Continuing Education Activity
The management of Pickwickian syndrome is challenging and complex. The clinical presence of disease should be suspected and defined 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.
- Describe the etiology of Pickwickian syndrome.
- Outline the pathophysiology of Pickwickian syndrome.
- Review the evaluation and treatment options for Pickwickian syndrome.
- Explain interprofessional team strategies for improving care coordination and communication to detect Pickwickian syndrome early and improve outcomes.
Obesity hypoventilation syndrome (or Pickwickian syndrome) is defined as the presence of awake alveolar hypoventilation characterized by daytime hypercapnia (arterial PCO2 greater than 45 mm Hg [5.9 kPa]) that is thought to be a consequence of diminished ventilatory drive and capacity related to obesity (BMI over 30) in the absence of an alternate neuromuscular, mechanical or metabolic explanation for hypoventilation. Individuals with a body mass index (BMI) of 35 or higher are at risk for obesity hypoventilation syndrome.
Obesity hypoventilation syndrome is thought to be a consequence of diminished ventilatory drive and capacity related to obesity. The load on the respiratory mechanics and blunting of the ventilatory response to carbon dioxide in obese individuals, especially the markedly obese, is thought to result in the characteristic daytime hypercapnia. Obesity hypoventilation syndrome is considered a diagnosis of exclusion, i.e., in the absence of an alternative neuromuscular, mechanical, or metabolic explanation for hypoventilation.
More than a third of the current population of the United States is obese. With increasing obesity prevalence, despite inadequate population estimates, the prevalence of obesity hypoventilation syndrome is assumed to be on the rise. The prevalence of obesity and morbid obesity (BMI greater than or equal to 40) among adults in the United States has increased from 35.1% to 37.7% and 6.5% to 7.7%, respectively, between 2011 to 2012 and 2013 to 2014. 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. 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. If half of the morbidly obese have obstructive sleep apnea (OSA) and 10% to 20% of the morbidly obese patients with OSA have OHS, then the estimated prevalence of OHS in the adult population would be 0.35% to 0.70% or approximately 1 in 150 to 1 in 300 adults. In one study of hospitalized patients with a BMI over 35 kg/m2, the prevalence of OHS was 31 percent.
Obesity hypoventilation syndrome results from the combination of the mechanical load on the respiratory pump leading to low tidal volumes and blunting of the chemoreflex to carbon dioxide leading to inappropriate central respiratory effort in those with marked obesity. This situation manifests from a complex interaction between multifactorial mechanisms, which are as follows:
- Sleep-disordered breathing: Obesity-related mechanisms like altered mechanics and impaired ventilatory control do play a role in promoting hypoventilation during wakefulness, but changes in gas exchange are most prominent during sleep. Sleep-disordered breathing is a universal finding in obesity hypoventilation syndrome and can be present in the form of OSA or nonobstructive central hypoventilation. The resolution of hypercapnia in a substantial fraction of the patients by the implementation of positive airway pressure or tracheostomy has established obstructive sleep apnea as common pathogenesis leading to obesity hypoventilation syndrome. In patients with only OSA, the hyperventilation phase following the apneic phase serves to eliminate the retained carbon dioxide (CO2). If done inadequately and a net hypercapnia results, the kidney acutely retains some bicarbonate buffer which serves to blunt the hypercapnic respiratory drive in the next sleep cycle. This chronic accumulation of incremental CO2 leads to chronic alveolar hypoventilation, hypercapnia, and compensated respiratory acidosis.
- 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. 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. This restrictive pattern of breathing can also contribute to increasing the dead space ventilation by a predominantly lowered tidal volume and increased respiratory rate. It is unclear whether respiratory musculature in itself weakens in patients with OHS given the lack of studies on diaphragmatic performance and transdiaphragmatic pressures.
- Blunted respiratory drive: The blunted drive gives a supportive hand in the explanation of the maintenance of the hypercapnic state rather than the origin. Research has shown that patients with OHS do not augment their minute ventilation when forced to breathe hypoxic ambient air and also when rebreathing CO2. They are, however, able to voluntarily hyperventilate to eucapnia and these are also correctible with positive airway pressure.
- 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 CO2 load. Patients with OHS have found to have elevated leptin levels compared to eucapnic patients, suggesting leptin resistance. These levels drop after the treatment with positive airway pressure.
History and Physical
The typical presentation of the patient with obesity hypoventilation syndrome may take place 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. The patient with OHS may also be seen in the outpatient setting by a sleep specialist or pulmonologist. The typical patient is obese, with BMI over 35 posing a higher risk bracket, with hypersomnolence and daytime sleepiness. Other classic signs of OSA like snoring, nocturnal choking, apneas that are witnessed by the partner, early morning headaches, daytime fatigue, impaired concentration and memory, and some degree of dyspnea may also be reported by patients.
The physical exam may reveal an obese individual with a ruddy complexion, 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.
Obesity hypoventilation syndrome often remains undiagnosed until late in the course of the disease. Early recognition is important, 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.
- Hypercapnia: A sensitive screen for chronic hypercapnia is an elevated serum bicarbonate level (greater than 27 mmol/L), and almost all patients with OHS have elevated bicarbonate. This is not a specific test, however, and elevation can occur in several other diagnoses including vomiting, dehydration, medications, etc. Arterial blood gas (ABG) is the more definitive test for alveolar hypoventilation and defines hypercapnia as the partial pressure of arterial CO2 (PaCO2) greater than 45 mmHg.
- Hypoxemia: Suspected clinically and subsequently measured noninvasively through pulse oximetry, hypoxemia during wakefulness is not common in simple OSA and has to be confirmed by an ABG showing PaO2<70 mmHg. Another tool used in the evaluation of OSA and OHS is the polysomnogram where the oxygen nadir and percent time spent below saturation percent of oxygen (SpO2) of 90% is useful to shore up the diagnosis.
- Complete blood count: Polycythemia as a result of chronic hypoventilation and hypoxia may be present. Blood tests can rule out secondary causes of erythrocytosis and other mimicking diagnoses like hypothyroidism.
- Pulmonary function testing (PFT) and imaging: If hypercapnia is confirmed, other causes of this 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. PFTs are more relevant to rule out other pulmonary pathologies.
- Sleep study: Polysomnography with continuous nocturnal CO2 monitoring is the gold standard for the evaluation of OHS and is necessary to detect OSA with an apnea-hypopnea index (AHI) along with an index of severity. AHI is normal despite similar clinical presentation in the 10% of the OHS population without OSA. The nocturnal oximetry gives an idea of the oxygen nadir and percent time below SpO2 of 90%.
- Cardiac studies: These are for assessing right heart enlargement and failure secondary to pulmonary hypertension that develops late in the course of OHS. These include an electrocardiogram (EKG) and echocardiogram.
Treatment / Management
There are currently no established guidelines from leading societies on the treatment of obesity hypoventilation syndrome. Individual treatment modalities that target the various distinct underlying mechanisms include addressing the sleep-disordered breathing, weight loss and lifestyle modifications, surgical interventions for the same, and other pharmacotherapy.
Positive airway pressure (PAP) therapy (continuous positive airway pressure (CPAP) or bi-level positive airway pressure (BiPAP) are first-line therapy. 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 the vast majority of patients with OHS (90%) have coexistent OSA, CPAP is considered the initial modality of choice. In those with sleep-related hypoventilation and fewer obstructive events during sleep, BiPAP is the first choice.
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, BiPAP is chosen. BiPAP 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). Although comparative trials are lacking, most would consider BiPAP the mode of choice to augment ventilation in CPAP failure or intolerance. For initiation of BiPAP, an inspiratory positive airway pressure (IPAP) and expiratory positive airway pressure (EPAP) are independently titrated and set. The delta or the pressure difference is the driving pressure, which is the main contributor to CO2 elimination.
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. The various administration devices are the nasal mask, full-face mask, nasal pillows, and other hybrid masks. Patient education about the disease process, types of devices, and the necessity for PAP to prevent progression to complications and morbidity must be thoroughly addressed to maintain satisfactory adherence.
Noninvasive PAP is reasonable in patients who can protect their airway. 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. If using PAP, arterial blood gases should be monitored to ensure clinical improvement. For patients presenting to the hospital with acute worsening of chronic hypoxic hypercapnic respiratory failure, a decision about the mode of ventilation must be made based on the severity of the respiratory failure. A trial of noninvasive positive pressure ventilation, as an initial choice, can be afforded to an arousable patient with an intact gag and cough reflex. However, when patients cannot protect their airway, do not tolerate bi-level positive airway pressure, or do not improve quickly, early intubation should be a consideration.
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. 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.
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.
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, these interventions have been shown in various studies to demonstrate mixed efficacy for long-term improvement in OSA symptoms, AHI, and maintenance of weight loss. 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 but 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. 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. Therefore, it is a usual practice to initiate PAP therapy immediately after extubation postoperatively, especially since there is no compelling evidence of PAP therapy-induced anastomotic complications. 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 end up requiring PAP therapy as it targets just the sleep-disordered breathing but does not alter the pulmonary mechanics, respiratory drive, or the neurohumoral milieu. 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. 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 kept in mind. 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 in practice.
Central sleep apnea: Central sleep apnea (CSA) is defined by an intermittent reduced central drive to breathe. It is not a hypoventilation syndrome, but patients tend to hyperventilate. Patients with CSA are generally normocapnic or slightly hypocapnic on blood gas testing.
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. Patients usually have clues on neurologic examination suggestive of typical features of ALS, such as muscle weakness and fasciculations, and hyperactive deep tendon reflexes.
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 are common.
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.
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.
Diaphragmatic weakness/phrenic nerve injury: The diaphragm is the primary muscle responsible for inspiration and accounts for more than two-thirds of the ventilatory work in humans. The C3-C5 cervical nerve roots form the phrenic nerves, which directly innervate the diaphragm. Patients with diaphragmatic weakness develop orthopnea, shallow breathing, and often paradoxical movement of the chest wall and abdomen. There might be a history of trauma or other accompanying neurological features.
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, and they may be hemodynamically unstable along with neurological deficits up to coma in extreme cases.
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 also compromise respiratory mechanics by exerting a significant cephalad force on the diaphragm. Commonly, extrapulmonary chest wall restriction causes poor ventilatory reserve without overt respiratory failure. However, acute insults such as infection or sedating medications can upset this delicate balance and precipitate hypercapnic respiratory failure.
Obesity hypoventilation syndrome 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 the major cause of mortality being cardiovascular disease. 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. Higher hospitalization rates, intensive care unit admissions, and post-discharge long-term care are also seen at higher rates in OHS compared with eucapnic obese individuals.
In progressive or untreated OHS, biventricular heart failure, pulmonary hypertension, and volume overload are common. Patients with obesity hypoventilation syndrome 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 compared to nonhypercapnic patients with sleep-disordered breathing alone.
Referral to a sleep specialist for polysomnography and arterial and venous blood gas testing is pertinent.
Deterrence and Patient Education
As outlined in the management section, patient education should focus primarily on diet and lifestyle modification and compliance with PAP therapy, which are the cornerstone of management and prevention of progress to 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 and venous study are recommendations 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 as well as nutritionists, nurses, and case managers in the event of hospitalization.