Pediatric Respirology and Critical Care Medicine

: 2017  |  Volume : 1  |  Issue : 4  |  Page : 72--76

Babies who don't get better: When it's not respiratory distress syndrome

Steven M Donn 
 Department of Pediatrics and Communicable Diseases, Division of Neonatal-Perinatal Medicine, C.S. Mott Children's Hospital, Michigan Medicine, Ann Arbor, Michigan, USA

Correspondence Address:
Steven M Donn
8-621 C.S. Mott Children's Hospital, 1540 E. Hospital Drive, Ann Arbor, Michigan 48109-4254


Most preterm and late preterm infants who require mechanical ventilation for respiratory failure resolve their disease process and can be extubated. A small percentage, however, continues to exhibit respiratory failure and remain ventilator dependent. There are myriad conditions that the clinician needs to consider, some of which are treatable, but some of which are lethal. Strategies for diagnosis and management are discussed herein.

How to cite this article:
Donn SM. Babies who don't get better: When it's not respiratory distress syndrome.Pediatr Respirol Crit Care Med 2017;1:72-76

How to cite this URL:
Donn SM. Babies who don't get better: When it's not respiratory distress syndrome. Pediatr Respirol Crit Care Med [serial online] 2017 [cited 2023 Mar 22 ];1:72-76
Available from:

Full Text


Respiratory failure is the most common problem facing the prematurely born infant. Morphological and anatomical lung abnormalities interfere with adequate pulmonary gas exchange and may lead to the need for mechanical intubation. It is widely recognized that the indications for intubation and mechanical ventilation include inadequate oxygenation and/or ventilation, apnea, airway obstruction, and the need for control of the airway. The goals of mechanical ventilation include assisting the baby to achieve adequate gas exchange, optimizing patient-ventilator interactions, minimizing lung injury, and enhancing patient comfort while decreasing the patient work of breathing.

A recent survey of European neonatal intensive care units by Van Kaam et al.[1] queried the reasons for mechanical ventilation in newborns [Table 1]. Although nearly half had respiratory distress syndrome, the remainder exhibited varying conditions including sepsis, congenital malformations, apnea, asphyxia, pneumonia, and others.{Table 1}

Fortunately, most babies improve and are able to be weaned from support. In the past decades, we have improved our understanding of the pathophysiology of these disorders. We have been provided with an expanding array of better technology and an expanded drug formulary. This population possesses the potential for growth, generation of new tissue, and the ability to heal, and it exhibits great plasticity. Yet, some babies get stuck. They may fail to wean, fail to grow, or fail to respond to treatment.

 Physiologic Essentials for Extubation

A number of conditions must be achieved before a baby can be successfully extubated. First, there must be reliable respiratory spontaneous expiratory drive, the baby must display neuromuscular competence (the ability to transmit impulses from the respiratory center to the phrenic nerve and diaphragm), and there must be evidence of a reduced respiratory system load, characterized by the maintenance of oxygenation without intrinsic end-expiratory pressure, and adequate minute ventilation (tidal volume X frequency >240 mL/kg/min).[2]

Numerous impediments to weaning and successful extubation have been recognized [Table 2]. Each of these factors alone can increase the work of breathing and complicate the process. Some, such as anemia and electrolyte imbalances, are easily correctable, while others are more problematic. When these conditions have been adequately addressed, and the infant is still dependent on mechanical ventilation, the clinician must consider the possibility of an unusual underlying pathologic entity.[3]{Table 2}

 Chronic Ventilator Dependence

From a diagnostic standpoint, it may be easiest to classify the underlying problem into one of four categories: primary pulmonary disease (affecting the airway, lung parenchyma, or both); neurologic disease (central or peripheral); myopathy; and metabolic disease.

[Table 3] lists malformations of the tracheobronchial tree. These conditions can be diagnosed by imaging (plain or contrast radiography, computed tomography, or magnetic resonance imaging) or airway endoscopy. Most – but not all – are amenable to surgical intervention. The advent of detailed fetal imaging has led to the prenatal diagnosis in many instances, and delivery room intervention (i.e., tracheostomy and EXIT procedure) can be planned in advance.{Table 3}

Malformations of the distal lung parenchyma are shown in [Table 4]. These represent a spectrum from easily treatable to lethal, so it is incumbent on the clinician to make an expeditious diagnosis to institute appropriate therapy or to limit patient pain and discomfort through redirection of care. I will consider a few of these disorders with disparate prognoses to illustrate this point.[4],[5],[6]{Table 4}

Alveolar capillary dysplasia

This morphologic disorder was first described by Janney et al. in 1981.[7] There have been about 150 cases described in the medical literature, although the disease is probably much more prevalent. The exact etiology is unknown, but there are five reports of its occurrence in concordant siblings. Thus far, no karyotypic or cytogenetic abnormalities have been found.

It is believed to represent abnormal lung development during the pseudoglandular phase (4–16 weeks) and is characterized by arrested lung growth and development. The pulmonary veins adjacent to the pulmonary artery branches are displaced, and the arteries are also abnormal. The vessels share the arteriolar adventitia. The interlobular septa are abnormally broad with decreased numbers of capillaries, which fail to make contact with the alveolar epithelium. Thus, the blood-gas barrier is not formed normally, there is reduced pulmonary surface area, inadequate gas exchange, and pulmonary hypertension.

The usual clinical presentation is severe and intractable persistent pulmonary hypertension with unrelenting hypoxemia. Alveolar capillary dysplasia (ACD) occurs in term infants 90% of the time, often after normal Apgar scores. Half of the affected newborns present in the first 24 h. A later onset form has been reported, with signs appearing as late as 4–6 weeks. Pneumothorax is seen in half of the cases. Associated anomalies [Table 5] occur on 50%–65% of infants.{Table 5}

The chest radiograph in ACD may be initially unremarkable, or it may show mild haziness. Before 2000, more than 90% of cases were diagnosed by postmortem examination. Definitive diagnosis can be made by open lung biopsy.

ACD is a lethal disorder, with death occurring in the 1st day to weeks of age. There has been one reported survivor after lung transplant at 5 months of age.[8]

Surfactant protein deficiency diseases

Pulmonary surfactant is a complex mixture of phospholipids (90%) and proteins (10%). The first attempts at synthetic surfactant repletion in the 1960s, which failed, emphasized the importance of the surfactant-associated proteins.[9]

The proteins, SP-A, SP-B, SP-C, and SP-D, were named in order of their discovery. SP-A is a 35kD hydrophilic monomer, whose major functions are pathogen clearance, modulation of innate immunity, regulation of inflammation, and stabilization of tubular myelin. SP-B is an 8.7 kD amphipathic homodimer, whose functions include surface tension reduction, and surfactant organization and homeostasis. SP-C is a 3.7 kD hydrophobic monopolymer, with functions similar to SP-B. SP-D is a 37.7 kD hydrophilic dodecamer, whose functions include those ascribed to SP-A plus a role in surfactant metabolism.[9]

SP-B deficiency

SP-B was first characterized in 1987.[10] This protein consists of alpha-helices containing multiple amphipathic domains, allowing it to interact with phospholipid polar heads at the edge of the lipid bilayer. The amphipathic domains allow both hydrophobic and hydrophilic interactions, improving surfactant adsorption and reduction in alveolar surface tension. SP-B also aids in preventing alveolar collapse at end-expiration and facilitates recruitment during inspiration.

SP-B deficiency occurs in about 1 per million live births. Multiple different gene mutations, including nonsense, missense, frameshift, and splice site mutations have been identified. Infants with SP-B deficiency develop unresponsive respiratory failure, often resulting in unsuccessful extracorporeal membrane oxygenation therapy, and palliative care. The condition may show a temporary response to animal-derived surfactant administration but is uniformly lethal.[11]

SP-C deficiency

SP-C increases the fluidity of the surfactant phospholipid bilayer accounting for its role in reducing alveolar surface tension. Its deficiency has a high phenotypic variance. Missense, frameshift, insertion, deletion, and splice site mutations have all been identified. In fact, there have been more than 35 dominantly expressed mutations, of which 55% are spontaneous. SP-C deficiency may be diagnosed at any age from early infancy to adulthood. The clinical spectrum ranges from asymptomatic to chronic respiratory insufficiency, and significant disease progressing to death or the need for lung transplantation.[11] It has been postulated that the possible mechanism of disease is the misfolding of proproteins that inhibit protein trafficking and result in cellular stress, injury, and apoptosis. Histopathologic changes include alveolar proteinosis, interstitial pneumonitis, and disorganized lamellar bodies.

The diagnosis of either SP-B or SP-C deficiency can be made from a biochemical analysis of fluid obtained by tracheal aspiration. Genetic (DNA) sequencing can also be done (including ABCA3 mutations). Ultrastructural examination of lung biopsy specimens by electron microscopy can also be useful.

ABCA3 mutations

The exact frequency of ABCA3 mutations is unknown, but it may be the most common disorder of surfactant homeostasis. More than 70 recessive mutations have been identified in lethal RDS in newborns and chronic respiratory insufficiency in children. The precise role of ABCA3 in surfactant metabolism remains elusive. Surfactant isolated from bronchoalveolar lavage fluid from ABCA3-deficient infants has significantly decreased phosphatidylcholine and markedly reduced function, suggesting that the ABCA3 mutation mediates phosphatidylcholine transport into lamellar bodies (which appear small and dense on electron microscopy). The absence of ABCA3 may also affect the trafficking of SP-B and SP-C.[12]

Different classes of mutations that result in the absence, misrouting, or altered function of the ABCA3 protein likely lead to differences in the clinical expression of disease.

 Interstitial Lung Diseases

Interstitial lung diseases (ILDs) refer to a group of pulmonary disorders involving both the airspaces and compartments of the lung. They are relatively rare, but they can be associated with significant morbidity as well as mortality. A comprehensive review by Nogee was recently published and is highly recommended.[13]

 Pulmonary Interstitial Glycogenosis

One of these entities is pulmonary interstitial glycogenosis (PIG), and because it is a nonlethal disorder, distinction of PIG from other lethal disorders is critical. The PIG was first described by Canakis et al. in 2002.[14] It is an atypical, noninfectious respiratory disorder, which may represent a possible developmental disorder of the lung. It should be distinguished from other forms of ILD, especially unusual interstitial pneumonitis, desquamative interstitial pneumonitis, and lymphoid interstitial pneumonitis.

On light microscopy, the lung tissue shows diffuse interstitial thickening, and the interalveolar septae are uniformly expanded by spindle type cells. Electron microscopy shows abnormalities of the interstitial cells, which have features of primitive mesenchymal cells, and they contain low contrast granular material suggestive of glycogen.

The clinical course of PIG is usually respiratory distress on the 1st day of life. Mechanical ventilation is generally required. The chest radiograph demonstrates large lung volumes, a coarse interstitial pattern, nonspecific haziness, and pneumothorax is common. The diagnosis can be confirmed by chest computed tomography or open lung biopsy.

In general, favorable outcomes have been reported for PIG. In the original series of Canakis et al., six of seven survived, and three had clinical resolution by the age of 6 years.[14] Thus, it is clear that this disorder must be distinguished from ACD and SP-B deficiency.

 Neuromuscular Disorders

While it is beyond the scope of this review to present an in-depth discussion of all neuromuscular diseases that result in chronic respiratory insufficiency, several of the more common entities will be addressed. What these disorders have in common is a weakness of the respiratory muscles and the inability to compensate for increased respiratory loads. Airway clearance and recurrent pneumonia are also seen frequently. Ventilatory management of affected infants was recently reviewed by Alexiou and Piccione.[15]

 Neonatal Onset Spinal Muscular Atrophy (Type 1, Werdnig–hoffman Disease)

This lethal disorder is inherited as an autosomal recessive disease. It occurs in approximately 1/6000–1/10,000 live births and results from the absence of the SMN1 gene. Progressive destruction of the anterior horn cell leads to increasing weakness and loss of muscular function.[16]

 Spinal Muscular Atrophy With Respiratory Distress, Type 1

This is another fatal infantile motor neuron disease. It causes diaphragmatic palsy, distal muscular weakness, muscle atrophy, sensory neuropathy, and autonomic nerve dysfunction. The IGHMBP2 gene has been implicated.[17]

 Congenital Myopathies

This group of disorders includes diseases which primarily affect skeletal muscle fibers and are present at birth. An example is myotubular myopathy, an X-linked infantile myopathy. Muscle weakness and hypotonia, with resultant respiratory insufficiency, are the prominent findings. Affected fetuses may have reduced fetal movement, polyhydramnios (from a lack of swallowing), and thin ribs. After birth, there is severe hypotonia, muscle wasting, and generalized weakness. The majority of affected infants die in the 1st month of life. The diagnosis may be suspected by elevated muscle enzymes or abnormalities on electromyography, but only a muscle biopsy is confirmatory.[18]

Congenital muscular dystrophies

These are progressive disorders that lead to degeneration of muscle fibers. Congenital muscular dystrophy occurs in 0.68–2.5/100,000 live births. They are inherited as autosomal recessive diseases, although an autosomal dominant pattern has been reported. The specific type of muscular dystrophy can be determined by advanced diagnostic testing, including biochemical, genetic, and electromyographic.[18]

Congenital myasthenic syndrome

This is an inherited neuromuscular disorder caused by defects of the neuromuscular junction (either presynaptic, synaptic, or postsynaptic) and occurs once in half a million live births. It should be distinguished from the syndrome which affects infants born to mothers with myasthenia gravis, which is transient and improves with supportive care.[19]

Prader–Willi syndrome

This syndrome, characterized by hypotonia (and hence respiratory insufficiency), hypogonadism, hypomentia, and obesity, is seen in 1/25,000–1/10,000 live births. It results from a deletion in the paternal chromosome 15 (q 11–13). Infants are often depressed or lethargic at birth and exhibit feeding difficulties as well as respiratory problems.[20]

 Evaluation of Intractable Respiratory Failure in the Newborn

The evaluation of a newborn with intractable respiratory failure should begin with low-invasive, high-yield studies and only progress to the more invasive studies as the differential diagnosis is honed [Table 6]. Imaging, especially chest radiography, is usually the first step. If indicated, chest computed tomography or magnetic resonance imaging may yield important information or rule out some entities. Flexible bronchoscopy is used to evaluate the upper airway and trachea, and is relatively safe when performed by skilled and experienced operators. Evaluation of lung fluid obtained by bronchoalveolar lavage is becoming a more widely utilized diagnostic test. Genetic studies should be obtained after consultation with a geneticist, who can help decide the appropriate analysis and adjuvant studies.{Table 6}

In cases where surgical biopsy is indicated, whether open lung or muscle, the diagnostic accuracy depends on the appropriate processing of the biopsy specimen. Care should be taken to orchestrate the entire procedure, among the various teams-surgery, laboratory, pathology, and ancillary services.

Finally, for patients who die without a definitive diagnosis, efforts should be taken to obtain a postmortem examination. While families are sometimes reluctant to give consent, a discussion which emphasizes the importance of finding an answer, as well as influencing subsequent family planning can do much to persuade parents to move forward.[21]

 Redirection of Care

The decision to withdraw or withhold life support is a difficult one, subject to both individual beliefs and institutional practices and legal imperatives. It would seem reasonable that once the diagnosis of a lethal disorder has been made, efforts should focus on alleviation of pain and avoidance of suffering. In the case of a baby who is failing to respond, but does not have a specific diagnosis, it is less clear. A reasonable attempt to obtain a diagnosis and a reasonable attempt at therapeutic measures seems appropriate. It is up to the clinician and the family to determine what constitutes “reasonable.”

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.


1van Kaam AH, Rimensberger PC, Borensztajn D, De Jaegere AP; Neovent Study Group. Ventilation practices in the neonatal Intensive Care Unit: A cross-sectional study. J Pediatr 2010;157:767-71.e1-3.
2Sinha SK, Donn SM. Weaning infants from mechanical ventilation: Art or science? Arch Dis Child 2000;83:F64-70.
3Donn SM, Sinha SK. Weaning and extubation. In: Donn SM, Sinha SK, editors. Manual of Neonatal Respiratory Care. 4th ed. New York: Springer Science+Business Media; 2017. p. 633-9.
4Lioy J, Sobel SE, editors. Disorders of the Neonatal Airway: Fundamentals for Practice. New York: Springer; 2015.
5Lioy J, Greubel E, Sobel S. Malformations, deformations, and disorders of the neonatal airway. In: Donn SM, Sinha SK, editors. Manual of Neonatal Respiratory Care. 4th ed. New York: Springer; 2017. p. 13-35.
6Attar MA, Sarkar S. Developmental lung anomalies. In: Donn SM, Sinha SK, editors. Manual of Neonatal Respiratory Care. 4th ed. New York: Springer; 2017. p. 37-40.
7Janney CG, Askin FB, Kuhn C 3rd. Congenital alveolar capillary dysplasia – An unusual cause of respiratory distress in the newborn. Am J Clin Pathol 1981;76:722-7.
8Swenson AW, Donn SM. Alveolar capillary dysplasia: A lethal developmental lung malformation. Curr Respir Med Rev 2009;5:110-4.
9Ketko AK, Donn SM. Surfactant-associated proteins: Structure, function and clinical implications. Curr Pediatr Rev 2014;10:162-7.
10Curstedt T, Jörnvall H, Robertson B, Bergman T, Berggren P. Two hydrophobic low-molecular-mass protein fractions of pulmonary surfactant. Characterization and biophysical activity. Eur J Biochem 1987;168:255-62.
11Hamvas A. Inherited surfactant protein-B deficiency and surfactant protein-C associated disease: Clinical features and evaluation. Semin Perinatol 2006;30:316-26.
12Hamvas A, Cole FS, Nogee LM. Genetic disorders of surfactant proteins. Neonatology 2007;91:311-7.
13Nogee LM. Interstitial lung disease in newborns. Semin Fetal Neonatal Med 2017;22:227-33.
14Canakis AM, Cutz E, Manson D, O'Brodovich H. Pulmonary interstitial glycogenosis: A new variant of neonatal interstitial lung disease. Am J Respir Crit Care Med 2002;165:1557-65.
15Alexiou S, Piccione J. Neuromuscular disorders and chronic ventilation. Semin Fetal Neonatal Med 2017;22:256-9.
16Prior TW. Perspectives and diagnostic considerations in spinal muscular atrophy. Genet Med 2010;12:145-52.
17Messina MF, Messina S, Gaeta M, Rodolico C, Salpietro Damiano AM, Lombardo F, et al. Infantile spinal muscular atrophy with respiratory distress type I (SMARD 1): An atypical phenotype and review of the literature. Eur J Paediatr Neurol 2012;16:90-4.
18Schorling DC, Kirschner J, Bönnemann CG. Congenital muscular dystrophies and myopathies: An overview and update. Neuropediatrics 2017;48:247-61.
19Engel AG, Shen XM, Selcen D, Sine SM. Congenital myasthenic syndromes: Pathogenesis, diagnosis, and treatment. Lancet Neurol 2015;14:420-34.
20Tan HL, Urquhart DS. Respiratory complications in children with Prader Willi syndrome. Paediatr Respir Rev 2017;22:52-9.
21Donn SM, Sinha SK. Pulmonary diagnostics. Semin Fetal Neonatal Med 2017;22:200-5.