Alternatively known as Pickwickian syndrome, after Joe, a fat, red-faced character in Charles Dickens’ The Pickwick Papers, obesity hypoventilation syndrome is characterized by bluish color in the lips, fingers, toes, or skin; reddish complexion; short thick neck and small airway passage in the mouth; and signs of right-side heart failure (edema of feet and legs, shortness of breath, feeling tired after little effort). It is characterized by excessive daytime sleepiness, falling asleep during the day, increased risk for accidents or mistakes at work, and depression-ed.

The term obesity hypoventilation syndrome (OHS) refers to the constellation of obesity and chronic hypercapnia that cannot be attributed to underlying cardiopulmonary disease. Recently, it has become apparent that patients with OHS have underlying respiratory sleep disorders that could provide a mechanism for the hypercapnic respiratory failure. While daytime arterial Pco2 levels might normalize in some patients with continuous positive airway pressure (CPAP) therapy alone,1,2 other individuals can require the addition of positive-pressure ventilation, suggesting that there are multiple pathophysiologic mechanisms that may lead to chronic hypercapnia.3 This article will review OHS and will present a case to illustrate a clinically useful algorithm for diagnosis and management that can result in normalization of Paco2.

Case Presentation

A 52-year-old woman with a history of fluid retention and severe obesity presented to the emergency department with increasing dyspnea for 2 months. She reported a long history of fluid retention and dyspnea that required treatment with furosemide. Symptoms progressed despite therapy, and for the preceding 2 weeks she had been unable to ambulate within her apartment. The night prior to admission, she fell asleep sitting in bed and awoke lying on the floor, unable to stand.

Examination in the emergency department revealed an awake woman resting comfortably in bed. Vital signs were normal, and her weight was measured at 570 pounds. The physical examination was limited by the extreme obesity, but severe 4+ edema was noted in both legs with bilateral lower-extremity cellulitis.

Respiratory evaluation also was limited by morbid obesity, but the patient was breathing comfortably and was able to speak in full sentences. Breath sounds were distant, but no wheezes were audible, and the expiratory phase of respiration was not prolonged. Oxygen saturation was assessed noninvasively by pulse oximetry and revealed severe hypoxemia with O2 saturation = 64%. Supplemental oxygen was administered and arterial blood gas analysis was obtained while the patient was breathing 60% oxygen. The data revealed severe chronic respiratory acidosis and hypoxemia with pH = 7.34, Paco2 = 63 mm Hg, Pao2 = 34 mm Hg, and Hco3 = 34 mEq/L.

The patient was intubated and mechanically ventilated. Ventilator parameters were set with the goal of normalizing both Paco2 and Hco3 concentration. Intravenous furosemide was administered, and a brisk diuresis ensued. Extubation was performed 2 weeks later following a 100-pound diuresis.

Following extubation, loud snoring was noted and the patient reported a history of severe daytime hypersomnolence. Pulmonary function studies revealed obstructive dysfunction, although the severity of disease was relatively mild (FEV1 = 62% predicted, FEV1/FVC = 64%). Evaluation of respiratory control revealed a markedly reduced ventilatory response to increasing Paco2 (0.5 L/min/mm Hg, normal >1.5). Nocturnal polysomnography revealed obstructive sleep apnea with an apnea-hypopnea index = 31. Treatment with CPAP was initiated. At a pressure of 16 cm H2O, there was no evidence for upper airway obstruction and oxygen saturation was normal, indicating that there was no central hypoventilation. Over the next 3 months, body weight continued to decrease to 350 pounds. Repeat arterial blood gas analysis revealed normalization of Paco2 = 40 mm Hg and serum Hco3 = 26 mEq/L.


The clinical presentation of patients with OHS is highly variable and ranges from outpatient evaluation of hypersomnolence and snoring to presentation to an intensive care unit with acute hypercapnic and hypoxemic respiratory failure. Each of these extremes poses different diagnostic challenges. In the outpatient setting, approximately 5% to 15% of patients will have chronic hypercapnia,4,5 thus screening of all subjects with arterial blood gas analysis is not generally performed. A reasonable approach is to evaluate arterial blood gases in selected patients based on elevation of serum bicarbonate concentration as assessed by routine chemistry analysis of venous blood. An elevated serum bicarbonate concentration may be a marker of renal compensation for chronic CO2 retention. In contrast, for patients presenting to an intensive care unit, hypercapnia is readily identified based on arterial blood gas analysis; but hypercapnia may be attributed to underlying cardiopulmonary disease, and treatment may be inappropriate. The most important clinical finding that suggests a diagnosis of sleep-disordered breathing is absence of signs and symptoms of underlying cardiac and/or pulmonary disease.

The patient described in the case study showed no evidence for dyspnea, she was able to speak comfortably, respiratory rate was normal, and lung examination revealed no abnormalities suggestive of obstructive lung disease. In fact, arterial blood gas analysis was performed only because of the hypoxemia that was incidentally noted on pulse oximetry.

The approach to evaluation and treatment of sleep-disordered breathing disorders also requires customization to the clinical condition of the patient. For individuals who are clinically stable, the initial diagnostic nocturnal polysomnography and subsequent treatment titration studies should be performed in the sleep laboratory. This approach maximizes the likelihood of choosing both the most appropriate treatment modality (CPAP versus bilevel ventilation) and the optimal pressure(s) and minimizes the likelihood of poor compliance with long-term treatment.

For patients who present in decompensated respiratory failure, the first priority must be to stabilize the patient’s condition; and intubation with mechanical ventilation may be required. Following intubation, a target value for Paco2 must be chosen to guide ventilator management. In the patient described in the case study, no prior history was available, and morbid obesity limited physical examination. Although COPD could not be excluded, examination was sufficient to determine that the severity of any underlying disease was likely inadequate to produce chronic hypercapnia. Based on these considerations, minute ventilation was increased using an assist-control mode until Paco2 normalized. This high level of ventilation was continued for several days until the Hco3 concentration also normalized. It is important not to try spontaneous breathing trials until this occurs, because an elevated Hco3 concentration will necessitate a recrudescence of hypercapnia in order to maintain a physiologic pH. Extubation can be considered once acid-base status returns to near normal, but either CPAP and/or bilevel ventilation should be available to treat the underlying sleep disorder. Overnight respiratory monitoring to guide therapy is best, but, if this is not available, bedside observation with saturation monitoring is an alternative. The pattern of oxygen desaturation can indicate the underlying ventilatory disorder: short 10- to 60-second episodes of desaturation are consistent with apnea/hypopneas, while prolonged desaturation is consistent with central hypoventilation. It is important to adjust supplemental oxygen therapy to a level that results in an oxygen saturation < 90% to: 1) prevent masking of desaturation; and 2) prevent oxygen-induced hypercapnia. Once the patient is stable, a referral to a sleep center can be made to optimize therapy.

Diagnosis and Treatment

Chronic hypercapnia may result from different types of sleep-disordered breathing, including obstructive sleep apnea syndrome (OSAS) and the sleep hypoventilation syndrome (SHVS).3 These disorders cannot be differentiated on patient presentation, and in many patients, both phenomena are present. A diagnostic/treatment algorithm can be used during nocturnal polysomnography to identify the specific respiratory sleep disturbances in a given patient.3 Because multiple types of respiratory abnormalities may coexist, the algorithm is designed to sequentially eliminate the different disorders so as to uncover the full spectrum of abnormality. The stepwise elimination of disorders is accomplished through therapy.

Berger KI et al. Obesity hypoventilation syndrome as a spectrum of respiratory disturbances during sleep. Chest. 2001; 20:1231-8. Reprinted with permission.

The algorithm3 (Figure 1) first addresses identification and treatment of upper airway obstruction by increasing CPAP to obliterate apnea and hypopnea. If persistent flow limitation is identified by a flattening of the inspiratory portion of the flow-time waveform, CPAP should be increased further until the inspiratory flow contour normalizes. If O2 saturation is adequate with CPAP therapy alone (ie, saturation > 90%), the patient is diagnosed with OSAS and treatment is prescribed at the pressure determined by the algorithm. If persistent O2 desaturation is noted despite treatment for upper airway obstruction, the patient is diagnosed with SHVS and nocturnal bilevel ventilation should be initiated. The expiratory airway pressure is set equal to the CPAP required for treatment of the upper airway obstruction, and the inspiratory airway pressure is increased until the O2 saturation is > 90%. If O2 saturation cannot be maintained at > 90% despite the addition of ventilation, either supplemental O2 or a mandatory respiratory rate can be prescribed.

We recently published a review of our laboratory’s experience utilizing this algorithm in patients with chronic daytime hypercapnia.3 In this study, 23 patients underwent NPSG on at least one occasion and had arterial blood gas analysis performed prior to and following initiation of either CPAP or nocturnal bilevel ventilation. The apnea-hypopnea index varied widely in these patients and ranged from 9 to 167 events per hour, indicating a spectrum of disease from severe SHVS (AHI 9) to OSAS (AHI 167). Using the algorithm, we targeted the underlying ventilatory abnormality (Figure 2). Paco2 remained unchanged in patients who were noncompliant with therapy but was corrected to near-normal values in compliant patients (from 57 ± 6 to 41 ± 4 mm Hg; P < 0.001). Analysis of the individual patient data revealed that approximately half the patients were diagnosed with OSAS and required therapy with CPAP alone, and half the patients were diagnosed with SHVS and required therapy with noninvasive bilevel ventilation in addition to CPAP.

Berger KI et al. Obesity hypoventilation syndrome as a spectrum of respiratory disturbances during sleep. Chest. 2001; 20:1231-8. Reprinted with permission.

Mechanism for Chronic Hypercapnia

Multiple mechanisms for chronic hypercapnia in patients with OHS have been suggested. They include: 1) primary central hypoventilation6; 2) abnormal pulmonary mechanics and work of breathing (mass loading effects)7,8; 3) elevated serum bicarbonate pool (blunted CO2 sensitivity)9,10; and 4) associated cardiorespiratory disease.11 All of these mechanisms can play a role in the development of chronic hypercapnia; specific contributions from each mechanism can vary between patients. Of note, the specific role of respiratory disturbances during sleep as a mechanism for development of chronic hypercapnia during wakefulness remains unclear.

All respiratory events (apnea, hypopneas, or sustained central hypoventilation) must be associated with transient acute hypercapnia during the event per se. In this setting, maintenance of average Pco2 at eucapnic levels during a full night of sleep requires compensation for the acute hypercapnia during the subsequent interevent period.12 Impaired compensation has been demonstrated, due to either blunted CO2 responsiveness with resultant reduction in interevent ventilation or reduction in the duration of the interevent ventilatory period.13,14 These abnormalities would predispose susceptible patients to awakening in the morning with persistent elevations in arterial Pco2.

Establishment of chronic hypercapnia during wakefulness still requires a second step, since patients may increase ventilation during the daytime, thereby excreting any excess CO2. A model of the respiratory system15 has demonstrated that acute hypercapnia during sleep-disordered breathing would initiate Hco3 retention. Although the magnitude of this retention during 1 night is likely to be small, the time required for excretion of Hco3 is longer than that for Pco2, and this small increase in Hco3 may not be fully excreted prior to the next period of sleep. Furthermore, elevated Hco3 concentration blunts respiratory drive, leading to further hypercapnia during sleep, eventually creating a self-perpetuating state of chronic hypercapnia. Thus, while persistence of elevated Hco3 defines the state of chronic hypercapnia, it also provides a mechanism for the development and perpetuation of this state through blunting of respiratory drive.10,15

This mechanism for development of chronic hypercapnia is applicable to any type of respiratory event, including repetitive short apneas/hypopneas as in OSAS and sustained periods of central hypoventilation as in SHVS. Obesity and underlying chronic lung disease would have an additive effect as they would further impair unloading of CO2, in accord with clinical observations that chronic hypercapnia is noted predominately in morbidly obese subjects and/or in subjects with mild to moderate COPD.


The case study highlights several important aspects of the medical evaluation and treatment of hypercapnic patients with sleep-disordered breathing. Careful clinical evaluation at the bedside and subsequently in the pulmonary laboratory can exclude underlying cardiopulmonary disease, even in critically ill patients. Chronic hypercapnia can occur in the presence of OSAS alone.1-3 A markedly reduced ventilatory response to increasing CO2 is frequently present, which impairs the compensatory response to apnea/sleep-disordered breathing and predisposes patients to development of acute hypercapnia during sleep.13,16 A nocturnal polysomnography algorithm can be used to diagnose the specific underlying sleep disorder and determine optimal treatment.3


Chronic hypercapnia during wakefulness can occur as a complication of a variety of distinct pathophysiologic disturbances during sleep that cannot be distinguished clinically at time of presentation.3 Treatment targeted at the specific underlying ventilatory disturbance can result in correction of hypercapnia.3 For patients with OSAS alone, hypercapnia can be corrected by treatment of upper airway obstruction using CPAP, indicating that the acute hypercapnia resulting from respiratory events during sleep can provide the basis for chronic sustained hypercapnia during wakefulness.1,2 For patients with SHVS, treatment of nocturnal O2 desaturation by bilevel ventilation can result in correction of chronic hypercapnia. Although underlying lung disease coexists with these disorders in some patients, its contribution to the development of chronic hypercapnia is variable.

Kenneth I. Berger, MD, is assistant professor of medicine, physiology, and neuroscience, New York University School of Medicine.


  1. Rapoport DM, Garay SM, Epstein H, et al. Hypercapnia in the obstructive sleep apnea syndrome. A reevaluation of the “Pickwickian syndrome.” Chest. 1986;89:627-35
  2. Sullivan CE, Berthon-Jones M, Issa FG. Remission of severe obesity-hypoventilation syndrome after short-term treatment during sleep with nasal continuous positive airway pressure. Am Rev Respir Dis. 1983;128:177-81.
  3. Berger KI, Ayappa I, Chatr-Amontri B, et al. Obesity hypoventilation syndrome as a spectrum of respiratory disturbances during sleep. Chest. 2001;120:1231-8.
  4. Laaban JP, Chailleux E. Daytime hypercapnia in adult patients with obstructive sleep apnea syndrome in France, before initiating nocturnal nasal continuous positive airway pressure therapy [see comment]. Chest. 2005;127:710-5.
  5. Kawata N, Tatsumi K, Terada J, et al. Daytime hypercapnia in obstructive sleep apnea syndrome [see comment]. Chest. 2007;132:1832-8.
  6. Severinghaus JW, Mitchell RA. Ondine’s curse—failure of respiratory center automaticity while awake. Clin Res. 1952;10:122.
  7. Rochester DF, Enson Y. Current concepts in the pathogenesis of the obesity hypoventilation syndrome: mechanical and circulatory factors. Am J Med. 1974;57:402-20
  8. Lopata M, Onal E. Mass loading, sleep apnea, and the pathogenesis of obesity hypoventilation. Am Rev Respir Dis. 1982;126:640-5.
  9. Goldring RM, Heinemann HO, Turino GM. Regulation of alveolar ventilation in respiratory failure. Am J Med Sci. 1975;269:160-70.
  10. Tenney SM. Respiratory control in chronic pulmonary emphysema: a compromise adaptation. J Maine Med Assoc. 1957;48:375.
  11. Bradley TD, Rutherford R, Lue F, et al. Role of diffuse airway obstruction in the hypercapnia of obstructive sleep apnea. Am Rev Respir Dis. 1986;134:920-4.
  12. Berger KI, Ayappa I, Sorkin IB, Norman RG, Rapoport DM, Goldring RM. CO2 homeostasis during periodic breathing in obstructive sleep apnea. J Appl Physiol. 2000;88:257-64.
  13. Berger KI, Ayappa I, Sorkin IB, Norman RG, Rapoport DM, Goldring RM. Postevent ventilation as a function of CO2 load during respiratory events in obstructive sleep apnea. J Appl Physiol. 2002;93:917-24.
  14. Ayappa I, Berger KI, Norman RG, Oppenheimer BW, Rapoport DM, Goldring RM. Hypercapnia and ventilatory periodicity in obstructive sleep apnea syndrome. Am J Respir Crit Care Med. 2002;166:1112-5.
  15. Norman RG, Goldring RM, Clain JM, et al. Transition from acute to chronic hypercapnia in patients with periodic breathing: predictions from a computer model. J Appl Physiol. 2006;100:1733-41.
  16. Garay SM, Rapoport D, Sorkin B, Epstein H, Feinberg I, Goldring RM. Regulation of ventilation in the obstructive sleep apnea syndrome. Am Rev Respir Dis. 1981;124:451-7.