Vgontzas AN, Papanicolaou DA, Bixler EO, Hopper K, Lotsikas A, Lin. HM, Klaes A ... tom as to the reported use of various pesticides, frequency of their use, and ...
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Effros and coworkers have made an important contribution that will likely permit a semiquantitative analysis of nonvolatile substances in respiratory lining fluid. If Julius Comroe were still with us, he might now comment: “It’s about time you guys settle down and figure out what you are measuring.” RICHARD W. HYDE, M.D. University of Rochester Medical Center Rochester, New York References 1. Mutlu GM, Garey KW, Robbins RA, Danziger LH, Rubenstein I. Pulmonary Perspective: collection and analysis of exhaled breath condensates in humans. Am J Respir Crit Care Med 2001;164:731–737.
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2. Effros RM, Wahlen K, Bosbous M, Castillo D, Foss B, Dunning M, Gare M, Lin W, Sun F. Dilution of respiratory solutes in exhaled condensates. Am J Respir Crit Care Med 2002;165:663–669. 3. Jayaraman S, Song Y, Vetrivel L, Shankar L, Verkman AS. Noninvasive in vivo fluorescence measurement of airway-surface liquid depth, salt concentration, and pH. J Clin Invest 2001;107:317–324. 4. Effros RM, Feng D, Mason G, Sietsema K, Silverman P, Hukkanen J. Solute concentrations of the epithelial lining fluid of anesthetized rats. J Appl Physiol 1990;68:275–281. 5. Adamson TM, Boyd RDDH, Platt HS, Strang LB. Composition of alveolar liquid in the foetal lamb. J Physiol (Lond) 1969;204:159–168. 6. Hunt JF, Fang K, Malik R, Snyder A, Malhotra N, Platts-Mills TAE, Gaston B. Endogenous airway acidification: implications for asthma pathology. Am J Respir Crit Care Med 2000;161:694–699. DOI: 10.1164/rccm.2201001
Sleep-Disordered Breathing and the Current Epidemic of Obesity Consequence or Contributing Factor? Sleep-disordered breathing (SDB) is an increasingly common chronic condition that is characterized by repetitive episodes of partial or complete upper airway obstruction during sleep. Although the natural history of SDB remains to be fully elucidated, generalized sympathetic nervous activation has been clearly implicated and population-based studies have demonstrated an independent association between SDB and cardiovascular disease (1). In the present issue of the AJRCCM, two separate well-documented studies (2, 3), both involving large sample sizes and careful assessments of SDB by full polysomnography, add to a growing body of recent evidence supporting the existence of a link between SDB and insulin resistance independent of the degree of obesity. For example, Vgontzas and coworkers (4) recently reported that fasting glucose and insulin levels were significantly higher in patients with SDB when compared with weight-matched control subjects. Similarly, a large population-based study in normoglycemic hypertensive men indicated a significant correlation between the variables of SDB and indices of glucose metabolism after adjusting for measures of central obesity (5). If confirmed, the existence of a link between SDB and insulin resistance would imply that respiratory dysfunction during sleep represents an independent risk factor for the so-called metabolic syndrome, i.e., the association of insulin resistance, obesity, and hypertension that is highly prevalent in modern society. Not all previous studies that have examined the association between SDB and abnormal glucose metabolism have had positive conclusions. In a cross-sectional study that tested middle-aged healthy volunteers for the presence or absence of SDB, Stoohs and colleagues (6) found that elevated insulin resistance in individuals with SDB was entirely dependent on body mass. These findings appeared to be in agreement with those of Davies and coworkers (7), who showed no significant hyperinsulinemia in sleep apneics and snorers when compared with control subjects individually matched for age, gender, body mass index, and smoking and drinking habits. It is noteworthy that both of these negative studies included a much smaller number of patients with SDB (n 15 in both studies)
than either the study by Punjabi and coworkers (n 93) (pp. 677–682) or the study by Ip and colleagues (n 185) (pp. 670– 676) in the present issue of the AJRCCM (2, 3). These previous studies may thus not have had the statistical power needed to detect an effect of SDB independent of degree of obesity. Evidence against an independent link between SDB and insulin resistance has also been derived from studies that have shown that treatment of SDB with continuous positive airway pressure (CPAP) failed to improve parameters of insulin-glucose regulation (8). Because the duration of CPAP treatment was short in all these studies, ranging from a single night to a maximum of 6 months, it is not surprising that insulin resistance associated with years of SDB and the attending alterations of metabolic and endocrine functions may not have been corrected by such a short-term intervention. In support of the hypothesis that correction of SDB by CPAP may have long-term beneficial metabolic effects are the findings that CPAP use decreases intra-abdominal visceral fat and normalizes leptin levels (9, 10). In obese diabetic patients with SDB, Brooks and coworkers (11) have reported a moderate improvement in insulin sensitivity after CPAP treatment. Taken together, the findings of Punjabi and colleagues and Ip and coworkers provide compelling evidence in favor of an independent association between SDB and insulin resistance. Importantly, Ip and associates (3) observe that the association between obstructive sleep apnea and insulin resistance is present even in nonobese subjects. Furthermore, these authors indicate that increases in the number of apnea or hypopnea per hour are associated with increases in markers of insulin resistance. A key feature from the work by Punjabi and colleagues (2) is the demonstration of a significant relationship between the severity of intermittent hypoxemia associated with respiratory events and the magnitude of reductions in glucose tolerance after adjusting for percent body fat, body mass index, and apnea-hypopnea index. Indeed, the presence of recurrent hypoxemia and abnormal nocturnal sympathetic output, which are well demonstrated hemodynamic properties of obstructive sleep apnea, has been proposed as the mediat-
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ing mechanism in the causal link between SDB and insulin resistance. As pointed out by Punjabi and coworkers (2), sleep loss achieved by bedtime curtailment in normal healthy young adults results in marked alterations of glucose metabolism and endocrine function (12), suggesting that sleep loss per se, in the absence of breathing abnormalities, may promote insulin resistance. The state of “sleep debt” is in itself associated with increased sympathetic nervous activity and there is preliminary evidence that sleep restriction increases the severity of SDB. Conversely, sleep disruption by frequent arousal, as occurs in SDB, is likely to result in an ever-accumulating sleep debt in these patients. Thus, a feedforward cascade of negative effects may be generated by the interaction between SDB and the accompanying sleep debt to not only worsen the sleep disorder itself, but also contribute to the development of adverse metabolic consequences such as insulin resistance, further weight gain, and diabetes. “Normal” sleep duration has decreased from approximately 9 hours in 1910 to an average of 7 hours today, and many individuals are in bed 5–6 hours per night on a chronic basis. Consistent with such short habitual bedtimes, time in bed in the patients who participated in the study by Punjabi and colleagues (2) was between 6.5 and 7 hours. Social pressures, and particularly the pressures of the working environment, impose such short bedtimes to an increasingly large number of individuals in western societies. It is likely that the prevalence and severity of SBD are increased by chronic sleep curtailment. The possibility that the current epidemic of obesity, diabetes, and SDB in the United States may be partly related to insufficient sleep has been recently recognized. The alarming increase in obesity, diabetes, and SDB represents a major public health problem, as a substantial proportion of these patients also have increased cardiovascular morbidity and mortality. Finally, it should be noted that compliance with CPAP treatment in patients with SDB is dismally low. On average, one third of patients are noncompliant with CPAP use. The development of better-tolerated novel treatments, grounded in an improved understanding of the complex interaction between SDB, insulin resistance, and obesity, is thus urgently needed and may have considerable implications for lowering the risk of adverse cardiovascular outcome in this patient population.
ESRA TASALI, M.D. EVE VAN CAUTER, PH.D. Department of Medicine University of Chicago Chicago, Illinois References 1. Peppard PE, Young T, Palta M, Skatrud J. Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med 2000;342:1378–1384. 2. Punjabi NM, Sorkin JD, Katzel L, Goldberg A, Schwartz A, Smith PL. Sleep-disordered breathing and insulin resistance in middle aged and overweight men. Am J Respir Crit Care Med 2002;165:677–682. 3. Ip SM, Lam B, Ng M, Lam WK, Tsang KW, Lam KS. Obstructive sleep apnea is independently associated with insulin resistance. Am J Respir Crit Care Med 2002;165:670–676. 4. Vgontzas AN, Papanicolaou DA, Bixler EO, Hopper K, Lotsikas A, Lin HM, Klaes A, Chrousos GP. Sleep apnea and daytime sleepiness and fatigue: related to visceral obesity, insulin resistance, and hypercytokinemia. J Clin Endocrinol Metab 2000;85:1151–1158. 5. Elmasry A, Lindberg E, Berne C, Janson C, Gislason T, Awadtageldin M, Boman G. Sleep-disordered breathing and glucose metabolism in hypertensive men: a population-based study. J Inter Med 2001;249:153–161. 6. Stoohs R, Facchini F, Guilleminault C. Insulin resistance and sleep disordered breathing in healthy humans. Am J Respir Crit Care Med 1996; 154:170–174. 7. Davies RJ, Turner R, Crosby J, Stradling JR. Plasma insulin and lipid levels in untreated obstructive sleep apnea and snoring: their comparison with matched controls and response to treatment. J Sleep Res 1994;3:180–185. 8. Smurra M, Philip P, Guilleminault C, Bioulac B, Gin H. CPAP treatment does not affect glucose-insulin metabolism in sleep apneic patients. Sleep Medicine 2001;2:207–213. 9. Chin K, Shimizu K, Nakamura T, Narai N, Masuzaki H, Ogawa Y, Mishima M, Nakamura T, Nakao K, Ohi M. Changes in intra-abdominal visceral fat and serum leptin levels in patients with obstructive sleep apnea syndrome following nasal continuous positive airway pressure therapy. Circulation 1999;100:706–712. 10. Ip SM, Lam KS, Ho C, Tsang KW, Lam WK. Serum leptin and vascular risk factors in obstructive sleep apnea. Chest 2000;118:580–586. 11. Brooks B, Cistulli PA, Borkman M, Ross G, McGhee S, Grunstein RR, Sullivan CE, Yue DK. Obstructive sleep apnea in obese noninsulin-dependent diabetic patients: effect of continuous positive airway pressure treatment on insulin responsiveness. J Clin Endocrinol Metab 1994;79:1681–1685. 12. Spiegel K, Leproult R, Van Cauter E. Impact of sleep debt on metabolic and endocrine function. Lancet 1999;354:1435–1439. DOI: 10.1164/rccm.2201008
Pesticide Exposure and Asthma Occupational exposures have been recognized as causes of asthma and asthma-like syndromes since the early 18th century (1). Recent estimates suggest that between 5% and 10% of asthma in young adults may be directly attributable to substances encountered at work (2). Among the occupational groups with the highest risk of asthma, one finds farmers and agricultural workers (2). Farmers and agricultural workers are exposed to various allergens of plant, animal, and chemical origin that are associated with classic IgE-mediated allergic asthma; to irritants that might aggravate pre-existent asthma or, at high doses, result in irritant-induced asthma; and to plant dusts (for example, grain and cotton dusts) that cause a nonallergic asthma-like syndrome (3). Although exposure to pesticides is common in both agricultural and nonagricultural settings (4), these have not featured prominently in lists of substances associated with occupational asthma (5).
In the current issue of the AJRCCM, Hoppin and colleagues (pp. 683–689) describe a cohort of 20,000 farmers, certified pesticide applicators, from Iowa and North Carolina, who participated in a study originally designed to look at cancer risk in relation to pesticide exposure (6). Among these mostly white male farmers, those who reported wheeze in the past year were compared with those not reporting this symptom as to the reported use of various pesticides, frequency of their use, and application techniques. Ever use of 11 of 40 pesticides, mostly insecticides and herbicides, was associated with a greater likelihood of reported wheeze, and for most of these, the likelihood of wheeze increased with the frequency of exposure in the last year. Some of the strongest associations were seen with application of insecticides to animals with methods in which the insecticide is aerosolized. We are told by the authors that these associations persisted after adjustment
