2. REFERENCES
Journal/ Literature Review:
Persistent Pulmonary Hypertension of the newborn (Ann R Stark, MD December 2017)
Clinical features and diagnosis of meconium aspiration syndrome (Joseph A Garcia-Prats, MD January 2018)
Prevention and management of meconium aspiration syndrome (Joseph A Garcia-Prats, MD January 2018)
3. MECONIUM ASPIRATION SYNDROME
Meconium aspiration syndrome (MAS) is defined as respiratory
distress in newborn infants born through meconium-stained
amniotic fluid (MSAF) whose symptoms cannot be otherwise
explained
MAS can present with varying degrees of severity from mild
respiratory distress to life-threatening respiratory failure.
It typically occurs in full-term or postmature infants. Fetal
aspiration of the meconium then causes obstruction of small
airways with associated atelectasis and air trapping.
4. Is a thick, black-green, odorless material first demonstrable in the fetal intestine during
the third month of gestation.
Results from the accumulation of debris including:
Desquamated cells from the intestine and skin
Gastrointestinal mucin
Lanugo hair
Fatty material from the vernix caseosa
Amniotic fluid
Intestinal secretions
Sterile when aspirated into the lung, it may stimulate the release of cytokines and
other vasoactive substances that lead to cardiovascular and inflammatory responses in
the fetus and newborn
WHAT IS MECONIUM?
5. • The incidence of MSAF varies from 8% to 20% of all deliveries.
• The risk of MAS and MSAF is greatest in postmature and small for gestational age
infants
• Increases from 1.6% at 34 to 37 weeks to 30% at ≥42 weeks.
• Of infants born through MSAF, approximately 5% go on to develop meconium
aspiration syndrome (MAS).
• The rates of MSAF were higher in black (22.6 percent) and South Asian infants (16.8
percent) compared with those who were white (15.7 percent).
• Changes in obstetric care, with the reduction in postmature births: the incidence of MAS
is decreased.
INCIDENCE
6. RISK FACTORS
• Aging of the placenta if the pregnancy goes far past the due
date (Post term pregnancy)
• Decreased oxygen to the infant while in the uterus
• Diabetes in the pregnant mother
• Difficult delivery or long labor
• High blood pressure in the pregnant mother
• Maternal Heavy cigarette smoking
• Maternal chronic respiratory or Cardio vascular disease
• Oligohydramnios
• IUGR
• Abnormal fetal Heart rate pattern
7. PATHOPHYSIOLOGY
• Pathophysiology of MAS involves intrauterine passage of meconium,
aspiration, and pulmonary disease, which results in hypoxemia and
acidosis
• Persistent pulmonary hypertension of the newborn (PPHN) frequently
accompanies severe MAS and contributes to hypoxemia
• Birth depression occurs in 20 to 33 percent of infants born through
meconium-stained amniotic fluid (MSAF) caused by pathologic
intrauterine processes, primarily chronic asphyxia and infection
intrauterine stress leads to the passage and aspiration of meconium
by the fetus.
9. • Passage of meconium occurs early in the first trimester of pregnancy
• Fetal defecation slows after 16 weeks gestation and becomes infrequent by 20
weeks, concurrent with innervation of the anal sphincter
• From approximately 20 to 34 weeks, fetal passage of meconium remains
infrequent
• Meconium passage may be caused by increased peristalsis and relaxation of
the anal sphincter due to increased vagal outflow associated with umbilical
cord compression or increased sympathetic inflow during hypoxia.
MECONIUM PASSAGE
11. • Meconium in amniotic fluid can be aspirated during fetal gasping or in
the initial breaths after delivery.
• Prolonged hypoxia stimulates fetal breathing and gasping that can lead
to inhalation of amniotic fluid.
• Meconium that remains in the hypopharynx or trachea after delivery
can be aspirated during the initial breaths.
• This is more likely to occur in a depressed infant.
ASPIRATION
13. • Aspirated meconium can interfere with normal breathing by several
mechanisms.
• These include:
Airway obstruction
Chemical Irritation and Inflammation
Infection
Surfactant inactivation
• It is likely that most cases of severe MAS are primarily caused by intrauterine
pathologic processes, primarily asphyxia and infection, rather than the
aspiration of meconium by itself
PULMONARY DISEASE
15. • Airway obstruction can be complete or partial.
Complete obstruction leads to distal atelectasis.
Partial airway obstruction occurs when particulate
meconium partly occludes the airway.
AIRWAY OBSTRUCTION
16. MECHANICAL OBSTRUCTION OF AIRWAYS
• airway diameter is larger in inspiration, gas can enter around the partial
obstruction
• airway narrows during exhalation meconium plug occludes the airway
completely, trapping the gas distally Ball valve effect over distention of
the lung and alveolar rupture pneumothorax or other air leak
complications
18. • Components of meconium cause inflammation of the lung that
is apparent 24 to 48 hours after inhalation.
• Direct injury and inflammation result in an exudative and
inflammatory pneumonitis with epithelial disruption,
proteinaceous exudation with alveolar collapse, and cellular
necrosis
CHEMICAL IRRITATION AND INFLAMMATION
20. • MSAF is a risk factor for bacterial infection of the amniotic cavity
• Meconium is sterile, the mucopolysaccharide component provides
an excellent growth medium for microorganisms, especially
Escherichia coli
• Meconium also may inhibit phagocytosis by polymorphonuclear
cells and their oxidative burst.
INFECTION
22. • meconium aspiration demonstrate inactivation of surfactant with
increased surface tension, and decreased lung volume,
compliance, and oxygenation
• The free fatty acids in meconium can strip surfactant from the
surface of the alveoli.
• Meconium also impacts surfactant production and clearance by
affecting phosphatidylcholine metabolism.
SURFACTANT INACTIVATION
24. • Hypoxemia results from several causes, including decreased
alveolar ventilation related to lung injury, and ventilation-
perfusion imbalance with continued perfusion of poorly
ventilated lung units.
• PPHN frequently accompanies MAS, with right-to-left shunting
caused by increased pulmonary vascular resistance, and
resultant hypoxemia.
HYPOXEMIA
26. GENERAL FEATURES:
History of meconium-stained amniotic fluid (MSAF) or
evidence of meconium staining on physical examination of
the infant
Vernix, umbilical cord, and nails may be meconium-stained
CLINICAL FEATURES
27. • Pulmonary findings
• respiratory distress : tachypnea and cyanosis
• Use of accessory muscles of respiration
• Intercostal and Subxiphoid retractions and abdominal (paradoxical)
breathing
• Grunting and nasal flaring
• barrel-shaped chest with an increased anterior-posterior diameter
• Auscultation reveals rales and rhonchi
In patients with severe MAS, pneumothorax and pneumomediastinum are
common findings.
Infants with pulmonary hypertension and right-to-left shunting may have a
gradient in oxygenation between pre- and postductal arterial blood samples.
In addition, echocardiography may demonstrate right-to-left shunting.
CLINICAL FEATURES
28. • Laboratory studies:
ABG reveals hypoxemia, respiratory alkalosis (mild cases), and respiratory acidosis (severe
cases)
DIAGNOSIS
• Chest Radiographs:
reveal hyperinflation of the lung fields and flattened
diaphragms. There are coarse, irregular patchy infiltrates.
• Point-of-care lung ultrasonography:
large consolidation area with irregular edges with air bronchogram
pleural line anomalies and disappearance of A lines
alveolar-interstitial syndrome or B line in the nonconsolidation area
Atelectasis and pleural effusion
29. • Cardiac echocardiogram:
Pulmonary hypertension and subsequent hypoxemia from right-to-left
and ductal shunt are frequently associated findings in infants with
meconium aspiration pneumonia.
DIAGNOSIS
• Placental evaluation:
Funisitis (inflammation of the connective tissue of the umbilical cord)
occurs prenatally in MAS, and the stage of funisitis and chorionic vascular
muscle necrosis may be a marker for MAS and predict the severity of
MAS.
30. A. PRENATAL MANAGEMENT
1. Identification of high-risk pregnancies
2. Monitoring during labor
3. Amnioinfusion - instillation of isotonic fluid into the amniotic cavity
MANAGEMENT
B. DELIVERY ROOM MANAGEMENT
1. Vigorous infants: do not recommend suctioning in
the vigorous infant with MSAF, as it does not improve
outcome and may cause complications
2. Nonvigorous infants
31. A. General management
Maintain a neutral thermal environment
Minimal handling protocol to avoid agitation
Maintain adequate blood pressure and perfusion
Correct any metabolic abnormalities such as
hypocalcemia, or metabolic acidosis
Sedation may be needed in infants on mechanical
ventilation
MANAGEMENT OF THE NEWBORN
WITH MECONIUM ASPIRATION
32. A. Respiratory management
Pulmonary toilet
Arterial blood gas levels
Oxygen monitoring : Pulse Oximeter
Chest radiograph
Antibiotic coverage: broad-spectrum antibiotics
Supplemental oxygen
Continuous positive airway pressure (CPAP)
Mechanical ventilation: High-frequency ventilation
Surfactant therapy
Inhaled nitric oxide
Extracorporeal life support (ECLS)
MANAGEMENT OF THE NEWBORN
WITH MECONIUM ASPIRATION
36. PERSISTENT PULMONARY HYPERTENSION OF
THE NEWBORN (PPHN)
It is a condition characterized by marked pulmonary
hypertension resulting from elevated pulmonary vascular
resistance (PVR) and altered pulmonary vasoreactivity, leading
to right-to-left extrapulmonary shunting of blood across the
foramen ovale and the ductus arteriosus, if it is patent.
This in turn leads to severe hypoxemia that may not respond to
conventional respiratory support.
INCIDENCE: 2 to 6 per 1000 live births.
37. • Lung disease: Meconium aspiration, respiratory distress syndrome (RDS),
pneumonia, pulmonary hypoplasia, cystic lung disease, diaphragmatic
and congenital alveolar capillary dysplasia.
• Systemic disorders: Polycythemia, hypoglycemia, hypoxia, acidosis,
hypocalcemia, hypothermia, and sepsis.
• Congenital heart disease: total anomalous venous return, hypoplastic left
heart syndrome, transient tricuspid insufficiency (transient myocardial
ischemia), coarctation of the aorta, critical aortic stenosis, endocardial
defects, Ebstein anomaly, transposition of the great arteries, endocardial
fibroelastosis, and cerebral venous malformations.
• Perinatal factors: Asphyxia, perinatal hypoxia, and maternal ingestion of
aspirin or indomethacin.
RISK FACTORS
39. • Prenatal factors:
Fetal heart rate abnormalities (ie, bradycardia and tachycardia)
meconium-stained amniotic fluid
• Neonatal findings:
signs of respiratory distress (eg, tachypnea, retractions, and grunting) and cyanosis
low APGAR scores
meconium staining of skin and nails
The cardiac examination of infants with PPHN may be notable for a prominent
impulse, and a narrowly split and accentuated second heart sound. A harsh systolic
murmur consistent with tricuspid insufficiency sometimes is heard at the lower left
sternal border.
CLINICAL FEATURES
40. • Pulse oximetry assessment: preductal and postductal monitoring of oxygen
saturation
• Arterial blood gas: show low PaO2 below 100 mmHg in patients receiving 100
percent inspired oxygen concentration
• Chest radiograph: The chest radiograph is usually normal or demonstrates the
findings of an associated pulmonary condition (eg, parenchymal disease, air
or CDH). The heart size typically is normal or slightly enlarged. Pulmonary blood
flow may appear normal or reduced.
• ECHOCARDIOGRAPHY: demonstrates normal structural cardiac anatomy with
evidence of pulmonary hypertension (PH) (eg, flattened or displaced ventricular
septum). Doppler studies show right-to-left shunting through the patent ductus
arteriosus and/or foramen ovale.
DIAGNOSIS
41. • General management:
Fluid management
Normal serum glucose and calcium should be maintained
Temperature control
Significant acidosis should be avoided
Use 2 pulse oximeters: 1 preductal and 1 postductal
Empiric Antibiotics
• Minimal Handling: Noise level and physical manipulation should be kept to a
minimum.
• Sedation: since agitation may result in ventilator asynchrony which can worsen
hypoxemia.
• Surfactant: should be considered in patients with associated parenchymal lung
disease, in whom there is either a suspected surfactant deficiency
MANAGEMENT
42. • Mechanical ventilation:
The goal is to maintain adequate and stable oxygenation using the
lowest possible mean airway pressures.
Hyperventilation should be avoided, and as a guide, PaCO2 values
be kept >30 mm Hg if possible; levels of 40 to 50 mm Hg, or even
are also acceptable if there is no associated compromise in oxygenation.
Initially, it would be wise to ventilate with 100% inspired oxygen
concentration.
Weaning should be gradual and in small steps.
In infants who cannot be adequately oxygenated with conventional
ventilation, high-frequency oscillatory ventilation (HFOV) should be
considered early.
MANAGEMENT
43. • Pressor agents:
Dopamine is the most commonly used drug at a starting dose of 2.5 mcg/kg per minute
and titrate the infusion rate (usually to a maximum dose of 20 mcg/kg per minute) to
maintain the mean arterial BP at a targeted level that minimizes right-to-left shunting.
Dobutamine may improve cardiac output if ventricular dysfunction is present, but does
not reliably increase BP in neonates.
Epinephrine can increase both systemic BP and left ventricular (LV) output but increased
LV afterload due to increased PVR may exacerbate right ventricle (RV) afterload.
Milrinone, a type 3 PDE inhibitor, is also sometimes employed to improve cardiac output.
However, the use of milrinone has been associated with occasional cases of systemic
hypotension in adults and of higher heart rates in neonates.
MANAGEMENT
44. Inhaled nitric oxide (iNO)
improves oxygenation and reduces the need for ECMO in term and late preterm
infants with severe PPHN
when given by inhalation, reduces PVR and improves oxygenation and outcomes
outcomes in a significant proportion of term and near-term neonates with PPHN.
MANAGEMENT
Mode of action:
Endogenous NO regulates vascular tone by causing relaxation of vascular
smooth muscle.
Exogenous iNO is a selective pulmonary vasodilator that acts by decreasing the
pulmonary artery pressure and pulmonary-to-systemic arterial pressure ratio
45. Magnesium sulfate:
Magnesium causes vasodilation by antagonizing calcium ion entry into smooth muscle
cells.
Adenosine:
Adenosine causes vasodilation by stimulation of adenosine receptors on endothelial cells
and release of endothelial NO.
Inhaled/nebulized prostaglandin I2 (iloprost):
This is a stable PGI2 analogue with a longer half-life, and it acts by stimulating adenyl
cyclase and increasing cyclic adenosine monophosphate. It is gaining wider acceptance
to its selective pulmonary vasodilation without decreasing systemic blood pressure.
Sildenafil:
a phosphodiesterase inhibitor type 5, is an agent that has been shown to selectively
pulmonary vascular resistance in both animal models and adult humans.
MANAGEMENT
46. Extracorporeal membrane oxygenation
is a form of cardiopulmonary bypass that augments systemic perfusion
and provides gas exchange.
The goal of this treatment is to maintain adequate tissue oxygen delivery
and avoid irreversible lung injury from mechanical ventilation while PVR
decreases and pulmonary hypertension resolves.
Criteria for institution of ECMO include an elevated OI that is consistently
consistently ≥40.
Most patients with PPHN are weaned from ECMO within seven days.
The survival rate with ECLS is reportedly >80%, although only the most
severely afflicted infants are referred for this treatment.
MANAGEMENT
47. Assessment of severity using oxygenation index
The oxygenation index (OI) is used to assess the severity of hypoxemia in
PPHN and to guide the timing of interventions, such as iNO administration
ECMO support.
The OI is calculated as follows:
OI = [mean airway pressure x FiO2 ÷ PaO2] x 100
A high OI indicates severe hypoxemic respiratory failure. A term or late
preterm infant with an OI ≥25 should receive care in a center where high-
frequency oscillatory ventilation (HFOV), iNO, and ECMO are readily
in addition to general supportive care
In patients with OI <25, general supportive care is typically adequate and no
further invasive intervention is usually required.
MANAGEMENT
48. Supplemental oxygen should be initially administered in a concentration of 100
% to infants with PPHN in an attempt to reverse pulmonary vasoconstriction
PaO2 should be maintained subsequently in the range of 50 to 90 mmHg
(preductal oxygen saturation 90 to 95 percent) to minimize lung toxicity.
The oxygenation index (OI) is used to assess the severity of hypoxemia in PPHN
and is used to determine whether additional interventions (eg, iNO and ECMO)
are warranted.
Mechanical ventilation: to initially maintain PaCO2 between 40 and 50 mmHg.
Maintenance of adequate systemic blood pressure by providing sufficient
vascular volume and the use of inotropic agents.
APPROACH TO TREATING INFANTS WITH
PPHN INCLUDES THE FOLLOWING:
49. In term and preterm infants with a gestational age greater than 34 weeks and
who have severe PPHN, defined as an OI ≥25, It is recommend that iNO be
administered at a dose of 20 ppm
It is not recommend enteral sildenafil as initial therapy if iNO is available.vIt
may be considered in a resource-limited setting.
In patients who have an OI ≥40 despite the use of iNO and high ventilatory
support, it is recommended to use ECMO
Blood cultures should be obtained and empiric antimicrobial therapy initiated
APPROACH TO TREATING INFANTS WITH
PPHN INCLUDES THE FOLLOWING:
Meconium passage — Passage of meconium occurs early in the first trimester of pregnancy [18]. Fetal defecation slows after 16 weeks gestation and becomes infrequent by 20 weeks, concurrent with innervation of the anal sphincter [19]. From approximately 20 to 34 weeks, fetal passage of meconium remains infrequent [20]. Almost all fetuses and newborn infants who pass meconium are at term or postterm gestation.
Meconium passage may be caused by increased peristalsis and relaxation of the anal sphincter due to increased vagal outflow associated with umbilical cord compression or increased sympathetic inflow during hypoxia [21-24]. In one study, fetuses that passed meconium prior to birth had higher motilin levels in cord blood compared to those who did not [24]. The higher levels of motilin, a regulatory intestinal peptide, were thought to be related to increased parasympathetic tone due to fetal hypoxia. (See "Overview of the development of the gastrointestinal tract", section on 'Hormonal regulation'.)
Aspiration — Meconium in amniotic fluid can be aspirated during fetal gasping or in the initial breaths after delivery. Normally, fetal breathing activity results in movement of lung fluid out of the trachea [25]. However, as shown in animals, prolonged hypoxia stimulates fetal breathing and gasping that can lead to inhalation of amniotic fluid [25-29]. Pathologic evidence suggests that this process also occurs in humans. Meconium has been found in the lungs of infants who were stillborn [30] or who died soon after birth without a history of aspiration at delivery [31,32].
Meconium that remains in the hypopharynx or trachea after delivery can be aspirated during the initial breaths. This is more likely to occur in a depressed infant.
Pulmonary disease — Aspirated meconium can interfere with normal breathing by several mechanisms. These include airway obstruction, chemical irritation and inflammation, infection, and surfactant inactivation. However, it is likely that most cases of severe MAS are primarily caused by intrauterine pathologic processes, primarily asphyxia and infection, rather than the aspiration of meconium by itself
Airway obstruction — Airway obstruction can be complete or partial. Complete obstruction leads to distal atelectasis. Partial airway obstruction occurs when particulate meconium partly occludes the airway. Because the airway diameter is larger in inspiration, gas can enter around the partial obstruction. However, as the airway narrows during exhalation, the meconium plug occludes the airway completely, trapping the gas distally. This process is known as a ball valve effect and can lead to overdistention of the lung and alveolar rupture, with resulting pneumothorax or other air leak complications
Because the airway diameter is larger in inspiration, gas can enter around the partial obstruction. However, as the airway narrows during exhalation, the meconium plug occludes the airway completely, trapping the gas distally. This process is known as a ball valve effect and can lead to overdistention of the lung and alveolar rupture, with resulting pneumothorax or other air leak complications
Chemical irritation and inflammation — Components of meconium cause inflammation of the lung that is apparent 24 to 48 hours after inhalation. Direct injury and inflammation result in an exudative and inflammatory pneumonitis with epithelial disruption, proteinaceous exudation with alveolar collapse, and cellular necrosis [35-39]. In animal studies, pancreatic phospholipase A2 appears to directly contribute to lung injury [17].
Infection — MSAF is a risk factor for bacterial infection of the amniotic cavity and should alert the clinician to the potential for increased neonatal morbidity [40-42] Although meconium is sterile, the mucopolysaccharide component provides an excellent growth medium for microorganisms, especially Escherichia coli [43]. Meconium also may inhibit phagocytosis by polymorphonuclear cells and their oxidative burst [44]. (See "Neonatal pneumonia".)
Surfactant
meconium aspiration demonstrate inactivation of surfactant with increased surface tension, and decreased lung volume, compliance, and oxygenation
●Increased inactivation – Animal models of meconium aspiration demonstrate inactivation of surfactant with increased surface tension, and decreased lung volume, compliance, and oxygenation [45-49]. In human infants, concentrations of surfactant inhibitors (eg, total protein, albumin, membrane-derived phospholipid) were higher in lung lavage fluid in those with MAS than in controls [36]. However, surfactant phospholipid and surfactant protein A levels were not different. In addition, several meconium components (eg, free fatty acids) have a higher minimal surface area and may displace surfactant from the alveolar surface.
●Decreased synthesis – In a small study, there was a trend toward lower surfactant synthesis in neonates with MAS or persistent pulmonary hypertension (PPHN) who required extracorporeal membrane oxygenation, compared to control infants who required ventilatory support for nonpulmonary indications [50]. Lower tracheal aspirate concentrations of phosphatidylcholine (PC), a component of surfactant, and lower incorporation of radiolabeled carbon in PC were seen in infants with MAS or PPHN compared to controls.
Hypoxemia — Hypoxemia results from several causes, including decreased alveolar ventilation related to lung injury, and ventilation-perfusion imbalance with continued perfusion of poorly ventilated lung units. PPHN frequently accompanies MAS, with right-to-left shunting caused by increased pulmonary vascular resistance, and resultant hypoxemia.
A history of meconium-stained amniotic fluid (MSAF) or evidence of meconium staining on physical examination of the infant.
he vernix, umbilical cord, and nails may be meconium-stained, depending upon how long the infant has been exposed in utero [51].
In general, nails will become stained after six hours and vernix after 12 to 14 hours of exposure.
GOMELLA: Infants with MAS often exhibit signs of postmaturity. Respiratory distress
is evident at birth or in the transition period. Respiratory depression, poor respiratory
effort, and decreased tone are often accompanied by perinatal asphyxia.
Meconium-stained skin is proportional to the length of exposure and meconium
concentration. Fifteen minutes of exposure to thick MSAF or 1 hour to lightly
stained fluid will begin to stain the umbilical cord. Yellow staining of the newborn’s
nails requires 4 to 6 hours; staining of the vernix caseosa takes approximately
12 hours.
Laboratory studies. Arterial blood gas results characteristically reveal hypoxemia.
In mild cases, hyperventilation may result in respiratory alkalosis. Infants with severe
disease usually have a respiratory acidosis due to airway obstruction, atelectasis,
and pneumonitis. With concomitant perinatal asphyxia, combined respiratory and
metabolic acidosis is present.
Chest radiographs typically reveal hyperinflation of the lung fields and flattened
diaphragms. There are coarse, irregular patchy infiltrates. A pneumothorax or
pneumomediastinum may be present. The severity of radiographic findings does
not always correlate with the clinical disease.
Point-of-care lung ultrasonography can be used to diagnose MAS. The most
specific finding in MAS was a large consolidation area with irregular edges with air
bronchograms (100% of cases). Other findings include pleural line anomalies and
disappearance of A lines (100% of cases), alveolar-interstitial syndrome or B line in
the nonconsolidation area (100%), atelectasis (16%), and pleural effusion (∼14%).
Laboratory studies. Arterial blood gas results characteristically reveal hypoxemia.
In mild cases, hyperventilation may result in respiratory alkalosis. Infants with severe
disease usually have a respiratory acidosis due to airway obstruction, atelectasis,
and pneumonitis. With concomitant perinatal asphyxia, combined respiratory and
metabolic acidosis is present.
Chest radiographs typically reveal hyperinflation of the lung fields and flattened
diaphragms. There are coarse, irregular patchy infiltrates. A pneumothorax or
pneumomediastinum may be present. The severity of radiographic findings does
not always correlate with the clinical disease.
Point-of-care lung ultrasonography can be used to diagnose MAS. The most
specific finding in MAS was a large consolidation area with irregular edges with air
bronchograms (100% of cases). Other findings include pleural line anomalies and
disappearance of A lines (100% of cases), alveolar-interstitial syndrome or B line in
the nonconsolidation area (100%), atelectasis (16%), and pleural effusion (∼14%).
A. Prenatal management. The key to management of meconium aspiration lies in prevention
of fetal distress during the prenatal period.
1. Identification of high-risk pregnancies. The approach to prevention begins with
recognition of predisposing maternal factors that may result in fetal hypoxia during
labor. Risk of MAS is highest in infants with gestational ages >41 weeks. Thus,
induction as early as 41 weeks may help prevent meconium aspiration.
2. Monitoring. During labor, any sign of fetal distress (eg, appearance of meconium-
stained fluid, loss of beat-to-beat variability, fetal tachycardia, or deceleration
patterns) warrants assessment of fetal well-being. If the assessment identifies
a compromised fetus, corrective measures should be undertaken or the infant
should be delivered in a timely manner.
3. Amnioinfusion. The efficiency of amnioinfusion (instilling isotonic fluid into
the amniotic cavity) in altering the risk or severity of meconium aspiration has
not been demonstrated except in settings with limited perinatal surveillance.
In this setting, amnioinfusion is associated with substantial improvements in
perinatal outcomes. A Cochrane 2014 review notes that amnioinfusion for
MSAF is associated with substantive improvements in perinatal outcome only
in settings where perinatal surveillance is limited. The American Congress
of Obstetricians and Gynecologists (2016) states that “routine prophylactic
amnioinfusion is not recommended for dilution of meconium-stained amniotic
fluid. It should only be done in the setting of additional clinical trials.” It
is recommended in the treatment of repetitive variable decelerations, whether
or not there is MSAF.
NELSONS
the presence of meconium-stained amniotic fluid in
a nonvigorous infant required tracheal intubation to attempt to aspirate
meconium below the cords; NRP recommendations (7th edition) no
longer support this practice. If an infant is born through meconiumstained
amniotic fluid, it does not matter whether they are vigorous or
nonvigorous; the infant should receive the same initial steps of basic
resuscitation and should be assessed as any other infant. Tracheal
intubation may delay the initiation of effective PPV, which will help
the baby to breathe and achieve effective gas exchange.
1. General management. Infants who have aspirated meconium and require resuscitation
often develop metabolic abnormalities such as hypoxia, acidosis, hypoglycemia,
and hypocalcemia. Because these patients may have suffered perinatal
asphyxia, surveillance for any end-organ damage is essential.
a. Maintain a neutral thermal environment.
b. Minimal handling protocol to avoid agitation.
c. Maintain adequate blood pressure and perfusion. Volume expansion may
be necessary with normal saline or packed red blood as well as vasopressor
support such as dopamine. Maintaining a hematocrit >40% to 45% will optimize
tissue oxygen delivery.
d. Correct any metabolic abnormalities such as hypoglycemia, hypocalcemia,
or metabolic acidosis.
e. Sedation may be needed in infants on mechanical ventilation. Intravenous
morphine (loading dose 100–150 mcg/kg over 1 hour, continuous infusion of
10–20 mcg/kg/h) and fentanyl (1–5 mcg/kg/h) can be used. A neuromuscular
blocker (eg, pancuronium, 0.1 mg/kg push per dose) can be used.
2. Respiratory management
a. Pulmonary toilet. If suctioning the trachea does not result in clearing of
secretions, it may be advisable to leave an ETT in place in symptomatic infants
for pulmonary toilet. Chest physiotherapy every 30 minutes to 1 hour, as
tolerated, will aid in clearing the airway (controversial). Chest physiotherapy
is contraindicated in labile infants when associated PPHN is suspected. Some
neonatologists avoid chest physiotherapy in all infants because of possible
PPHN.
b. Arterial blood gas levels. On admission to the neonatal intensive care unit,
obtain blood gas measurements to assess ventilatory compromise and supplemental
oxygen requirements. If the patient requires >0.4 FiO2 or demonstrates
pronounced labiality, an arterial catheter for frequent sampling should be
inserted.
c. Oxygen monitoring. A pulse oximeter provides information regarding the
severity of the infant’s respiratory status. Comparing oxygen saturation values
from a pulse oximeter on the right arm to those placed on the lower extremities
may help identify infants with right-to-left ductal shunting secondary to
MAS-associated pulmonary hypertension.
d. A chest radiograph should be obtained after delivery if the infant is in distress.
It may also help determine which patients will experience respiratory distress.
However, radiographs often poorly correlate with the clinical presentation.
mild MASHIDE ALL
1st line – oxygen therapy plus supportive care
Infants should be placed in Isolette, or under an infant warmer, and oxygen saturation should be monitored continuously.
Oxygen should be given by hood or nasal cannula to maintain oxygen saturations at 92% to 97%. Usually, may require FiO2 <0.40 for a short duration of 48 to 72 hours. As respiratory distress begins to improve, FiO2 should be decreased by 5% at a time, as tolerated, depending on pulse oximeter reading.
Intravenous fluids (10% dextrose in water) should be started on day 1. On subsequent days, switching to nasogastric or oral feeds, as tolerated, should be considered if infant's respiratory status improves. If feedings are not adequate, intravenous fluid should be increased (80-90 mL/kg/day, adding NaCl 2-4 mEq/kg/day plus amino acids) to meet the daily requirement. Giving intravenous fluids containing glucose 6-8 mg/minute/kg is indicated in those with hypoglycemia until resolution.
Other measures may include providing partial exchange to lower the hematocrit and improve blood flow in infants with high hemoglobin, or blood transfusion if hemoglobin is low (<13 g/dL).
MODERATE MS:
In infants with spontaneous breathing and good respiratory effort, CPAP should be started with nasal prongs if FiO2 needs exceed 0.40 to maintain saturations within normal limits. Starting CPAP is 4 to 6 cm of H2O. Further increase of CPAP level is determined by presence of atelectasis and work of breathing. CPAP should be avoided in the presence of air leaks and air trapping on CXR. Complications include abdominal distension, air trapping because of underlying ball-valve mechanisms or excessive flow, and distending pressure. These potential complications warrant close monitoring.
ABGs should be obtained every 4 to 6 hours, and FiO2 should be adjusted to maintain oxygen saturations between 92% and 97% or higher, and PaO2 of 80 to 100 mmHg (10.3-13.0 kPa).
Persistent pulmonary hypertension of the newborn (PPHN) is a
condition characterized by marked pulmonary hypertension resulting from elevated
pulmonary vascular resistance (PVR) and altered pulmonary vasoreactivity, leading
to right-to-left extrapulmonary shunting of blood across the foramen ovale and the
ductus arteriosus, if it is patent. It is associated with a wide array of cardiopulmonary
disorders that may also cause intrapulmonary shunting. When this disorder is of
unknown cause and is the primary cause of cardiopulmonary distress, it is often
called idiopathic PPHN or persistent fetal circulation.
NELSON
Some patients with PPHN have low plasma arginine and NO metabolite concentrations
and polymorphisms of the carbamoyl phosphate synthase gene, findings suggestive of a possible subtle defect in NO production.
IV. Risk factors. The following factors or conditions may be associated with PPHN:
A. Lung disease. Meconium aspiration, respiratory distress syndrome (RDS), pneumonia,
pulmonary hypoplasia, cystic lung disease (including congenital cystic adenomatoid
malformation and congenital lobar emphysema), diaphragmatic hernia,
and congenital alveolar capillary dysplasia.
B. Systemic disorders. Polycythemia, hypoglycemia, hypoxia, acidosis, hypocalcemia,
hypothermia, and sepsis.
C. Congenital heart disease. Particularly, total anomalous venous return, hypoplastic
left heart syndrome, transient tricuspid insufficiency (transient myocardial ischemia),
coarctation of the aorta, critical aortic stenosis, endocardial cushion defects,
Ebstein anomaly, transposition of the great arteries, endocardial fibroelastosis, and
cerebral venous malformations.
D. Perinatal factors. Asphyxia, perinatal hypoxia, and maternal ingestion of aspirin
or indomethacin.
E. Miscellaneous. Central nervous system disorders, neuromuscular disease, and
upper airway obstruction. Although still contentious, some observational studies
have suggested that the use of selective serotonin reuptake inhibitors during the last
half of pregnancy may be associated with PPHN in the newborn.
Persistence of the fetal circulatory pattern of right-to-left shunting
through the PDA and foramen ovale after birth is a result of excessively
high pulmonary vascular resistance (PVR). Fetal PVR is usually elevated
relative to fetal systemic or postnatal pulmonary pressure. This fetal
state normally permits shunting of oxygenated umbilical venous blood
to the left atrium (and brain) through the foramen ovale, from which
it bypasses the lungs through the ductus arteriosus and passes to the
descending aorta. After birth, PVR normally declines rapidly as a
consequence of vasodilation secondary to lung inflation, a rise in postnatal
PaO2, a reduction in PaCO2, increased pH, and release of vasoactive
substances. Increased neonatal PVR may be (1) maladaptive from an
acute injury (not demonstrating normal vasodilation in response to
increased O2 and other changes after birth); (2) the result of increased
pulmonary artery medial muscle thickness and extension of smooth
muscle layers into the usually nonmuscular, more peripheral pulmonary
arterioles in response to chronic fetal hypoxia; (3) a consequence of
pulmonary hypoplasia (diaphragmatic hernia, Potter syndrome); or
(4) obstructive as a result of polycythemia, total anomalous pulmonary
venous return (TAPVR), or congenital diffuse development disorders
of acinar lung development.
Prenatal factors — Prenatal findings associated with PPHN are thought to be signs of intrauterine and perinatal asphyxia. These include fetal heart rate abnormalities (ie, bradycardia and tachycardia) and meconium-stained amniotic fluid [1]. In utero exposure of selective serotonin reuptake inhibitors (SSRIs) during the second half of pregnancy has also been associated with a sixfold increased risk of PPHN compared with nonexposed infants.
Neonatal findings — Most neonates with PPHN present within the first 24 hours of life with signs of respiratory distress (eg, tachypnea, retractions, and grunting) and cyanosis. In the NICHD study, more than half of the infants had low apgar scores and almost all of the patients received delivery room interventions including oxygen therapy, bag and mask ventilation, and endotracheal intubation [1].
As noted above, the physical examination is characterized by cyanosis and signs of respiratory distress. In addition, there may be meconium staining of skin and nails, which may be indicative of intrauterine stress. The cardiac examination of infants with PPHN may be notable for a prominent precordial impulse, and a narrowly split and accentuated second heart sound. A harsh systolic murmur consistent with tricuspid insufficiency sometimes is heard at the lower left sternal border.
Pulse oximetry assessment — Pulse oximetry assessment generally demonstrates a difference of greater than 10 percent between the pre- and postductal (right thumb and either great toe) oxygen saturation. This differential is due to right-to-left shunting through the patent ductus arteriosus (PDA). However, it is important to recognize that the absence of a pre- and postductal gradient in oxygenation does notexclude the diagnosis of PPHN, since right-to-left shunting can occur predominantly through the foramen ovale rather than the PDA.
Arterial blood gas — An arterial blood gas sample typically will show low arterial partial pressure of oxygen (PaO2 below 100 mmHg in patients receiving 100 percent inspired oxygen concentration), particularly samples that are postductal. However, in contrast to infants with cyanotic lesions, many infants with PPHN have at least one measurement of PaO2 >100 mmHg early in the course of their illness. The arterial partial pressure of carbon dioxide (PaCO2) is normal in infants without accompanying lung disease. The right-to-left shunting of blood through the PDA can also be documented in differences in PaO2 between samples obtained from the right radial artery (preductal sample) and the umbilical artery (postductal sample).
Hyperventilation test. (See pages 489 and 490.) PPHN should be considered if
marked improvement in oxygenation (>30 mm Hg increase in PaO2) is noted on
hyperventilating the infant (lowering arterial partial pressure of carbon dioxide
[PaCO2] and increasing pH). When a “critical” pH value is reached (often ∼7.55 or
greater), PVR decreases, there is less right-to-left shunting, and Pao2 increases. This
test may differentiate PPHN from cyanotic congenital heart disease. Little or no
response is expected in infants with the latter diagnoses. It has been suggested that
infants subjected to this test should be hyperventilated for 10 minutes. Prolonged
hyperventilation is not recommended, however, particularly in premature infants
General management. Infants with PPHN clearly require careful and intensive
monitoring. Fluid management is important because hypovolemia aggravates
the right-to-left shunt. However, once normovolemia can be assumed, there is
no known benefit to be gained from repeated administration of either colloids or
crystalloids. Normal serum glucose and calcium should be maintained because
hypoglycemia and hypocalcemia aggravate PPHN. Temperature control is also
crucial. Significant acidosis should be avoided. It is useful to use 2 pulse oximeters:
1 preductal and 1 postductal.
Minimal handling. Because infants with PPHN are extremely labile with significant
deterioration after seemingly “minor” stimuli, this aspect of care deserves
special mention. Endotracheal tube suctioning, in particular, should be performed
only if indicated and not as a matter of routine. Noise level and physical manipulation
should be kept to a minimum.
Sedation. The lability of these infants has been mentioned previously, and hence,
sedation is commonly used. Pentobarbital (1–5 mg/kg) or midazolam (0.1 mg/
kg) is frequently used, and analgesia with morphine (0.05–0.2 mg/kg) is also used.
Surfactant — Surfactant therapy does not appear to be effective when PPHN is the primary diagnosis [25]. However, it should be considered in patients with associated parenchymal lung disease, in whom there is either a suspected surfactant deficiency (eg, neonatal RDS) or impairment (meconium aspiration syndrome [MAS])
Mechanical ventilation. Often needed to ensure adequate oxygenation and should
first be attempted using “conventional” ventilation. The goal is to maintain adequate
and stable oxygenation using the lowest possible mean airway pressures. The lowest
possible positive end-expiratory pressure should also be sought. However, atelectasis
should be avoided because it may aggravate pulmonary hypertension (PH) and
also impair effective delivery of inhaled NO (iNO) to the lungs. Hyperventilation
should be avoided, and as a guide, PaCO2 values should be kept >30 mm Hg if
possible; levels of 40 to 50 mm Hg, or even higher, are also acceptable if there is
no associated compromise in oxygenation. Initially, it would be wise to ventilate
with 100% inspired oxygen concentration. Weaning should be gradual and in small
steps. In infants who cannot be adequately oxygenated with conventional ventilation,
high-frequency oscillatory ventilation (HFOV) should be considered early. In
the presence of parenchymal lung disease, infants treated with HFOV combined
with iNO were less likely to be referred for ECLS than those treated with either
therapy alone.
Pressor agents. Some infants with PPHN have reduced cardiac output. In addition,
increasing systemic blood pressure reduces the right-to-left shunt. Hence, at least a
normal blood pressure should be maintained, and some recommend maintaining
blood pressure of >40 mm Hg. Dopamine is the most commonly used drug for
this purpose. Dobutamine has the disadvantage, in this context, that, although
it may improve cardiac output, it has less of a pressor effect than dopamine.
Milrinone, a type 3 PDE inhibitor, is also sometimes employed to improve cardiac
output. Milrinone reduces PH in experimental animal models, and a few small case
series have reported on its beneficial effects in neonates with PPHN. However, the
use of milrinone has been associated with occasional cases of systemic hypotension
in adults and of higher heart rates in neonates. Hence, more data are needed before
widespread use of milrinone can be recommended.
Inhaled nitric oxide (iNO) improves oxygenation and reduces the need for ECMO in term and late preterm infants with severe PPHN
Mode of action — Endogenous NO regulates vascular tone by causing relaxation of vascular smooth muscle. Exogenous iNO is a selective pulmonary vasodilator that acts by decreasing the pulmonary artery pressure and pulmonary-to-systemic arterial pressure ratio [35]. Oxygenation improves as vessels are dilated in well-ventilated parts of the lung, thereby redistributing blood flow from regions with decreased ventilation and reducing intrapulmonary shunting. In the circulation, NO combines with hemoglobin and is rapidly converted to methemoglobin and nitrate. As a result, there is little effect on SVR and systemic blood pressure.
Magnesium sulfate. Magnesium causes vasodilation by antagonizing calcium ion
entry into smooth muscle cells. A few small observational studies have suggested
that magnesium sulfate (MgSO4) may effectively treat PPHN, but the evidence is
conflicting, and there is some risk of systemic hypotension. The dose reported is a
loading dosage of 200 mg/kg followed by an infusion of 20 to 150 mg/kg/h (the drug
is given IV). Two small trials in neonates with PPHN have shown that sildenafil
and iNO are each superior to IV MgSO4.
Adenosine. Adenosine causes vasodilation by stimulation of adenosine receptors
on endothelial cells and release of endothelial NO. A small randomized trial
reported the effectiveness of adenosine infusion (25–50 mcg/kg/min) in treating
PPHN in term babies. Subsequently, a few further cases have been published.
Despite initial favorable data, the drug has not attracted attention, and its use awaits
further clinical trials.
Inhaled/nebulized prostaglandin I2 (iloprost). This is a stable PGI2 analogue with
a longer half-life, and it acts by stimulating adenyl cyclase and increasing cyclic
adenosine monophosphate. It is gaining wider acceptance due to its selective pulmonary
vasodilation without decreasing systemic blood pressure. Randomized trials
in adults have shown its effectiveness and safety, but the pediatric and neonatal
literature consists of a few case series and case reports, some including infants who
were resistant to treatment with iNO. No systemic vascular effects were noted.
Dosage varies between reports but is mostly in the range of 0.25 to 2.5 mcg/kg per
inhalation, with inhalations being given over 5 to 10 minutes every 2 to 4 hours.
Sildenafil — Sildenafil, a phosphodiesterase inhibitor type 5, is an agent that has been shown to selectively reduce pulmonary vascular resistance in both animal models and adult humans. It has also been reported to be successful in the treatment of infants with PPHN [43-47].
Extracorporeal membrane oxygenation — Approximately 40 percent of infants with severe PPHN remain hypoxemic on maximal ventilatory support despite administration of iNO [27]. In these patients who fail to respond to iNO, ECMO therapy should be considered. The goal of this treatment is to maintain adequate tissue oxygen delivery and avoid irreversible lung injury from mechanical ventilation while PVR decreases and pulmonary hypertension resolves.
Criteria for institution of ECMO include an elevated OI that is consistently ≥40. However, because MAPs are higher on HFOV than conventional ventilation, some clinicians wait until OI is ≥60 when HFOV is used.
Most patients with PPHN are weaned from ECMO within seven days [41]. However, two or more weeks occasionally may be necessary for adequate remodeling of the pulmonary circulation in severe cases. Patients who fail to improve may have an irreversible condition, such as alveolar capillary dysplasia (ACD) [42] or severe pulmonary hypoplasia.
In one large series from a single institution from 2000 to 2010, the survival rate following ECMO support was 81 percent [41].
Assessment of severity using oxygenation index — The oxygenation index (OI) is used to assess the severity of hypoxemia in PPHN and to guide the timing of interventions, such as iNO administration or ECMO support. The OI is calculated as follows:
OI = [mean airway pressure x FiO2 ÷ PaO2] x 100
In most cases when the OI is used, the infant is receiving a fraction of inspired oxygen (FiO2) of 1 and is being mechanically ventilated. Thus, the OI can be calculated easily from the mean airway pressure (MAP) displayed on the ventilator and the arterial partial pressure of oxygen (PaO2).
A high OI indicates severe hypoxemic respiratory failure. A term or late preterm infant with an OI ≥25 should receive care in a center where high-frequency oscillatory ventilation (HFOV), iNO, and ECMO are readily available in addition to general supportive care [15].
In patients with OI <25, general supportive care is typically adequate and no further invasive intervention is usually required.
