Respiratory system: Mini case reviews week #6 – ARDS, SIDS, Bronchopulmonary dysplasia, sleep apnea


A 57-year-old white male, with a history of abusing alcohol, is admitted to the ICU with gram –positive pneumonia and sepsis. He is dyspneic. The chest X-ray shows generalized pulmonary infiltrates without evidence of left-sided cardiac failure. His PaO2 divided by the FiO2 is < 200 mmHg (normal >500 mmHg). Based on Berlin consensus criteria, he is diagnosed with moderate ARDS and begun on lung-protective ventilation.

Fraction of inspired oxygen is the fraction or percentage of oxygen in the volume being measured. Medical patients experiencing difficulty breathing are provided with oxygen-enriched air, which means a higher-than-atmospheric FiO₂

  • Describe the main features of ARDS

Clinical presentation — The clinical features of ARDS usually appear within 6 to 72 hours of an inciting event and worsen rapidly [3]. Patients typically present with dyspnea, cyanosis (ie, hypoxemia), and diffuse crackles. Respiratory distress is usually evident, including tachypnea, tachycardia, diaphoresis, and use of accessory muscles of respiration. A cough and chest pain may also exist.

Clinical findings related to the precipitant may also exist at presentation. As an example, in patients with ARDS due to sepsis, there may be fever, hypotension, leukocytosis, lactic acidosis, and disseminated intravascular coagulation (DIC).

Arterial blood gases reveal hypoxemia, which is often accompanied by acute respiratory alkalosis and an elevated alveolar-arterial oxygen gradient (calculator 1). High concentrations of supplemental oxygen are generally required to maintain adequate oxygenation.

The initial chest radiograph typically has bilateral alveolar infiltrates while computed tomography (CT) usually reveals widespread patchy or coalescent airspace opacities that are usually more apparent in the dependent lung zones. The infiltrates do not have to be diffuse or severe, as bilateral infiltrates of any severity are sufficient.

  • List disorders associated with development of ARDS

The most common underlying causes of ARDS include:

  • Sepsis. The most common cause of ARDS is sepsis, a serious and widespread infection of the bloodstream.
  • Inhalation of harmful substances. Breathing high concentrations of smoke or chemical fumes can result in ARDS, as can inhaling (aspirating) vomit or near-drowning episodes.
  • Severe pneumonia. Severe cases of pneumonia usually affect all five lobes of the lungs.
  • Head, chest or other major injury. Accidents, such as falls or car crashes, can directly damage the lungs or the portion of the brain that controls breathing.
  • Others. Pancreatitis (inflammation of the pancreas), massive blood transfusions and burns.

Risk factors

Most people who develop ARDS are already hospitalized for another condition, and many are critically ill. You’re especially at risk if you have a widespread infection in your bloodstream (sepsis).

People who have a history of chronic alcoholism are at higher risk of developing ARDS. They’re also more likely to die of ARDS.


If you have ARDS, you can develop other medical problems while in the hospital. The most common problems are:

  • Blood clots. Lying still in the hospital while you’re on a ventilator can increase your risk of developing blood clots, particularly in the deep veins in your legs. If a clot forms in your leg, a portion of it can break off and travel to one or both of your lungs (pulmonary embolism) — where it blocks blood flow.
  • Collapsed lung (pneumothorax). In most ARDS cases, a breathing machine called a ventilator is used to increase oxygen in the body and force fluid out of the lungs. However, the pressure and air volume of the ventilator can force gas to go through a small hole in the very outside of a lung and cause that lung to collapse.
  • Infections. Because the ventilator is attached directly to a tube inserted in your windpipe, this makes it much easier for germs to infect and further injure your lungs.
  • Scarring (pulmonary fibrosis). Scarring and thickening of the tissue between the air sacs can occur within a few weeks of the onset of ARDS. This stiffens your lungs, making it even more difficult for oxygen to flow from the air sacs into your bloodstream.

Thanks to improved treatments, more people are surviving ARDS. However, many survivors end up with potentially serious and sometimes lasting effects:

  • Breathing problems. Many people with ARDS recover most of their lung function within several months to two years, but others may have breathing problems for the rest of their lives. Even people who do well usually have shortness of breath and fatigue and may need supplemental oxygen at home for a few months.
  • Depression. Most ARDS survivors also report going through a period of depression, which is treatable.
  • Problems with memory and thinking clearly. Sedatives and low levels of oxygen in the blood can lead to memory loss and cognitive problems after ARDS. In some cases, the effects may lessen over time, but in others, the damage may be permanent.
  • Tiredness and muscle weakness. Being in the hospital and on a ventilator can cause your muscles to weaken. You also may feel very tired following treatment.
  • Describe the pathobiology of the response to various lung insults that culminate in ARDS
  • Firstly…Diffuse alveolar damage (DAD) is manifested by injury to alveolar lining and endothelial cells, pulmonary edema, hyaline membrane formation and later by proliferative changes involving alveolar and bronchiolar lining cells and interstitial cells (Am J Pathol 1976;85:209)
as for the Essential features you would see –
  • Acute and rapidly progressive hypoxia with bilateral pulmonary edema due to alveolar injury caused by pulmonary or systemic insults
  • 40% die within 28 days from onset of ARDS, mainly due to septic shock and multiple organ dysfunction syndrome (MODS)
  • DAD is the most common morphological pattern of ARDS; however the clinical syndrome of ARDS is not synonymous with the pathologic diagnosis of DAD
  • DAD pattern is often characterized by hyaline membranes in acute phase but shows a wide variety of findings that makes the diagnosis challenging
  • Describe the initial inflammatory process marked by neutrophils in the alveolar fluid and hyaline membrane formation in some patients

The classic pathological finding in ARDS is a combination of widespread epithelial injury with stripping of the alveolar epithelium, endothelial injury leading to interstitial and alveolar edema, accumulation of neutrophils, macrophages, red blood cells, surfactant dysfunction, and deposition of hyaline membranes in the alveoli [35].

As the disease progresses, there is infiltration of fibroblasts and collagen deposition.

The physiologic consequences of these changes include impaired gas exchange, decreased lung compliance, and increased work of breathing. There are several pathways involved in the development of ARDS but a key feature is inflammation due to activation of neutrophils.

Several proinflammatory mediators such as tumor necrosis factor (TNF), IL-1, and IL-6 are involved in ARDS pathogenesis [36]. There is an imbalance between proinflammatory and antiinflammatory cytokines, oxidants and antioxidants, procoagulants and anticoagulants, proteases and protease inhibitors, and neutrophil recruitment and clearance.

  • Describe how resolution of ARDS depends in part on restoration of a functional alveolar barrier, which is capable of removing alveolar edema by active Na+-transport.

ARDS is caused by protein-rich pulmonary edema that causes severe hypoxemia and impaired carbon dioxide excretion.

Resolution is delayed because of injury to the lung epithelial barrier, which prevents removal of alveolar edema fluid and deprives the lung of adequate quantities of surfactant. Lymphocytes may play a role in resolution of lung injury.

The first step toward resolution of ALI/ARDS is to remove the alveolar edema fluid to the lung interstitium, where net clearance can occur through lung lymphatics, the pulmonary microcirculation, and even bulk flow into the pleural space.

Removal of alveolar edema fluid from the air spaces requires vectorial transport of sodium and chloride across the apical and basolateral membranes of alveolar epithelial type I and II cells, which creates a miniosmotic gradient for the reabsorption of water (Figure 6) (6061).

Thus, sodium is actively absorbed across the apical surface of alveolar epithelial type I and II cells, predominantly by the epithelial sodium channel; the sodium is extruded from the cell by the Na/K-ATPase pumps on the basolateral membrane, thereby creating a miniosmotic gradient for the absorption of water from the alveoli. Chloride is transported by the transcellular and perhaps the paracellular route, although the molecular pathways are not completely understood.

  • Describe the role of pro-fibrotic processes in impaired lung function in ARDS

  • Summarize the main physiologic abnormalities in ARDS

  • Review the time course of appearance of clinical manifestations in ARDS

Acute respiratory distress syndrome (ARDS) is characterized by the development of acute dyspnea and hypoxemia within hours to days of an inciting event, such as trauma, sepsis, drug overdose, massive transfusion, acute pancreatitis, or aspiration. In many cases, the inciting event is obvious, but, in others (eg, drug overdose), it may be harder to identify.

Patients developing ARDS are critically ill, often with multisystem organ failure, and they may not be capable of providing historical information.

Typically, the illness develops within 12-48 hours after the inciting event, although, in rare instances, it may take up to a few days.

With the onset of lung injury, patients initially note dyspnea with exertion. This rapidly progresses to severe dyspnea at rest, tachypnea, anxiety, agitation, and the need for increasingly high concentrations of inspired oxygen.

  • Discuss cardiogenic pulmonary edema

Cardiogenic pulmonary edema (CPE) is defined as pulmonary edema due to increased capillary hydrostatic pressure secondary to elevated pulmonary venous pressure. CPE reflects the accumulation of fluid with a low-protein content in the lung interstitium and alveoli as a result of cardiac dysfunction

Pulmonary edema can be caused by the following major pathophysiologic mechanisms:

  • Imbalance of Starling forces – Ie, increased pulmonary capillary pressure, decreased plasma oncotic pressure, increased negative interstitial pressure
  • Damage to the alveolar-capillary barrier
  • Lymphatic obstruction
  • Idiopathic (unknown) mechanism

Increased hydrostatic pressure leading to pulmonary edema may result from many causes, including excessive intravascular volume administration, pulmonary venous outflow obstruction (eg, mitral stenosis or left atrial [LA] myxoma), and LV failure secondary to systolic or diastolic dysfunction of the left ventricle. CPE leads to progressive deterioration of alveolar gas exchange and respiratory failure. Without prompt recognition and treatment, a patient’s condition can deteriorate rapidly.

  • Describe how lung protective ventilation with lower tidal volumes and airway pressures reduces mortality in ARDS.

Recently, it has been recognized that mechanical ventilation, although potentially lifesaving, can contribute to the worsening of lung injury. This phenomenon is called ventilator-induced lung injury.

The volume of aerated lung in patients with ARDS is considerably reduced because of edema and atelectasis. As a result, ventilation with the use of high tidal volumes may cause hyperinflation of relatively normal regions of aerated lung.

Since nonaerated lung tissue is stiffer than normal lung tissue, compliance is reduced and airway pressure is increased. Excessive volume and pressure, with correspondingly high transpulmonary pressure (the difference in pressure between the airway and the pleural space), contribute to ventilator-induced lung injury.

In addition, the inflation of normal alveoli adjacent to noninflated, abnormal alveoli may create high shear forces that can contribute to injury of the lung parenchyma, even at modest applied pressures.

The consequences of lung overdistention include direct physical damage, with disruption of the alveolar epithelium and capillary endothelium, as well as the induction of an inflammatory response, with the release of cytokines and other mediators.8,10–13 Some evidence suggests that the inflammatory response induced during ventilator-induced lung injury has systemic consequences, contributing to the pathogenesis of multisystem organ failure in patients with ARDS.14,15


The entity called new BPD is a disease primarily of infants with a birth weight <1000 g who are born at <28 w gestation, and who are treated with antenatal steroids and postnatal surfactant to minimize development of respiratory distress syndrome (RDS). These infants have little or no lung disease at birth, but develop progressive respiratory failure over the 1st w of life. The lung histology found in infants with the new BPD includes alveolar hypoplasia, variable saccular wall fibrosis, and minimal airway disease. These findings indicate interference with normal alveolar septations and microvascular maturation.

  • Describe the pathogenesis of BPD with alveolar collapse, over-distension of lung, and injury by oxygen-induced free radicals and inflammation

Bronchopulmonary dysplasia (BPD) is a form of chronic lung disease that affects newborns (mostly premature) and infants. It results from damage to the lungs caused by mechanical ventilation (respirator) and long-term use of oxygen. Most infants recover from BPD, but some may have long-term breathing difficulty.

While a relatively high amount of inhaled oxygen over several days may be necessary to support life, it may also cause damage to the alveoli. This is sometimes made worse when the ventilator blows air into the lung, overstretching the alveoli. Less well understood, inflammation can damage the inside lining of the airways, the alveoli and even the blood vessels around them. These effects are particularly damaging on the premature lung, and BPD is considered to be primarily a complication of prematurity.

Free radical (FR) generation is largely recognized as the major cause of lung damage. Oxidative stress (OS) is the final common endpoint for a complex convergence of events, some genetically determined and some triggered by in utero stressors. Inflammatory placental disorders and chorioamnionitis also play an important role due to the coexistence of inflammatory and oxidative lesions. In addition, the contribution of airway inflammation has been extensively studied. The link between inflammation and OS injury involves the direct activation of inflammatory cells, especially granulocytes, which potentiates the inflammatory reaction. Individualized interventions to support ventilation, minimize oxygen exposure, minimize apnea, and encourage growth should decrease both the frequency and severity of BPD.

  • Comment on the role of over-hydration in development of BPD, and a protective role for vitamin A supplementation

Babies with BPD are very sensitive to the amount of fluids they get.
Excessive fluid loss can lead to dangerous dehydration (too little fluid in the body, leading to lower blood pressure, and reduced urination). Excess fluid loss can be caused by excessive temperature in the house (for example, on hot summer days), fever, vomiting, diarrhea, and increased doses of water pills.

Symptoms of dehydration include reducing urinating, lack of tears when the baby cries, tiredness (or fatigue), and sunken eyes. Babies on water pills, who have less water in the body to start with, are more easily prone to becoming dehydrated in these situations. Particularly if your baby is on a water pill, you should make sure that your baby is not becoming dehydrated during hot weather, or during the “stomach flu” or “gastro.”

Remember that treating dehydration with too much fluid can also be dangerous for a baby with BPD, so you should discuss with your doctor how much fluid should your baby get in these situations.If your baby gets too much fluid, they can get swelling, and increased fluid in the lungs (or pulmonary edema).

Vitamin A concentrations are lower in BPD infants which may result in a reduction of the antioxidant protection. It has been found to up regulate genes necessary for fetal lung growth and increase surfactant production in animal models and is also involved in the modulation of immunological and inflammatory responses by regulation of cytokine production. Retinoic acid plays a key role in lung development improving alveolar septation. Evidence exists that vitamin A supplementation for very low birth weight (VLBW) infants, beyond that routinely given in multivitamin preparations, is associated with a reduction in death or BPD. So, parenteral administration of vitamin A to the newborn is one of the current recommended preventive therapies for BPD

  • Discuss the diagnostic criteria for BPD

Earlier criteria

The classic diagnosis of BPD may be assigned at 28 days of life if the following criteria are met:

  1. Positive pressure ventilation during the first 2 weeks of life for a minimum of 3 days.
  2. Clinical signs of abnormal respiratory function.
  3. Requirements for supplemental oxygen for longer than 28 days of age to maintain PaO2 above 50 mm Hg.
  4. Chest radiograph with diffuse abnormal findings characteristic of BPD.

Newer criteria

The newer National Institute of Health (US) criteria for BPD (for neonates treated with more than 21% oxygen for at least 28 days)[5] is as follows:,[6][7]

  • Breathing room air at 36 weeks’ post-menstrual age or discharge (whichever comes first) for babies born before 32 weeks, or
  • breathing room air by 56 days’ postnatal age, or discharge (whichever comes first) for babies born after 32 weeks’ gestation.
  • Need for <30% oxygen at 36 weeks’ postmenstrual age, or discharge (whichever comes first) for babies born before 32 weeks, or
  • need for <30% oxygen to 56 days’ postnatal age, or discharge (whichever comes first) for babies born after 32 weeks’ gestation.
  • Need for >30% oxygen, with or without positive pressure ventilation or continuous positive pressure at 36 weeks’ postmenstrual age, or discharge (whichever comes first) for babies born before 32 weeks, or
  • need for >30% oxygen with or without positive pressure ventilation or continuous positive pressure at 56 days’ postnatal age, or discharge (whichever comes first) for babies born after 32 weeks’ gestation.
  • Describe acceptable blood gas concentrations in a newborn with BPD

Blood gas measurements are as important for ill newborns as for other critically ill patients, but rapidly changing physiology, difficult access to arterial and mixed venous sampling sites, and small blood volumes present unique challenges.

Normal values for arterial blood gases are very dependent on postnatal age (Fig. 1⇓ ).

The most accurate method of measuring Pao2 and Sao2 involves placement of an indwelling catheter in either the aorta via an umbilical artery or in a peripheral artery; however, use of such catheters must be restricted to critically ill neonates because of frequent and serious thrombotic and infectious complications (1)(2).

The clinician must establish a target or acceptable range for Paco2 for a given patient. Although the normal range of Paco2 after the first hours of life can be considered 4.66–6 kPa (35–45 mm Hg), desirable CO2 values for a specific situation may be either higher or lower.

For instance, in persistent pulmonary hypertension of the newborn, pulmonary artery pressures can be lowered by either respiratory or metabolic alkalosis (18). Modest respiratory alkalosis can rapidly lower pulmonary vascular resistance in some such patients. Because marked hypocapnea can decrease cerebral blood flow and has been associated with neurologic deficits, most clinicians no longer aim for Pco2 values <3.33 kPa (<25 mm Hg) (19). Infants with BPD (chronic lung disease) often tolerate Pco2 values of 6.66–8 kPa (50–60 mm Hg) (20), essentially “deciding” that normal blood gas status is not worth the markedly increased work of breathing necessary to achieve it. An approach termed “permissive hypercapnia” or “gentle ventilation” with lower ventilator pressures while tolerating slightly increased Paco2 resulted in decreased chronic lung disease for premature infants with RDS (21).

  • Describe the use of inhaled bronchodilators and post-natal dexamethasone

Postnatal dexamethasone is associated with reduction in bronchopulmonary dysplasia.

Clinical trials have shown that postnatal corticosteroid therapy administered systemically improves short-term lung function and outcome of infants with established bronchopulmonary dysplasia (BPD), and reduces the risk of BPD in high-risk preterm infants.

However, systemic corticosteroid administration (primarily dexamethasone) is associated with serious adverse effects. As a result, currently available evidence suggests that the potential benefits of routine administration of postnatal corticosteroids are outweighed by its short- and long-term complications.

Bronchodilators are frequently administered to infants with BPD at U.S. children’s hospitals with increasing use during the first hospital month. Increasing positive pressure exposure best predicts bronchodilator use. Frequency and treatment duration vary markedly by institution even after adjustment for confounding variables.

  • Review clinical manifestations of BPD and explain why growth failure may be an element of BPD

Many infants born with bronchopulmonary dysplasia exhibit signs and symptoms of respiratory distress syndrome, including the following:

  • Tachypnea
  • Tachycardia
  • Increased respiratory effort (with retractions, nasal flaring, and grunting)
  • Frequent desaturations

These infants are often extremely immature, have a very low birth weight, and have significant weight loss during the first 10 days of life. Their requirements for oxygen and ventilatory support often increase in the first 2 weeks of life. At weeks 2-4, oxygen supplementation, ventilator support, or both are often increased to maintain adequate ventilation and oxygenation.

Growth failure is a major problem in infants with bronchopulmonary dysplasia (BPD), but the cause is unknown.
One study  speculated that growth failure in infants with BPD is partially the result of increased metabolic demands from increased work of breathing but that other mechanisms may act to elevate the metabolic expenditure of these infants.
  • Review treatment of BPD, including β-agonists, inhaled glucocorticoids, and distinguish among the various forms of BPD

First the forms of BPD

  • Describe challenges to adequate calorie intake in BPD

The pathogenesis of bronchopulmonary dysplasia (BPD) is multifactorial. In addition to prenatal inflammation, postnatal malnutrition also affects lung development.

In addition to prenatal inflammation, nutrition plays an important role in normal lung development and maturation [2,3] Nutrition has a direct effect on the developing lung because it can modulate lung structure.

Sufficient nutrition is often difficult to achieve in preterm infants. Due to various problems associated with immaturity, extremely preterm infants receive only minimal enteral nutrition during the first weeks of life and require supplemental parenteral nutrition. However, there is an ongoing debate concerning the required amount of protein, carbohydrates and calories [8]. A sufficient amount of protein and calories seems to be necessary for organ growth; thus, a low protein or caloric intake could impair lung development, resulting in BPD.

One study showed :

Preterm infants developing BPD received less enteral feeding, even though it was well compensated by the parenteral nutrient supply. Data suggest that a critical minimal amount of enteral feeding is required to prevent development of BPD; however, a large prospective clinical study is needed to prove this assumption.

  • Describe measures to prevent transmission of viral illnesses in infants with BPD

In a study, looking at

Palivizumab for the prevention of respiratory syncytial virus infection

A total of 1502 children who were premature (ie, gestation for less than or equal to 35 weeks) or who had bronchopulmonary dysplasia (BPD) were randomized to receive injections of either palivizumab (15 mg/kg) or an equivalent volume of placebo by intramuscular injection every 30 days for 5 months.5 Palivizumab prophylaxis resulted in a 5.8% absolute reduction in hospitalization for RSV (10.6% placebo vs 4.8% palivizumab, number needed to treat [NNT] = 17).

  • Review prognosis of BPD

Bronchopulmonary dysplasia (BPD) remains a major complication of prematurity resulting in significant mortality and morbidity.

Infants with severe BPD have a higher risk of mortality than unaffected infants or those with mild disease of the same gestational age (GA). Death usually is caused by respiratory failure, unremitting pulmonary hypertension with cor pulmonale, or sepsis. Increased mortality is associated with longer duration of mechanical ventilation, episodes of sepsis, and pulmonary artery hypertension (PAH). (See ‘Mortality’ above.)

Survivors of prematurity and BPD are at increased risk for respiratory disease, including respiratory infection, asthma-like disease, and pulmonary artery hypertension. Persistent abnormalities in pulmonary function are also common in patients who had BPD as infants, and depend upon the severity of BPD. (See “Complications and long-term pulmonary outcomes of bronchopulmonary dysplasia”.)

BPD is associated with an increased risk for neurodevelopmental impairment, which affects both motor and cognitive function. The severity of BPD increases both the risk and severity of neurodevelopmental disability. (See ‘Neurodevelopment outcome’ above.)

It remains uncertain whether BPD has a direct impact on long-term growth. After adjusting for confounding factors, no significant differences were detected in growth at school age in children who had BPD compared with those who did not have BPD. (See ‘Growth’ above.)


A 56-year-old man complained of excessive sleepiness, particularly when driving and of sleep that was not refreshing. He had a history of snoring since age 20 years, and his wife had witnessed apnea for at least 20 years. Excessive daytime sleepiness had appeared in the last 10 y. Over the past several years he has gained 20 pounds to weigh 105 kg. His height was 171 cm and neck circumference was 48 cm. His wife noted loud snoring and reported that he had episodes of gasping during sleep. On examination, he was obese and had a long soft palate and uvula and peritonsillar hypertrophy. A polysomnogram revealed 57 obstructive hypopneas and apneas per hour of sleep. The minimum oxygen saturation was 51% during a 48-sec apnea during REM sleep. With nasal CPAP at 11 cm of water pressure, he had almost complete resolution of obstructive sleep apnea. He began using CPAP at home and 6 months later said he felt much improved. He slept much better and daytime drowsiness had all but disappeared.

Hypopnea or hypopnoea is overly shallow breathing or an abnormally low respiratory rate.

Apnea or apnoea is suspension of breathing. During apnea, there is no movement of the muscles of inhalation, and the volume of the lungs initially remains unchanged. Depending on how blocked the airways are (patency), there may or may not be a flow of gas between the lungs and the environment

  • Discuss obstructive versus central apnea

Central sleep apnea

INTRODUCTION — Central sleep apnea (CSA) is a disorder characterized by repetitive cessation or decrease of both airflow and ventilatory effort during sleep. The condition can be primary (ie, idiopathic CSA) or secondary. Secondary CSA can arise, for example, in association with Cheyne-Stokes breathing, a medical condition, a drug or substance, or high altitude periodic breathing [1]. CSA associated with Cheyne-Stokes breathing is particularly common, especially among patients who have heart failure or have had a stroke. It is characterized by central apneas that occur during the decrescendo portion of the cyclic crescendo-decrescendo respiratory pattern.

CSA can alternatively be categorized as hyperventilation- or hypoventilation-related. Hyperventilation-related CSA encompasses most of the types of CSA mentioned above; one exception is CSA associated with a drug or substance. Hypoventilation-related CSA occurs in disorders in which there is alveolar hypoventilation that is so severe that central apneas occur when the patient falls asleep because the wakefulness stimulus to breathe disappears. Central apneas tend to be a minor component of such disorders. Examples of contexts in which hypoventilation-related CSA may occur include central nervous system diseases, central nervous system suppressing drugs or substances, neuromuscular diseases, and severe abnormalities in pulmonary mechanics (eg, kyphoscoliosis).

Obstructive sleep apnea (most common)

Obstructive sleep apnea (OSA) is a common chronic disorder that often requires lifelong care [1]. Cardinal features in adults include:

●Obstructive apneas, hypopneas, or respiratory effort related arousals

●Daytime symptoms attributable to disrupted sleep, such as sleepiness, fatigue, or poor concentration

●Signs of disturbed sleep, such as snoring, restlessness, or resuscitative snorts

OSA is an important disorder because patients are at increased risk for poor neurocognitive performance and adverse medical outcomes, due to repeated arousals and/or hypoxemia during sleep over months to years. The severity and duration of OSA for development of these sequelae vary among individuals [2]. In addition, severe untreated OSA is associated with increased all-cause and cardiovascular mortality.

  • What are the causes of central apnea?

The symptoms of central sleep apnea are for the most part the same as those of obstructive sleep apnea. They include chronic fatigue, daytime sleepiness, morning headaches and restless sleep. But if the cause is a neurological disease, the CSA sufferer may also experience difficulty swallowing, voice changes, and an overall sense of weakness and numbness.

A thorough sleep study with polysomnography will show whether the lapses in breathing result from airway blockage or irregular breathe signals from the brain.

CSA frequently occurs among people who are seriously ill from other causes: chronic heart failure; diseases of and injuries to the brainstem, the upper terminus of the spine, which controls breathing; Parkinson’s disease; stroke; kidney failure; even severe arthritis with degenerative changes to the cervical spine and base of the skull. It is seen among users of opiates. . “For idiopathic apnea, the outlook is generally favorable,”

  • List criteria for continuous positive airway pressure (CPAP)A positive test for OSA is established if either of the following criterion using the Apnea-Hypopnea Index (AHI) or Respiratory Disturbance Index (RDI) are met:
  1.  AHI or RDI greater than or equal to 15 events per hour, or
    • AHI or RDI greater than or equal to 5 and less than or equal to 14 events per hour with documented symptoms of excessive daytime sleepiness, impaired cognition, mood disorders or insomnia, or documented hypertension, ischemic heart disease, or history of stroke.

    The AHI is equal to the average number of episodes of apnea and hypopnea per hour. The RDI is equal to the average number of respiratory disturbances per hour.

  2. If the AHI or RDI is calculated based on less than two hours of continuous recorded sleep, the total number of recorded events to calculate the AHI or RDI during sleep testing is at least the number of events that would have been required in a two hour period.
  • Describe the epidemiology of obstructive sleep apnea

OSA is the most common sleep-related breathing disorder. Prevalence estimates vary according to the way in which OSA metrics are collected and the distribution of risk factors in the population being studied. The estimated prevalence in North America is approximately 20 to 30 percent in males and 10 to 15 percent in females when OSA is defined broadly as an apnea-hypopnea index (AHI) greater than five events per hour as measured by a polysomnogram [3,4].

When more stringent definitions are used, either combining an AHI ≥5 events per hour with report of at least one symptom of disturbed sleep (eg, daytime sleepiness) or using an AHI ≥15 events per hour, the estimated prevalence is approximately 15 percent in males and 5 percent in females [3-5]. The prevalence of OSA in the United States appears to be increasing due to rising rates of obesity. (See ‘Obesity’below.)

The prevalence of OSA also varies by race and ethnicity. OSA is more prevalent in African Americans who are younger than 35 years old compared with Caucasians of the same age group, independent of body weight [6,7]. The prevalence of OSA in Asia is similar to that in the United States, despite lower rates of obesity, and linked risk related to craniofacial anatomy.

  • Describe the consequences of increased sympatheytic stimulationThe sympathetic nervous system and obstructive sleep apnea: implications for hypertension.
  • Pts with sleep apnea experience repetitive apneic events during sleep, with consequent hypoxia and hypercapnia. Hypoxia and hypercapnia, acting via the chemoreflexes, elicit increases in sympathetic nerve activity.The sympathetic responses to hypoxia and hypercapnia are potentiated during apnea, when the sympathetic inhibitory influence of the thoracic afferent nerves is eliminated. As a consequence of the sympathetic vasoconstrictor response to apneic events, patients with obstructive sleep apnea manifest marked increases in blood pressure during sleep, especially evident at the end of the apnea. The increases in sympathetic activity and blood pressure during sleep in these patients appear to carry over into the daytime such that patients with sleep apnea have an increased prevalence of hypertension and high levels of sympathetic nerve activity.Although the mechanism underlying the persistent elevation in sympathetic activity during the daytime is not known, it is likely that the increased sympathetic drive is implicated in the higher daytime blood pressures in these patients.Whereas patients with sleep apnea have an increased prevalence of hypertension, in those patients with sleep apnea who do have hypertension, the sympathetic response to apneic events may be potentiated. This may be secondary to impaired baroreflex sensitivity, since the baroreflexes exert an inhibitory influence on the chemoreflex responses to hypoxia.

    Treatment with continuous positive airway pressure results in an acute reduction in blood pressure and sympathetic activity during sleep. Prolonged effective treatment of sleep apnea may also reduce daytime blood pressure levels.

  • Describe the clinical manifestations of obstructive sleep apnea

Snoring and wake-time sleepiness are common presenting complaints of OSA. Both symptoms are relatively sensitive, but they lack specificity for a diagnosis.

In a systematic review of the accuracy of the clinical examination in the diagnosis of OSA, the most useful individual finding for identifying patients with OSA was nocturnal choking or gasping, which was associated with a sensitivity and specificity of 52 and 84 percent.

Sleep apnea in women tends to present with complaints of insomnia and sleepiness, and mood changes rather than loud snoring and witnessed apneas.

Additional symptoms and signs may include restless sleep, periods of silence terminated by loud snoring, fatigue, poor concentration, nocturnal angina, nocturia, and morning headaches. Common findings on physical examination include obesity, a crowded oropharyngeal airway, large neck circumference, and hypertension.

  • Describe differential diagnosis of sleep-related breathing disorders

A 56-year-old man complained of excessive sleepiness, particularly when driving and of sleep that was not refreshing. He had a history of snoring since age 20 years, and his wife had witnessed apnea for at least 20 years. Excessive daytime sleepiness had appeared in the last 10 y. Over the past several years he has gained 20 pounds to weigh 105 kg. His height was 171 cm and neck circumference was 48 cm. His wife noted loud snoring and reported that he had episodes of gasping during sleep. On examination, he was obese and had a long soft palate and uvula and peritonsillar hypertrophy. A polysomnogram revealed 57 obstructive hypopneas and apneas per hour of sleep. The minimum oxygen saturation was 51% during a 48-sec apnea during REM sleep. With nasal CPAP at 11 cm of water pressure, he had almost complete resolution of obstructive sleep apnea. He began using CPAP at home and 6 months later said he felt much improved. He slept much better and daytime drowsiness had all but disappeared.

In addition to the conditions listed in the differential diagnosis, stimulant abuse (eg, amphetamine abuse) should also be considered.

Anxiety Disorders

Bipolar Affective Disorder

Breathing-Related Sleep Disorder

Chronic Obstructive Pulmonary Disease (COPD)



Hyperthyroidism and Thyrotoxicosis


Obstructive Sleep Apnea

Opioid Abuse

Posttraumatic Stress Disorder

  • Describe polysomnography

Simply put, a PSG is both a research tool used for studying sleep, and a diagnostic tool used to determine sleep disorders.

pegs are usually performed overnight either at a hospital, or at a sleep clinic, under the supervision of a sleep technician. The facilities usually have the look and feel of a comfortable hotel room rather than a sterile hospital room.

Polysomnograms are used to monitor a patient’s sleep stages and cycles to determine the presence of disturbances that can be attributed to sleep disorders. PSGs use a variety of equipment that monitors brain activity, muscle activity, breathing activity, and more to get a comprehensive interpretation of what disorder (if any) the patient is suffering from.

  • Describe CPAP and other mechanical therapies[Continuous positive airway pressure (CPAP) is a form of positive airway pressure ventilator, which applies mild air pressure on a continuous basis to keep the airways continuously open in people who are able to breathe spontaneously on their own.It is an alternative to positive end-expiratory pressure (PEEP). Both modalities stent the lungs’ alveoli open and thus recruit more of the lung’s surface area for ventilation. But while PEEP refers to devices that impose positive pressure only at the end of the exhalation, CPAP devices apply continuous positive airway pressure throughout the breathing cycle. Thus, the ventilator itself does not cycle during CPAP, no additional pressure above the level of CPAP is provided, and patients must initiate all of their breaths.
  • Discuss prognosis

Although there is no cure for obstructive sleep apnea (OSA), the prognosis for patients is very good if properly treated and managed. For mild OSA, the first line of treatment may include lifestyle changes such as losing weight, quitting smoking, and limiting alcohol consumption.

This can lead to increased daytime function, improved memory and concentration, reduced moodiness, and increased safety, especially while operating a motor vehicle.  CPAP has also been shown to reduce hypertension, a known risk factor for cardiovascular disease.


The clinical history of sudden infant death syndrome (SIDS) is a sudden, unexpected death of an infant that is unexplained by a thorough post-mortem examination.

Sudden Unexpected Infant Deaths (SUIDs)

  • Explain why an autopsy is important to identify possible congenital anomalies, infection, or traumatic child abuse in cases of suspected SIDS

It is diagnosed only after a thorough investigation of the scene, interview of caregivers, and a complete forensic autopsy.

After a thorough case investigation, some of these SUIDs may be explained. Poisoning, metabolic disorders, hyper- or hypothermia, child abuse and neglect resulting in homicide, and suffocation are all explainable, but much less common, causes of SUID.

  • Review the epidemiology of SIDS

SIDS is the leading cause of infant mortality between one month and one year of age in the United States [4]. The risk of SIDS in the United States is <1 per 1000 live births [5-7]. Higher rates (two to three times the national average) are found in black and American Indian/Alaskan native children [8,9]. A disproportionately high rate (15 to 20 percent) of SIDS cases occurs in child care settings [10,11]. The risk of SIDS is slightly increased in boys (multivariate OR 1.49 [95% CI 1.14-1.83] in one large European case-control study) [12].

The incidence of SIDS has declined dramatically in countries that have adopted policies encouraging non-prone sleeping (“Back to Sleep” campaigns). The initial campaigns were in Europe, Australia, and New Zealand [13]. In the United States, the incidence of SIDS has declined by more than 50 percent since the mid-1980s, and the greatest reduction occurred after 1992, when the American Academy of Pediatrics (AAP) issued a recommendation to reduce the risk of SIDS by placing infants in a supine position for sleep [13-15]. Between 1992 and 2001, the SIDS rate in the United States fell from 1.2 to 0.56 per 1000 live births, while the proportion of infants sleeping in the supine position increased from 13 to 72 percent [16,17]. The rate of SIDS then remained constant between 2001 and 2006 [18]. Similar declines have occurred in other countries after campaigns to encourage non-prone sleeping [19,20].

  • Comment on the impact of actively promoting the supine sleeping position for infants in reducing the number of SIDS deaths

Since 1992, the optimal sleeping position for infants in the United States has been supine. This position has been shown to greatly reduce the rate of Sudden Infant Death Syndrome (Skadberg, Morild, & Markestad, 1998).

Prior to the 1990s, nearly all infants in the United States were placed for sleep in the prone or “tummy” position (Willinger et al., 1998). In 1992, the American Academy of Pediatrics (AAP) published a position statement recommending that all infants be placed in nonprone positioning for sleep with the intended purpose of decreasing the incidence of Sudden Infant Death Syndrome (SIDS). In 1996, the AAP position was amended to promote supine sleep as the preferred position. Although lateral-sleeping position confers a lower risk when compared to prone positioning, it still has a higher risk when compared to supine sleeping position (AAP, 1996). Over the past 10 years, the AAP, U.S. Public Health Service, SIDS Alliance, and the Association of SIDS and Infant Mortality Programs have provided much education to the general public, including the well-known “Back to Sleep” campaign (AAP, 1996).

  • Describe pathologic findings in the brainstem of infants with SIDS, including abnormalities in the retrotrapezoid nucleus (RTN), a brainstem region whose neurons respond vigorously to increases in local pCO2

The RTN is part of caudal pons and comprises cluster of glutamatergic and non-aminergic neurons that are responsible for the homeodomain transcription factor Phox2b (a transcriptional factor involved in congenital central hypoventilation syndrome) expression (58). Immunohistochemical expression of Phox2b neurons inside the caudal pons points out the developmental abnormalities of the human RTN (Table  (Table1).1). It may acutely affect the chemoreception control, thus, performing a vital part in the pathogenesis of SIUDS and SIDS (46).

  • Discuss the significance of neurons that express transcription factor Phox 2b

Mutations in human PHOX2B cause a rare disease of the visceral nervous system (dysautonomia): congenital central hypoventilation syndrome (associated with respiratory arrests during sleep and, occasionally, wakefulness), Hirschsprung’s disease (partial agenesis of the enteric nervous system), ROHHAD, and tumours of the sympathetic ganglia. In most people, Exon 3 of the gene contains a sequence of 20 polyalanine repeats. An increase in the number of repeats is associated with congenital central hypoventilation syndrome. There may also be other pathogenic mutations further along the gene.

  • Describe the role of the ventral medulla, which plays an integrative role in breathing, arousal, and chemosensory function, in SIDS

  • Review the evidence for altered serotonin (5-HT) homeostasis as a contributor to the development of SIDS

It has been reported that ∼40% of SIDS deaths are associated with abnormalities in serotonin (5-hydroxytryptamine, 5-HT) in regions of the brainstem critical in homeostatic regulation. One study we tested the hypothesis that SIDS is associated with an alteration in serum 5-HT levels. Serum 5-HT, adjusted for postconceptional age, was significantly elevated (95%) in SIDS infants (n = 61) compared with autopsied controls (n = 15) [SIDS, 177.2 ± 15.1 (mean ± SE) ng/mL versus controls, 91.1 ± 30.6 ng/mL] (P = 0.014), as determined by ELISA.

This study demonstrated that SIDS is associated with peripheral abnormalities in the 5-HT pathway. High serum 5-HT may serve as a potential forensic biomarker in autopsied infants with SIDS with serotonergic defects.

  • Note that being less than 6 months of age and a lower socioeconomic status have been associated with a higher risk for SIDS

A low socio-economic status is reported to be a relevant risk factor for SIDS [31]. The age of the pregnant mother, the ethnicity and the education of the mother are related to her socioeconomic status. A low socio-economic status is associated with a higher mortality risk of the infant around pregnancy and birth. For example most of the teenage-mothers have a low socio-economic status and so their babies have a higher risk for SIDS [32].

Although elements such as co-sleeping and stomach sleeping may also factor into the causes of SIDS, the age of the child is one major component. Importantly, there is a sharp drop-off of SIDS risk once a child is six months old or older, as noted by Live Science. In fact, 90 percent of SIDS cases occur in children younger than six months of age, according to Baby Center. This may be due to the fact that by this time of development, babies have the mental and physical abilities to cope with potential sleeping hazards, as the Baby Center further noted. For instance, a very young infant may succumb to suffocation by loose bedding rather easily, whereas an older baby may have the bodily strength and/or brain development required to lift her head away from potential suffocation hazards.

  • Comment on pregnancy-related factors, cigarette smoking, and peri-conceptional alcohol use on the risk of SIDS

  • Comment on the protective effect of breastfeeding on SIDS and the use of a pacifier

In general, health care professionals have not encouraged the use of a pacifier (“dummy” or “soother”) for infants. … pacifier use is more prevalent among the more deprived socioeconomic groups, and in families in which one or both parents smoked, and that it is associated with a significantly higher incidence of minor illnesses, particularly respiratory and gastrointestinal infections. The association with illness persisted after taking account of socioeconomic factors and parental smoking, suggesting that it was a feature of pacifier use rather than of the conditions in which such use occurred.1

  • There was no difference between victims of SIDS and control infants in routine use of a pacifier (“dummy” or “soother”) for day or night sleeps

  • The use of a pacifier was associated with a lower prevalence and shorter duration of breast feeding, lower socioeconomic status, and mothers who smoked more heavily

  • There was no association between pacifier use and sleeping position

  • More control infants used a pacifier for the last/reference sleep, giving an apparent “protective” effect against SIDS; the significance of this association increased when controlled for other factors

  • Further epidemiological evidence and physiological studies are needed before we can recommend pacifier use as protective against SIDS

  • Review genetic risk factors which implicate arrhythmogenic disorders in the development of SIDS, such as long QT syndrome and short QT syndrome

The triple risk model for the pathogenesis of SIDS points to the coincidence of a vulnerable infant, a critical developmental period, and an exogenous stressor. Primary electrical diseases of the heart, which may cause lethal arrhythmias as a result of dysfunctioning cardiac ion channels (“cardiac ion channelopathies”) and are not detectable during a standard postmortem examination, may create the vulnerable infant and thus contribute to SIDS. Evidence comes from clinical correlations between the long QT syndrome and SIDS as well as genetic analyses in cohorts of SIDS victims (“molecular autopsy”), which have revealed a large number of mutations in ion channel-related genes linked to inheritable arrhythmogenic syndromes, in particular the long QT syndrome, the short QT syndrome, the Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia. Combining data from population-based cohort studies, it can be concluded that at least one out of five SIDS victims carries a mutation in a cardiac ion channel-related gene and that the majority of these mutations are of a known malignant phenotype.

  • Describe polymorphisms in 3 pro-inflammatory cytokines (VEGF, IL-6, and tumor necrosis factor-α)

Several studies report signs of slight infection prior to death in cases of sudden infant death syndrome (SIDS). Based on this, a hypothesis of an altered immunological homeostasis has been postulated. The cytokines are important cellular mediators that are crucial for infant health by regulating cell activity during the inflammatory process. The pro-inflammatory cytokines favor inflammation; the most important of these are IL-1α, IL-1β, IL-6, IL-8, IL-12, IL-18, TNF-α, and IFN-γ. These cytokines are controlled by the anti-inflammatory cytokines. This is accomplished by reducing the pro-inflammatory cytokine production, and thus counteracts their biological effect. The major anti-inflammatory cytokines are interleukin-1 receptor antagonist (IL-1ra), IL-4, IL-10, IL-11, and IL-13. The last decade there has been focused on genetic studies within genes that are important for the immune system, for SIDS with a special interest of the genes encoding the cytokines. This is because the cytokine genes are considered to be the genes most likely to explain the vulnerability to infection, and several studies have investigated these genes in an attempt to uncover associations between SIDS and different genetic variants. So far, the genes encoding IL-1, IL-6, IL-10, and TNF-α are the most investigated within SIDS research, and several studies indicate associations between specific variants of these genes and SIDS. Taken together, this may indicate that in at least a subset of SIDS predisposing genetic variants of the immune genes are involved. However, the immune system and the cytokine network are complex, and more studies are needed in order to better understand the interplay between different genetic variations and how this may contribute to an unfavorable immunological response.

  • Describe the triple risk model for SIDS
  • Describe characteristics of infant groups at increased risk for SIDS


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