if arterial pO2 increases, follow with continuous IV infusion of 1-2 mg/kg/h |
|
Drug Name |
Nitroprusside (Nitropress) |
|
Pediatric Dose |
0.25-0.5 mcg/kg/min continuous IV infusion; titrate to effect |
Drug Category: Respiratory gases — Inhaled nitric oxide (NO) has the direct effect of pulmonary vasodilatation without the adverse effect of systemic hypotension. Approved for use if concomitant hypoxemic respiratory failure occurs.
|
Drug Name |
Nitric oxide, inhaled (INOmax) |
|
Pediatric Dose |
20 ppm inhaled via respirator initially; not to exceed 80 ppm; most children respond at 20 ppm and can be weaned to lower doses; effect of pulmonary vasodilatation may still be observed at 5 ppm |
Drug Category: Systemic vasoconstrictors — Used to prevent right-to-left shunting by raising systemic pressure above pulmonary pressure. Systemic vasoconstrictors include dopamine, dobutamine, and epinephrine. Dopamine is the most commonly used.
|
Drug Name |
Dopamine (Intropin) |
|
Pediatric Dose |
5-20 mcg/kg/min IV |
Drug Category: Sedatives — Maximizes efficiency of mechanical ventilation and minimizes oxygen consumption.
|
Drug Name |
Morphine |
|
Pediatric Dose |
0.05-0.2 mg/kg/dose IV over 5 min q2-4h prn |
|
Drug Name |
Fentanyl (Sublimaze) — Potent opioid used for analgesia, sedation, and anesthesia. Has a shorter duration of action than morphine. |
|
Pediatric Dose |
1-4 mcg/kg/dose IV slow push |
|
Drug Name |
Phenobarbital (Luminal) |
|
Pediatric Dose |
20 mg/kg IV as a single dose, administer slowly over 10-15 min |
|
Drug Name |
Pentobarbital (Nembutal) |
|
Pediatric Dose |
2-6 mg/kg IV slow push |
Drug Category: Neuromuscular blocking agents — Used for skeletal muscle paralysis to maximize ventilation by improving oxygenation and ventilation. Also used to reduce barotrauma and minimize oxygen consumption.
|
Drug Name |
Pancuronium (Pavulon) |
|
Pediatric Dose |
Initial dose: 0.1 mg/kg (0.04-0.15 mg/kg) IV push |
Further Inpatient Care:
· Thorough cardiac examination is necessary to eliminate the possibility of cyanotic heart disease.
· Confirming the degree of pulmonary hypertension, prior to instituting therapy, is extremely important.
Complications:
· A few infants with MAS have increased incidence of infections in the first year of life because the lungs are still recovering.
· Children with MAS may develop chronic lung disease as a result of intense pulmonary intervention.
Prognosis:
· Nearly all infants with MAS have complete recovery of pulmonary function.
· Events initiating the meconium passage may cause the infant to have long-term neurologic deficits, including CNS damage, seizures, mental retardation, and cerebral palsy.
Pulmonary Interstitial Emphysema: Pulmonary interstitial emphysema (PIE) is a collection of gases outside of the normal air passages and inside the connective tissue of the peribronchovascular sheaths, interlobular septa, and visceral pleura secondary to alveolar and terminal bronchiolar rupture. PIE is more frequent in premature infants who require mechanical ventilation for severe lung disease. Once PIE is diagnosed, intensive respiratory management is required to reduce mortality and morbidity. The mortality rate associated with PIE is reported
The process often occurs in conjunction with respiratory distress syndrome (RDS). Other predisposing etiologic factors include meconium aspiration syndrome (MAS), amniotic fluid aspiration, and infection.
Positive pressure ventilation (PPV) and reduced lung compliance are significant predisposing factors. However, in extremely premature infants, pulmonary interstitial emphysema can occur at low mean airway pressure and probably reflects the underdeveloped lung’s increased sensitivity to stretch. Pulmonary interstitial emphysema has been rarely reported in the absence of mechanical ventilation or continuous positive airway pressure.
Infants with RDS have an initial increase in interstitial and perivascular fluid that rapidly declines over the first few days of life. This fluid may obstruct the movement of gas from ruptured alveoli or airways to the mediastinum, causing an increase of pulmonary interstitial emphysema.
Another possible mechanism for entrapment of air in the interstitium is the increased amount of pulmonary connective tissue in the immature lung. The entrapment of air in the interstitium may initiate a vicious cycle in which compression atelectasis of the adjacent lung theecessitates a further increase in ventilatory pressure with still more escape of air into the interstitial tissues.
Plenat et al described two topographic varieties of air leak:
1) intrapulmonary pneumatosis
2) intrapleural pneumatosis.
In the intrapulmonary type, which is more common in premature infants, the air remains trapped inside the lung and frequently appears on the surface of the lung, bulging under the pleura in the area of interlobular septa. This phenomenon develops with high frequency on the costal surface and the anterior and inferior edges but can involve all of the pulmonary areas.
In the intrapleural variety, which is more common in more mature infants with compliant lungs, the abnormal air pockets are confined to the visceral pleura, often affecting the mediastinal pleura. The air of pulmonary interstitial emphysema can be located inside the pulmonary lymphatic network.[4]
The extent of pulmonary interstitial emphysema can vary. It can present as an isolated interstitial bubble, several slits, lesions involving the entire portion of one lung, or diffuse involvement of both lungs. Pulmonary interstitial emphysema does not preferentially localize in any one of the 5 pulmonary lobes.
Pulmonary interstitial emphysema compresses adjacent functional lung tissue and vascular structures and hinders both ventilation and pulmonary blood flow, thus impeding oxygenation, ventilation, and blood pressure. This further compromises the already critically ill infant and significant increases mortality and morbidity. Pulmonary interstitial emphysema can completely regress or decompress into adjacent spaces, causing pneumomediastinum, pneumothorax, pneumopericardium, pneumoperitoneum, or subcutaneous emphysema
Epidemiology
The prevalence of pulmonary interstitial emphysema widely varies with the population studied. In a study by Gaylord et al, pulmonary interstitial emphysema developed in 3% of infants admitted to the neonatal intensive care unit (NICU).
In a retrospective case-controlled study, 11 (24%) of 45 extremely low birth weight infants developed pulmonary interstitial emphysema. This study was done in the present era of tocolysis, antenatal steroids, and postnatal surfactant administration; however, all infants included in the study were treated with conventional ventilator in the assist-control mode before the onset of pulmonary interstitial emphysema.
The reported incidence of pulmonary interstitial emphysema in published clinical trials can be useful. In a randomized trial of surfactant replacement therapy at birth, in premature infants born at 25-29 weeks’ gestation, Kendig et al reported pulmonary interstitial emphysema in 8 (26%) of 31 control neonates and in 5 (15%) of 34 surfactant-treated neonates.
Another randomized controlled trial of prophylaxis versus treatment with bovine surfactant ieonates born at less than 30 weeks’ gestation included 2 (3%) of 62 early surfactant-treated neonates, 5 (8%) of 60 late surfactant-treated neonates, and 15 (25%) of 60 control neonates with pulmonary interstitial emphysema.
International statistics
Studies reflecting international frequency demonstrated that 2-3% of all infants in NICUs develop pulmonary interstitial emphysema. When limiting the population studied to premature infants, this frequency increases to 20-30%, with the highest frequencies occurring in infants weighing fewer than
In another study of low birth weight infants, the incidence of pulmonary interstitial emphysema was 42% in infants with birth weight of 500-
Sex- and age-related demographics
In a study by Plenat et al, pulmonary interstitial emphysema developed equally in both sexes (21 males, 18 females). Although these data also included cases with intrapleural pneumatosis, no relationship between sex and type of interstitial pneumatosis is noted.
Pulmonary interstitial emphysema is more common in infants of lower gestational age. Pulmonary interstitial emphysema usually occurs within the first weeks of life. Development of pulmonary interstitial emphysema within the first 24-48 hours after birth is often associated with extreme prematurity, very low birth weight, perinatal asphyxia, and/or neonatal sepsis and frequently indicates a grave prognosis.
Pathophysiology: PIE often occurs in conjunction with respiratory distress syndrome (RDS), but other predisposing etiologic factors include meconium aspiration syndrome (MAS), amniotic fluid aspiration, and infection.
Causes: Risk factors
· Prematurity
· Respiratory distress syndrome
· Meconium aspiration syndrome
· Amniotic fluid aspiration
· Infection – Neonatal sepsis, pneumonia, or both
· Low Apgar score or need for PPV during resuscitation at birth
· Use of high peak airway pressures on mechanical ventilation
· Incorrect positioning of the endotracheal tube in one bronchus
CLINICAL History: PIE is a radiographic and pathologic diagnosis. In most cases, the discovery of PIE may be preceded by a decline in the baby’s clinical condition. Hypotension and difficulty in oxygenation and ventilation can suggest the development of PIE. Alternatively, the baby can present with the signs of one of the complications of PIE, such as pneumothorax. Sometimes, PIE becomes apparent following reexpansion of a collapsed lung after drainage of a pneumothorax.
Physical: No specific signs of PIE exist. Overinflation of the chest wall and crepitations on auscultation on the affected side may be present.
Diagnostic Considerations
The roentgenologic appearance of pulmonary interstitial emphysema (PIE) can be confused with the following :
- Air-bronchogram in respiratory distress syndrome (RDS)
- Aspiration pneumonia
- Pulmonary edema
- Distended airways in patients on a ventilator
Other differential diagnosis of persistent pulmonary interstitial emphysema includes the following:
- Congenital cystic adenomatoid malformation
- Lymphangiectasia
- Bronchogenic cysts
- Congenital lobar emphysema
- Cystic lymphangioma
- Sequel of prior infection
- Diaphragmatic hernia
Medical Care: Different treatment modalities have been used to manage pulmonary interstitial emphysema (PIE), with variable success. Admission/transfer to a neonatal intensive care unit (NICU) is indicated for these patients. A thoracentesis set should be readily available due to the possibility of air leak, including pneumothorax and pneumopericardium.
Although the primary risk factor for pulmonary interstitial emphysema, prematurity, is rarely preventable, attention should be given to the use of as little mechanical ventilatory support as is necessary for the patient’s very fragile lungs.
Because pneumothorax is a known complication, anticipatory guidance for this possibility should be provided for all those caring for the infant. Appropriate personnel should be readily available to address this complication.
In addition to pulmonary treatment, the overall importance of appropriate nutritional management of these ill newborns cannot be overstressed. Most of these infants are treated with total parenteral nutrition and require diligent attention.
All infants with pulmonary interstitial emphysema need to be under the care of a neonatologist. In some cases, pediatric pulmonology and pediatric surgery consultations are appropriate.
Lateral Decubitus Positioning
This conservative approach has been used with success and is most effective in infants with unilateral pulmonary interstitial emphysema. The infant is placed in the lateral decubitus position with the affected lung dependent. This therapy can result in plugging of dependent airways and improved oxygenation of the nondependent lung. The latter allows for overall decreased ventilatory settings. The combination of the above factors helps in resolution of pulmonary interstitial emphysema.
In different case studies of lateral decubitus positioning as a treatment of unilateral pulmonary interstitial emphysema in infants, pulmonary interstitial emphysema resolved in 48 hours to 6 days with minimal recurrence and a low failure rate. Lateral decubitus positioning should be considered as an early first-line therapy in the management of unilateral pulmonary interstitial emphysema. Lateral decubitus positioning has been used successfully for patients with bilateral pulmonary interstitial emphysema when one side is more significantly affected.
Selective Main Bronchial Intubation and Occlusion
Many case reports detail successful treatment of infants with severe localized pulmonary interstitial emphysema by selective intubation of the contralateral bronchus. This maneuver decompresses the overdistended lung tissue and avoids exposing it to high positive inflationary pressures. Selective bronchial intubation of the right main bronchus is not a difficult procedure; the left side may be more difficult.
This procedure uses an endotracheal tube of the same diameter as for a regular intubation. However, the tube is inserted 2-
Weintraub et al have described a method for left selective bronchus intubation using a regular Portex endotracheal tube in which an elliptical hole
Another method of selective intubation is the use of a small fiberoptic bronchoscope to direct the endotracheal tube tip into the desired bronchus. Selective intubation under fluoroscopy can also be considered.
Potential complications of the selective intubation/ventilation include the following:
- Atelectasis in the affected lung
- Injury to bronchial mucosa with subsequent scarring and stenosis
- Acute hypoventilation or hypoxemia if ventilating one lung is inadequate
- Excessive secretions
- Hyperinflation of the intubated (nonoccluded) lung
- Upper lobe collapse when intubating the right lung
- Bradycardia
Despite potential risks, selective bronchial intubation is a desirable alternative to lobectomy in a patient with persistent, severe, localized pulmonary interstitial emphysema causing mediastinal shift and compression atelectasis that is not responding to conservative management. This procedure should be attempted before any surgical intervention.
High-Frequency Ventilation
Keszler et al found that high-frequency jet ventilation (HFJV) was safe and more effective than rapid-rate conventional ventilation in the treatment of newborns with pulmonary interstitial emphysema. Their study in 144 newborns with pulmonary interstitial emphysema showed that with HFJV, similar oxygenation and ventilation was obtained at lower peak and mean airway pressures. These results suggested that less air would leak into the interstitial spaces in these infants.
Similar effects can be achieved by use of high-frequency oscillatory ventilation (HFOV). A study by Clark et al demonstrated the efficacy of HFOV in 27 low-birth-weight infants who developed pulmonary interstitial emphysema and respiratory failure while on conventional ventilation.
Overall survival ionseptic patients was 80%. Surviving patients showed continued improvement in oxygenation and ventilation at an increasingly lower fraction of inspired oxygen (FiO2) and proximal airway pressure with resolution of pulmonary interstitial emphysema, whereas nonsurvivors progressively developed chronic respiratory insufficiency with continued pulmonary interstitial emphysema from which recovery was not possible.
Clark et al hypothesized that interstitial air leak is decreased during HFOV because adequate ventilation is provided at lower peak distal airway pressures. Although this mode of ventilation has inherent risks, it can be a very effective tool in experienced hands for the treatment of severe diffuse pulmonary interstitial emphysema. Care must be taken in smaller infants who require a high amplitude to ventilate because the active exhalation during HFOV may cause small airway collapse and exacerbate gas trapping.
Squires et al also found that HFOV had some benefits for preterm infants with severe pulmonary interstitial emphysema. Of the 19 cases studied, 15 infants survived.
Lobectomy
Lobectomy is indicated in a small number of patients with localized pulmonary interstitial emphysema when spontaneous regression is not occurring and medical management has failed. Although, a recent case report of spontaneous resolution of diffuse persistent pulmonary interstitial emphysema with pneumomediastinum supports a consideration of nonsurgical approach in a stable infant with persistent pulmonary interstitial emphysema. Thus, clear guidelines for surgical intervention are difficult to establish, lobectomy should be reserved for infants in whom the risks of recurring complications outweigh those of surgery. It seems most helpful in infants who develop severe lobar emphysema.
Other Treatment Modalities
Case reports and/or case series describe a variety of other approaches for the management of pulmonary interstitial emphysema, including the following:
- A 3-day course of dexamethasone (0.5 mg/kg/d)
- Chest physiotherapy with intermittent 100% oxygen in localized and persistent compressive pulmonary interstitial emphysema
- Artificial pneumothorax
- Multiple pleurotomies
- Heliox with inhaled nitric oxide
Despite success claimed by the authors, the efficacy of these treatment modalities from these case reports seems questionable. With advancements in respiratory care, these treatment modalities are rarely used.
Prognosis
Pulmonary interstitial emphysema can predispose an infant to other air leaks. In a study by Greenough et al, 31 of 41 infants with pulmonary interstitial emphysema developed pneumothorax, compared with 41 of 169 infants without pulmonary interstitial emphysema. In addition, 21 of 41 babies with pulmonary interstitial emphysema developed intraventricular hemorrhage (IVH), compared with 39 of 169 among infants without pulmonary interstitial emphysema.
Pulmonary interstitial emphysema may not resolve for 2-3 weeks; therefore, it can increase the length of time of mechanical ventilation and the incidence of bronchopulmonary dysplasia. Some infants may develop chronic lobar emphysema, which may require surgical lobectomies.
In a more recent study in the postsurfactant era, 4 of 11 infants with pulmonary interstitial emphysema developed severe IVH (grade 2 or higher) compared with 4 of 34 infants without pulmonary interstitial emphysema. Additionally, pulmonary interstitial emphysema remained significantly associated with death (odds ratio, 14.4; 95% confidence interval [CI], 1-208; P = .05).
Long-term follow-up data are scarce. Gaylord et al demonstrated a high (54%) incidence of chronic lung disease in survivors of pulmonary interstitial emphysema compared with their nursery’s overall incidence of 32%. In addition, 19% of the infants developed chronic lobar emphysema; 50% received surgical lobectomies.
The mortality rate associated with pulmonary interstitial emphysema is reported to be as high as 53-67%.Lower mortality rates of 24% and 38% reported in other studies could result from differences in population selection. Morisot et al reported an 80% mortality rate with pulmonary interstitial emphysema in infants with birth weight of fewer than
The early appearance of pulmonary interstitial emphysema (< 48 h after birth) is associated with increased mortality. However, this may reflect the severity of the underlying parenchymal disease.
Prevention of Pulmonary Interstitial Emphysema
Surfactant
Prophylactic surfactant administration to infants (< 30-32 weeks’ gestation) judged to be at risk of developing respiratory distress syndrome (RDS) compared with selective use of surfactant in infants with established RDS has been demonstrated to decrease the risk of pulmonary interstitial emphysema.
Meta-analysis of early surfactant replacement therapy with brief ventilation compared with later, selective surfactant replacement and continued mechanical ventilation suggests a trend towards a decreased incidence of air leak syndromes in premature infants in the early surfactant group. Early surfactant treatment, less invasive ventilatory support, or both could be responsible factors for the observed beneficial trend.
According to one report, in infants with respiratory distress, multiple doses of animal-derived surfactant extract resulted in greater improvements in oxygenation and ventilatory requirements, a decreased risk of pneumothorax, and a trend toward improved survival.
High-frequency ventilation
In a study comparing high-frequency positive pressure ventilation (HFPPV) to conventional ventilation, Pohlandt et al reported a reduction in the risk of pulmonary interstitial emphysema with HFPPV. Review of different trials of elective high-frequency oscillatory ventilation (HFOV) versus conventional ventilation for acute pulmonary dysfunction in preterm infants suggests an increase in the incidence of air leak syndromes, including but not limited to pulmonary interstitial emphysema in the HFOV group.
In contrast, a prospective randomized multicenter study of HFOV versus conventional ventilation in premature infants with RDS showed no difference in the incidence of pulmonary interstitial emphysema. Limited data regarding rescue HFOV for pulmonary dysfunction in the preterm infant also showed no difference in the rate of pulmonary interstitial emphysema.
Cochrane reviews of trials of elective high-frequency jet ventilation (HFJV) versus conventional ventilation for RDS demonstrated no significant difference in the incidence of air leak syndrome in the individual trials or in the overall analysis.
In summary, current literature suggests elective or rescue high-frequency ventilation does not prevent the development of pulmonary interstitial emphysema.
Other considerations
Different modes of conventional ventilation do not appear to affect the risk of pulmonary interstitial emphysema. No significant difference in the rate of pulmonary interstitial emphysema was found either in pooled analysis within subgroups or overall pooled analysis of trials comparing volume-targeted versus pressure-limited ventilation in the neonate.
Avoid use of high peak inspiratory pressure (PIP). Be careful (watch the manometer) during manual ventilation.
Long-Term Monitoring
Monitoring for physical and psychomotor development in a neonatal follow-up care program or equivalent program is important because most infants with pulmonary interstitial emphysema are premature and are at risk for developmental delay. In addition, pulmonary interstitial emphysema has been associated with increased risks of intraventricular hemorrhage (IVH) and periventricular leukomalacia (PVL), which also increase the risks of developmental delay in these infants.
Patients with chronic lung disease may need pediatric pulmonology follow-up care.
References:
1. Avery‘s neonatology: pathophysiology and management of the newborn / G. B. Avery, M. G. MacDonald, M. M. K. Seshia [et al.]. – 6th ed. – Philadelphia : Lippincott Williams and Wilkins, 2005. – 354 p.
2. Nelson Textbook of Pediatrics, 19th Edition. – Expert Consult Premium Edition – Enhanced Online Features and Print / by Robert M. Kliegman, MD, Bonita M.D. Stanton, MD, Joseph St. Geme, Nina Schor, MD, PhD and Richard E. Behrman, MD. – 2011. – 2680 p.
3. Pediatrics / Edited by O.V. Tiazhka, T.V. Pochinok, A.M. Antoshkina/ – Vinnytsa: Nova Knyha Publishers, 2011. – 584 p.
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