CONTENTS
- Sleep-disordered breathing basics
- Obstructive sleep apnea (OSA)
- Obesity hypoventilation syndrome (OHS)
- Central sleep apnea (CSA) overview
- Sleep-induced hypoxemia
- Questions & discussion
abbreviations used in the pulmonary section: 6
- ABPA: Allergic bronchopulmonary aspergillosis 📖
- AE-ILD: Acute exacerbation of ILD 📖
- AEP: Acute eosinophilic pneumonia 📖
- AFB: Acid fast bacilli
- AIP: Acute interstitial pneumonia (Hamman-Rich syndrome) 📖
- ANA: Antinuclear antibody 📖
- ANCA: Antineutrophil cytoplasmic antibodies 📖
- ARDS: Acute respiratory distress syndrome 📖
- ASS: Antisynthetase syndrome 📖
- BAL: Bronchoalveolar lavage 📖
- BiPAP: Bilevel positive airway pressure 📖
- CEP: Chronic eosinophilic pneumonia 📖
- CF: Cystic fibrosis 📖
- COP: Cryptogenic organizing pneumonia 📖
- CPAP: Continuous positive airway pressure 📖
- CPFE: Combined pulmonary fibrosis and emphysema 📖
- CTD-ILD: Connective tissue disease associated interstitial lung disease 📖
- CTEPH: Chronic thromboembolic pulmonary hypertension 📖
- DAD: Diffuse alveolar damage 📖
- DAH: Diffuse alveolar hemorrhage 📖
- DIP: Desquamative interstitial pneumonia 📖
- DLCO: Diffusing capacity for carbon monoxide 📖
- DRESS: Drug reaction with eosinophilia and systemic symptoms 📖
- EGPA: Eosinophilic granulomatosis with polyangiitis 📖
- FEV1: Forced expiratory volume in 1 second 📖
- FVC: Forced vital capacity 📖
- GGO: Ground glass opacity 📖
- GLILD: Granulomatous and lymphocytic interstitial lung disease 📖
- HFNC: High flow nasal cannula 📖
- HP: Hypersensitivity pneumonitis 📖
- IPAF: Interstitial pneumonia with autoimmune features 📖
- IPF: Idiopathic pulmonary fibrosis 📖
- IVIG: Intravenous immunoglobulin 📖
- LAM: Lymphangioleiomyomatosis 📖
- LIP: Lymphocytic interstitial pneumonia 📖
- MAC: Mycobacterium avium complex 📖
- MCTD: Mixed connective tissue disease 📖
- NIV: Noninvasive ventilation (including CPAP or BiPAP) 📖
- NSIP: Nonspecific interstitial pneumonia 📖
- NTM: Non-tuberculous mycobacteria 📖
- OHS: Obesity hypoventilation syndrome 📖
- OP: Organizing pneumonia 📖
- OSA: Obstructive sleep apnea 📖
- PAP: Pulmonary alveolar proteinosis 📖
- PE: Pulmonary embolism 📖
- PFT: Pulmonary function test 📖
- PLCH: Pulmonary Langerhans cell histiocytosis 📖
- PPFE: Pleuroparenchymal fibroelastosis 📖
- PPF: Progressive pulmonary fibrosis 📖
- PVOD/PCH Pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis 📖
- RB-ILD: Respiratory bronchiolitis-associated interstitial lung disease 📖
- RP-ILD: Rapidly progressive interstitial lung disease 📖
- TNF: tumor necrosis factor
- UIP: Usual interstitial pneumonia 📖
sleep-disordered events
- Apnea:
- Defined as an event lasting >10 seconds with >90% cessation of airflow (with or without associated desaturation or microarousal).
- Obstructive apneas: sustained respiratory effort, but absence of flow due to obstruction.
- Central apneas: absence of respiratory effort.
- Mixed apneas: events that begin as central apneas, but then become obstructive (respiratory effort begins, but there continues to be no air flow). Mixed apneas are generally managed similarly to obstructive apneas.
- Hypopnea:
- Defined as an event lasting >10 seconds with 30-90% reduction from baseline peak nasal pressure inspiratory airflow, which is associated with either a >3% desaturation or a microarousal on EEG.
- Scored as an obstructive hypopnea if there is snoring, inspiratory airflow limitation, or paradoxical thoracoabdominal motion. If none of these elements is present, the hypopnea is scored as a central hypopnea.
- Respiratory effort-related arousal (RERA):
- Defined as an event lasting >10 seconds with increasing respiratory effort or inspiratory flattening of the nasal pressure flow signal that culminates in a microarousal. The magnitude of flow reduction isn't large enough to meet criteria for a hypopnea.
- Sleep-associated hypoventilation:
- An event lasting >10 minutes that includes one of the following:
- Increase in PaCO2 to >55 mm for >10 minutes.
- Increase in arterial PaCO2 to >10 mm Hg above awake supine values to >50 mm Hg.
- An event lasting >10 minutes that includes one of the following:
- Sleep-associated hypoxemia:
- An event lasting >5 minutes with sustained reduction in oxygen saturation <88%.
- (Either CO2 is not recorded, or the CO2 parameters don't meet criteria for sleep-associated hypoventilation.)
apnea-hypopnea index (AHI)
- Defined as the total number of apneas or hypopneas per hour.
- Interpretation in the context of suspected obstructive sleep apnea (OSA):
- AHI <5 is normal.
- AHI 5-15 is consistent with mild OSA. A diagnosis of OSA requires the addition of clinical symptoms.
- AHI 16-30 indicates moderate OSA.
- AHI >30 indicates severe OSA.
- Respiratory event index (REI) is defined as the number of apneas and hypopneas per hour monitoring time using a home sleep apnea test (since the total sleep time can only be estimated). This may underestimate the true AHI, if sleep time is overestimated.
- Respiratory disturbance index (RDI) is defined as the number of apneas, hypopneas, and RERAs (respiratory effort related arousals) per hour of sleep.
Epworth Sleepiness Scale
- The score ranges from zero to 24.
- ≧11 indicates excessive sleepiness.
overnight oximetry – discussed further below 📖
basics of obstructive sleep apnea (OSA)
- Mechanical obstruction of the upper airway during sleep leads to transient obstructive events. These are usually terminated by arousals, leading to poor-quality sleep and autonomic activation.
epidemiology of OSA, associations, downstream events
overall epidemiology of OSA
- The rough prevalence of OSA may be ~14% in men and ~5% in women. (Murray 2022)
- Studies vary in the precise incidence, partially due to the use of varying definitions.
- Increasing rates of obesity and aging of the population will increase OSA rates in the coming years.
risk factors for OSA
- Epidemiological risk factors:
- Older age (OSA can mimic dementia).
- Male sex (2- to 3-fold risk, but differences may diminish >50 years old). (Shah 2019)
- Pregnancy (~25% of women may be affected). (Murray 2022)
- Family history of OSA.
- Obesity: ~60% of patients with moderate-to-severe OSA are obese. (Murray 2022)
- Insulin-resistant endocrinological disorders:
- Type-2 diabetes (~75% may have OSA). (Murray 2022)
- Metabolic syndrome.
- Polycystic ovarian syndrome (PCOS).
- Cushing disease.
- Nonalcoholic fatty liver disease.
- Hypothyroidism.
- Alcohol use, sedative/hypnotic medications.
- Airway anatomic phenotypes (discussed further below in the section on physical examination).
- Head and neck cancers (may relate to tumor, or surgical/radiation induced changes). (Murray 2022)
- Specific genetic disorders (e.g., Down syndrome).
OSA is a risk factor for other disorders:
- Systemic hypertension (extremely common cause of refractory hypertension).
- Pulmonary hypertension.
- OSA by itself doesn't tend to cause substantial pulmonary hypertension.
- OSA may contribute to significant pulmonary hypertension in combination with other disorders (e.g., COPD, OHS).
- Heart failure:
- Negative intrathoracic pressure increases afterload.
- CPAP therapy may improve left ventricular ejection fraction. (Murray 2022)
- Arrhythmias:
- Atrial fibrillation (CPAP therapy reduces AF recurrence with a relative risk of ~0.6). (Murray 2022)
- Ventricular arrhythmias, including sudden cardiac death.
- Coronary artery disease.
- Stroke.
- Insulin resistance, type-2 diabetes.
clinical features & assessment of OSA
history
- Nocturnal symptoms:
- Loud snoring, witnessed apneas or choking.
- Nocturnal awakening, insomnia due to disturbed sleep.
- Daytime symptoms:
- Morning headache (suggests superimposed obesity hypoventilation syndrome).
- Nonrestorative sleep.
- Excessive daytime sleepiness is a hallmark symptom.
- However, only about half of patients with OSA have excessive sleepiness.
- Sleepiness may correlate with elevated risk of cardiac events. (Fishman 2023)
- Cognitive dysfunction, irritability.
physical examination features that may increase risk
- Neck circumference >16-17 inches.
- Modified Mallampati score of 3-4 (i.e., inability to visualize the uvula tip).
- Retrognathia (“underbite” – lower jaw is relatively posterior); micrognathia.
- Macroglossia.
- Tonsillar hypertrophy, enlarged uvula.
- High arched/narrow hard palate.
STOP-BANG risk stratification tool 🧮
- Questions
- Snore loudly?
- Tired during the day?
- Observed apneas at night?
- Pressure elevation (Bp)?
- BMI >35?
- Age >50 years?
- Neck >40 cm (18 inches)?
- Gender is male?
- Interpretation:
- 0-2: Low risk for moderate-to-severe OSA.
- 3-4: Intermediate risk for moderate-to-severe OSA.
- 5-8: High risk for moderate-to-severe OSA.
- Performance:
diagnosis of OSA
home sleep apnea testing (HSAT)
- Home testing may be appropriate for patients with high pretest probability of moderate-to-severe OSA.
- Contraindications to home testing: (Shah 2019)
- (1) Major medical comorbidities, for example:
- Heart failure.
- Pulmonary disease (e.g., awake hypoxemia or hypercapnia, severe COPD).
- Neuromuscular disease.
- (2) Suspected concomitant sleep disorder, for example:
- Conditions that increase the risk for central sleep apnea.
- Clinical suspicion for parasomnias or narcolepsy (e.g., significant insomnia).
- (1) Major medical comorbidities, for example:
- How to utilize the results:
- If test is positive for OSA (e.g., AHI ≧5 with symptoms) ➡️ Treat OSA (e.g., with an autotitrating CPAP device).
- If test is negative for OSA (e.g., AHI <5) ➡️ Consider in-laboratory polysomnography.
- Among patients at high risk of OSA, even if the HSAT is negative, a majority of these patients may still have OSA.
in-laboratory polysomnography
- This is the gold standard for diagnosing sleep-disordered breathing.
diagnostic criteria for OSA
- ≧15 obstructive events per hour (apneas, hypopneas, or RERAs).
- -OR-
- ≧5 obstructive events per hour (apneas, hypopneas, or RERAs) -PLUS- at least one of the following:
- Patient reports daytime sleepiness, unrefreshing sleep, fatigue, or insomnia.
- Patient wakens with breath-holding, gasping, or choking.
- Bed partner reports habitual snoring, breathing interruptions, or both.
- Patient has been diagnosed with hypertension, mood disorder, cognitive dysfunction, coronary artery disease, congestive heart failure, stroke, atrial fibrillation, or type-2 diabetes.
treatment of OSA
basics
- Avoid sedatives, opioids, and/or alcohol (these may decrease upper airway patency, exacerbating obstruction).
- Weight loss may be helpful for patients who are overweight.
- Indications for treatment include:
- Higher AHI (apnea-hypopnea index).
- Daytime sleepiness (non-sleepy patients benefit less).
- Need for reduced risk of motor vehicle collision.
- Hypertension or other health consequences of OSA (discussed above: ⚡️)
positive airway pressure (PAP) therapy
different modes
- Continuous positive airway pressure (CPAP) is generally the most effective therapy. It is the front-line treatment for most patients, if it can be tolerated.
- Fixed CPAP levels may be determined during polysomnography. CPAP usually ranges from 4-20 cm. (Murray 2022)
- Autotitrating CPAP involves a device which continually adjusts the CPAP level, in efforts to eliminate apneas.
- Autotitrating CPAP could be suboptimal for patients with complex sleep disorders (e.g., patients with heart failure who have central apneas).
- Compared to fixed CPAP, autotitrating CPAP may reduce the pressure during time periods when less pressure is needed (e.g., sleeping in a lateral position, or NREM sleep). This may allow autotitrating CPAP to use less pressure on average, which could be better tolerated for patients experiencing aerophagia. (Murray 2022)
- Autotitrating CPAP may be superior for patients who are undergoing rapid weight gain or weight loss (e.g., pregnancy, bariatric surgery).
- Bilevel positive airway pressure (BiPAP) may occasionally be utilized. (Shah 2019) Some patients who have difficulty tolerating CPAP due to pressure intolerance or aerophagia may benefit from BiPAP. (Murray 2022)
orofacial vs. nasal interface
- Overall, studies haven't demonstrated any overall difference in effectiveness between nasal versus orofacial masks.
- Advantages of nasal interface:
- An oronasal mask use may exacerbate obstruction, due to pulling the mandible backwards (thereby decreasing space in the pharynx).
- Nasal interface may reduce air leak (since it is easier to fit than an orofacial mask).
- Advantages of orofacial interface:
- More effective in patients with nasal congestion.
- Preferable in patients who are unable to keep their mouth closed.
initial approaches to some common problems:
- Nasal congestion or irritation:
- Increasing humidification.
- Checking for mask leak or mouth breathing (with a nasal mask).
- Nasal steroids.
- Nasal saline rinse.
- Air leaks:
- Change to a different mask.
- Chinstrap (if mouth breathing with a nasal interface).
- Shaving of facial hair.
- Claustrophobia:
- Low-profile mask.
- Helmet mask.
- Anxiolytic medication therapy.
- Pressure too low (air hunger, subjective suffocation):
- Increase set pressure.
- Increase minimum pressure, if utilizing an autotitrating device.
- Pressure perceived as too high and/or aerophagia:
- Reduce the set pressure.
- Expiratory pressure relief (drop in pressure following inspiration, assisting with exhalation).
- Transition from fixed CPAP to autotitrating CPAP (which will continually minimize the pressure). If this is inadequate then transition to BiPAP, with a reduction in the EPAP (as compared to prior CPAP setting). Using BiPAP, escalating the inspiratory pressure may be utilized to treat residual hypopneas. (Murray 2022)
other treatment options
mandibular advancement device (MAD)
- The mechanism of action involves pulling the lower jaw forward, to open the upper airway.
- Oral appliances are not as effective as positive airway pressure therapy, so they are generally limited to patients with mild or moderate OSA. (Shah 2019) 65% of patients achieve a 50% reduction in their apnea hypopnea index. (ERS handbook 3rd ed.)
- Adherence with mandibular advancement devices may be superior to that of CPAP therapy. This may explain why mandibular advancement devices often achieve similar improvements in quality of life as compared to CPAP therapy. (29129030)
- Optimal candidates for mandibular advancement device:
- Retrognathia with adequate jaw mobility.
- Mild-moderate OSA.
- Healthy periodontal tissue, with at least eight upper and lower teeth.
- Inability to tolerate CPAP therapy, or preference for an oral appliance.
maxillomandibular advancement surgery
- This is one of the most effective surgeries, which may compare favorably with CPAP. A meta-analysis found that mean AHI decreased from ~64 to ~10 following surgery. (Murray 2022)
- Indications include:
- Moderate to severe OSA (especially if there is dentofacial deformity such as retrognathia).
- Concentric and lateral pharyngeal wall collapse seen with DISE (drug-induced sleep endoscopy).
- Failure to respond to PAP therapy and oral appliance treatment.
- Predictors for surgical success:
- Younger age.
- Lower BMI (surgery probably should be avoided in morbid obesity). (Fishman 2023)
- Greater degree of mandibular advancement.
- Outcomes from surgery:
- ~80% of surgeries are deemed successful (>50% reduction in AHI, with final AHI <20).
- ~40% of patients achieve cure (AHI <5). Cure is more likely with lower preoperative AHI.
positional OSA & positional therapy
- Positional OSA has various definitions, but often encompasses the following concepts:
- i) Supine AHI that is ≧2 times the lateral AHI.
- ii) Reasonable amount of sleep (e.g., >20 minutes) spent in both positions.
- Positional OSA may occur in ~50% of mild OSA, 20% of moderate OSA, and 5% of severe OSA. (Murray 2022)
- Positional therapy involves wearing a device which prevents sleeping in the supine position, or the use of a vibrational alarm to remind patients not to remain supine. For patients who have a very low AHI in the non-supine position, positional therapy may be highly effective. (20572416) Adherence to positional therapy is higher than adherence to CPAP.
hypoglossal nerve stimulation
- The STAR trial demonstrated a 70% improvement in AHI among patients meeting the following inclusion criteria: (24401051)
- AHI 20-50 (although the FDA has licensed this for AHI 15-65).
- <25% of respiratory events are central or mixed apneas/hypopneas.
- Age >22 years old.
- Supine-predominant disease (AHI non-supine <10).
- Inability to use CPAP.
- Lack of anatomic abnormalities that would prevent effective use of upper-airway stimulation (e.g., markedly enlarged tonsils).
- Lack of complete concentric collapse of the velum during DISE (drug-induced sleep endoscopy).
- BMI <32.
- No neuromuscular disease or hypoglossal nerve palsy.
- Absence of severe pulmonary disease, moderate-to-severe pulmonary arterial hypertension, severe valvular heart disease, class III-IV heart failure, myocardial infarction or severe cardiac arrhythmia within six months, persistent uncontrolled hypertension, or active psychiatric disease.
supplemental nocturnal oxygen
- Effects of nocturnal supplemental oxygen without PAP therapy for patients with OSA: (33610579)
- Improved oxygen saturation.
- May increase apnea duration.
- Supplemental oxygen might improve blood pressure among patients with moderate-to-severe OSA, if given at a high dose (5 liters/min).
- Effects of oxygen on daytime sleepiness is unclear.
- Overall, nocturnal supplemental oxygen isn't an effective treatment for OSA. However, supplemental oxygen does appear to be safe among patients with untreated OSA. Therefore, OSA is not a contraindication to oxygen administration, if oxygen is indicated for another reason.
tracheostomy
- Tracheostomy is virtually 100% effective at eliminating obstructive apneas.
- Limited by negative effect on quality of life.
- May be considered in:
- Severe OSA.
- Failure of less aggressive medical and surgical therapies.
- Severe complications (e.g., malignant arrhythmias).
treatment of residual sleepiness
- Medication therapy may be utilized to treat residual fatigue that persists despite successful treatment of OSA (with low residual apnea-hypopnea index) and exclusion of other etiologies.
- Options include modafinil (200-400 mg qAM), armodafinil, or solriamfetol (a selective dopamine and norepinephrine reuptake inhibitor). Note that modafinil or armodafinil may render oral contraception ineffective.
epidemiology of OHS
general epidemiology of OHS
- Risk of OHS as related to BMI is discussed in the section below.
- The population prevalence of OHS has been estimated at ~0.4%. (ERS handbook 3rd ed.) The population prevalence of severe obesity has roughly doubled over the past two decades, so the prevalence of OHS is increasing over time.
- Epidemiological risk factors:
- Male predominance.
- Age range is typically ~40-60 years old.
relationships between OSA and OHS
- Among patients with OSA, 10-15% also have OHS (especially obese patients with OSA). (26118913)
- Among patients with OHS:
- 70% also have severe OSA (which may be a primary driver of hypercapnia).
- 20% have mild-moderate OSA (apnea hypopnea index 5-30).
- 10% don't have OSA.
signs and symptoms of OHS
obesity
- Obesity is a defining feature of OHS. All patients are obese (BMI >30), by definition.
- Risk of OHS roughly relates to BMI: (31368798)
- BMI 30-35 (Class I obesity): 5% prevalence of OHS.
- BMI 35-40 (Class II obesity): 10% prevalence of OHS.
- BMI >40 (Class III or severe obesity): 20% prevalence of OHS.
obstructive sleep apnea (OSA)
- OSA occurs in 90% of patients with OHS.
- Clinical features include:
- Loud snoring.
- Witnessed nocturnal apneas.
- Excessive daytime somnolence.
- (Further discussion of OSA above: 📖).
greater physiological aberration than in uncomplicated OSA:
- Hypoventilation:
- Morning headache.
- Patients can present with acute hypercapnic respiratory failure (acute exacerbation of OHS; discussed in the section below).
- Hypoxemia:
- Daytime hypoxemia commonly may result from hypercapnia.
- Saturation <94% in a patient with other features of OHS should prompt consideration to obtain an ABG/VBG to evaluate for hypercapnia. (21037018)
- Dyspnea is more likely to be a symptom in OHS (as compared to uncomplicated OSA). Causes of dyspnea may include pulmonary hypertension and/or restrictive physiology due to obesity.
- Systemic congestion due to right heart failure often occurs in advanced OHS:
- Peripheral edema.
- Jugular vein distension.
evaluation & diagnosis of OHS
laboratory evidence of OHS
- Elevated bicarbonate is often a clue that the patient has chronic hypercapnia (due to chronic metabolic compensation).
- Bicarbonate >27 mEq/L has a sensitivity of 86% and specificity of 77% for OHS. (31368798) However, in practice one should be mindful of other causes of chronic metabolic alkalosis (e.g., diuretic use, COPD). 📖
- The ATS (American Thoracic Society) position statement on OHS suggests blood gas measurement rather than relying on serum bicarbonate among patients strongly suspected of having OHS. (31368798)
- Hypercapnia:
- By definition, patients with OHS should have hypercapnia when awake during the day (PaCO2 > 45 mm, or >6 kPa).
- PaCO2 generally increases by >10 mm during sleep.
- Polycythemia may occur in patients with chronic hypoxemia who aren't receiving adequate supplemental oxygen.
- TSH (thyroid stimulating hormone) level should be considered to exclude hypothyroidism.
other studies to obtain:
- Chest imaging (at least a chest radiograph).
- Pulmonary function tests:
- Spirometry to exclude obstruction.
- Negative inspiratory force and forced vital capacity to evaluate for neuromuscular weakness.
- Polysomnography:
- Requisite component of the evaluation. (Shah 2019)
- Various findings may occur in OHS:
- 90% of patients with OHS will have OSA (with obstructive apneas and/or hypopneas).
- 10% of patients show increased upper airway resistance and/or central hypoventilation. (ERS handbook 3rd ed.)
diagnostic criteria for OHS
- (1) Obesity: Patients with OHS must have a BMI >30 (based on the definition of OHS).
- (2) Chronic alveolar hypoventilation causing daytime hypercapnia (PaCO2 >45 mm or >6 kPa).
- (3) Exclusion of alternative etiology of hypoventilation. 📖
treatment of chronic OHS
basics
- Avoid respiratory suppression: Patients with OHS are especially sensitive to medications that suppress the respiratory drive (e.g., benzodiazepines, opioids, barbiturates).
- Weight loss is ideal, but difficult to achieve. This often requires bariatric surgery and/or medication therapy (e.g., semaglutide).
- Other therapies for OSA: 90% of patients with OHS have OSA. Such patients may benefit from additional therapies for OSA, as discussed above: 📖
initial positive airway pressure therapy
- Combined OHS plus severe OSA (apnea-hypopnea index >30):
- ~70% of patients with OHS also have severe OSA.
- CPAP therapy alone may be adequate for some of these patients. An initial trial of CPAP may be performed for 2-4 weeks. (ERS handbook 3rd ed.)
- BiPAP therapy is indicated if CPAP fails to establish a normal oxygen saturation, or if there is persistent hypercapnia.
- Tracheostomy alone (without attachment to nocturnal ventilation) may also be effective. This is only rarely used, but it could be an option for a patient who is unable to tolerate CPAP/BiPAP therapy.
- OHS without severe OSA (apnea hypopnea index <30)
- ~30% of patients with OHS don't have severe OSA. This includes ~20% of patients who have mild-moderate OSA (with an apnea-hypopnea index of 5-29) and 10% of patients who don't have sleep apnea at all.
- Treatment of these patients should begin with BiPAP therapy.
settings used with NIV (noninvasive ventilation)
- Mode selection:
- BiPAP is effective for most patients. However, some patients fail to respond to BiPAP, due to low respiratory rate that yields a low minute ventilation. Such patients require more aggressive support with either BiPAP-ST or AVAPS.
- BiPAP:
- Common setting would include an iPAP of 16-20 cm, and ePAP of 6-10 cm, and a driving pressure of at least 8-10 cm. (Fishman 2023)
- BiPAP-ST:
- This is an augmented BiPAP mode that includes a set backup rate as well as a fixed inspiratory time.
- Extending the inspiratory time may augment the tidal volume.
- The backup rate is usually set to ~2 breaths/minute below the patient's spontaneous respiratory rate when awake. (Murray 2022)
- AVAPS (average volume-assured pressure support)
- May be set to a tidal volume of 8-10 cc/kg ideal body weight.
- AVAPS is probably the most powerful mode for treatment of hypercapnia.
oxygen therapy
- Up to half of patients will require supplemental oxygen in addition to positive airway pressure therapy. (Murray 2023) This typically involves bleeding oxygen into the CPAP or BiPAP device.
- Supplemental oxygen alone (without positive airway pressure) has potential risk, in terms of worsening hypercapnia (due to impairing ventilation/perfusion matching).
defining acute exacerbation of obesity hypoventilation syndrome (AEOHS)
basic concept of AEOHS
- AEOHS refers to a patient with OHS who develops acute-on-chronic hypercapnic respiratory failure. This is analogous to an acute exacerbation of COPD.
- AEOHS may result from an acute illness that is not typically associated with hypercapnia (e.g., pneumonia). This occurs because patients with OHS are fundamentally unstable, so any acute insult may tip them over into acute-on-chronic hypercapnic respiratory failure.
- ⚠️ Patients with AEOHS are usually initially misdiagnosed as having an exacerbation of asthma or COPD. This differentiation can be challenging, since many patients may have a combination of both OHS plus either asthma or COPD. To make matters even more confusing, patients with AEOHS will often respond clinically to therapy for COPD or asthma (which frequently involves generalized supportive care measures including oxygen and BiPAP) – which may perpetuate the incorrect diagnosis.
usual clinical features of AEOHS
- Pre-existing diagnosis or clinical evidence of underlying OHS (discussed in the section above).
- In many patients, AEOHS may be the initial presentation of OHS to medical care.
- Patients frequently lack a pre-existing diagnosis of OHS (or they have been mislabeled with a diagnosis of COPD or asthma).
- Obesity that is usually severe (e.g., BMI >35-40).
- Metabolic syndrome is generally present (e.g., diabetes, hyperlipidemia, hypertension). (22564878)
- Severe hypercapnia.
- Laboratory data supports the presence of an acute-on-chronic respiratory acidosis:
- If baseline ABG/VBG data are available, the pCO2 should be substantially above baseline.
- If no baseline ABG/VBG data are available, acute-on-chronic respiratory acidosis may be inferred by an imbalance of the PaCO2 in comparison to the bicarbonate level. However, caution is required here because it is impossible to be sure that the patient hasn't suffered from an acute metabolic acidosis that decreased their serum bicarbonate level from its baseline value.
- Polycythemia may support the presence of chronic hypoxemia, if present.
- Altered mental status that appears to be caused largely by the hypercapnia.
causes & investigation of AEOHS
AEOHS can be caused by a diverse range of pathologies which impair respiratory function or respiratory drive. The following discussion explores common causes, but it isn't exhaustive.
common causes of AEOHS
- OHS-specific:
- Nonadherence with PAP (positive airway pressure) therapy.
- Change in sleeping position (some patients with OHS usually sleep in a chair and are unable to breathe in a supine position; if forced to lie supine they may decompensate).
- Upper airway obstruction (e.g., tonsillitis, viral upper respiratory tract infection).
- Any cause of respiratory failure, for example:
- Pneumonia.
- Pulmonary embolism.
- Atelectasis, mucus plugging.
- Cardiogenic pulmonary edema.
- Any cause of impaired respiratory drive, for example:
- Sedating medications (even relatively mild sedative/hypnotic medications may exacerbate hypoventilation).
- Hypothyroidism.
- Excessive oxygen administration. (30592453)
investigation of the cause of AEOHS may include
- History and physical examination, focusing on:
- Adherence with PAP (positive airway pressure) therapy.
- Sleeping conditions.
- Medication changes.
- Weight changes (acute changes suggest volume overload; chronic weight gain may suggest worsening obesity which is destabilizing OHS).
- Laboratory evaluation, including:
- ABG/VBG.
- Electrolytes, complete blood count with differential.
- TSH (thyroid stimulating hormone).
- BNP (brain natriuretic peptide).
- Imaging including:
- Chest radiograph at a minimum.
- Chest CT scan is often helpful (patients are at high risk for pulmonary embolism, and the chest radiograph quality is often limited by body habitus).
- Echocardiogram may be considered to evaluate volume status and determine if there is underlying pulmonary hypertension and/or left ventricular dysfunction (both of which are common in this patient population). (22564878)
- Pulmonary mechanics (e.g., negative inspiratory force, forced vital capacity) to evaluate for neuromuscular weakness. However, this evaluation will typically need to be delayed until the patient has improved and is more awake.
treatment for AEOHS
basics
- Treat any identifiable precipitating cause.
- Sedating medications should be held.
- DVT prophylaxis that is dosed adequately (higher doses are needed in obesity).
- Consider holding or avoiding negative inotropes (e.g., beta-blockers) in patients with decompensated right ventricular failure.
- Patient positioning: If possible, the use of reverse Trendelenburg may help offload the abdomen from the diaphragm (i.e., tilting the entire bed so that the head is elevated). (22050666) The ideal positioning might be to configure the bed into a “chair” position – but this frequently isn't feasible.
BiPAP
- BiPAP is generally the preferred mode for noninvasive ventilatory support for OHS (ideally via an orofacial mask). BiPAP is usually applied as much as possible during the first ~24-36 hours of therapy, with subsequent weaning to treatment at night only. (30872398)
- Inspiratory pressure (IPAP) titration:
- Adjusted to target an adequate tidal volume (e.g., ideally >6-8 cc/kg). (22050666) Pay attention to the mask leak (in the presence of a significant leak, titrate to the exhaled tidal volume rather than the delivered tidal volume).
- IPAP should ideally be limited to 20 cm or less (to reduce the risk of gastric insufflation and emesis).
- The IPAP usually needs to be at least 8-10 cm above the EPAP in order to generate a sufficient driving pressure to support breathing and clear CO2. (26118913)
- Inspiratory pressure (EPAP) titration:
- EPAP is adjusted to the lowest level which is sufficient to eliminate apneas (obstructive events).
- Substantial atelectasis is another indication to increase the level of EPAP.
- Inspired oxygen (FiO2) should be titrated to target a saturation of ~88-92%. (30592453)
diuresis with attention to acid-base status
- Diuresis is often beneficial:
- Hypoxia and hypercapnia will tend to cause pulmonary vasoconstriction, leading to right ventricular failure and volume retention. Consequently, patients with AEOHS are frequently volume overloaded.
- Volume overload may exacerbate tissue edema in the pharynx, which worsens airway obstruction and hypoventilation.
- Patients with OHS often exist in a precarious state with a compensatory metabolic alkalosis. Excessive alterations of bicarbonate in either direction may be dangerous:
- Reduction of the bicarbonate to a normal value eliminates metabolic compensation, which may unmask uncompensated respiratory acidosis. This could theoretically increase work of breathing, precipitating tachypnea and respiratory exhaustion.
- Elevation of their bicarbonate (e.g., due to contraction alkalosis during diuresis) may decrease respiratory drive, thereby promoting worsening respiratory acidosis and increased obtundation.
- For a patient presenting with acute-on-chronic OHS, a combination of furosemide plus acetazolamide may be useful. Acetazolamide may increase the respiratory drive, which would often be beneficial in patients with severe hypercapnia and obtundation (but increasing respiratory drive wouldn't be helpful for a patient who is already clinically dyspneic). 🌊 (20979670, 17023566)
intubation if truly required
- Intubation is generally not preferred, but it may be needed for some patients.
- Indications for intubation may include:
- Multiorgan failure.
- Severe obtundation.
- Emesis, or risk of aspiration.
- Substantial secretions.
- Inability to tolerate noninvasive ventilation.
- Failure of noninvasive ventilation to cause clinical improvement (noting that improvement often takes many hours).
- Additional causes of respiratory failure that often don't respond well to BiPAP (e.g., pneumonia).
- Morbid obesity is a risk factor for difficult intubation, so appropriate precautions should be taken.
- Following intubation, elevated levels of PEEP are usually needed to prevent atelectasis.
- If intubation is required, it's generally wise to continue ventilatory support for at least a day to allow for diaphragmatic rest.
- Extubation to BiPAP or CPAP may help maintain lung inflation and reduce the risk of re-intubation.
follow-up care
- American Thoracic Society guidelines recommend continuation of nocturnal BiPAP therapy until an outpatient sleep study can be performed (which should ideally be done within three months after hospital discharge). (31368798)
- Management of comorbidities is usually required (e.g., diabetes, heart failure, hypertension, dyslipidemia).
definitions of central sleep apnea syndrome
- Central apneas or central hypopneas are defined above. ⚡️
- A central sleep apnea disorder is defined as an AHI (apnea-hypopnea index) ≧5 wherein the majority of events are central.
- A central sleep apnea syndrome is defined as a central sleep apnea disorder combined with symptoms (discussed further below; these may include nocturnal awakening, morning headaches, or excessive daytime sleepiness). (Murray 2022)
central sleep apnea syndrome may be hypercapnic or nonhypercapnic
- Hypercapnic CSA results from outright defects in the respiratory control center or neuromuscular apparatus. Daytime hypercapnia often occurs, but hypercapnia is more severe at night when the waking neural drive to breathe is absent. (Murray 2022)
- Nonhypercapnic CSA results from a fundamentally intact respiratory control center that is unstable, leading to fluctuations in the respiratory drive (between periods of hypoventilation and periods of hyperventilation). There are various drivers of this instability, for example:
- Severe heart failure with low cardiac output causes a delay in the brain's ability to sense and respond to CO2 levels. This causes delayed and prolonged responses to hypocapnia or hypercapnia. Oscillating hyperventilation and hypoventilation may result from the brain perpetually struggling to achieve a normal CO2 level, but in a sluggish fashion that is repeatedly overshooting or undershooting.
- Normally, sleep causes a lower central sensitivity to CO2, leading to mild hypoventilation. If the patient is suffering from repeated microarousals that transiently shift the brain between an awake CO2 sensitivity and an asleep CO2 sensitivity, this will lead to oscillating periods of apnea and hyperventilation. Every time the brain falls asleep it will become less sensitive to CO2, causing an apneic event. Alternatively, every time the brain wakes up following a micro-arousal, it will become more sensitive to CO2, leading to transient hyperventilation.
- Differing symptoms: Both hypercapnic and nonhypercapnic CSA may cause daytime sleepiness. However, they tend to produce different patterns of clinical manifestations.
hypercapnic central sleep apnea (CSA)
clinical features of hypercapnic CSA
- Overall, patients often present with chronic respiratory failure (including hypercapnia and hypoxemia). For example, clinical features may include:
- Polycythemia.
- Pulmonary hypertension with right ventricular failure, and with peripheral edema.
- History of respiratory failure.
- Symptoms referable to central sleep apnea are often less notable, but these may include:
- Morning headaches.
- Restless sleep, excessive daytime sleepiness.
causes of hypercapnic central sleep apnea
- Primary central alveolar hypoventilation syndrome.
- Usually a rare, genetic disorder.
- May occur in adults following a severe respiratory infection. (Murray 2022)
- Medications:
- Opioids.
- Opioid use for >2 months increases risk.
- Central sleep apnea occurs in up to 30% of patients on methadone for opioid use disorder.
- Can be treated successfully with ASV (adaptive servo ventilation) among patients with normocapnia, or BiPAP among patients with hypercapnia.
- GABA-A agonists (e.g., benzodiazepines).
- GABA-B agonists (baclofen).
- P2Y12 antagonists (e.g., ticagrelor) – actually increases the activity of the respiratory center but may nonetheless cause CSA. (37228430)
- Opioids.
- CNS disease involving the brainstem:
- Tumors affecting the medulla or pons.
- Stroke involving the nucleus tractus solitarius region of the medulla.
- Multiple sclerosis.
- Neurodegenerative disorders (e.g., multiple system atrophy, Parkinson disease).
- Neuromuscular failure to sustain the respiratory workload, e.g.:
- Amyotrophic lateral sclerosis.
- Muscular dystrophies.
- Myasthenia gravis (if severe).
- Spinal cord injury causing quadriplegia.
- Chest wall abnormalities (e.g., kyphoscoliosis).
- OHS (obesity hypoventilation syndrome) – most patients with OHS have obstructive events, but a minority of patients with OHS have predominantly central apnea. This may reflect a relative neuromuscular failure of the diaphragm, in the context of increased workload.
management of hypercapnic central sleep apnea
- Treat any underlying etiology (if possible).
- Avoid sedative medications, which may aggravate hypoventilation.
- Noninvasive ventilation is generally utilized initially (e.g., BiPAP). If there is a failure to respond, tracheotomy and invasive ventilation may be needed.
nonhypercapnic central sleep apnea (CSA)
clinical features of nonhypercapnic CSA may include:
- Nocturnal snoring or choking.
- Nocturnal awakenings and insomnia. (Murray 2022) Central sleep apnea might contribute to paroxysmal nocturnal dyspnea (PND) among patients with heart failure. (ERS handbook 3rd ed.)
causes of nonhypercapnic central sleep apnea
- Heart failure (Cheyne-Stokes respiration): 📖
- Treatment-emergent central sleep apnea (TECSA): 📖
- CNS disease:
- Cerebrovascular disease.
- CNS tumors.
- Opioid use (discussed further under hypercapnic CSA, above).
- High altitude: Hypoxemia stimulates breathing, which decreases the CO2 level downwards towards the apneic threshold.
- Treatments may include:
- Acetazolamide causes metabolic acidosis, which stimulates the respiratory center.
- Supplemental oxygen, which eliminates the elevated hypoxemic stimulus for breathing.
- Treatments may include:
- Renal failure (may be promoted by volume retention and chronic metabolic acidosis in end-stage renal disease).
- Hypothyroidism (will resolve with thyroid replacement therapy).
- Idiopathic (aka primary) central sleep apnea (rare)
- This is a rare condition which seems to occur almost exclusively in men. (Murray 2022)
- Diagnostic criteria include:
- Central event index >5/hour.
- Absence of Cheyne-Stokes respiratory pattern.
- Absence of daytime hypercapnia (patients can actually have a low PaCO2).
- No alternative explanation for central sleep apnea.
- Clinical presentation tends to mimic obstructive sleep apnea (e.g., middle-aged or older men presenting with excessive daytime sleepiness, insomnia, and sometimes snoring). (Murray 2022)
- Treatment is unclear due to a lack of evidence.
- Sedatives may reduce arousability and thereby decrease the apnea-hypopnea index (e.g., zolpidem, triazolam).
- Supplemental oxygen may be helpful (possibly by decreasing CO2 chemosensitivity and thereby avoiding apneic episodes).
pathophysiology
- The pathophysiology is complex, remaining somewhat controversial.
- Key components of Cheyne-Stokes respiration seem to be:
- Pulmonary congestion leading to hyperventilation. This causes the baseline PaCO2 to be low, close to a level that would cause the brain to cease respiratory efforts (the apnea threshold).
- Reduced cardiac output causes the brain's response to CO2 fluctuations to be sluggish. This leads to instability, since the brain's response to any CO2 shifts will be delayed and excessively prolonged.
- Cheyne-Stokes respiration probably aggravates heart failure, due to repeated arousals leading to sympathetic activation at night.
- Two phenotypes of Cheyne-Stokes respiration may be distinguished:
- Positive pattern: only inspiratory muscles are involved (causing the end-expiratory lung volume to be at or above the functional residual capacity). This pattern associates with better cardiac function.
- Negative pattern: both inspiration and expiration are active processes (causing the end-expiratory lung volume to be below the functional residual capacity). This pattern is associated with worse cardiac function. Active expiration may increase the intrathoracic pressure, thereby compressing the heart and augmenting cardiac output (similar to external chest compressions during CPR). Thus, Cheyne-Stokes respiration with active expiration could function as a form of autoresuscitation that helps maintain stroke volume in severe heart failure. (Murray 2022)
epidemiology
- The incidence of OSA (obstructive sleep apnea) and/or CSA (central sleep apnea) is high among patients who have heart failure due to reduced ejection fraction. Central sleep apnea and obstructive sleep apnea may coexist, sometimes alternating over the course of a night. (ERS handbook 3rd ed.) Among patients who experience both OSA and CSA, worsening cardiac output and pulmonary congestion may tend to favor the generation of central sleep apnea. (Murray 2022)
- Risk factors for central sleep apnea due to heart failure include:
- Severe systolic heart failure, with low cardiac output.
- Age >60 years old.
- Male sex.
- Atrial fibrillation.
- Higher pulmonary capillary wedge pressure, higher BNP (brain natriuretic peptide) level.
diagnosis
- Cheyne-Stokes respiration is the primary clinical finding.
- In less severe cases, Cheyne-Stokes respiration may occur only during sleep (especially during NREM sleep, when respiration is most strongly controlled by PaCO2).
- With greater severity, Cheyne-Stokes respiration also occurs during wakefulness.
- Key clinical features of Cheyne-Stokes respiration:
- Respirations have a smooth crescendo-decrescendo pattern.
- The duration of hyperventilation is longer than in other forms of central sleep apnea, often ~40-90 seconds. (Murray 2022; Fishman 2023)
- Some patients experience poor sleep quality and daytime sleepiness, but many are asymptomatic. (Fishman 2023)
management of CSA due to heart failure
importance of therapy is unclear
- Cheyne-Stokes respiration correlates with poor outcomes, but it generally doesn't cause significant symptoms. In asymptomatic patients, it is unclear to what extent treatment of the Cheyne-Stokes respiration may improve patient-centered outcomes.
- To date, no therapies for Cheyne-Stokes respiration have been shown to improve patient outcomes in randomized controlled trials.
heart failure management
- Drivers of Cheyne-Stokes respiration include pulmonary congestion and impaired cardiac output. Theoretically, diuresis and augmentation of cardiac output (e.g., with afterload reduction) would be beneficial for these patients.
- However, heart failure management should generally be based on usual treatment parameters and principles (rather than focusing on abolishing Cheyne-Stokes respiration).
CPAP is the first-line therapy
- Heart failure patients with CSA may benefit from CPAP therapy in terms of: (CANPAP trial 16282177; ERS handbook 3rd ed.)
- Improved apnea-hypopnea index.
- Improve nocturnal oxygen saturation.
- Improved six-minute walk distance.
- Improved LV ejection fraction.
- Among patients in the CANPAP trial who achieved an AHI <15 with CPAP therapy, there was an improvement in heart transplant-free survival. (16282177)
- Achievement of an AHI <15 with CPAP therapy suggests treatment efficacy.
- If the AHI remains >15 with CPAP therapy, CPAP discontinuation should be considered due to the potential for harm. (Murray 2022)
- Physiological mechanisms of CPAP in patients with central sleep apnea:
- (1) CPAP may cause pulmonary decongestion, which decreases the baseline respiratory drive and thereby increases the CO2 tension to a level that is higher above the apneic threshold. This may prevent the initiation of oscillating hypoventilation and hyperventilation.
- (2) CPAP may decrease the afterload, thereby improving cardiac output.
- (3) Patients often have a combination of obstructive and central apneas (e.g., central apneas often cause airway occlusion). CPAP will directly improve obstructive apneas.
nocturnal oxygen support
- Mechanistically: oxygen supplementation may decrease the brain's sensitivity to apneic events, thereby reducing the AHI in patients with Cheyne-Stokes respiration.
- Small RCTs have suggested the following benefits from supplemental oxygen (e.g., 3 liters/minute): (33610579, 16377916)
- Substantial reduction in the apnea-hypopnea index.
- Improvement in oxygen saturation (which could reduce sympathetic nervous system activation).
- May cause a slight improvement in ejection fraction.
- Among patients who have a combination of central sleep apnea and obstructive sleep apnea, supplemental oxygen may improve central sleep apnea while worsening obstructive sleep apnea.
- Overall, nocturnal oxygen may be considered as a second-line therapy for Cheyne-Stokes respiration (after CPAP).
(Adaptive Servo Ventilation, ASV)
- ASV provides a fixed amount of expiratory pressure (ePAP) with varying levels of inspiratory pressure (iPAP). Inspiratory pressure is adjusted using a breath-by-breath adjustment to target a certain tidal volume. There is additionally a backup respiratory rate which will take effect if the patient becomes apneic. ASV can stabilize ventilatory fluctuations, thereby eliminating central sleep apnea.
- ⚠️ ASV is not recommended for treatment of patients with central sleep apnea and ejection fraction <45%, based on findings of harm in this patient population. (SERVE-HF trial, 26323938)
- ASV was found to be effective in decreasing the apnea-hypopnea index (AHI). However, the use of ASV caused an increase in all-cause and cardiovascular death.
basics
- CSA may emerge following treatment of OSA with CPAP in ~10% of patients. It can also occur following treatment with other therapies (e.g., tracheostomy, mandibular advancement devices). TECSA may relate to chronically elevated respiratory drive in OSA, which may cause hyperventilation if unopposed by anatomic obstruction.
- Risk factors for TESCA: (37228430)
- Male sex.
- Older age.
- Lower body mass index.
- Higher baseline AHI.
- Higher baseline central apnea index.
- Chronic medical issues such as heart failure.
- Opioid use.
- Higher CPAP settings, BiPAP use.
- Over three months, TECSA usually dissipates. (ERS handbook 3rd ed.) However, ~20% of patients may have persistent central sleep apnea. Persistent central sleep apnea is more likely among patients with additional risk factors for central sleep apnea (e.g., chronic opioid use, heart failure).
- TECSA may cause persistent sleep disruption and daytime sleepiness.
treatment
- (1) Initial conservative therapy:
- TECSA usually resolves over time, so a trial of CPAP therapy is generally reasonable.
- In the case of TECSA due to autotitrating CPAP, narrowing the pressure range or changing to fixed CPAP with lower settings may be tried. (34673024)
- (2) Treatment for persistent TECSA (especially if symptomatic):
- TECSA may be treated with ASV (adaptive servo ventilation) or BiPAP with a backup rate (Bilevel-ST). (Murray 2022) However, note that ASV is contraindicated in patients with left ventricular ejection fraction <45%.
basics
- There are numerous factors which promote hypoxemia and hypercapnia during sleep, including: (Murray 2022)
- Increased ventilation-perfusion mismatch (due to increased perfusion to poorly ventilated areas).
- Elimination of behavioral input into ventilation.
- Decreased chemosensitivity to hypoxemia and hypercapnia leading to mild hypoventilation.
- Upward shift in the ventilatory set point for arterial PaCO2 by ~2-3 mm Hg.
- Impairment of respiratory mechanics (especially in patients with obesity or abdominal distension).
- If present, OSA may exacerbate gas exchange by causing cyclic desaturation and derecruitment.
- Among normal people, these factors do not cause nocturnal hypoxemia or hypercapnia. However, nocturnal hypoxemia may occur among patients with limited physiological reserve (e.g., COPD, interstitial lung disease).
nocturnal oximetry study
- Utility:
- May identify patients who would benefit from additional testing.
- May be used to assess the efficacy of treatment.
- Limitations:
- May underestimate the severity of sleep disordered breathing (unable to detect arousals).
- Cannot differentiate between obstructive sleep apnea versus central sleep apnea.
- Differential diagnosis of reduced nocturnal oxygen indices may include:
- Obstructive sleep apnea.
- Hypoventilation.
- Nocturnal hypoxemia due to ventilation/perfusion mismatch.
- Contraindications to overnight oximetry as a screening test among hospitalized patients: (34673024)
- Oxygen requirement >30% FiO2 (≧ 3 liters/minute).
- Reported difficulty initiating or maintaining sleep (<2 hours of consecutive sleep).
- Altered mental status or encephalopathy.
- Anticipated sleep disruptions during the night (e.g., imaging, testing, surgeries).
management
- (#1) Evaluate for obstructive sleep apnea (OSA). If OSA is found, this should be treated (e.g., with CPAP therapy).
- (#2) Evaluate for various causes of respiratory failure. Treat any reversible disorders.
- (#3) If no acutely treatable process is identified, then management might include nocturnal oxygen support and/or nocturnal BiPAP support (for hypercapnia). However, evidence supporting these interventions varies, depending on the underlying illness. For example:
- COPD patients with isolated nocturnal hypoxemia weren't found to benefit from nocturnal oxygen therapy. 📖
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References
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- 22050666 Bahammam AS, Al-Jawder SE. Managing acute respiratory decompensation in the morbidly obese. Respirology. 2012 Jul;17(5):759-71. doi: 10.1111/j.1440-1843.2011.02099.x [PubMed]
- 22564878 Marik PE, Desai H. Characteristics of patients with the “malignant obesity hypoventilation syndrome” admitted to an ICU. J Intensive Care Med. 2013 Mar-Apr;28(2):124-30. doi: 10.1177/0885066612444261 [PubMed]
- 26118913 Jones SF, Brito V, Ghamande S. Obesity hypoventilation syndrome in the critically ill. Crit Care Clin. 2015 Jul;31(3):419-34. doi: 10.1016/j.ccc.2015.03.013 [PubMed]
- 30592453 Lanks CW, Sue DY, Rossiter HB. A Pickwickian Problem: How Is Breathing Controlled? Ann Am Thorac Soc. 2019 Jan;16(1):138-143. doi: 10.1513/AnnalsATS.201806-411CC [PubMed]
- 30726328 Athayde RAB, Oliveira Filho JRB, Lorenzi Filho G, Genta PR. Obesity hypoventilation syndrome: a current review. J Bras Pneumol. 2018 Nov-Dec;44(6):510-518. doi: 10.1590/S1806-37562017000000332 [PubMed]
- 30872398 Masa JF, Pépin JL, Borel JC, Mokhlesi B, Murphy PB, Sánchez-Quiroga MÁ. Obesity hypoventilation syndrome. Eur Respir Rev. 2019 Mar 14;28(151):180097. doi: 10.1183/16000617.0097-2018 [PubMed]
- 31368798 Mokhlesi B, Masa JF, Brozek JL, Gurubhagavatula I, Murphy PB, Piper AJ, Tulaimat A, Afshar M, Balachandran JS, Dweik RA, Grunstein RR, Hart N, Kaw R, Lorenzi-Filho G, Pamidi S, Patel BK, Patil SP, Pépin JL, Soghier I, Tamae Kakazu M, Teodorescu M. Evaluation and Management of Obesity Hypoventilation Syndrome. An Official American Thoracic Society Clinical Practice Guideline. Am J Respir Crit Care Med. 2019 Aug 1;200(3):e6-e24. doi: 10.1164/rccm.201905-1071ST [PubMed]
- 33610579 Zeineddine S, Rowley JA, Chowdhuri S. Oxygen Therapy in Sleep-Disordered Breathing. Chest. 2021 Aug;160(2):701-717. doi: 10.1016/j.chest.2021.02.017 [PubMed]
- 33713177 Lee JJ, Sundar KM. Evaluation and Management of Adults with Obstructive Sleep Apnea Syndrome. Lung. 2021 Apr;199(2):87-101. doi: 10.1007/s00408-021-00426-w [PubMed]
- 34673024 Sharma S, Stansbury R. Sleep-Disordered Breathing in Hospitalized Patients: A Game Changer? Chest. 2022 Apr;161(4):1083-1091. doi: 10.1016/j.chest.2021.10.016 [PubMed]
- 37228430 Regn DD, Davis AH, Smith WD, Blasser CJ, Ford CM. Central Sleep Apnea in Adults: Diagnosis and Treatment. Fed Pract. 2023 Mar;40(3):78-86. doi: 10.12788/fp.0367 [PubMed]
Books:
- Shah, P. L., Herth, F. J., Lee, G., & Criner, G. J. (2018). Essentials of Clinical pulmonology. In CRC Press eBooks. https://doi.org/10.1201/9781315113807
- Shepard, JO. (2019). Thoracic Imaging The Requisites (Requisites in Radiology) (3rd ed.). Elsevier.
- Walker C & Chung JH (2019). Muller’s Imaging of the Chest: Expert Radiology Series. Elsevier.
- Palange, P., & Rohde, G. (2019). ERS Handbook of Respiratory Medicine. European Respiratory Society.
- Rosado-De-Christenson, M. L., Facr, M. L. R. M., & Martínez-Jiménez, S. (2021). Diagnostic imaging: chest. Elsevier.
- Murray & Nadel: Broaddus, V. C., Ernst, J. D., MD, King, T. E., Jr, Lazarus, S. C., Sarmiento, K. F., Schnapp, L. M., Stapleton, R. D., & Gotway, M. B. (2021). Murray & Nadel’s Textbook of Respiratory Medicine, 2-Volume set. Elsevier.
- Fishman's: Grippi, M., Antin-Ozerkis, D. E., Cruz, C. D. S., Kotloff, R., Kotton, C. N., & Pack, A. (2023). Fishman’s Pulmonary Diseases and Disorders, Sixth Edition (6th ed.). McGraw Hill / Medical.