Pickwickian Syndrome

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Continuing Education Activity

Obesity hypoventilation syndrome (OHS or Pickwickian syndrome) is defined as the presence of awake alveolar hypoventilation characterized by daytime hypercapnia (arterial PaCO2 greater than 45 mmHg [5.9 kPa]) that is thought to be a consequence of diminished ventilatory drive and capacity related to obesity (BMI over 30 kg/m^2) in the absence of an alternate respiratory, neuromuscular, or metabolic explanation for hypoventilation. The management of Pickwickian syndrome is challenging and complex, and the clinical presentation of the disease should be suspected early to achieve good outcomes. This activity reviews the epidemiology, etiopathogenesis, clinical features, management, prognosis and highlights the role of the interprofessional team in caring for patients with this condition.

Objectives:

  • Describe the etiology of Pickwickian syndrome.
  • Outline the evaluation process for Pickwickian syndrome.
  • Review the management options for Pickwickian syndrome.
  • Explain interprofessional team strategies for improving care coordination and communication to detect Pickwickian syndrome early and improve outcomes.

Introduction

Obesity hypoventilation syndrome (OHS or Pickwickian syndrome) was described as early as 1886, well before obstructive sleep apnea (OSA) was first reported in 1969.[1][2] OHS is defined as the presence of awake alveolar hypoventilation characterized by daytime hypercapnia (arterial PaCO2 greater than 45 mmHg [5.9 kPa]) that is thought to be a consequence of diminished ventilatory drive and capacity related to obesity (BMI over 30 kg/m^2) in the absence of an alternate respiratory, neuromuscular, or metabolic explanation for hypoventilation.[3] This activity reviews the epidemiology, etiology, clinical features, and management of OHS. Other types of sleep-disordered breathing are discussed in different sections.[4][5][6]

Etiology

Obesity hypoventilation syndrome (OHS) results from diminished ventilatory drive and capacity related to obesity. The load on the respiratory mechanics and blunting of the ventilatory response to carbon dioxide (CO2) in obese individuals (body-mass index-BMI of >30 kg/m2) results in daytime hypercapnia. OHS is considered a diagnosis of exclusion, i.e., in the absence of an alternative neuromuscular, mechanical, or metabolic explanation for hypoventilation. OHS is commonly associated with OSA (defined by an apnea-hypopnea index-AHI ≥ five events/hour). However, not every patient with OHS usually has OSA (approximately 10% do not have comorbid OSA and OHS or non-obstructive sleep hypoventilation), suggesting a different phenotype. The majority of patients (about 70%) have severe OSA (AHI ≥ 30 events/hour).[7] 

Epidemiology

More than a third of the current population of the United States is obese. With increasing obesity, the prevalence of OHS is assumed to be on the rise. The prevalence of morbid obesity (BMI greater than or equal to 40 kg/m^2) is 8% among adults in the United States.[8][9] The prevalence of obesity varies by gender, ethnicity, education, and age, with the highest prevalence among women, non-Hispanic Black persons, those with less education, and those aged 40 to 59 years.[10] The prevalence of OHS in a community-based cohort is unknown, but we can get a rough estimate based on the above data for obesity prevalence. The prevalence of OHS in individuals with OSA is estimated to be between 20 to 30%.[11] In one study of hospitalized patients with a BMI over 35 kg/m2, the prevalence of OHS was 31 percent.[12]

Pathophysiology

Obesity hypoventilation syndrome results from the mechanical load on the respiratory pump leading to low tidal volumes and blunting of the chemoreflex to CO, leading to inappropriate central respiratory effort in individuals with obesity. This situation manifests from a complex interaction between multifactorial mechanisms, which are as follows:

  1. Sleep-disordered breathing: Obesity-related mechanisms like altered upper airway mechanics and impaired ventilatory control play a significant role in promoting hypoventilation during wakefulness and sleep. In obese individuals, particularly those with narrow airways or increased upper airway resistance is associated with increased end-tidal CO (PCO), as illustrated in the figure below. Following the apneic phase in patients with only OSA, the hyperventilation phase eliminates the retained carbon dioxide (CO). If CO accumulates beyond the ventilatory capacity to be cleared, the kidney starts to retain bicarbonate to compensate for respiratory acidosis. This chronic accumulation of CO leads to chronic hypercapnia and compensated respiratory acidosis.[13] 
  2. Impaired pulmonary mechanics: Although unclear about the role in the pathogenesis of OHS, patients with OHS are found to have a higher upper airway resistance in sitting and supine positions compared with individuals with OSA who are eucapnic.[14] What is somewhat clearer is that the spirometry analysis of patients with OHS reveals a predominantly restrictive defect with lower forced vital capacity (FVC) and forced expiratory volume in one second (FEV1) but a normal FEV1/FVC ratio, likely from a combination of the inertial load of the increased fat around the chest wall and abdomen further worsened by the effect of gravity during sleep.[15][16] This restrictive breathing pattern can also increase dead space ventilation by a predominantly lowered tidal volume and increased respiratory rate. It is unclear whether respiratory musculature weakens in patients with OHS, given the lack of studies on diaphragmatic performance and transdiaphragmatic pressures.
  3. Blunted respiratory drive: In individuals with OSA without hypercapnia, PaCO levels do not increase due to the ventilatory compensation, which allows the clearance of excessive amounts of CO. However, in patients with OHS, the compensatory mechanism is compromised, causing hypercapnia. Research has shown that patients with OHS do not augment their minute ventilation when forced to breathe hypoxic ambient air and when rebreathing CO.[17][18] They are, however, able to voluntarily hyperventilate to eucapnia, and these are also correctible with positive airway pressure.[19] 
  4. Leptin resistance: Leptin is a satiety hormone produced by adipose tissues, which stimulates hyperventilation and can be found in increasing levels in the obese population to compensate for the increased CO load.[20][21] Patients with OHS have been found to have elevated leptin levels compared to eucapnic patients, suggesting leptin resistance. These levels drop after the treatment with positive airway pressure.[22]

History and Physical

The typical presentation of the patient with obesity hypoventilation syndrome may occur in the medical intensive care unit (ICU) with acute exacerbation of chronic hypoxemic and hypercapnic respiratory failure needing ventilatory support in the form of non-invasive or invasive positive pressure ventilation. A sleep specialist or pulmonologist may also see the patient with OHS in the outpatient setting. The typical patient is obese, with BMI over 35 kg/m^2 is considered at high risk with hypersomnolence and daytime sleepiness. Other classic signs of OSA like snoring, nocturnal choking, apneas witnessed by the partner, early morning headaches, daytime fatigue, impaired concentration and memory, and dyspnea may also be reported by patients.

The physical exam may reveal an obese individual with a short and wide neck, crowded oropharynx, and low-lying uvula. Signs of right heart failure from pulmonary hypertension, including elevated jugular venous pressure, a prominent pulmonic component of the second heart sound, hepatomegaly, and lower extremity edema, may be present.

Evaluation

Obesity hypoventilation syndrome often remains undiagnosed until late in the disease. Early recognition is essential, as these patients have significant morbidity and mortality. Acute hypercapnic respiratory failure due to obesity hypoventilation syndrome is a diagnosis of exclusion; once there is clinical suspicion, other differentials must be excluded to ensure correct diagnosis, which will dictate the management. The discussion of differential diagnoses is in subsequent sections.

  1. Hypercapnia: A sensitive screening test for chronic hypercapnia is an elevated serum bicarbonate level (greater than 27 mEq/L), and almost all patients with OHS have elevated bicarbonate. However, this is not a specific test, and elevation can occur in several other diagnoses, including vomiting, dehydration, medications, etc. Arterial blood gas (ABG) is a more definitive test for alveolar hypoventilation and defines hypercapnia as the partial pressure of arterial CO (PaCO) greater than 45 mmHg.
  2. Hypoxemia: Hypoxemia during wakefulness is not common in OSA alone and requires confirmation by an ABG showing PaO<70 mmHg.Hypoxia can be measured noninvasively through pulse oximetry. Another tool used in evaluating OSA and OHS is the polysomnogram.
  3. Complete blood count: Polycythemia due to chronic hypoventilation and hypoxia may be present. Blood tests can rule out secondary causes of erythrocytosis and other mimicking diagnoses like hypothyroidism.
  4. Pulmonary function testing (PFT) and imaging: If hypercapnia is confirmed, other causes should be ruled out with PFTs and chest X-ray or computed tomography (CT) scan as clinically indicated. The PFT results in OHS can reveal a moderate restrictive defect without evidence of airway obstruction but may also be normal. 
  5. Sleep study: Polysomnography with continuous nocturnal CO monitoring is the gold standard for evaluating OHS. In addition, the oxygen nadir and percent time spent below O saturation (SpO) of 90% (T90) help suspect OHS.
  6. Cardiac studies: Electrocardiogram (EKG) and echocardiogram help assess right heart enlargement and failure secondary to pulmonary hypertension that develops late in OHS. 

Treatment / Management

There are newly established guidelines from leading societies on treating obesity hypoventilation syndrome.[23][24][25] Individual treatment modalities that target the various distinct underlying mechanisms include addressing sleep-disordered breathing, weight loss and lifestyle modifications, surgical interventions for the same, and other pharmacotherapy.

Positive airway pressure (PAP) therapy, including continuous positive airway pressure (CPAP) or bi-level positive airway pressure (BPAP), is first-line therapy.[23][26] This therapy should not be delayed while the patient tries to lose weight. Supplemental oxygen may be necessary, and its continued need should undergo an assessment at subsequent visits. Given that most patients with OHS (90%) have coexistent OSA, CPAP is considered the initial modality of choice.[27] In those with sleep-related hypoventilation and fewer obstructive events during sleep, BPAP is the first choice.[28]

CPAP delivers constant pressure through the entire respiratory cycle, helping maintain the upper airway patency and reducing obstructive events. In the subset of patients with a lack of improvement in hypercapnia despite objective evidence of adequate adherence to CPAP, BPAP is chosen. BPAP should also be the option if the patient is intolerant of CPAP or demonstrates a need for higher pressures in CPAP (over 15 cm H2O).[29] Although comparative trials are lacking, most would consider BPAP the mode of choice to augment ventilation when CPAP fails or becomes intolerant. For initiation of BPAP, an inspiratory positive airway pressure (IPAP) and expiratory positive airway pressure (EPAP) are independently titrated and set.[30]

The delta or the pressure difference between IPAP and EPAP is the driving pressure, the main contributor to ventilation and CO2 elimination. High levels of positive pressure are often needed because of poor chest wall compliance from obesity, diminished lung compliance from atelectasis, and cephalad displacement of the diaphragm from central adiposity during sleep. Using PAP, arterial blood gases should be monitored closely to ensure clinical improvement. For patients presenting to the hospital with acute worsening of chronic hypoxic hypercapnic respiratory failure, a decision about the ventilation mode must be made based on the severity of the respiratory failure. A trial of non-invasive positive pressure ventilation, as an initial choice, can be afforded to an arousable patient with an intact gag and cough reflex. However, early intubation should be considered when patients cannot protect their airway, do not tolerate bi-level positive airway pressure, or do not improve quickly. Patients admitted to the hospital due to acute, chronic hypercapnia respiratory failure often do not have a formal diagnosis of OSA or known PAP pressures (based on official titration); therefore, empirical treatment is used. In these cases that require empirical therapy with non-invasive ventilation, the choice of pressures (IPAP and EPAP) depends on the severity of respiratory acidosis and body weight (to maintain upper airway patency while providing adequate pressure support for ventilation). See more details in the separate section on non-invasive ventilation.[30]

Adherence to PAP therapy, measured as the average hours of daily use in the past 30 days, is among the most challenging aspects of management of OHS; this may be due to difficulty with the device and the masks, patient non-compliance, lack of education or financial constraints. In a meta-analysis that included 25 studies, PAP was associated with improving OHS symptoms and mortality. Further PAP treatment improved gas exchange, daytime sleepiness, sleep quality, quality of life, and frequency of emergency department visits.[31] Various types and sizes of masks can be used in patients diagnosed with OHS. Therefore patient education about the disease process, availability of several kinds of masks, and the necessity for PAP to prevent progression to complications and morbidity must be thoroughly addressed to maintain satisfactory adherence. 

Supplemental oxygen therapy is necessary for patients with OHS and hypoxemia despite PAP use. This situation occurs in up to 50% of patients in the literature.[32] Over time, the correct use of PAP may correct the hypoxemia to an acceptable level. This cohort of patients on PAP with supplemental oxygen has to be regularly followed to avoid the long-term cost and toxicity of continued oxygen therapy. Oxygen therapy alone in the absence of PAP is strongly discouraged as it will not augment ventilation and may have poor outcomes with worsening CO2 retention.[26][33] In a recent randomized crossover, a clinical study found that supplemental oxygen of 100% causes worsening hypercapnia (CO2 increased by 5.0 mmHg compared with room air) and decreased minute ventilation (by 1.4 L/min) in stable patients with obesity-associated hypoventilation.[34][26]

All patients with OHS should be encouraged towards diet and lifestyle modification aiming at weight loss. This weight loss should be controlled and supervised, preferably in a weight loss program. Weight loss improves ventilation and has been shown in various other cardiac and respiratory pathologies to reduce the risk of complications such as pulmonary hypertension. Weight loss improves nocturnal oxyhemoglobin saturation, decreases the frequency of respiratory apneas hypopneas, and improves pulmonary function.[35] The weight-loss target is recommended to be 25 to 30% of actual body weight to achieve hypoventilation effectively.[24]

Given that lifestyle and dietary modifications are not sustainable for the vast majority of patients, in the long run, there are surgical interventions for weight loss, including bariatric surgery. Referral to surgery should be when dietary and lifestyle interventions fail, there is low tolerance to high PAP pressures, or there is a progression of OHS symptoms and hypercapnia. Although dedicated studies for patients with OHS are lacking, various studies have shown these interventions to demonstrate mixed efficacy for long-term improvement in OSA symptoms, AHI, and weight loss maintenance. In a meta-analysis done in 2009, including 12 different studies, patients undergoing sleep study before and after maximal weight loss from bariatric surgery reported a 71% reduction in AHI. Still, only 38% achieved a cure, defined as AHI less than 5/hour. Nearly two-thirds had residual disease, with most of them having persistent moderate OSA, defined as AHI greater than or equal to 15/hour.[36] With outcomes debatable, bariatric surgery still poses significant risks and complications. The perioperative mortality is high, and that for OSA and OHS may be higher.[37] Therefore, it is usual to initiate PAP therapy immediately after extubation, especially since there is no compelling evidence of PAP therapy-induced anastomotic complications.[38][39] 

Tracheostomy is the surgical modality aimed at sleep-disordered breathing and is generally only for those intolerant of or consistently non-adherent to PAP therapy and those in whom disease progression to complications including cor pulmonale occurs. Most people with a tracheostomy for OHS still require PAP therapy. It targets just the sleep-disordered breathing but does not alter the pulmonary mechanics, respiratory drive, or the neurohumoral milieu.[40] Also inherent to the procedure are surgical risks and procedural difficulties in the obese population.

Respiratory stimulants, such as acetazolamide, medroxyprogesterone, and theophylline, offer a compelling theoretical benefit to patients with chronic hypercapnia or depressed respiratory drive but have limited data supporting their use in a practical setting.[41] They have sometimes been considered adjunctive therapies of last resort for patients who chronically continue to have hypoventilation despite BPAP therapy and weight loss. By blocking carbon dioxide conversion to bicarbonate, acetazolamide can lower pH in the brain and theoretically increase central ventilatory drive and minute ventilation.

Medroxyprogesterone serves as a respiratory stimulant at the hypothalamic level, but results from studies have been insufficient and contradictory, along with increased risks of hypercoagulability and venous thromboembolism. Other side effects like decreased libido and erectile dysfunction in men and uterine bleeding in women should be considered.[42] Theophylline is a bronchodilator as well as a direct respiratory stimulant. Its use in obesity-hypoventilation syndrome has never been studied and is currently not recommended. Other pharmacological therapies that stimulate the respiratory system (such as buspirone and mirtazapine) and hypnotics (such as zolpidem) have been studied recently in patients with sleep-disordered breathing and high-risk patients such as spinal cord injury.[43][44][45][44] Still, no studies are available in patients with OHS. 

Differential Diagnosis

Central sleep apnea: Central sleep apnea (CSA) is defined by an intermittent reduced central drive to breathe. It is not hypoventilation syndrome, but patients tend to hyperventilate. Patients with CSA are generally normocapnic or slightly hypocapnic on blood gas testing.

Obstructive lung disease: Patients with chronic obstructive pulmonary disease (COPD) who are hypercapnia and obese commonly have sleep-disordered breathing.[46] Therefore, a complete pulmonary function test and arterial blood gas are critical in establishing the diagnosis. Patients who have evidence of obstructive ventilatory defect cannot be given a diagnosis of OHS as discussed in the introduction and evaluation. 

Restrictive diseases from disorders affecting the pulmonary parenchyma may lead to hypoxemia without hypercapnia. Acute hypercapnic respiratory failure is more common in patients with extrapulmonary chest wall restriction (pectus deformity, scoliosis, kyphosis), which causes compromised respiratory mechanics. Ascites and severe bowel distention can compromise respiratory mechanics by exerting a significant cephalad force on the diaphragm. Extrapulmonary chest wall restriction commonly causes poor ventilatory reserve without overt respiratory failure. 

Neuromuscular disease: Neuromuscular diseases that can affect the respiratory system merit consideration in the differential diagnosis of hypoventilation syndromes. Amyotrophic lateral sclerosis (ALS) often leads to hypercapnic respiratory failure.[47] Patients usually have clues on neurologic examination suggestive of typical features of ALS, such as muscle weakness and fasciculations, and hyperactive deep tendon reflexes. In addition, patients with spinal cord injuries can present with sleep-disordered breathing and chronic hypercapnia during sleep and wakefulness.[48][49] Thes patients are not usually obese and have a history of acute injury or trauma that led to neurological deficits. However, patients with SCI commonly have sleep-disordered breathing and restrictive ventilatory defects mimicking OHS.[50][51] Muscular dystrophy such as Duchenne or Becker can cause hypercapnic respiratory failure but have multiple other features like overall muscular weakness, growth delay, cardiomyopathies, lab abnormalities like elevated creatinine kinase (CK), making the diagnosis apparent in a pediatric age group. Becker muscular dystrophy has a slightly more variable and benign course but remains with similar overall clinical features.

Patients with Guillain-Barre syndrome generally present with rapid onset of ascending, symmetric paralysis, and areflexia occurring over 2 to 4 weeks. Dysautonomia is common and can cause hemodynamic instability or cardiac arrhythmias.

In myasthenia gravis, the hallmark feature is muscle fatigability, diplopia, ptosis, dysarthria, limb weakness, and weak cough.

Poliomyelitis and post-polio syndrome are associated with acute flaccid paralysis or new weakness and fatigability, but vaccination has largely eradicated these from the US.

Myxedema: Extremely low levels of circulating free thyroid hormones can present with respiratory insufficiency and hypercapnic failure but will have coexistent features of hypothermia including bradycardia sluggish tendon reflexes they may be hemodynamically unstable along with neurological deficits up to coma in extreme cases.

Prognosis

Obesity hypoventilation syndrome is commonly misdiagnosed even in patients with morbid obesity resulting in frequent hospitalizations with hypercapnic respiratory failure.[52] The clinical course of OHS tends to be progressive and is associated with cardiovascular complications, including pulmonary hypertension and right heart failure, ultimately leading to high morbidity and mortality, with cardiovascular disease's primary cause.[53] The impact of therapy, particularly noninvasive PAP, on complications and mortality is positive, but even when treated with positive airway pressure therapy, the mortality in those with severe OHS remains substantially worse than individuals with OSA alone.[54] Higher hospitalization rates, intensive care unit admissions, and post-discharge long-term care are also higher OHS rates than eucapnic obese individuals.

Complications

In progressive or untreated OHS, biventricular heart failure, pulmonary hypertension (PH), and volume overload are common.[55] Patients with OHS have a lower quality of life with a higher overall symptom course, continued daytime sleepiness, and increased healthcare expenses. They are also at a higher risk of increased pulmonary and right-sided pressure overload complications, significantly increasing morbidity, and have overall early mortality than non-hypercapnic patients with sleep-disordered breathing alone. A post hoc analysis of the Pickwick trial found that 122 patients of the 246 participants who had OHS had elevated systolic pulmonary artery pressures (of 40 mmHg or more).[55] While obesity and early/late diastolic peak flow relationship were predictors of PH in the non-severe OSA group, low wake PaO2 levels and BMI were risk factors for PH in those with OHS and severe OSA.

Consultations

In a patient suspected of having obesity hypoventilation syndrome, an early referral to a sleep specialist for polysomnography and arterial blood gas testing is recommended. 

Deterrence and Patient Education

As outlined in the management section, patient education should focus primarily on the natural history of the disease and its relationship with sleep-disordered breathing. Physicians should start the counseling early on the importance of weight loss and lifestyle modification. In addition, it is essential to educate patients on the importance of adherence to PAP therapy and its impact on long-term complications.

Enhancing Healthcare Team Outcomes

Although patients are initially evaluated in the primary care office, a sleep specialist should be included in the healthcare team early on. Polysomnography with an arterial blood gas study and assessment of pulmonary function testing is recommended as soon as there is suspicion for OSA/OHS. Evaluation of other potential causes of the presentation merit consideration. Care should be coordinated with the patient, spouse, or family members to ensure adequate adherence to PAP therapy and nutritionists, nurses, and case managers in the event of hospitalization.



(Click Image to Enlarge)
A polygraph depicting the relationship between increased airway resistance during respiratory events and increased end-tidal CO2 (PETCO2) and alternating periods of hypoventilation and hyperventilation corresponding to hypopnea and hyperpnea respectively throughout sleep. Abbreviations: Psg, supraglottic pharyngeal pressure; Pmask, mask pressure; PETCO2, end-tidal CO2; SaO2, Oxygen saturation using pulse oximetry; Peso, esophageal pressure; PETO2, end-tidal O2.
A polygraph depicting the relationship between increased airway resistance during respiratory events and increased end-tidal CO2 (PETCO2) and alternating periods of hypoventilation and hyperventilation corresponding to hypopnea and hyperpnea respectively throughout sleep. Abbreviations: Psg, supraglottic pharyngeal pressure; Pmask, mask pressure; PETCO2, end-tidal CO2; SaO2, Oxygen saturation using pulse oximetry; Peso, esophageal pressure; PETO2, end-tidal O2.
Contributed by Abdulghani Sankari, MD, PhD (courtesy to M. Safwan Badr, MD)
Article Details

Article Author

Pranita Ghimire

Article Author

Abdulghani Sankari

Article Editor:

Pratibha Kaul

Updated:

5/1/2022 9:04:13 AM

PubMed Link:

Pickwickian Syndrome

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