Meconium aspiration syndrome (MAS) also known as neonatal aspiration of meconium is a medical condition affecting newborn infants. It describes the spectrum of disorders and pathophysiology of newborns born in meconium-stained amniotic fluid (MSAF) and have
meconium
Meconium is the earliest stool of a mammalian infant resulting from defecation. Unlike later feces, meconium is composed of materials ingested during the time the infant spends in the uterus: intestinal epithelial cells, lanugo, mucus, amniotic ...
within their lungs. Therefore, MAS has a wide range of severity depending on what conditions and complications develop after parturition. Furthermore, the pathophysiology of MAS is multifactorial and extremely complex which is why it is the leading cause of morbidity and mortality in term infants.
The word ''meconium'' is derived from the Greek word ''mēkōnion'' meaning ''juice from the opium poppy'' as the sedative effects it had on the foetus were observed by
Aristotle.
Meconium is a sticky dark-green substance which contains gastrointestinal secretions,
amniotic fluid
The amniotic fluid is the protective liquid contained by the amniotic sac of a gravid amniote. This fluid serves as a cushion for the growing fetus, but also serves to facilitate the exchange of nutrients, water, and biochemical products betwee ...
,
bile acid
Bile acids are steroid acids found predominantly in the bile of mammals and other vertebrates. Diverse bile acids are synthesized in the liver. Bile acids are conjugated with taurine or glycine residues to give anions called bile salts.
Primary b ...
s,
bile
Bile (from Latin ''bilis''), or gall, is a dark-green-to-yellowish-brown fluid produced by the liver of most vertebrates that aids the digestion of lipids in the small intestine. In humans, bile is produced continuously by the liver (liver bile ...
, blood,
mucus,
cholesterol, pancreatic secretions,
lanugo
Lanugo is very thin, soft, usually unpigmented, downy hair that is sometimes found on the body of a fetus or newborn. It is the first hair to be produced by the fetal hair follicles, and it usually appears around sixteen weeks of gestation and is ...
,
vernix caseosa and cellular debris.
Meconium accumulates in the foetal
gastrointestinal tract
The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organ (biology), organs of the digestive syste ...
throughout the third trimester of pregnancy and it is the first intestinal discharge released within the first 48 hours after birth.
Notably, since meconium and the whole content of the gastrointestinal tract is located 'extracorporeally,' its constituents are hidden and normally not recognised by the foetal immune system.
For the meconium within the amniotic fluid to successfully cause MAS, it has to enter the
respiratory system during the period when the fluid-filled lungs transition into an air-filled organ capable of
gas exchange.
Causes
The main theories of meconium passage into amniotic fluid are caused by fetal maturity or from foetal stress as a result of
hypoxia
Hypoxia means a lower than normal level of oxygen, and may refer to:
Reduced or insufficient oxygen
* Hypoxia (environmental), abnormally low oxygen content of the specific environment
* Hypoxia (medical), abnormally low level of oxygen in the tis ...
or infection.
Other factors that promote the passage of meconium ''in utero'' include placental insufficiency, maternal hypertension,
pre-eclampsia
Pre-eclampsia is a disorder of pregnancy characterized by the onset of high blood pressure and often a significant amount of protein in the urine. When it arises, the condition begins after 20 weeks of pregnancy. In severe cases of the disease ...
and maternal drug use of
tobacco and
cocaine.
However, the exact mechanism for meconium passage into the amniotic fluid is not completely understood and it may be a combination of several factors.
Meconium passage as a result of foetal distress
There may be an important association between foetal distress and
hypoxia
Hypoxia means a lower than normal level of oxygen, and may refer to:
Reduced or insufficient oxygen
* Hypoxia (environmental), abnormally low oxygen content of the specific environment
* Hypoxia (medical), abnormally low level of oxygen in the tis ...
with MSAF.
It is believed that foetal distress develops into foetal hypoxia causing the foetus to defecate meconium resulting in MSAF and then perhaps MAS.
Other stressors which causes foetal distress, and therefore meconium passage, includes when umbilical vein oxygen saturation is below 30%.
Foetal hypoxic stress during parturition can stimulate colonic activity, by enhancing intestinal
peristalsis and relaxing the anal sphincter, which results in the passage of meconium. Then, because of intrauterine gasping or from the first few breaths after delivery, MAS may develop. Furthermore, aspiration of thick meconium leads to obstruction of airways resulting in a more severe
hypoxia
Hypoxia means a lower than normal level of oxygen, and may refer to:
Reduced or insufficient oxygen
* Hypoxia (environmental), abnormally low oxygen content of the specific environment
* Hypoxia (medical), abnormally low level of oxygen in the tis ...
.
The association between foetal distress and meconium passage is not a definite cause-effect relationship as over of infants with MSAF are vigorous at birth and do not have any distress or hypoxia.
Additionally, foetal distress occurs frequently without the passage of meconium as well.
Meconium passage as a result of foetal maturity
Although meconium is present in the
gastrointestinal tract
The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organ (biology), organs of the digestive syste ...
early in development, MSAF rarely occurs before 34 weeks
gestation
Gestation is the period of development during the carrying of an embryo, and later fetus, inside viviparous animals (the embryo develops within the parent). It is typical for mammals, but also occurs for some non-mammals. Mammals during pregna ...
.
Peristalsis of the foetal intestines is present as early as 8 weeks gestation and the anal sphincter develops at about 20–22 weeks. The early control mechanisms of the anal sphincter are not well understood, however there is evidence that the foetus does defecate routinely into the
amniotic cavity even in the absence of distress. The presence of fetal intestinal enzymes have been found in the amniotic fluid of women who are as early as 14–22 weeks pregnant. Thus, suggesting there is free passage of the intestinal contents into the amniotic fluid.
Motilin is found in higher concentrations in post-term than pre-term foetal gastrointestinal tracts. Similarly, intestinal parasympathetic innervation and
myelination
Myelin is a lipid-rich material that surrounds nerve cell axons (the nervous system's "wires") to insulate them and increase the rate at which electrical impulses (called action potentials) are passed along the axon. The myelinated axon can be l ...
also increases in later gestations. Therefore, the increased incidence of MAS in post-term pregnancies may reflect the maturation and development of the peristalsis within the gastrointestinal tract in the newborn.
Pathophysiology
As MAS describes a spectrum of disorders of newborns born through MSAF, without any congenital respiratory disorders or other underlying pathology, there are numerous hypothesised mechanisms and causes for the onset of this syndrome. Long-term consequences may arise from these disorders, for example, infants that develop MAS have higher rates of developing neurodevelopmental defects due to poor respiration.
Airway obstruction
In the first 15 minutes of meconium aspiration, there is obstruction of larger airways which causes increased lung resistance, decreased
lung compliance
Lung compliance, or pulmonary compliance, is a measure of the lung's ability to stretch and expand (distensibility of elastic tissue). In clinical practice it is separated into two different measurements, static compliance and dynamic compliance. ...
, acute
hypoxemia,
hypercapnia,
atelectasis and
respiratory acidosis. After 60 minutes of exposure, the meconium travels further down into the smaller airways. Once within the terminal bronchioles and alveoli, the meconium triggers inflammation,
pulmonary edema,
vasoconstriction,
bronchoconstriction, collapse of airways and inactivation of
surfactant
Surfactants are chemical compounds that decrease the surface tension between two liquids, between a gas and a liquid, or interfacial tension between a liquid and a solid. Surfactants may act as detergents, wetting agents, emulsifiers, foaming ...
.
Foetal hypoxia
The lung areas which do not or only partially participate in
ventilation, because of obstruction and/or destruction, will become hypoxic and an inflammatory response may consequently occur. Partial obstruction will lead to air trapping and
hyperinflation of certain lung areas and
pneumothorax may follow. Chronic hypoxia will lead to an increase in pulmonary vascular smooth muscle tone and
persistent pulmonary hypertension causing respiratory and circulatory failure.
Infection
Microorganisms, most commonly
Gram-negative rods, and
endotoxins
Lipopolysaccharides (LPS) are large molecules consisting of a lipid and a polysaccharide that are bacterial toxins. They are composed of an O-antigen, an outer core, and an inner core all joined by a covalent bond, and are found in the outer me ...
are found in samples of MSAF at a higher rate than in clear amniotic fluid, for example 46.9% of patients with MSAF also had endotoxins present. A microbial invasion of the amniotic cavity (MIAC) is more common in patients with MSAF and this could ultimately lead to an intra-amniotic inflammatory response. MIAC is associated with high concentrations of
cytokines (such as
IL-6),
chemokines (such as
IL-8 and
monocyte chemoattractant protein-1
''For the ICAO airport code see Candle Lake Airpark, for the diradical compound see Dichlorocarbene.''
The chemokine (C-C motif) ligand 2 (CCL2) is also referred to as monocyte chemoattractant protein 1 (MCP1) and small inducible cytokine A2. CC ...
),
complement,
phospholipase A2 and matrix-degrading enzymes. Therefore, these aforementioned mediators within the amniotic fluid during MIAC and intra-amniotic infection could, when aspirated ''in'' ''utero'', induce lung inflammation within the foetus.
Pulmonary inflammation
Meconium has a complex chemical composition, so it is difficult to identify a single agent responsible for the several diseases that arise. As meconium is stored inside the
intestines, and is partly unexposed to the
immune system, when it becomes aspirated the
innate immune system
The innate, or nonspecific, immune system is one of the two main immunity strategies (the other being the adaptive immune system) in vertebrates. The innate immune system is an older evolutionary defense strategy, relatively speaking, and is the ...
recognises as a foreign and dangerous substance. The immune system, which is present at birth, responds within minutes with a low specificity and no memory in order to try to eliminate
microbes. Meconium perhaps leads to
chemical pneumonitis
Chemical pneumonitis is inflammation of the lung caused by aspirating or inhaling irritants. It is sometimes called a "chemical pneumonia", though it is not infectious. There are two general types of chemical pneumonitis: acute and chronic.
Irri ...
as it is a potent activator of inflammatory mediators which include
cytokines,
complement,
prostaglandin
The prostaglandins (PG) are a group of physiologically active lipid compounds called eicosanoids having diverse hormone-like effects in animals. Prostaglandins have been found in almost every tissue in humans and other animals. They are derive ...
s and
reactive oxygen species.
Meconium is a source of pro-inflammatory
cytokines, including
tumour necrosis factor (TNF) and
interleukins (
IL-1,
IL-6,
IL-8), and mediators produced by
neutrophils,
macrophage
Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer cel ...
s and epithelial cells that may injure the lung tissue directly or indirectly. For example,
proteolytic enzymes
Proteolysis is the breakdown of proteins into smaller polypeptides or amino acids. Uncatalysed, the hydrolysis of peptide bonds is extremely slow, taking hundreds of years. Proteolysis is typically catalysed by cellular enzymes called proteases, ...
are released from neutrophilic granules and these may damage the lung membrane and surfactant proteins. Additionally, activated
leukocytes and cytokines generate
reactive nitrogen
Reactive nitrogen ("Nr"), also known as fixed nitrogen, refers to all forms of nitrogen present in the environment except for molecular nitrogen (). While nitrogen is an essential element for life on Earth, molecular nitrogen is comparatively un ...
and
oxygen species which have
cytotoxic
Cytotoxicity is the quality of being toxic to cells. Examples of toxic agents are an immune cell or some types of venom, e.g. from the puff adder (''Bitis arietans'') or brown recluse spider (''Loxosceles reclusa'').
Cell physiology
Treating cells ...
effects.
Oxidative stress results in
vasoconstriction,
bronchoconstriction,
platelet aggregation and accelerated cellular
apoptosis
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
.
Recently, it has been hypothesised that meconium is a potent activator of
toll-like receptor (TLRs) and
complement, key mediators in inflammation, and may thus contribute to the inflammatory response in MAS.
Meconium contains high amounts of
phospholipase A2 (PLA
2), a potent proinflammatory enzyme, which may directly (or through the stimulation of
arachidonic acid
Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega-6 fatty acid 20:4(ω-6), or 20:4(5,8,11,14). It is structurally related to the saturated arachidic acid found in cupuaçu butter. Its name derives from the New Latin word ''arachi ...
) lead to surfactant dysfunction, lung epithelium destruction, tissue
necrosis
Necrosis () is a form of cell injury which results in the premature death of cells in living tissue by autolysis. Necrosis is caused by factors external to the cell or tissue, such as infection, or trauma which result in the unregulated dige ...
and an increase in
apoptosis
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
.
Meconium can also activate the
coagulation cascade
Coagulation, also known as clotting, is the process by which blood changes from a liquid to a gel, forming a blood clot. It potentially results in hemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The mechanism o ...
, production of
platelet-activating factor (PAF) and other vasoactive substances that may lead to destruction of capillary
endothelium and
basement membrane
The basement membrane is a thin, pliable sheet-like type of extracellular matrix that provides cell and tissue support and acts as a platform for complex signalling. The basement membrane sits between Epithelium, epithelial tissues including mesot ...
s. Injury to the alveolocapillary membrane results in leakage of liquid, plasma proteins, and cells into the
interstitium
The interstitium is a contiguous fluid-filled space existing between a structural barrier, such as a cell membrane or the skin, and internal structures, such as organs, including muscles and the circulatory system. The fluid in this space is cal ...
and
alveolar Alveolus (; pl. alveoli, adj. alveolar) is a general anatomical term for a concave cavity or pit.
Uses in anatomy and zoology
* Pulmonary alveolus, an air sac in the lungs
** Alveolar cell or pneumocyte
** Alveolar duct
** Alveolar macrophage
* ...
spaces.
Surfactant inactivation
Surfactant
Surfactants are chemical compounds that decrease the surface tension between two liquids, between a gas and a liquid, or interfacial tension between a liquid and a solid. Surfactants may act as detergents, wetting agents, emulsifiers, foaming ...
is synthesised by
type II alveolar cells and is made of a complex of
phospholipid
Phospholipids, are a class of lipids whose molecule has a hydrophilic "head" containing a phosphate group and two hydrophobic "tails" derived from fatty acids, joined by an alcohol residue (usually a glycerol molecule). Marine phospholipids typ ...
s, proteins and
saccharides. It functions to lower
surface tension
Surface tension is the tendency of liquid surfaces at rest to shrink into the minimum surface area possible. Surface tension is what allows objects with a higher density than water such as razor blades and insects (e.g. water striders) to f ...
(to allow for lung expansion during
inspiration
Inspiration, inspire, or inspired often refers to:
* Artistic inspiration, sudden creativity in artistic production
* Biblical inspiration, the doctrine in Judeo-Christian theology concerned with the divine origin of the Bible
* Creative inspirat ...
), stabilise
alveoli Alveolus (; pl. alveoli, adj. alveolar) is a general anatomical term for a concave cavity or pit.
Uses in anatomy and zoology
* Pulmonary alveolus, an air sac in the lungs
** Alveolar cell or pneumocyte
** Alveolar duct
** Alveolar macrophage
* ...
at the end of
expiration
Expiration or expiration date may refer to:
Expiration
Expiration may refer to:
*Death
*Exhalation of breath, breathing out
*Expiration (options), the legal termination of an option to take an action
*Shelf life, or the time after which a product ...
(to prevent alveolar collapse) and prevents lung
oedema. Surfactant also contributes to lung protection and defence as it is also an anti-inflammatory agent. Surfactant enhances the removal of inhaled particles and
senescent
Senescence () or biological aging is the gradual deterioration of functional characteristics in living organisms. The word ''senescence'' can refer to either cellular senescence or to senescence of the whole organism. Organismal senescence invol ...
cells away from the alveolar structure.
The extent of surfactant inhibition depends on both the concentration of surfactant and meconium. If the surfactant concentration is low, even very highly diluted meconium can inhibit surfactant function whereas, in high surfactant concentrations, the effects of meconium are limited. Meconium may impact surfactant mechanisms by preventing surfactant from spreading over the alveolar surface, decreasing the concentration of surfactant proteins (
SP-A and
SP-B
Surfactant protein B is an essential lipid-associated protein found in pulmonary surfactant. Without it, the lung would not be able to inflate after a deep breath out. It rearranges lipid molecules in the fluid lining the lung so that tiny air sac ...
), and by changing the viscosity and structure of surfactant.
Several morphological changes occur after meconium exposure, the most notable being the detachment of airway epithelium from
stroma and the shedding of
epithelial cells into the airway. These indicate a direct detrimental effect on lung alveolar cells because of the introduction of meconium into the lungs.
Persistent Pulmonary Hypertension
Persistent pulmonary hypertension (PPHN) is the failure of the foetal circulation to adapt to extra-uterine conditions after birth. PPHN is associated with various respiratory diseases, including MAS (as 15-20% of infants with MAS develop PPHN), but also
pneumonia and
sepsis. A combination of
hypoxia
Hypoxia means a lower than normal level of oxygen, and may refer to:
Reduced or insufficient oxygen
* Hypoxia (environmental), abnormally low oxygen content of the specific environment
* Hypoxia (medical), abnormally low level of oxygen in the tis ...
, pulmonary
vasoconstriction and
ventilation/
perfusion
Perfusion is the passage of fluid through the circulatory system or lymphatic system to an organ or a tissue, usually referring to the delivery of blood to a capillary bed in tissue. Perfusion is measured as the rate at which blood is deliver ...
mismatch can trigger PPHN, depending on the concentration of meconium within the
respiratory tract
The respiratory tract is the subdivision of the respiratory system involved with the process of respiration in mammals. The respiratory tract is lined with respiratory epithelium as respiratory mucosa.
Air is breathed in through the nose to th ...
.
PPHN in newborns is the leading cause of death in MAS.
Apoptosis
Apoptosis
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
is an important mechanism in the clearance of injured cells and in tissue repair, however too much apoptosis may cause harm, such as acute lung injury. Meconium induces apoptosis and
DNA cleavage of lung airway epithelial cells, this is detected by the presence of fragmented DNA within the airways and in alveolar epithelial nuclei. Meconium induces an inflammatory reaction within the lungs as there is an increase of
autophagocytic cells and levels of
caspase 3 after exposure. After 8 hours of meconium exposure, in rabbit foetuses, the total amount of apoptotic cells is 54%. Therefore, the majority of meconium-induced lung damage may be due to the apoptosis of lung epithelium.
Diagnosis
Respiratory distress in an infant born through the darkly coloured MSAF as well as meconium obstructing the airways is usually sufficient enough to diagnose MAS. Additionally, newborns with MAS can have other types of respiratory distress such as
tachypnea and
hypercapnia. Sometimes it is hard to diagnose MAS as it can be confused with other diseases that also cause respiratory distress, such as
pneumonia. Additionally, X-rays and lung ultrasounds can be quick, easy and cheap imaging techniques to diagnose lung diseases like MAS.
Prevention
In general, the incidence of MAS has been significantly reduced over the past two decades as the number of post-term deliveries has minimized.
Prevention during pregnancy
Prevention during pregnancy may include amnioinfusion and antibiotics but the effectiveness of these treatments are questionable.
Prevention during parturition
As previously mentioned,
oropharyngeal and
nasopharyngeal suctioning is not an ideal preventative treatment for both vigorous and depressed (not breathing) infants.
Treatment
Most infants born through MSAF do not require any treatments (other than routine postnatal care) as they show no signs of respiratory distress, as only approximately 5% of infants born through MSAF develop MAS.
However, infants which do develop MAS need to be admitted to a neonatal unit where they will be closely observed and provided any treatments needed. Observations include monitoring
heart rate,
respiratory rate,
oxygen saturation and
blood glucose (to detect worsening
respiratory acidosis or the development of
hypoglycemia).
In general, treatment of MAS is more supportive in nature.
Assisted ventilation techniques
To clear the airways of meconium,
tracheal suctioning can be used however, the efficacy of this method is in question and it can cause harm.
In cases of MAS, there is a need for supplemental oxygen for at least 12 hours in order to maintain oxygen saturation of haemoglobin at 92% or more. The severity of respiratory distress can vary significantly between newborns with MAS, as some require minimal or no supplemental oxygen requirement and, in severe cases, mechanical ventilation may be needed.
The desired oxygen saturation is between 90 and 95% and
PaO2 may be as high as 90mmHg.
In cases where there is thick meconium deep within the lungs,
mechanical ventilation may be required. In extreme cases,
extracorporeal membrane oxygenation
Extracorporeal membrane oxygenation (ECMO), also known as extracorporeal life support (ECLS), is an extracorporeal technique of providing prolonged cardiac and respiratory support to persons whose heart and lungs are unable to provide an adequat ...
(ECMO) may be utilised in infants who fail to respond to ventilation therapy.
While on ECMO, the body can have time to absorb the meconium and for all the associated disorders to resolve. There has been an excellent response to this treatment, as the survival rate of MAS while on ECMO is more than 94%.
Ventilation of infants with MAS can be challenging and, as MAS can affect each individual differently, ventilation administration may need to be customised. Some newborns with MAS can have homogenous lung changes and others can have inconsistent and patchy changes to their lungs. It is common for sedation and muscle relaxants to be used to optimise ventilation and minimise the risk of
pneumothorax associated with dyssynchronous breathing.
Inhaled nitric oxide
Inhaled
nitric oxide
Nitric oxide (nitrogen oxide or nitrogen monoxide) is a colorless gas with the formula . It is one of the principal oxides of nitrogen. Nitric oxide is a free radical: it has an unpaired electron, which is sometimes denoted by a dot in its che ...
(iNO) acts on
vascular smooth muscle causing selective pulmonary
vasodilation. This is ideal in the treatment of
PPHN as it causes vasodilation within ventilated areas of the lung thus, decreasing the ventilation-perfusion mismatch and thereby, improves oxygenation. Treatment utilising iNO decreases the need for
ECMO
Extracorporeal membrane oxygenation (ECMO), also known as extracorporeal life support (ECLS), is an extracorporeal technique of providing prolonged cardiac and respiratory support to persons whose heart and lungs are unable to provide an adequate ...
and mortality in newborns with hypoxic respiratory failure and PPHN as a result of MAS. However, approximately 30-50% of infants with PPHN do not respond to iNO therapy.
Antiinflammatories
As inflammation is such a huge issue in MAS, treatment has consisted of anti-inflammatories.
Glucocorticoids
Glucocorticoids have a strong anti-inflammatory activity and works to reduce the migration and activation of
neutrophils,
eosinophils,
mononuclear
Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can cellular differentiation, differentiate into macrophages and conventional dendritic cells. As a part of the vertebrate innate immune s ...
cells, and other cells. They reduce the migration of neutrophils into the lungs ergo, decreasing their adherence to the
endothelium. Thus, there is a reduction in the action of mediators released from these cells and therefore, a reduced inflammatory response.
Glucocorticoids also possess a genomic mechanism of action in which, once bound to a
glucocorticoid receptor, the activated complex moves into the
nucleus
Nucleus ( : nuclei) is a Latin word for the seed inside a fruit. It most often refers to:
*Atomic nucleus, the very dense central region of an atom
*Cell nucleus, a central organelle of a eukaryotic cell, containing most of the cell's DNA
Nucle ...
and inhibits
transcription
Transcription refers to the process of converting sounds (voice, music etc.) into letters or musical notes, or producing a copy of something in another medium, including:
Genetics
* Transcription (biology), the copying of DNA into RNA, the fir ...
of
mRNA. Ultimately, effecting whether various proteins get produced or not. Inhibiting the transcription of nuclear factor (
NF-κB) and protein activator (
AP-1) attenuates the expression of pro-inflammatory cytokines (
IL-1,
IL-6,
IL-8 and
TNF etc.), enzymes (
PLA2,
COX-2,
iNOs
Nitric oxide synthases () (NOSs) are a family of enzymes catalyzing the production of nitric oxide (NO) from L-arginine. NO is an important cellular signaling molecule. It helps modulate vascular tone, insulin secretion, airway tone, and perista ...
etc.) and other biologically active substances.
The anti-inflammatory effect of glucocorticoids is also demonstrated by enhancing the activity of lipocortines which inhibit the activity of PLA
2 and therefore, decrease the production of
arachidonic acid
Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega-6 fatty acid 20:4(ω-6), or 20:4(5,8,11,14). It is structurally related to the saturated arachidic acid found in cupuaçu butter. Its name derives from the New Latin word ''arachi ...
and mediators of
lipoxygenase and
cyclooxygenase pathways.
Anti-inflammatories
Anti-inflammatory is the property of a substance or treatment that reduces inflammation or swelling. Anti-inflammatory drugs, also called anti-inflammatories, make up about half of analgesics. These drugs remedy pain by reducing inflammation as o ...
need to be administered as quickly as possible as the effect of these drugs can diminish even just an hour after meconium aspiration. For example, early administration of
dexamethasone significantly enhanced
gas exchange, reduced ventilatory pressures, decreased the number of
neutrophils in the bronchoalveolar area, reduced
oedema formation and oxidative lung injury.
However, glucocorticoids may increase the risk of infection and this risk increases with the dose and duration of glucocorticoid treatment. Other issues can arise, such as aggravation of
diabetes mellitus,
osteoporosis
Osteoporosis is a systemic skeletal disorder characterized by low bone mass, micro-architectural deterioration of bone tissue leading to bone fragility, and consequent increase in fracture risk. It is the most common reason for a broken bone ...
, skin
atrophy
Atrophy is the partial or complete wasting away of a part of the body. Causes of atrophy include mutations (which can destroy the gene to build up the organ), poor nourishment, poor circulation, loss of hormonal support, loss of nerve supply t ...
and
growth retardation in children.
Inhibitors of phosphodiesterase
Phosphodiesterases (PDE) degrades
cAMP
Camp may refer to:
Outdoor accommodation and recreation
* Campsite or campground, a recreational outdoor sleeping and eating site
* a temporary settlement for nomads
* Camp, a term used in New England, Northern Ontario and New Brunswick to descri ...
and
cGMP CGMP is an initialism. It can refer to:
*cyclic guanosine monophosphate (cGMP)
*current good manufacturing practice (cGMP)
*CGMP, Cisco Group Management Protocol, the Cisco version of Internet Group Management Protocol
The Internet Group Managem ...
and, within the
respiratory system of a newborn with MAS, various isoforms of PDE may be involved due to their pro-inflammatory and
smooth muscle
Smooth muscle is an involuntary non-striated muscle, so-called because it has no sarcomeres and therefore no striations (''bands'' or ''stripes''). It is divided into two subgroups, single-unit and multiunit smooth muscle. Within single-unit mus ...
contractile activity. Therefore, non-selective and selective inhibitors of PDE could potentially be used in MAS therapy. However, the use of PDE inhibitors can cause
cardiovascular side effects. Non-selective PDE inhibitors, such as
methylxanthines, increase concentrations of cAMP and cGMP in the cells leading to
bronchodilation
A bronchodilator or broncholytic (although the latter occasionally includes secretory inhibition as well) is a substance that dilates the bronchi and bronchioles, decreasing resistance in the respiratory airway and increasing airflow to the lungs ...
and
vasodilation. Additionally, methylxanthines decreases the concentrations of calcium,
acetylcholine
Acetylcholine (ACh) is an organic chemical that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Part ...
and
monoamines, this controls the release of various mediators of inflammation and
bronchoconstriction, including
prostaglandin
The prostaglandins (PG) are a group of physiologically active lipid compounds called eicosanoids having diverse hormone-like effects in animals. Prostaglandins have been found in almost every tissue in humans and other animals. They are derive ...
s. Selective PDE inhibitors target one subtype of
phosphodiesterase and in MAS the activities of
PDE-3,
PDE-4,
PDE-5 and PDE-7 may become enhanced.
For example,
Milrinone (a selective PDE3 inhibitor) improved oxygenation and survival of neonates with MAS.
Inhibitors of cyclooxygenase
Arachidonic acid
Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega-6 fatty acid 20:4(ω-6), or 20:4(5,8,11,14). It is structurally related to the saturated arachidic acid found in cupuaçu butter. Its name derives from the New Latin word ''arachi ...
is metabolised, via
cyclooxygenase (COX) and
lipoxygenase, to various substances including
prostaglandin
The prostaglandins (PG) are a group of physiologically active lipid compounds called eicosanoids having diverse hormone-like effects in animals. Prostaglandins have been found in almost every tissue in humans and other animals. They are derive ...
s and
leukotrienes, which exhibit potent pro-inflammatory and
vasoactive
A vasoactive substance is an endogenous agent or pharmaceutical drug that has the effect of either increasing or decreasing blood pressure and/or heart rate through its vasoactivity, that is, vascular activity (effect on blood vessels). By adju ...
effects. By inhibiting COX, and more specifically
COX-2, (either through selective or non-selective drugs) inflammation and oedema can be reduced. However, COX inhibitors may induce
peptic ulcers and cause
hyperkalemia and
hypernatremia. Additionally, COX inhibitors have not shown any great response in the treatment of MAS.
Antibiotics
Meconium is typically sterile however, it can contain various cultures of bacteria so appropriate antibiotics may need to be prescribed.
Surfactant treatment
Lung lavage
Bronchoalveolar lavage (BAL) (also known as bronchoalveolar washing) is a diagnostic method of the lower respiratory system in which a bronchoscope is passed through the mouth or nose into an appropriate airway in the lungs, with a measured amou ...
with diluted
surfactant
Surfactants are chemical compounds that decrease the surface tension between two liquids, between a gas and a liquid, or interfacial tension between a liquid and a solid. Surfactants may act as detergents, wetting agents, emulsifiers, foaming ...
is a new treatment with potentially beneficial results depending on how early it is administered in newborns with MAS. This treatment shows promise as it has a significant effect on air leaks,
pneumothorax, the need for
ECMO
Extracorporeal membrane oxygenation (ECMO), also known as extracorporeal life support (ECLS), is an extracorporeal technique of providing prolonged cardiac and respiratory support to persons whose heart and lungs are unable to provide an adequate ...
and death. Early intervention and using it on newborns with mild MAS is more effective. However, there are risks as a large volume of fluid instillation to the lung of a newborn can be dangerous (particularly in cases of severe MAS with
pulmonary hypertension) as it can exacerbate
hypoxia
Hypoxia means a lower than normal level of oxygen, and may refer to:
Reduced or insufficient oxygen
* Hypoxia (environmental), abnormally low oxygen content of the specific environment
* Hypoxia (medical), abnormally low level of oxygen in the tis ...
and lead to mortality.
Previous treatments
Originally, it was believed that MAS developed as a result of the meconium being a physical blockage of the airways. Thus, to prevent newborns, who were born through MSAF, from developing MAS, suctioning of the
oropharyngeal and
nasopharyngeal area before delivery of the shoulders followed by
tracheal aspiration was utilised for 20 years. This treatment was believed to be effective as it was reported to significantly decrease the incidence of MAS compared to those newborns born through MSAF who were not treated. This claim was later disproved and future studies concluded that oropharyngeal and nasopharyngeal suctioning, before delivery of the shoulders in infants born through MSAF, does not prevent MAS or its complications.
In fact, it can cause more issues and damage (e.g.
mucosal
A mucous membrane or mucosa is a membrane that lines various cavities in the body of an organism and covers the surface of internal organs. It consists of one or more layers of epithelial cells overlying a layer of loose connective tissue. It is ...
damage), thus it is not a recommended preventative treatment.
Suctioning may not significantly reduce the incidence of MAS as meconium passage and aspiration may occur ''in-utero.'' Thereby making the suctioning redundant and useless as the meconium may already be deep within the lungs at the time of birth.
Historically,
amnioinfusion
Amnioinfusion is a method in which isotonic fluid is instilled into the uterine cavity.
It was introduced in the 1960s as a means of terminating pregnancy and inducing labor in intrauterine death, but is currently used as a treatment in order to c ...
has been used when MSAF was present, which involves a transcervical infusion of fluid during labour. The idea was to dilute the thick meconium to reduce its potential pathophysiology and reduce cases of MAS, since MAS is more prevalent in cases of thick meconium.
However, there are associated risks, such as
umbilical cord prolapse and prolongation of labour. The UK National Institute of Health and Clinical Excellence (NICE) Guidelines recommend against the use of amnioinfusion in women with MSAF.
Prevalence
1 in every 7 pregnancies have MSAF and, of these cases, approximately 5% of these infants develop MAS.
MSAF is observed 23-52% in pregnancies at 42 weeks therefore, the frequency of MAS increases as the length of
gestation
Gestation is the period of development during the carrying of an embryo, and later fetus, inside viviparous animals (the embryo develops within the parent). It is typical for mammals, but also occurs for some non-mammals. Mammals during pregna ...
increases, such that the prevalence is greatest in post-term pregnancies. Conversely,
preterm births are not frequently associated with MSAF (only approximately 5% in total contain MSAF). The rate of MAS declines in populations where labour is induced in women that have pregnancies exceeding 41 weeks.
There are many suspected pre-disposing factors that are thought to increase the risk of MAS. For example, the risk of MSAF is higher in African American, African and Pacific Islander mothers, compared to mothers from other ethnic groups.
Future research
Research is being focused on developing both a successful method for preventing MAS as well as an effective treatment. For example, investigations are being made in the efficiency of
anti-inflammatory agents, surfactant replacement therapy and
antibiotic
An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting bacterial infections, and antibiotic medications are widely used in the treatment and prevention of ...
therapy. More research needs to be conducted on the pharmacological properties of, for example,
glucocorticoids, including dosages, administration, timing or any drug interactions.
Additionally, there is still research being conducted on whether intubation and suctioning of meconium in newborns with MAS is beneficial, harmful or is simply a redundant and outdated treatment. In general, there is still no generally accepted therapeutic protocol and effective treatment plan for MAS.
See also
*
Aspiration pneumonia
References
External links
eMedicine's article about meconium aspiration syndrome
{{DEFAULTSORT:Meconium Aspiration Syndrome
Neonatology
Syndromes