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* From the Division of Respiratory Rehabilitation (Drs. Patruno, Aiolfi, and Murgia), S. Marta Hospital, Rivolta d’Adda, "Ospedale Maggiore", Crema; and Department of Clinical Sciences (Drs. Costantino, Selmi, Malliani, and Montano), Internal Medicine II, L. Sacco Hospital, University of Milan, Milan, Italy.
Correspondence to: Nicola Montano, MD, PhD, Department of Clinical Sciences, L. Sacco Hospital, University of Milan, via GB Grassi 74, 20157 Milano, Italy; e-mail: nicola.montano{at}unimi.it
Abstract
Background: A strong association between obstructive sleep apnea (OSA) and the risk for cardiovascular and cerebrovascular diseases has been reported. Continuous positive airway pressure (CPAP) is the first-line therapy for OSA, able not only to reduce daytime sleepiness but also to improve cardiovascular and metabolic outcomes. Autoadjusting CPAP (APAP), an alternative treatment to CPAP, can reduce OSA symptoms while increasing long-term CPAP compliance without the high costs of CPAP titration. However, no data are available on the effects of APAP on cardiovascular risk factors
Methods: We performed standard full polysomnography; obtained plasma levels of glucose, insulin, and C-reactive protein (CRP); and measured systolic BP (SBP) and diastolic BP (DBP) in 31 patients with newly diagnosed, severe OSA. After standard CPAP titration, all subjects were randomized to CPAP or APAP treatment. Measurements were obtained at baseline and after 3 months of treatment.
Results: The two groups were similar in terms of age, sex, body mass index (BMI), and severity of OSA. SBP, DBP, heart rate (HR), homeostasis model assessment index (HOMA-IR), and CRP were similar in the two groups. After 3 months of treatment, BMI, HR, and compliance to therapy were also comparable. OSA indexes were significantly reduced in both groups. Significant reductions in SBP, DBP, and HOMA-IR were observed in the CPAP group but not in the APAP group, while CRP plasma levels were similarly reduced.
Conclusions: Our results suggest that CPAP and APAP, despite significant effects on OSA indexes and symptoms, do not improve cardiovascular risk factors in the same fashion.
Key Words: BP • continuous positive airway pressure • inflammation • insulin resistance • obstructive sleep apnea
In recent years, obstructive sleep apnea (OSA) syndrome has been linked to a higher relative risk for cardiovascular diseases such as arterial hypertension, congestive heart failure, arrhythmias, and sudden cardiac death.1234 Moreover, it has been reported5 that OSA is a risk factor for the development of metabolic syndrome.
Continuous positive airway pressure (CPAP) is the first-line therapy for OSA and has been reported to reduce not only OSA symptoms such as hypersomnolence and snoring, but also cardiovascular mortality and morbidity.67 This protective effect seems to be related to the efficacy of CPAP treatment in counteracting several cardiovascular risk factors.8 Indeed, findings support that CPAP therapy in patients with OSA is capable of reducing BP, C-reactive protein (CRP), and proinflammatory cytokines, while improving glucose control.91011 These results may in part be due either to the normalization of the breathing and the sleep patterns per se, or to the decrease in the adrenergic tone, mainly mediated by the reduction of hypoxia-related chemoreflex activation.12
A fundamental cornerstone in the treatment strategy of OSA is represented by the reduction of cardiovascular risk factors. The clinical implication of this consideration might lead to the treatment of OSA on the basis of not only apnea-hypopnea index (AHI) and hypersomnolence, but also of cardiovascular risk factors.
Autoadjusting CPAP (APAP) devices are a recent alternative treatment to traditional CPAP and are able to improve symptoms while reducing the high costs of CPAP titration.1314 However, different from CPAP, the impact of APAP therapy on cardiovascular and metabolic outcomes in OSA patients remains unknown, and a study15 has reported that APAP therapy may not be able to reduce diurnal arterial BP. Due to the increase popularity of APAP as an alternative to the traditional CPAP treatment, the aim of our study was to evaluate the effects induced by CPAP or APAP treatment on arterial BP, insulin resistance, and inflammation in patients with OSA.
Methods and Materials
Population Study and Baseline Measurements
We enrolled 40 consecutive patients with newly diagnosed OSA (AHI > 20/h, and diurnal hypersomnolence: Epworth sleepiness scale [ESS] score > 12) who were free of diseases other than arterial hypertension (n = 22) and had never been treated for OSA. Only angiotensin-converting enzyme inhibitors, calcium-channel blockers, and diuretic treatments were allowed. Informed consent was obtained from all patients, and the study was approved by the institutional ethics committee.
All subjects underwent a diagnostic cardiopulmonary sleep study (Embletta; Medcare Flaga; Reykjavik, Iceland) in the attended setting of the sleep laboratory in baseline conditions. Apneas (nasal cannula airflow cessation > 10 s); hypopneas (abnormal respiratory event with at least a 30% reduction in thoracoabdominal movement or airflow as compared to baseline lasting at least 10 s, and with > 3% oxygen desaturation); oxygen desaturations (drops in arterial oxygen saturation [SaO2] > 3%), SaO2 mean, SaO2 nadir, and cutoff time 90 (CT90) [total time with SaO2 < 90%] were evaluated according to the latest American Academy of Sleep Medicine recommendations.16 We analyzed each recording between sleep onset and awakening as derived from the sleep log of the patient and the sleep log of technician attending the study. The AHI refers to the number of apneas plus hypopneas per hour of recording. Oxyhemoglobin desaturation index (ODI) refers to the number of SaO2 drops > 3% from baseline. Average time (± SD) of the analyzed recordings was 6.8 ± 0.2 h.
Body mass index (BMI), ESS score, arterial BP, and heart rate (HR) were registered between 8 AM and 9 AM following full polysomnography (Heritage Grass; AstroMed; West Warwick, RI) for CPAP titration before administration of the usual antihypertensive drugs, if any. Arterial BP was measured using a pneumoelectric microprocessor-controlled instrument (Lifestat 200; Physio-Control Corporation, Medtronic Emergency Response Systems; Redmond, WA). The arterial BP value was calculated as the average of three consecutive readings during a 5-min period following 15 min of rest in a supine position. A venous blood sample for the measurement of fasting blood glucose (oxidase method), plasma insulin (radioimmunoassay), and plasma CRP levels was also collected at the time of awakening. The quantitative determination of high-sensitive CRP was done by latex particle-enhanced immunoturbidimetric assay. As an index of insulin resistance, we evaluated the Homeostasis Model Assessment Index (HOMA-IR) [glucose x insulin/22.5].
Experimental Protocol
Fixed CPAP titration was performed in the sleep laboratory using a standardized polysomnography procedure. Initial CPAP pressure was set at 4 cm H2O and then increased progressively by increments of 1 cm H2O until obstructive apnea, hypopnea, snoring, and flow-limited breathing associated with arousals disappeared. Obstructive events were identified by the presence of increased thoracoabdominal movements and/or paradoxes associated with abolition or decrease in instantaneous flow. Each titration procedure was obtained with the subjects reaching rapid eye movement sleep and sleeping supine. After CPAP titration, all subjects were randomized to receive either fixed-level CPAP (Somnoconfort; Weinmann; Hamburg, Germany) or APAP (Autoset T; ResMed; Sydney, Australia) for 3 months. This latter instrument works by administering variable CPAP levels, starting from a minimum of 4 cm H2O, and increasing pressure at a rate of 0.2 cm H2O per breath after automatic detection of flow limitation, evaluated as an average flow/time ratio below a conventional threshold value of 0.15. If snoring or apneas with a closed upper airway > 10 s appear without previous flow limitation, the system reacts by increasing the CPAP level more rapidly. Detection of apneas with open upper airway (identified by cardiac oscillations present on the flow signal) does not lead to CPAP increase. As unobstructed breathing is resumed, pressure is decreased toward 4 cm H2O with a time constant of 20 min. Reliability of this APAP device as an autoadjusting machine has been confirmed in previous studies.1718 Data relevant to the administered pressure and daily use are stored on a computer and may be retrieved. In this study, fixed CPAP was set at the level determined during titration study, while APAP was set so as to deliver pressure levels from 4 to 15 cm H2O.
At the end of the 3-month treatment period, data collected by the ventilatory devices were downloaded to evaluate their use and all subjects underwent a repeat cardiopulmonary sleep study in the attended setting of the sleep laboratory during APAP or CPAP treatment. The next day, after awakening between 8 AM and 10 AM, HR and arterial BP were evaluated and a venous blood sample (for measurement of CRP, glycemia, and insulin) was collected.
Thirty-one patients (25 men and 6 women; 17 patients with hypertension) completed the study protocol. Nine patients (eight men; five patients with hypertension; BMI, 35 ± 5 kg/m2, average age [± SD], 45 ± 7 years; ESS score, 13 ± 3; AHI, 45 ± 10/h) were excluded because they voluntarily withdrew from the study (n = 6) or had an inadequate compliance to therapy (average daily use < 4 h; n = 3).
Statistical Analysis
Data are expressed as mean + SD. Statistical analysis was performed using statistical software (Sigma Stat 3.0; Jandel Scientific; San Rafael, CA). Comparisons between variables recorded at the beginning and end of the study in each group were performed by paired Student t test; comparison between variables recorded in the two different groups was performed by unpaired Student t test. Two-way, repeated-measures analysis of variance was performed to evaluate differences considering interactions within both treatment and time. A p value < 0.05 was considered statistically significant.
Results
Baseline Measurements
Table 1
illustrates the characteristics of the study populations arrayed by OSA treatment. The two groups did not differ at baseline in terms of age, sex distribution, BMI, and severity of OSA (ie, AHI, ODI, SaO2 mean, SaO2 nadir, CT90, and ESS score). Hypertensive patients were equally distributed within the two groups (nine patients in the CPAP group and eight patients in the APAP group), and all were receiving diuretics and/or angiotensin-converting enzyme inhibitors as the sole treatment throughout the study. Systolic BP (SBP), diastolic BP (DBP), HR, HOMA-IR, and CRP were also similar in the two groups (Table 1). Finally, CPAP titration values were similar in the CPAP group and APAP group (10.8 ± 1.6 cm H2O vs 9.45 ± 1 cm H2O; p = not significant [ns]).
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AHI, ODI, SaO2 mean, SaO2 nadir, CT90, and ESS score were significantly reduced in both groups following 3 months of treatment (Table 2 ). However, AHI achieved with CPAP was significantly lower than that achieved with APAP (2 ± 1.6/h vs 6 ± 2.3/h; p < 0.001). Similarly, the ODI with CPAP was lower than with APAP (1.1 ± 1.3/h vs 4.8 ± 2.1/h; p < 0.001).
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This is the first study to support the different effects of CPAP and APAP treatment on cardiovascular risk factors in OSA patients. In our data, CPAP but not APAP was associated with a significant reduction in arterial BP and insulin resistance index after 3 months of treatment for OSA. Conversely, both treatments were able to reduce the inflammatory state that is known to be enhanced in OSA patients. These findings might be in part ascribed to a different efficacy of the two types of treatment in reducing apnea or desaturation indexes. Indeed, while adherence to both treatments was similar, the APAP group showed residual AHI and ODI slightly but significantly greater than the CPAP group. However, considering that the residual apneas were limited, the mechanisms responsible for the observed discrepancy remain to be clarified.
The relationship between OSA and cardiovascular risk factors, such as sympathetic activity, arterial BP, CRP levels, and insulin resistance15192021 is well established. In fact, several studies89112223 have reported the efficacy of CPAP not only in reducing apneas and hypersomnolence but also BP, CRP, insulin resistance, and sympathetic activity. Thus, CPAP treatment is capable of not only improving the quality of life in OSA, but also of providing a significant benefit in cardiovascular risk factors, possibly leading to the reported reduction of morbidity and mortality.7 However, the effect of CPAP in lowering arterial BP is still debated,24 and despite a recent study25 questioning the capability of CPAP of reducing arterial pressure, several other studies89222627 are supporting this hypothesis.
In OSA treatment, the use of APAP devices is progressively becoming more common, mainly due to the reduced cost of sleep laboratory titration in comparison with CPAP, despite achieving similar reductions in hypersomnolence and hypoxemia28 and similar compliance rates.17 APAP devices are based on the delivery of a positive airway pressure that is not fixed but variable during sleep, depending on the degree of upper-airway obstruction occurring during the different sleep stages and body positions.28 While several articles1728 have been published that evaluate the effects of APAP on sleep, OSA symptoms, and compliance, no data are available on the effects of long-term treatment with APAP on cardiovascular outcomes. Indeed, to our knowledge there are only two studies1529 reporting that APAP therapy did not decrease SBP and DBP in patients with OSA. However, one study15 evaluated only the acute 1-night effects on arterial pressure, while in the other study29 evaluated only 1 month of treatment in nonsleepy, hypertensive OSA patients.
The findings of our study assessing the effects of long-term CPAP treatment in OSA patients confirm what has been described in literature. Indeed, following CPAP treatment, a reduction in arterial pressure for both continuous beat-to-beat and 24-h ambulatory BP monitoring222326 as well as the reduction in insulin resistance and CRP levels were reported.1011 However, somehow surprisingly, we did not observe a significant reduction in BP and insulin resistance in the APAP group, while only CRP was consistently reduced by both treatments. The underlying mechanisms leading to these observations remain enigmatic. Intermittent hypoxemia has been strongly associated with the development of hypertension.3031 Both treatments in our study were effective in reducing the number of obstructive episodes, while the residual AHI and ODI were significantly higher in the APAP than in the CPAP group. This could be due to the APAP algorithm, allowing a more sliding control of obstructive events throughout the night. However, we noted that these indexes remained within what is generally considered an acceptable therapeutic range,32 thus not allowing to rule out that other mechanisms could be involved, such as sleep fragmentation. This has been demonstrated to determine an increased nighttime, but not daytime, arterial BP in canine models.33 It has also been reported that APAP is associated with an increased number of arousals during sleep34; since we did not analyze sleep patterns in the present study, we cannot rule out the possibility that the lack of reduction in arterial pressure of the APAP group might be in fact secondary to sleep fragmentation. However, CRP levels were significantly reduced by both treatments. As the CRP release is increased in hypoxemic conditions,35 we hypothesize that the similar effects on CRP levels might be due to the significant reduction in nocturnal intermittent hypoxemia observed with both treatments.
In conclusion, we hypothesize that the different effects of APAP compared to CPAP are due to intrinsic characteristics of the algorithm driving the automatic device. We further surmise that APAP might be more permissive in controlling obstructive respiratory events by lowering CPAP until an event occurs and then increasing pressure to bring such event under control, to perpetuate this cycle throughout the night. However, our work was not designed to address this issue, and ad hoc studies will be warranted to verify this hypothesis.
Limitations of the Study
We enrolled a limited number of patients with OSA in the present study. However, we submit that the original intent of our study was primarily exploratory, aimed at determining specific differences between the two treatments, while the discrimination of the best treatment in relation to a comprehensive set of clinical end points was beyond our aims. The present data may now provide the rationale for larger randomized clinical trials evaluating the effects of CPAP and APAP on cardiovascular morbidity and mortality of patients with OSA in a longitudinal fashion. In addition, we would like to underline that we evaluated two well-matched groups of patients, and the results obtained were highly consistent with the individual behaviors of the measured variables.
We did not measure sleep-stage variables in our subjects. However, this issue had already been addressed in other studies1332 demonstrating that both treatments were similar in normalizing OSA indexes and sleep fragmentation. Our main interest was to provide evidence of the similarity/dissimilarity of the two treatments based on the OSA scoring used in the clinical practice. Indeed, even assuming that the different effects of APAP were to be ascribed to some sleep fragmentation effect, this does not affect the clinical impact of our results.
Another possible limitation is represented by the fact that we used only one type of APAP device. Our results should be therefore regarded as limited to this specific device, since other APAP devices rely on different algorithms and might lead to different observations. We note, however, that the reason why we used the Autoset-T device is due to the fact that this is one of the most popular and most used devices, as well as the most quoted in literature1718 regarding APAP validation. Therefore, the results of our work are aimed to send a general warning in regards to the fact that CPAP and APAP treatments might be associated with different cardiovascular outcomes in OSA patients, notwithstanding a similar effectiveness in reducing apneas and hypopneas. This does not imply that APAP should be disregarded as a treatment option, based on its high potential in terms of cost-effectiveness. Quite interestingly, two very recent bench studies3637 evaluating the technical features of different APAP devices concluded that the available APAP devices work differently and that manufacturers should supply accurate information on algorithms to allow physicians to chose the best-tailored device for each patient. Accordingly, manufacturers should put greater effort in testing different algorithms for their automatic devices to obtain evidence for their efficacy in reducing not only apneas and hypopneas similar to CPAP, but also cardiovascular risk factors.
Conclusion
This is the first study to evaluate the effects of APAP on specific cardiovascular risk factors and to compare its effects on arterial pressure and insulin resistance from CPAP. We suggest that the two treatments, despite significant effects on OSA indexes and symptoms, do not appear to act on cardiovascular risk factors in the same fashion. This is important in the clinical practice when prescribing APAP for OSA treatment because it should be taken into account that there is still no solid and conclusive evidence that APAP is as efficient as CPAP in the intervention on major cardiovascular risk factors.
Acknowledgements
We thank the "Sleep Boys Group of Milan" for their helpful criticism.
Footnotes
Abbreviations: AHI = apnea-hypopnea index; APAP = autoadjusting continuous positive airway pressure; BMI = body mass index; CPAP = continuous positive airway pressure; CRP = C-reactive protein; CT90 = cutoff time 90; DBP = diastolic BP; ESS = Epworth sleepiness scale; HOMA-IR = homeostasis model assessment index; HR = heart rate; ns = not significant; ODI = oxyhemoglobin desaturation index; OSA = obstructive sleep apnea; SaO2 = arterial oxygen saturation; SBP = systolic BP
This work was supported by a University of Milan Fondo Interuniversitario per la Ricerca Scienfifica e Technologia Grant and a Minister for Instruction, University and Research Progetto di Ricerca di Interesse Nazionale 2003 grant to Dr. Montano.
The authors have no financial or other potential conflicts of interest to disclose.
Received for publication September 4, 2006. Accepted for publication January 13, 2007.
References
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