The Obesity-Hypoventilation Syndrome Revisited
2001; Elsevier BV; Volume: 120; Issue: 2 Linguagem: Inglês
10.1378/chest.120.2.336
ISSN1931-3543
Autores Tópico(s)Respiratory Support and Mechanisms
ResumoThe obesity-hypoventilation syndrome (OHS) was originally described in 1955 in subjects with obesity, chronic daytime hypercapnia and hypoxemia, polycythemia, hypersomnolence, and right ventricular failure.1Achincloss JH Cook E Renzetti AD Clinical and physiological aspects of a case of polycythemia and alveolar hypoventilation.J Clin Invest. 1955; 34: 1537-1545Crossref PubMed Scopus (66) Google Scholar In 1956, Burwell et al2Burwell CS Robin ED Whaley RD et al.Extreme obesity with alveolar hypoventilation: a Pickwickian syndrome.Am J Med. 1956; 21: 811-818Abstract Full Text PDF PubMed Scopus (544) Google Scholar coined the term pickwickian syndrome for these patients because they resemble the messenger boy Joe in Charles Dickens' The Pickwick Papers. OHS is one of the many disease states associated with chronic hypercapnia and alveolar hypoventilation. Lung, neuromuscular, chest wall, and metabolic diseases need to be excluded prior to making a diagnosis of OHS.3Martin TJ Sanders MH Chronic alveolar hypoventilation: a review for the clinician.Sleep. 1995; 18: 617-634Crossref PubMed Scopus (63) Google Scholar The daytime hypoxemia and raised alveolar-arterial oxygen gradient found in patients with OHS suggest that ventilation-perfusion inequality as well as alveolar hypoventilation is important in this condition.4Barrera F Hillyer P Ascanio G et al.The distribution of ventilation, diffusion and blood flow in obese patients with normal and abnormal blood gases.Am Rev Respir Dis. 1973; 108: 819-830PubMed Google Scholar With increasing knowledge of the effects of obesity and sleep on respiration, ventilatory control during sleep, and sleep-disordered breathing syndromes, we should be able to further explore the pathogenesis of OHS. Early recognition of OHS patients is important because management options for them have increased substantially in the last few years. In this issue of CHEST (see page 369), Kessler et al have, in a prospective study, further defined a cohort of OHS patients and have identified differences between this group, those with “pure” obstructive sleep apnea syndrome (OSAS) and those with COPD and OSAS. The study shows that OHS patients were older, more obese, and by definition had more deranged daytime arterial blood gas values, more restricted lung function, more severe arterial oxygen desaturation during sleep, and had higher pulmonary artery pressures and pulmonary vascular resistance than the patients in the pure OSAS group. When comparing the OHS patients to the COPD plus OSAS patients, the former were more obese, had more deranged daytime arterial blood gas values, and more severe arterial oxygen desaturation during sleep then the latter group. Interestingly, the OHS, and COPD plus OSAS patients had similarly raised pulmonary artery pressure and raised pulmonary vascular resistance. Fifty-eight percent of the OHS patients, 36% of the COPD plus OSAS patients, and 9% of the pure OSAS patients had pulmonary hypertension defined as mean pulmonary artery pressure > 20 mm Hg. Twenty-six of the 34 OHS patients studied underwent nocturnal polysomnography, and 23 patients had OSAS with an apnea/hypopnea index> 20/h. Twelve of the 26 OHS patients studied with polysomnography had evidence of central hypopnea, although no quantitative measurements of respiratory effort were made. Kessler et al also show that there is no significant correlation between body mass index and daytime Paco2 and Pao2 in the three groups of patients. The three patient groups had, on average, severe OSAS with no between-group differences in the apnea index and the apena and hypopnea index. The study has limitations in defining the patient groups and in the methods of measuring pulmonary hemodynamics. For example, only 23 of the 34 OHS patients underwent all the study investigations, 7 of the OHS patients had chronic bronchitis, and pulmonary artery-wedge pressure was not measured. Therefore, some OHS patients may have had coexistent mild COPD, and left ventricular systolic or diastolic dysfunction may have contributed to the pulmonary hypertension found in these patients. The latter is particularly important because of the entity of “obesity cardiomyopathy.”5Alpert MA Hashimi MW Obesity and the heart.Am J Med Sci. 1993; 306: 117-123Crossref PubMed Scopus (170) Google Scholar Notwithstanding these criticisms, the study is well performed and in a large population confirms and adds to previous findings in these patient groups.6Leech JA Onal E Baer P et al.Determinants of hypercapnia in occlusive sleep apnea syndrome.Chest. 1987; 92: 807-813Crossref PubMed Scopus (73) Google Scholar7Kessler R Chaouat E Weitzenblum M et al.Pulmonary Hypertension in the obstructive sleep apnoea syndrome: prevalence, causes and therapeutic consequences.Eur Respir J. 1996; 9: 787-794Crossref PubMed Scopus (187) Google Scholar8Resta O Foschino Barbaro MP Bonfitto P et al.Hypercapnia in obstructive sleep apnoea syndrome.Neth J Med. 2000; 56: 215-222Crossref PubMed Scopus (56) Google Scholar9Rapaport DA Garay SM Epstein H et al.Hypercapnia in the obstructive sleep apnea syndrome: a reevalution of the “Pickwickian syndrome.”.Chest. 1986; 89: 627-635Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar Clinically, the major “take home” messages are as follows: (1) OHS patients have high prevalence of OSAS in addition to nocturnal hypoventilation unrelated to upper-airway obstruction6Leech JA Onal E Baer P et al.Determinants of hypercapnia in occlusive sleep apnea syndrome.Chest. 1987; 92: 807-813Crossref PubMed Scopus (73) Google Scholar8Resta O Foschino Barbaro MP Bonfitto P et al.Hypercapnia in obstructive sleep apnoea syndrome.Neth J Med. 2000; 56: 215-222Crossref PubMed Scopus (56) Google Scholar9Rapaport DA Garay SM Epstein H et al.Hypercapnia in the obstructive sleep apnea syndrome: a reevalution of the “Pickwickian syndrome.”.Chest. 1986; 89: 627-635Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar; (2) pulmonary hypertension is uncommon in pure OSAS patients, especially in the presence of relatively normal daytime arterial blood gas levels6Leech JA Onal E Baer P et al.Determinants of hypercapnia in occlusive sleep apnea syndrome.Chest. 1987; 92: 807-813Crossref PubMed Scopus (73) Google Scholar; (3) patients with significant COPD plus OSAS and patients with OHS have a high prevalence of pulmonary hypertension7Kessler R Chaouat E Weitzenblum M et al.Pulmonary Hypertension in the obstructive sleep apnoea syndrome: prevalence, causes and therapeutic consequences.Eur Respir J. 1996; 9: 787-794Crossref PubMed Scopus (187) Google Scholar10Bradley TD Rutherford R Grossman RF et al.Role of daytime hypoxemia in the pathogenesis of right heart failure in the obstructive sleep apnea syndrome.Am Rev Respir Dis. 1985; 131: 835-839PubMed Google Scholar; (4) the severity of OSAS as measured by AI and AHI does not predict those patients with daytime hypercapnia and hypoxia, whatever the cause11Bradley TD Ruthreford R Lue F Role of diffuse airway obstruction in the hypercapnia of obstructive sleep apnea patients.Am Rev Respir Med. 1986; 134: 920-924Crossref PubMed Scopus (133) Google Scholar12Kreiger J Sforza E Apprill M Pulmonary hypertension, hypoxemia and hypercapnia in obstructive sleep apnea patients.Chest. 1989; 96: 729-737Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar; (5) patients with OHS have more profound arterial oxygen desaturation during sleep than pure OSAS patients and COPD plus OSAS patients8Resta O Foschino Barbaro MP Bonfitto P et al.Hypercapnia in obstructive sleep apnoea syndrome.Neth J Med. 2000; 56: 215-222Crossref PubMed Scopus (56) Google Scholar; and (6) COPD is not a prerequisite for the development of OHS.6Leech JA Onal E Baer P et al.Determinants of hypercapnia in occlusive sleep apnea syndrome.Chest. 1987; 92: 807-813Crossref PubMed Scopus (73) Google Scholar A number of questions come to mind regarding OHS, its pathogenesis, and relationship to sleep and OSAS. For example, why do a minority of obese subjects develop OHS? What are the relative contributions of abnormalities of chest wall mechanics, respiratory muscle fatigue, and of ventilatory drive in the development of OHS? What role if any does OSAS play in the pathogenesis of OHS? Can we prevent the development of OHS by recognizing those obese patients who are at risk? We do not know why only some obese subjects develop OHS, nor do we fully understand its pathogenesis, although it is almost certainly multifactorial in nature. Martin and Sanders3Martin TJ Sanders MH Chronic alveolar hypoventilation: a review for the clinician.Sleep. 1995; 18: 617-634Crossref PubMed Scopus (63) Google Scholar suggest that OHS is a mixed disorder of “can't breathe” (chest wall and respiratory muscle disorder) and “won't breathe” (decreased ventilatory drive disorder). Body weight per se does not correlate with chronic daytime hypercapnia, though weight loss in OHS patients can reverse daytime hypercapnia.13Garay SM Rapaport DM Sorkin B et al.Regulation of ventilation in the obstructive sleep apnea syndrome.Am Rev Respir Dis. 1981; 124: 451-457PubMed Google Scholar14Sugerman HJ Fairman PR Sood RK et al.Long-term effects of gastric surgery for treating respiratory insufficiency of obesity.Am J Clin Nutr. 1992; 55: 597S-601SPubMed Scopus (279) Google Scholar The increased respiratory system elastance and flow-resistive loads seen in obesity do not correlate with the degree of daytime hypercapnia, and some patients with OHS can voluntarily hyperventilate and normalize their Paco2 when requested to do so.15Sharp JT Henry JP Sweany SK et al.The total work of breathing in normal and obese men.J Clin Invest. 1964; 43: 728-739Crossref PubMed Scopus (229) Google Scholar16Leech J Onal E Aronson R et al.Voluntary hyperventilation in obesity hypoventilation.Chest. 1991; 100: 1334-1338Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar Reduced chest wall compliance seen in OHS patients can lead to increased energy cost of breathing and reduction in inspiratory muscle strength, maximum voluntary ventilation, and maximal inspiratory pressures.17Rochester DF Enson Y Current concepts of the obesity-hypoventilation syndrome.Am J Med. 1974; 57: 402-420Abstract Full Text PDF PubMed Scopus (204) Google Scholar18Lopata M Onal E Mass loading, sleep apnea, and the pathogenesis of obesity hypoventilation.Am Rev Respir Med. 1982; 126: 640-645PubMed Google Scholar However, weight loss in OHS patients is associated with increased maximum voluntary ventilation, FVC, and reduced Paco2, with little change in respiratory system compliance17Rochester DF Enson Y Current concepts of the obesity-hypoventilation syndrome.Am J Med. 1974; 57: 402-420Abstract Full Text PDF PubMed Scopus (204) Google Scholar and Pankow et al19Pankow W Hijjeh N Schuttler F et al.Influence of noninvasive positive pressure ventilation in obese subjects.Eur Respir J. 1997; 10: 2847-2852Crossref PubMed Scopus (97) Google Scholar have shown that noninvasive positive-pressure ventilation unloads the inspiratory muscles in patients with OHS. These results emphasize the role of respiratory muscle fatigue in patients with OHS. Ventilatory control is abnormal in OHS patients, with blunting of both hypercapnic and hypoxic ventilatory responsiveness.20Zwillich CW Sutton FD Pierson DJ et al.Decreased hypoxic ventilatory drive in the obesity-hypoventilation syndrome.Am J Med. 1975; 59: 343-348Abstract Full Text PDF PubMed Scopus (212) Google Scholar This does not mean that the abnormal ventilatory responses cause the physiologic abnormalities, as they may be secondary phenomena. Indeed, treating OHS patients with either weight reduction, tracheostomy, or nocturnal positive-pressure support improves daytime hypercapnia and hypoxia without changing the abnormal ventilatory responses in some patients.9Rapaport DA Garay SM Epstein H et al.Hypercapnia in the obstructive sleep apnea syndrome: a reevalution of the “Pickwickian syndrome.”.Chest. 1986; 89: 627-635Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar In recent years, leptin, a hormone that acts on the hypothalamus to suppress appetite has been shown to be variably increased in obesity.21Considine RV Sinha MK Heiman ML et al.Serum immunoreactive-leptin concentrations in normal-weight and obese humans.N Engl J Med. 1996; 334: 2292-2295Crossref Scopus (5547) Google Scholar Studies22Tankersly C Kleeberger S Russ B et al.Modified control of breathing in genetically obese (ob/ob) mice.J Appl Physiol. 1996; 81: 716-723PubMed Google Scholar in genetically obese mice (ob/ob) have shown that genetic determinants related to the ob locus influence hypercapnic ventilatory responsiveness prior to the emergence of obesity. Treating the genetically obese mouse with leptin attenuates the respiratory complications of the obese phenotype.23Tankersly CG O'Donnell C Daood MJ et al.Leptin attenuates respiratory complications associated with the obese phenotype.J Appl Physiol. 1998; 85: 2261-2269PubMed Google Scholar Indeed obese mice lacking circulating leptin also exhibit respiratory depression and increased Paco2, and treatment with leptin increased awake and asleep minute ventilation independently of food intake, weight, and carbon dioxide production.24O'Donnell CP Schaub CD Haines AS et al.Leptin prevents respiratory depression in obesity.Am Rev Respir Crit Care Med. 1999; 159: 1477-1484Crossref PubMed Scopus (346) Google Scholar These authors postulate that leptin deficiency and/or resistance may play a role in the pathogenesis of conditions with disordered control of breathing such as OHS.25O'Donnell CP Tankersley CG Polotsky V Leptin, obesity and respiratory function.Respir Physiol. 2000; 119: 163-170Crossref PubMed Scopus (41) Google Scholar In normal subjects, ventilation during nonrapid eye movement sleep decreases by 10 to 15% when compared to wakefulness, and in rapid eye movement sleep the changes in ventilation compared to wakefulness are variable.26Douglas NJ White DP Pickett CK et al.Respiration during sleep in normal men.Thorax. 1982; 37: 840-844Crossref PubMed Scopus (321) Google Scholar27White DP Weil JV Zwillich CW Metabolic rate and breathing during sleep.J Appl Physiol. 1985; 59: 384-391Crossref PubMed Scopus (122) Google Scholar Becker et al28Becker HF Piper AJ Flynn WE et al.Breathing during sleep in patients with nocturnal desaturation.Am J Respir Crit Care Med. 1999; 159: 112-118Crossref PubMed Scopus (214) Google Scholar have recently shown that minute ventilation in OHS patients is decreased by 21% in nonrapid eye movement sleep and by 39% in rapid eye movement sleep compared to wakefulness, with the majority of the decreased ventilation due to reduced tidal volume. They suggest that in patients with OHS, hypoventilation is an important factor in the genesis of nocturnal hypoxia and that treating the hypoventilation should be a major therapeutic strategy in these patients. The role of OSAS in the genesis of OHS is unclear, and OHS can occur without significant OSAS.14Sugerman HJ Fairman PR Sood RK et al.Long-term effects of gastric surgery for treating respiratory insufficiency of obesity.Am J Clin Nutr. 1992; 55: 597S-601SPubMed Scopus (279) Google Scholar The majority of patients with OHS, however, will also have evidence of nocturnal upper-airway obstruction, but a causal relationship between OSAS and OHS has not been found to date.8Resta O Foschino Barbaro MP Bonfitto P et al.Hypercapnia in obstructive sleep apnoea syndrome.Neth J Med. 2000; 56: 215-222Crossref PubMed Scopus (56) Google Scholar13Garay SM Rapaport DM Sorkin B et al.Regulation of ventilation in the obstructive sleep apnea syndrome.Am Rev Respir Dis. 1981; 124: 451-457PubMed Google Scholar Hypercapnic and hypoxic ventilatory responsiveness in pure OSAS patients have not been well studied, and most studies have assessed these in OSAS patients with daytime hypercapnia.10Bradley TD Rutherford R Grossman RF et al.Role of daytime hypoxemia in the pathogenesis of right heart failure in the obstructive sleep apnea syndrome.Am Rev Respir Dis. 1985; 131: 835-839PubMed Google Scholar12Kreiger J Sforza E Apprill M Pulmonary hypertension, hypoxemia and hypercapnia in obstructive sleep apnea patients.Chest. 1989; 96: 729-737Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar However, the literature available29Gold AR Swartz AR Wise RA et al.Pulmonary function and respiratory chemosensitivity in moderately obese patients with sleep apnea.Chest. 1993; 103: 1325-1329Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar30Berthon-Jones M Sullivan CE Time course of change in ventilatory responses to CO2 with long-term CPAP therapy for obstructive sleep apnea.Am Rev Respir Dis. 1987; 135: 144-147PubMed Google Scholar does suggest that ventilatory responses are reduced in obese patients with OSAS relative to obese patients without OSAS and nasal continuous positive airway pressure in OSAS patients improves hypercapnic ventilatory responsiveness. However, only about 10 to 15% of patients with OSAS have coexisting daytime hypercapnia and hypoxia, and chronic daytime hypoxemia appears to be a requirement for the development of right-heart failure in patients with OSAS.7Kessler R Chaouat E Weitzenblum M et al.Pulmonary Hypertension in the obstructive sleep apnoea syndrome: prevalence, causes and therapeutic consequences.Eur Respir J. 1996; 9: 787-794Crossref PubMed Scopus (187) Google Scholar Is it possible from our current knowledge to speculate about a unifying concept for the pathogenesis of OHS? As noted previously, these patients are susceptible to obesity-related respiratory muscle fatigue that may be worsened by coexistent OSAS or increased upper-airway resistance during sleep. In addition, they may either lack circulating leptin and/or have receptor insensitivity to circulating leptin with consequent decreased hypercapnic ventilatory responsiveness. These two mechanisms of “can't breathe” and “won't breathe,” should they coexist in OHS, would explain the chronic hypoventilation. We need to identify OHS patients earlier rather than later in their illness and to inform our colleagues about this interesting condition. Early recognition of these patients is important, as appropriate therapy will improve their physiologic and clinical parameters.3Martin TJ Sanders MH Chronic alveolar hypoventilation: a review for the clinician.Sleep. 1995; 18: 617-634Crossref PubMed Scopus (63) Google Scholar14Sugerman HJ Fairman PR Sood RK et al.Long-term effects of gastric surgery for treating respiratory insufficiency of obesity.Am J Clin Nutr. 1992; 55: 597S-601SPubMed Scopus (279) Google Scholar Current therapeutic options available for OHS patients are weight loss, continuous positive airway pressure, or bilevel pressure support ventilation, with or without supplemental oxygen, and repeated polysomnography studies may be required to optimize therapy.14Sugerman HJ Fairman PR Sood RK et al.Long-term effects of gastric surgery for treating respiratory insufficiency of obesity.Am J Clin Nutr. 1992; 55: 597S-601SPubMed Scopus (279) Google Scholar31Sullivan 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. 1982; 128: 177-181Crossref Scopus (126) Google Scholar32Clinical indications for noninvasive positive pressure ventilation in chronic respiratory failure due to restrictive lung disease, COPD, and nocturnal hypoventilation: consensus conference report.Chest. 1999; 116: 521-534Abstract Full Text Full Text PDF PubMed Scopus (737) Google Scholar The challenge for the future is to be able to identify those obese individuals prone to OHS and to prevent its development.
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