Obesity hypoventilation syndrome (OHS)/Pickwickian Syndrome-Full Article

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Obesity hypoventilation syndrome (OHS)/Pickwickian Syndrome

Full Article

 

Outline:

• Introduction

• Description of OHS/Pickwickian syndrome over history

• Etiology 

• Risk Factors

• Epidemiology

• Clinical Presentation

• Diagnosis

• Differential diagnosis

• Management and Treatment

• Complications

• Prognosis

• References

Introduction:

Obesity hypoventilation syndrome (OHS) or Pickwickian Syndrome is a combination of obesity with (body mass index (BMI) ≥30 kg·m−2),  daytime hypercapnia (arterial carbon dioxide tension (PaCO2) ≥45 mmHg [5.9 kPa] at sea level) during wakefulness) due decreased ventilatory drive and capacity, and sleep disordered breathing in absence of alternate central, neuromuscular, respiratory/chest wall disease, or mechanical or metabolic explanation for hypoventilation.

 

OHS was described in 1886-1889 as overweight individuals complaining of somnolence, while obstructive sleep apnea (OSA) was first described and reported in 1969. The term “Pickwickian syndrome” was first used in the 1950s after Charles Dickens’ first novel, “The Posthumous Papers of the Pickwick Club” in which a character, called Joe, was described as often falling asleep throughout the day and snoring while sleeping. The American Academy of Sleep Medicine (AASM) prefers the term OHS over the term Pickwickian syndrome as the latter is used to describe patients only with obesity or with obstructive sleep apnea alone, not specific for OHS.

 

OHS patients  are usually associated with OSA and this represents about 90% of OHS patients, however, the presence of OSA is not necessary for the diagnosis of OHS. OSA is characterized by an apnoea/hypopnoea index (AHI) ≥5 events·h-1. About 70% of OHS patients having severe OSA (AHI ≥30 events·h-1).

 

According to the American Academy of Sleep Medicine (AASM), sleep hypoventilation in adults is defined by the following criteria:

-PaCO2  >55 mmHg for >10 min or an increase in PaCO2  >10 mmHg compared to an awake supine level to a value >50 mmHg for >10 min. To detect and observe the pattern of nocturnal sleep-disordered breathing (hypoventilation), an overnight polysomnography or respiratory polygraphy is required. However, polysomnography is not necessary for the diagnosis of OHS as not all patients have OSA.

 

OHS is diagnosed by exclusion of other causes of hypercapnia. The hallmark of the disease is obesity. Therefore, there is an relation between the prevalence of the disease and the BMI. OHS patients may undergo exacerbation of their condition leading to respiratory failure.

 

The highest grade of OHS defined recently by the European Respiratory Society was characterized by daytime hypercapnia in addition to cardiovascular ( such as right-sided heart failure secondary to chronic hypoxemia and pulmonary hypertension) and metabolic disorders. Arterial hypertension and insulin resistance are common in OHS patients. OHS is associated with high rates of morbidity and mortality.

 

 

Description of OHS/Pickwickian syndrome over history:

 

-In 1886-1889, OHS was described as overweight individuals complaining of somnolence.

-A case describing a young overweight man with symptomatic alveolar hypoventilation that became diminished after weight loss, was reported.

-In 1950s, Richard Caton described a a 51-year-old patient complaining of severe daytime drowsiness with progressive weight gain. The patient had  chronic hypoxia and hypercapnia leading to nocturnal hypoventilation. The reduction in weight resulted in almost complete recovery from the drowsiness. Richard Caton asked for support from the Clinical Society of London. The president of this society found similarity between this case and the character named “Joe” in  Charles Dickens novel  “The Posthumous Papers of the Pickwick Club”.

-Another case was reported describing a sleepy card player with severe daytime somnolence that improved after reduction in weight.

-A Syndrome combined of obesity, cyanosis, somnolence, periodic breathing, and congestive cardiac failure, was found in six patients that improved after reduction in weight. These patients had the features of OHS.

-The American Academy of Sleep Medicine (AASM) defined the diagnostic criteria for OHS since 1999.

-The first electroencephalographic description of Pickwickian syndrome was published in German. They described periodic breathing with short apnoeas caused by rolling back of the tongue leading to airway obstruction. The symptoms were found associated with hypercapnia.

-Another case reported was an overweight female with daytime somnolence that had frequent apnoeas while sleeping. Weight loss improved the condition with nearly complete improvement of the daytime somnolence. The case was attributed to Pickwickian syndrome.

-The most recent international guidelines determined the cut-offs ( Cut-off means: A measurable value of a screening variable which distinguishes screen positive from screen negative results) of both BMI and daytime hypercapnia. The determined cut-off for BMI is 30 kg·m−2 and the European Respiratory Society (ERS) Task Force outcomes determined the cut-off for PaCO2 which is 45 mmHg. The American Thoracic Society (ATS) included sleep disordered breathing as a diagnostic criteria for OHS.

 

 

Etiology:

OHS is due to decreased ventilatory drive and capacity as a result of obesity (BMI >30 kg/m2). The increased load on respiratory system in addition to the diminished ventilatory response to carbon dioxide (CO2) lead to daytime hypercapnia. Due to obesity and the increased amount of fat in the body especially around the chest and abdomen, the space available for lung expansion is reduced, resulting in decreased ling capacity overtime. OHS patients do not have the same respiratory drive changes.

Due to decreased respiratory drive, inspiration and expiration do not adequately wash CO2 from the blood. Researchers attributed the decreased respiratory drive to multiple mechanisms: sleep-disordered breathing, certain genes, and leptin resistance.

 

Leptin is a hormone produced by adipose tissue (fatty tissue). The function of leptin is to induce the sense of satiety in addition to stimulation of breathing. In case of leptin resistance, leptin levels are elevated with decreased response of the body. Therefore, leptin resistance may affect satiety and breathing.

 

Risk factors:

The main risk factor of OHS is obesity with BMI > 30 kg/m2 according to the international guidelines. BMI > 40 kg/m2 is considered extreme obesity according to the  National Heart, Lung, and Blood Institute (NHLBI). About 0.15%-0.3% of adults with a BMI > 40 kg/m2 having OHS were estimated by experts.

 

Another risk factor for OHS is obstructive sleep apnoea (OSA). About 10-15% of patients having both obesity and OSA, also have OHS.

 

It was found that OHS is more common in males, African Americans, and in Asian communities at which OHS develops at a lower BMI.

 

 

Epidemiology:

 

Due to different sample characteristics, variant assessment processes, and different disease definition, the prevalence of OHS varies in different studies.

 

Globally:

-About 1 out of 3 adults are overweight with BMI ≥25 kg·m−2.

-About 1 out of 10 adults are obese with BMI ≥30 kg·m−2.

 

In the United States (US):

In the United States (US), obesity presents in more than a third of the current population. The prevalence of obesity depends on various factors such as age, gender, education, and ethnicity. The highest prevalence of obesity among 40-59 years old individuals, women, less educated, and non-Hispanic Black individuals. Due to the strong relation between Pickwickian syndrome and obesity, increasing obesity means increasing the prevalence of OHS. Recently, Among adults in the US, the prevalence of morbid obesity (BMI ≥40 kg·m−2) is nearly 7.6%-8% according to the Centres for Disease Control and Prevention (CDC). Therefore, the prevalence of OHS is increased in the US due to epidemic obesity.

 

The prevalence of morbid obesity increased 5-folds in the US with one individual affected out of 33 adults between 1986 and 2005. The prevalence of individuals with BMI  ≥50 kg·m−2 has increased in the US by 10-folds with one individual affected out of 230 adults.

 

In East Asian populations:

OHS may be found in patients with lower BMI compared to the non-Asian populations. Studies showed that the prevalence of OSA is more in males. The prevalence of OHS is nearly equal in both males and females despite that, a study in Saudi Arabia reported that OHS cases referred to the  sleep disorders clinic, were more prevalent in older females (15.6%) with mean age 61.5 years than in males (4.5%) with mean age 49.1 years.

 

 

Clinical Presentation:

 

The triad of OHS includes: obesity, hypercapnia, and the absence of other causes of gas exchange abnormalities (hypoventilation).

Patients of OHS may present with hypercapnia and exacerbation of chronic hypoxemia leading to respiratory failure that require ventilator support (non-invasive or invasive positive pressure ventilation) and have to be managed in the intensive care unit (ICU).

 

Symptoms:

Typically, patients of OHS are obese, BMI >35 kg/m^2 is associated with high risk of daytime sleepiness and hypersomnolence, snoring, dyspnea, apnea, nocturnal choking, difficulty breathing during exercise, wheezing, daytime fatigue, impaired concentration and memory, confusion, irritability, morning headaches, swelling in the feet, ankles, and legs, fever, flushed skin, increased sweating, nausea.

 

Physical examination:

An obese patient with short-wide neck, increased neck circumference, low-lying uvula, and crowded oropharynx. If associated with heart failure due to pulmonary hypertension, the patient presents with second heart sound with a prominent pulmonic component, elevated jugular venous pressure, hepatomegaly, and lower limb edema. Patients may have signs of cor pulmonale.

 

Typically, the diagnosis occurs between 50-60 years old patients due to delay in the diagnosis. A study showed that about 8% of patients admitted to the ICU presented with acute on top of chronic hypercapnic respiratory failure and met the diagnostic criteria of OHS:

-BMI >40 kg·m−2

-PaCO2 >45 mmHg

-No evidence of intrinsic lung disease or musculoskeletal disease

-No history of smoking

About 75% of these patients were misdiagnosed and were considered  obstructive lung disease cases for which they received treatment despite the pulmonary function tests showing no evidence of obstruction.

Severely obese patients (BMI ≥40 kg·m−2) have severe Obstructive sleep apnea (OSA) (≥30 events·h-1).

 

Diagnosis:

 

The diagnosis of OHS is often delayed and patients present with acute stages of respiratory failure or cardiac decompensation. Early diagnosis is crucial due to high morbidity and mortality.

The diagnosis of OHS is made by exclusion of other causes of hypoventilation (e.g., chest wall disorders such as kyphoscoliosis causing mechanical respiratory limitation, COPD, severe interstitial lung disease, myasthenia gravis, untreated hypothyroidism, cerebrovascular disease and other neurological diseases, and Ondine’s syndrome which is a congenital disease).

 

Diagnostic criteria:

The diagnostic criteria for OHS (released in 2014)  according to the American Academy of Sleep Medicine (AASM):

-Obese patients with BMI> 30 kg·m−2

-Hypoventilation during wakefulness

-Elevated blood levels of carbon dioxide > 45mm Hg

-Absence of other disorders and no history of medications

 

Suspected patients can be initially managed by: evaluation of serum levels of venous bicarbonate, and pulse oximetry.

 

Pulse oximetry:

A common finding is borderline oximetry. Pulse oximetry finding with the oxygen nadir and percent time spent below O2 saturation (SpO2) < 93% may be considered hypoventilation but does not confirm the diagnosis of OHS. Sustained hypoxemia without apneas in nocturnal oximetry suggest hypoventilation.

 

Serum levels of venous bicarbonate:

Serum levels of venous bicarbonate level ≥ 27 mEq/L can be used in screening. It has 92% sensitivity and 50% specificity values. It has a 97% negative predictive value for excluding a diagnosis of OHS. Eleveation of serum bicarbonate level may occur in other cases including: dehydration, vomiting, and some medications.

 

Arterial blood gases (ABGs) analysis:

ABG is more accurate and definitive test for hypoventilation showing the partial pressure of arterial CO2 (PaCO2) > 45 mmHg and PaO<70 mmHg.

Different techniques can be used to measure carbon dioxide level such as daytime arterial blood gases, venous blood gases, arterialised capillary blood gases, transcutaneous carbon dioxide and end-tidal carbon dioxide monitoring. Elevated carbon dioxide levels (≥45 mmHg) during wakefulness can indicate hypoventilation. Measuring carbon dioxide levels continuously during sleep by end-tidal or transcutaneous monitoring is the most reliable method for diagnosis of sleep hypoventilation. Hypoventilation and carbon dioxide levels are worsened during sleep particularly in the rapid eye movement (REM) stage of sleep.

 

Polysomnogram:

Gold standard for diagnosis of OHS is polysomnography with continuous nocturnal CO2 monitoring.

 

Complete blood count (CBC):

Chronic hypoventilation and hypoxia may lead to polycythemia. Exclude secondary causes of erythrocytosis.

 

Exclusion of other causes:

-For exclusion of other respiratory causes of hypoventilation: pulmonary function testing, chest X-ray or computed tomography (CT), assessment of respiratory muscle strength (MIP and MEP)

-For exclusion of thyroid causes: thyroid function testing to exclude hypothyroidism.

-For exclusion of cardiac causes: electrocardiography (ECG) and echocardiogram showing right heart enlargement and failure secondary to pulmonary hypertension occurring in late stages of OHS.

-Exclusion of drug administration: alcohol, opiates, sedatives, and hypnotics.

 

 

 

Differential Diagnosis:

 

1- Obstructive lung diseases:

Hypercapnic and obese patients with chronic obstructive pulmonary disease (COPD) commonly have breathing disorders during sleep. Arterial blood gases (ABGs) and a complete pulmonary function test are required to confirm the diagnosis.

 

2- Restrictive lung diseases:

May be associated with hypoxemia without hypercapnia. Patients with extrapulmonary chest wall restriction such as pectus deformity, scoliosis, and kyphosis commonly present with acute hypercapnic respiratory failure. Severe bowel distension and ascites can affect respiratory mechanism by applying a significant force on the diaphragm. Poor ventilatory reserve without significant respiratory failure are common in extrapulmonary chest wall restriction.

 

3- Central sleep apnea (CSA):

Characterized by intermittent reduced central drive to breathe. It is associated with hyperventilation, normocapnia or slightly hypocapnica on blood gas testing.

 

4- Myxedema:

Characterized by low levels of circulating free thyroid hormones, respiratory insufficiency and even hypercapnic failure, bradycardia, hypothermia, sluggish tendon reflexes, neurological deficits, hemodynamically unstable, and coma in severe cases.

 

5- Neuromuscular disease:

Amyotrophic lateral sclerosis (ALS) can lead to hypercapnic respiratory failure. Typical findings in ALS patients include muscle weakness, hyperactive deep tendon reflexes, and fasciculation.

In case of spinal cord injuries (SCI), patients are not usually obese, have history of acute injury or trauma, may present with chronic hypercapnia during sleep and wakefulness and sleep-disordered breathing.

 

6- Muscular dystrophies:

Muscular dystrophies associated with hypercapnic respiratory failure include Duchenne or Becker disease. It is characterized by muscle weakness, cardiomyopathies, delayed growth, elevated creatinine kinase (CK), with variable and benign course.

 

7- Autoimmune disorders:

Guillain-Barre syndrome is characterized by rapid onset of  ascending, symmetric paralysis with areflexia over 2-4 weeks.

Patients with dysautonomia commonly present with cardiac arrhythmias and are hemodynamically unstable

 

In case of Myasthenia gravis, the hallmark is muscle fatigue, limb weakness, dysarthria, diplopia, ptosis, and weak cough.

 

8- Poliomyelitis:

Patients of poliomyelitis and post-polio syndrome present with new weakness and fatigability or acute flaccid paralysis. Its incidence has declined due to vaccination.

 

Other disorders:

-Acute infection

-Vascular disorder

-Erythrocytosis

-Diaphragmatic weakness or phrenic nerve injury

-Medications (sedatives or illicit drugs)

 

 

Management and Treatment:

 

Treatment of OHS includes targeting weight loss, lifestyle modifications, managing sleep-disordered breathing, surgical methods, and drug therapy.

 

Positive Airway Pressure (PAP):

The first line of treatment is Positive Airway Pressure (PAP) including continuous positive airway pressure (CPAP) or bi-level positive airway pressure (BPAP).  Through constant pressure (over 15 cm H2O) throughout respiration, CPAP helps in maintaining the patency of upper airway leading to reducing the obstructive events. About 90% of  OHS patients are associated with Obstructive Sleep Apnea (OSA) therefore, CPAP is the modality of choice while BPAP is the first choice in OHS with sleep-related hypoventilation and few obstructive events during sleep.

Hypercapnia without improvement despite the adherence to CPAP and intolerance to CPAP require the use of BPAP. Titration of inspiratory positive airway pressure (IPAP) and expiratory positive airway pressure (EPAP) are used for initiation of BPAP. The main factor affecting ventilation and CO2 elimination is the delta or the pressure difference between IPAP and EPAP. In case of decreased lung compliance due to atelectasis and poor chest wall compliance due to require high positive pressure. Monitoring Arterial Blood Gases (ABGs) is required. The modality of ventilation depends on the severity of respiratory failure. Conscious patients with intact cough and gag reflex may respond to non-invasive positive pressure ventilation.

Patients not improving rapidly, unprotected airway, and intolerance to BPAP may require early intubation.

The average hours of daily use over the previous 30 days is used to assess adherence to PAP therapy. This is difficult and considered the most challenging aspect of managing OHS due to patient non-compliance, financial constraints, lack of education, and difficulty with the device and the masks. Patients should be informed that various types of masks can be used in treatment of OHS and should be educated about the disease.

A meta-analysis of 25 studies showed the advantages of using PAP in the management of OHS such as improving the symptoms and mortality of OHS, improving  daytime sleepiness, gas exchange, and improving the quality of sleep and life.

 

Oxygen supplementation:

Oxygen supplementation may be required and Arterial Blood Gases (ABGs) should be assessed regularly. Oxygen supplementation is required to correct hypoxemia that occur in 50% of OHS patients despite the use of PAP however, using PAP correctly may correct hypoxemia. Regular assessment is necessary to avoid the toxicity and long-term cost of oxygen supplementation therapy. Prolonged oxygen therapy may cause adverse effects. A recent study has shown that using 100% oxygen therapy may worsen CO2 retention and hypercapnia decreased minute ventilation (by 1.4 L/min) and (CO2 increased by 5.0 mmHg) in obesity-associated hypoventilation stable patients.

 

Lifestyle modifications:

Lifestyle modifications especially weight loss, should be encouraged in all OHS patients. The target weight loss is 25-30% of actual body weight.  Following a weight loss program improves ventilation and nocturnal oxy-hemoglobin saturation, improves pulmonary function, reduces the frequency of respiratory apneas hypopneas and the incidence of some complications including pulmonary hypertension.

When diet and lifestyle modifications fail with intolerance to PAP therapy or worsening of symptoms, surgeries such as bariatric surgery are recommended to achieve weight loss. However, bariatric surgery is associated with complications and high mortality rate which may become higher for OHS patients.

 

Tracheostomy:

Tracheostomy is needed in patients with intolerance or non-adherence to PAP therapy, or in patients with complications such as cor pulmonale. Tracheostomy does not alter the respiratory drive of pulmonary mechanism therefore, PAP therapy is still required. Tracheostomy may be limited in use due to the difficulty of the procedure and the surgical risks in obese patients.

 

Pharmacotherapy (Drug therapy):

The use of drugs including respiratory stimulants (e.g., acetazolamide, medroxyprogesterone, and theophylline) in treatment of OHS is controversial. Pharmacologic agents may be used when PAP therapy and weight loss fail to improve hypoventilation.

 

-Acetazolamide:

Theoretically, acetazolamide blocks CO2 conversion to bicarbonate therefore lowers the pH in the brain and increases central ventilatory drive.

 

-Medroxyprogesterone:

Medroxyprogesterone may stimulate respiration in hypothalamus but increases the risks of hypercoagulability and venous thromboembolism, increases uterine bleeding in females, and decreasing libido with erectile dysfunction in males.

 

-Theophylline:

Theophylline is a direct respiratory stimulant and bronchodilator. Other respiratory stimulants include buspirone and mirtazapine.

 

-Leptin (metreleptin):

Enough studies about the effects of leptin in OHS patients are not available  yet. The Subcutaneous injection of recombinant human leptin (metreleptin) has been approved by the US Food and Drug Administration in patients congenital or acquired generalized lipodystrophy to treat metabolic complications of leptin deficiency.

 

 

Complications:

 

Complications of OHS are multiple especially if not treated correctly including pulmonary hypertension, and volume overload, and biventricular heart failure increasing mortality rates compared to non-hypercapnic patients with sleep-disordered breathing only. Pulmonary Hypertension occurs in about 50% in OHS cases compared to OSA patients (15%). In general, obesity leads to other diseases such as  dyslipidemia, systemic arterial hypertension, diabetes, hypothyroidism, osteoarthritis, and liver dysfunction. A study involving 246 OHS patients, 122 patients out of the participants had elevated systolic pulmonary artery pressures (40 mmHg or more).

OHS in associated with lower quality of life, continued daytime sleepiness, with high healthcare costs and expenses. Early diagnosis and management of OHS decreases the risks of complications and mortality rates.

 

 

Prognosis:

OHS is characterized by progressive course and is associated with high risk of cardiovascular complications (Pulmonary hypertension and right heart failure) therefore, high morbidity and mortality rates. Due to misdiagnosis of OHS even in patients with morbid obesity, hospitalizations with hypercapnic respiratory failure is frequent.

Comorbidities such as heart failure, coronary artery disease, and cor pulmonale are more likely in OHS patients than in OSA or overlap syndrome. About 12-32% of 3-year mortality rate despite treatment with ventilator therapy is associated with OHS. The use of health care resources is high in OHS patients with increased frequency of invasive mechanical ventilation or Intensive Care Unit (ICU) admission. Pulmonary Hypertension occurs in about 50% in OHS cases compared to OSA patients (15%). In general, obesity leads to other diseases such as  dyslipidemia, systemic arterial hypertension, diabetes, and hypothyroidism.

According to studies, OHS associated with other medical conditions show high mortality rates within 18 months (23%), and within 50 months (46%). Early treatment of OHS with PAP therapy may lead to 10% reduction in mortality rates.

 

References:

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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9491327/ 

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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8753617/ 

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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6459748/ 

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https://www.sleepfoundation.org/sleep-apnea/pickwickian-syndrome