Obesity Research & Clinical Practice (2008) 2, 251—262

ORIGINAL ARTICLE

Weight reduction improves sleep, sleepiness and metabolic status in obese sleep apnoea patients Pia Nerfeldt a,∗, Bengt Y. Nilsson b, Liliana Mayor b, Joanna Uddén c, Stephan Rössner c, Danielle Friberg a a

Department of Clinical Science, Intervention and Technology, Division of Ear, Nose and Throat Diseases, Karolinska Institute, Karolinska University Hospital-Huddinge, SE-141 86, Stockholm, Sweden b Department of Clinical Neuroscience, Division of Clinical Neurophysiology, Karolinska Institute, Karolinska University Hospital-Huddinge, SE-141 86, Stockholm, Sweden c Department of Medicine, Huddinge, Division of Endocrinology, Karolinska Institute, Karolinska University Hospital-Huddinge, SE-141 86, Stockholm, Sweden Received 22 August 2008; accepted 24 August 2008

KEYWORDS Sleep apnoea; Obstructive sleep apnoea; Sleep disorders; Sleepiness; Sleep quality; Sleep architecture; Sleep state; Sleep pattern; Arousal index; Obesity; Weight loss; Weight reduction; Diet; Nocturnal respiration; Polysomnography;

Summary Method: In this prospective intervention study, 33 obese patients with obstructive sleep apnoea syndrome (OSAS) (24 men, 9 women) were consecutively enrolled for a weight reduction program at the Obesity Unit, Karolinska University Hospital. 23 of 33 patients used OSAS-device, 19 with Continuous Positive Airway Pressure and 4 with Mandibular Retaining Device. The patients were investigated with questionnaires, blood tests and ambulant nocturnal polysomnography before and after a 6-month program. Patients with OSAS-device slept without it during the sleep studies. The intervention consisted of 8 weeks low calorie diet and group meetings, followed by a day-care program of behaviour change support. Results: 27 of 33 patients (82%, 21 men and 6 women) completed the study. After the intervention there were highly significant decreases (p < 0.001) in Body Mass Index from mean(S.D.) 40(5) to 34(3), apnoea—hypopnoea index from 43(24) to 26(20) and Epworth Sleepiness Scale (ESS)-score from 9(4) to 6(4). Sleep quality (arousal index, sleep efficiency, percentage deep sleep) and metabolic status (blood pressure, blood glucose levels, lipidemia) were also significantly improved. There was a significant correlation between increased percentage deep sleep and reduced ESS-score. There were no differences due to gender or use/no use of OSAS-device.

∗ Corresponding author at: Karolinska University Hospital-Huddinge, ORL-dept B53, SE-141 86 Stockholm, Sweden. Tel.: +46 8 58580000; fax: +46 8 7467551. E-mail address: [email protected] (P. Nerfeldt).

1871-403X/$ — see front matter © 2008 Asian Oceanian Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.

doi:10.1016/j.orcp.2008.08.001

252 Diabetes mellitus; Glucose; Pre-diabetes; Dyslipidemia; Blood pressure; Hypertension

P. Nerfeldt et al. Conclusion: The results suggest that weight loss, induced by low calorie diet and behaviour change support, significantly improves nocturnal respiratory parameters, sleep quality, daytime sleepiness and metabolic status in obese OSAS patients after 6 months. © 2008 Asian Oceanian Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.

Introduction Obstructive sleep apnoea syndrome (OSAS) and obesity are considerable health problems by themselves and in combination they cause increased morbidity and mortality, particularly in cardiovascular diseases [1—12]. OSAS and snoring are also shown to predispose for insulin resistance and the metabolic syndrome [13—16]. OSAS has a prevalence of about 4% in males, and 2% in females [17]. The intermittent obstruction of the pharynx during sleep causes apnoeas and arousals resulting in sleep fragmentation and poor sleep quality [18,19] often in combination with an apparent daytime sleepiness [20]. Obesity, defined as Body Mass Index above 28 kg/m2 , is present in 60—90% of OSAS patients [21]. Fat disposition around the pharynx, as well as in the thorax and abdomen is actually considered a major cause of OSAS [22,23]. The treatment of obese OSAS patients is a challenge since the compliance is insufficient and the disease often is life-long. The effects of weight reduction of obese OSAS patients are not fully evaluated. Previous studies have shown that decreased body weight improves the apnoea frequency in a short-term perspective [24—27]. Reduction of the upper airway collapsibility [28] and increased size of the upper airway passage [29] are seen after weight reduction. There is a paucity of randomized control studies and such studies are called for [30]. Treatment methods including surgical intervention with the use of different types of gastric banding are increasingly used [31]. These methods show good results on indexes of sleep apnoea [29,32—34] but they also involve increased risk of complications and even mortality [35]. The conservative dietary weight reduction is a far more secure method, but in general it is not considered equally successful in a long-term perspective. The method of low calorie diet (LCD) in combination with behavioural modifying therapy has been investigated in previous studies. Lojander et al. [36] and Kajaste et al. [37] showed reduction in both weight and nocturnal respiration index. However, in these studies sleep quality was not investigated with polysomnography. Interest in OSAS patients’ impaired sleep quality and sleep fragmentation is increasing. In particu-

lar, focus is on the amount of deep sleep because it is considered to have an important restorative function [38]. For example, in a review article from 2000 Barvaux et al. [39] put the relationship between weight loss and sleep architecture in OSAS patients on the research agenda. This issue has previously been investigated by Noseda et al. [24], who evaluated patients treated with either dietary or surgical methods. In their study the average maintained weight loss was 3.4 kg in the dietary group at a one-year follow-up. The authors found a significant improvement on stage shift index (SSI), but none of the other sleep quality parameters, available with the polysomnography, showed significant changes. However, their inclusion criteria were wide and they used several types of intervention, and therefore their results are not straightforward and difficult to interpret. During 1999, obese OSAS male patients were included in a randomized controlled pilot study at the Obesity Unit, Karolinska University Hospital [40]. The intervention for weight reduction was 8 weeks of LCD ( 0.05). The same seven parameters were evaluated for gender differences. The men (n = 24) and women (n = 9) showed no significant differences in percentage weight reduction or BMI reduction. However, the data showed that the women lost less weight in kilograms compared to the men, which was the only observed gender difference. The Spearman rank correlation test showed a significant positive correlation between reduction in

BMI and AHI, r = 0.47 (p < 0.05), see Fig. 4, but not between AHI and ESS or arousal index. Further there was a significant negative correlation between changes in ESS-score and percentage deep sleep, r = −0.45 (p < 0.05), Fig. 5. In baseline data there was a significant correlation between the percentage body fat and baseline AHI, r = 0.41 (p < 0.05). In addition, there was a significant negative correlation between age and baseline sleep efficiency, r = −0.45, as well as between age and baseline total sleep time, r = −0.45 (both p < 0.05). There were no further significant correlations between metabolic and sleep apnoea parameters. Different treatment success levels (per protocol analysis) are presented in Table 3. The LCD treatment was well tolerated by all participants and there were no medical complications, i.e., no renal or other side effects. Out of

OSAS and weight reduction

257 Table 3 Different criteria of success were used for the results after 6 months’ weight reduction intervention (per protocol analysis)

Figure 4 Correlation between improvement in AHI and BMI reduction after the 6 months’ weight reduction intervention, (Spearman correlation (r) 0.47, p = 0.013).

the 9 diabetic patients, 1 was treated only with dietary restrictions and another patient dropped out, leaving 7 patients for evaluation. Six out of these seven patients could reduce their diabetes medication, and all insulin-treated patients, 3 out of the 7, could cease their injections. Out of the 14 pre-diabetics, 7 had normalized their glucose levels after the treatment period. The fP-glucose level was in mean reduced by 5.4%, and the fS-insulin

Figure 5 Correlation between the decrease of the ESSscore and the increase of percentage deep sleep after the 6 months’ weight reduction intervention, (Spearman correlation (r) −0.45, p = 0.02).

Success criteria

Success level (%)

Reduction of weight >10% Reduction of apnoea—hypopnoea index ≥ 50% and to a level of 0.05), see Table 1.

Discussion This study shows that the weight reduction program performed in groups of obese sleep apnoea patients reduced the degree of obesity as well as OSAS after 6 months. There were significant reductions in weight (in mean 17.7 kg, 14.2% from the baseline weight) and nocturnal respiration (in mean AHI 16, 34%), and the correlation between the two parameters was also significant. The significant correlation is well in line with the trend that each percentage weight reduction is associated with a three percentage reduction in AHI as shown by Young et al. [30]. In addition, the daytime sleepiness was significantly reduced and sleep quality, measured as arousal index, sleep efficiency, percentage deep sleep and total wake time, was significantly improved after the intervention. Interestingly, we found a significant correlation between increased percentage deep sleep and reduced ESS-score. Furthermore, metabolic status was significantly improved after treatment in terms of decreases in systolic as well as diastolic blood pressure, blood glucose levels, dyslipidemia and liver steatosis. There were no noteworthy differences in the baseline data among the subgroups, i.e., gender

258 and kind of other OSAS treatment (none, CPAP or MRD), and the subgroups also responded similarly to the dietary intervention. The only exception was the smaller weight loss for the women in comparisons with the men in terms of actual number of kilos. However, this gender difference was not found when the weight loss was calculated as ‘‘percentage weight reduction’’ or as ‘‘BMI’’, and can be explained by the women’s lower weight at start. Altogether, we conclude that there were no differences of clinical importance in results of the dietary intervention among the subgroups. Therefore, the results are presented as for one group. This conclusion agrees with data from Kajaste et al. [37], who reported no significant differences in weight loss between a randomized group given CPAP treatment in addition to weight reduction, and a group treated only with weight reduction. The term ‘‘sleep quality’’ has no strict definition and there are no defined criteria of success after intervention. Sleep quality can be assessed subjectively as a rating of how undisturbed and restorative the sleep has been. Objectively it can be measured as a series of parameters from polysomnographic recordings, most often as sleep efficiency but also as, for instance, arousal index. Furthermore, the subjective and objective measurements of sleep quality are not necessarily concordant. In the present study on OSAS patients we consider the significant decrease in arousal index and increase in sleep efficiency as important findings, since these parameters reflect the sleep fragmentation caused by the respiratory disturbances. At examination of also the other sleep parameters we found the percentage deep sleep to be significantly increased after the intervention. The increase in deep sleep is probably an effect of the reduced number of respiratory disturbances and arousals resulting in less sleep fragmentation. The deep sleep is known to be very important for the patient’s wellbeing, as for the heart rate, blood pressure, ventilation, metabolism and brain temperature decrease, all of which are crucial for the cerebral recovery [43]. In addition, there was a significant correlation between reduction of ESS-score and increase of percentage deep sleep. This correlation may be important, as it could reflect the mechanism of improvement in terms of daytime sleepiness after the intervention, that is, the increased deep sleep makes the patient feel less sleepy during the days. We would recommend sleep quality, especially in terms of arousal index and percentage deep sleep, to be calculated when evaluating OSAS treatment. In the present study, there was a significant decrease in respiratory disturbances but surpris-

P. Nerfeldt et al. ingly no significant correlations between changes in AHI/ODI to arousal index, sleep efficiency or daytime sleepiness. These results suggest that measuring only the changes in respiratory disturbances is not sufficient to explain the changes in symptoms, as it does not measure the restorative quality of the sleep. The effect of dietary weight reduction on sleep quality for obese OSAS patients has previously been reported only by Noseda et al. [24]. Their study combined several types of weight reduction interventions with the treatment of nasal congestion and CPAP. They showed a mean weight reduction of 3.4 kg in the dietary group, to be compared to our result of 17.7 kg. The single significant improvement in sleep architecture in their study was an improvement in stage shift index, which disagrees with our results of significant improvements in four other sleep architecture parameters. Noseda et al. made another interesting observation, which we could not reproduce; they found a significant correlation between changes in stage shift index and AHI. Possible reasons for our divergent results on sleep quality are: a limited number of patients, different types of interventions and degree of weight reduction. The success rate of our dietary treatment varies considerably depending on the different criteria. From a metabolic point of view, it has been shown that ten percent weight reduction has a positive influence on hypertension, glucose metabolism and dyslipidemias [44], and our findings of significant improvements in all these parameters agree with the previous results. With this weight reduction criterion, 81% of our patients were successfully treated. We also showed that 6 out of 7 treated diabetics decreased their medication as a result of improved glycaemic control. Furthermore, 14 patients, of whom 9 were diagnosed with cardiovascular disease, were discovered as pre-diabetics at baseline. The reduction of pre-diabetics was 50% at follow-up. When using a reduction of arousal index of at least 50% as a success criterion for sleep quality, the rate was 38%. Since the majority of the patients were already on treatment with CPAP and MRD, the baseline values of daytime sleepiness were not very high; the median level on the ESS was nine, which is generally not considered a pathological level [45]. The low baseline ESS-value could explain the small but significant reduction in sleepiness from median nine to six. Using the same success criteria as used by Kajaste et al. [37] in their weight reduction study on obese OSAS patients, i.e., a reduction of ODI4 ≥ 50%, our success rate was 43%, which is lower than theirs of 61%. Their study population had a somewhat

OSAS and weight reduction more severe degree of both obesity (mean BMI 44 as compared to ours of 40) and OSAS (mean ODI 51 as compared to ours of 42), and these differences could explain the differences between the success rates. Other possible explanations to the different results are that in the study by Kajaste et al. individual cognitive-behavioural therapy was used, which is a more standardized cognitive therapy mostly used by psychologists, while we used group discussions with behavioural change support run by a trained nurse. We purposefully used group therapy, because our experience is that group support is valuable, especially for patients who have both obesity and OSAS problems in common. The reason for the improved nocturnal respiration, sleep quality, daytime sleepiness and metabolic status after weight reduction in the present study is not fully understood, and is probably multi-factorial. Firstly, fat reduction may increase the lumen of the upper airways [46], thereby reducing the obstructive apnoeas and sleep fragmentation. It has been shown that OSAS patients have more fat in the lateral pharyngeal walls than non-OSAS patients, even if they have similar BMI [22,47,48]. The respiratory resistance from thoracic-abdominal fat is probably also reduced after weight reduction. Secondly, OSAS patients have hormonal and inflammatory imbalances; i.e., they have decreased levels of growth hormone [49], increased levels of cortisol [50], tumour necrosis factor alfa (TNF-alfa) and interleukin 6 (IL-6) [16], and these factors are shown to be influenced by impaired sleep quality [51,52]. The proinflammatory cytokines IL-6 and TNF-alfa are suggested to be mediators of daytime sleepiness [16,53]. There is also a reversed relationship as these factors can cause sleep disturbances, i.e., elevated evening cortisol secretion may promote sleep fragmentation [54,55], and raised levels of both IL-6 and cortisol together cause poor sleep [53]. With weight reduction, parameters of the metabolic syndrome (central obesity, hypertension, impaired glucose tolerance, dyslipidemia), from which these patients often suffer [12,14], were all significantly improved in this study. The metabolic syndrome itself may impair sleep quality, as it also affects the hormonal and inflammatory balance [16]. TNF-alfa and IL-6 correlate positively to Body Mass Index [15], and adipose tissue is shown to produce at least IL-6 [56]. By reducing fat, this may be a pathway to improved sleep quality. In addition, impaired sleep has been shown to cause obesity by hormonal imbalance of the appetite regulating leptin and ghrelin [57,58]. Thus, the obese OSAS patients are in a vicious circle, and weight

259 reduction is an important treatment with several possible mechanisms to improve general health and sleep. There are several weaknesses in our study, and the first is the lack of a randomized control group. However, we considered that our weight reduction program was already evaluated in a randomized controlled pilot study, which showed a significant weight reduction of in median 18.5 kg compared to 3 kg in the control group. Moreover there was a significant correlation between reduction in kg and ODI-values [40]. We therefore decided to continue with a simpler design in this study, more similar to the clinical situation. A second weakness in our study was the mixture of patients with and without OSAS-device (CPAP and MRD) and the limited number of patients in each group, i.e., only four in the group with MRD. Therefore, the statistical calculations were made between two groups, one with and one without device. However, this was justified since there were no major differences in baseline data between the patients with CPAP and MRD. The population in this study reflected the patient flow at the Obesity Unit. A majority had other OSAS treatment, and we did not want to exclude them from this program. However, this mixture may have caused an increased variability in the results. On the other hand, the statistical calculations between the groups with or without device did not show any significant differences. Thirdly, we did not restrain the patients from their treatment of CPAP or MRD for more than the registration night, since we considered that being without effective treatment could be a health risk. Thus, a remaining effect from the device cannot be ruled out, such as for example reduced mucosal oedema, systemic inflammation and ventilatory instability. On the other hand, Phillips et al. have shown an immediate return of the majority of the hypopnoea—apnoeas already after one night’s withdrawal of CPAP [59]. Further, in the present study the same procedure was used both at baseline and evaluation, and all subjects were adapted to the device since at least 3 months at study start. Fourthly, we did not have total control over possible confounding factors that may have influenced sleep quality and sleepiness during the study period. Such factors could be the number of hours per night the patients used their device as well as changes in their social and psychological status. Fifthly, the evaluation time was only 6 months and weight reduction is an unstable status, which needs to be followed for a longer period. Therefore we will re-evaluate the patients after 2 years. The strengths of the present study are firstly that the drop-out rate was quite low (18%), considering

260 the effort and devotion a lifestyle modification like this program demands. Secondly, the weight reduction program was surprisingly effective in reducing weight, improving symptoms and sleep, as well as highly tolerated and safe. Thirdly, there was a broad evaluation of different parameters, i.e., daytime sleepiness, nocturnal respiration, sleep quality and metabolic status, including laboratory blood sampling, blood pressure as well as bioelectrical impedance analysis. Fourthly, the fact that we included different patient groups, both with or without devices, gave us an opportunity to evaluate whether this had any influence on the weight reduction and other parameters. One could assume that patients with devices would have more energy to focus on the weight reduction program and therefore succeed better than those without. In the present study this could not be shown, which could be explained in part by the fact that there were small differences in daytime sleepiness at study start between these patient groups. Fifthly, the general applicability in the present study, as the included patients represented a mixed population, with different gender, age, with or without devices. In the clinical situation, we recommend treating well-motivated obese OSAS patients with weight reduction in group therapy. There are several benefits from a reduced weight, including improved nocturnal respiration, sleep quality and metabolic status, as well as reduced daytime sleepiness. The long-term effects of the intervention are of great interest in future research.

Conflict of interests Co-author Stephan Rössner has previously consulted for Cederroths AB, providing the Nutrilett® LCD.

Acknowledgements Financial support: The research fund of Acta Oto-laryngologica, Provider of the Nutrilett® LCD: Cederroths AB, Statistical assistance: Johan Bring, Statisticon, Nurses at the Obesity Unit at the Endocrinology-department: Lena Mannström, Maria Klingvall, Gunilla Åkerlund and at the department of Oto-rhino-laryngology: Lisbeth Blidberg, Neurophysiology technicians at the Department of Clinical Neurophysiology: Magdalena Aguirre and Ulrika Arnersten, Secretary at the department of Oto-rhino-laryngology: Eva Lundholm Larsson.

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Weight reduction improves sleep, sleepiness and metabolic status in obese sleep apnoea patients.

Weight reduction improves sleep, sleepiness and metabolic status in obese sleep apnoea patients. - PDF Download Free
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