Clinical Investigations

Clinical Heterogeneity among Patients with Obesity Hypoventilation Syndrome: Therapeutic Implications
Luis A. Pérez de Llano^a, Rafael Golpe^a, Montserrat Ortiz Piquer^a, Alejandro Veres Racamonde^a, Manuel Vázquez Caruncho^a, María J. López^a, María Carmen Fariñas<sup>b

a</sup>Respiratory Division and Sleep Disorders Unit, Hospital Xeral-Calde, Lugo, and
^bDepartment of Internal Medicine, Hospital Universitario Marques de Valdecilla, Santander, Spain

Address of Corresponding Author

Respiration 2008;75:34-39 (DOI: 10.1159/000105460)

 Outline

• Key Words
• Abstract
• Introduction
• Materials and Methods
• Patients
• Measurements
• Study Protocol
• Statistical Analysis
• Results
• Baseline Characteristics
• Results of the NIPPV Group
• Results of the CPAP Group
• Discussion
• References

• Author Contacts
• Article Information
• Publication Details
• Drug Dosage / Copyright

  Key Words

• Obesity hypoventilation syndrome
• Pickwickian syndrome
• Sleep apnea
• Noninvasive mechanical ventilation
• Continuous positive airway pressure

  Abstract

Background: Obesity hypoventilation syndrome (OHS) can be treated with noninvasive positive pressure ventilation (NIPPV). Once clinical stability is achieved, continuous positive airway pressure (CPAP) can be recommended in many cases. However, some patients respond only partially to CPAP and NIPPV is a better option for them. Objectives: To assess treatment effectiveness in 2 groups of patients: those who could be switched to CPAP after polysomnographic titration and those who required NIPPV. Methods: A prospective study of 24 OHS patients was conducted, 11 were treated with CPAP and 13 with NIPPV. Morning and evening arterial blood gases were measured. Daytime and overnight oximetric recordings were performed. A post hoc analysis compared both groups. Results: Neither group exhibited deterioration on morning-to-evening blood gases. All patients in the CPAP group presented SaO₂ of less than 90% (CT90%) for <15% of the time on nocturnal and daytime recordings. In the NIPPV group, 8 patients had either daytime or nocturnal CT90% 15%. There were no intergroup differences regarding age, body mass index, Epworth scale values or PaO₂/PaCO₂ prior to treatment. FVC in the NIPPV group was lower than in the CPAP group (p = 0.01). Apnea-hypopnea index was higher (56 ± 23 vs. 36 ± 23, p = 0.049) and baseline CT90% was lower (76 ± 19% vs. 92 ± 14%, p = 0.03) in the CPAP group. Conclusions: Two patient subtypes can be identified. Those controlled with CPAP have better spirometry and a significantly higher apnea-hypopnea index. None of these patients showed daytime hypoxemia and all exhibited satisfactory overnight oxygenation. However, 61% of the NIPPV group had suboptimal oximetry results. Nocturnal/diurnal oximetries should be made to assess treatment efficacy in stable OHS patients who fail to achieve good control with CPAP.

Copyright © 2007 S. Karger AG, Basel

 Introduction

Obesity hypoventilation syndrome (OHS) is a clinical entity characterized by the coexistence of obesity and hypercapnia during wakefulness [1]. Although its prevalence is currently unknown, hypoventilation has frequently been seen to complicate severe obesity in hospitalized adults and is associated with excess morbidity and mortality [2]. In 2004 in France, OHS was recognized as the main cause of chronic respiratory failure requiring home noninvasive positive pressure ventilation (NIPPV) [3]. Surprisingly, little is known about the physiopathology of this entity and its definition remains controversial [4, 5]. Recently, we have shown that NIPPV therapy is effective in the treatment of patients with OHS, providing significant improvement in clinical status and gas exchange parameters [6]. We have also found that a second sleep study, performed once patients had stabilized, made it possible to maintain the condition of a significant number of patients by means of nasal continuous positive airway pressure (CPAP) therapy alone.

In clinical practice, arterial blood gas status is currently assessed by taking a single sample early in the morning and is the cornerstone of clinical decision making with respect to NIPPV efficacy in several conditions requiring said therapy. However, we have speculated that evening gas exchange values (immediately prior to CPAP or NIPPV) may decline compared to morning measurements (just after CPAP or NIPPV) in some patients with OHS, reflecting suboptimal control of the disease. Moreover, significant desaturations can be seen during exercise equivalent to the activities of daily living in patients without concurrent hypoxemia at rest. This finding was reported by Christensen et al. [7] in 17 patients with chronic obstructive pulmonary disease (COPD), albeit it has yet to be investigated in patients with OHS.

The purpose of this study was to assess daytime and overnight (during ventilatory support) gas exchange in 2 groups of OHS patients: those who could be switched to CPAP alone and those who continued to require NIPPV. Furthermore, it sought to identify parameters that could predict the presence of significant desaturation. Finally, a post hoc analysis was performed to compare baseline characteristics [age, body mass index (BMI), lung function, apnea-hypopnea index (AHI), Epworth sleepiness scale (ESS), PaO₂ and PaCO₂] in both groups at diagnosis.

 Materials and Methods

 Patients

Subjects were recruited from outpatient services at the Xeral-Calde Hospital, Lugo, Spain. They were diagnosed as having OHS from 2002 to 2005. Eligible patients met all of the following criteria at the time of diagnosis: (1) obesity with a BMI of >30; (2) hypercapnic respiratory failure (PaCO₂ 50 mm Hg and PaO₂ <60 mm Hg); (3) FEV₁/FVC ratio of 70%; (4) absence of any respiratory disorder that could account for gas exchange disturbances (such as kyphoscoliosis or diaphragmatic paralysis). Patients had been treated initially with NIPPV, using the same methodology as described in a previous cohort (fig. 1) [6]. Polysomnography was performed once they were clinically stable, 56.6 (18.4) days after the diagnosis. During a second nighttime sleep study, performed 134.2 (42.7) days after the first study, the final NIPPV settings were established. CPAP was initially tested in all patients. CPAP was adjusted with the aim of preventing periods of apnea and hypopnea during all stages of sleep. When oxygen desaturation persisted after apneas and hypopneas had been eliminated with CPAP, we changed to a bi-level positive pressure ventilation. The level of positive airway pressure that suppressed apneas and hypopneas was used during expiration and positive inspiratory pressure was gradually increased until oxygen saturation was steadily over 90% or high pressures (that is 20 cm H₂O) were reached. Oxygen was added when significant oxygen desaturation persisted despite the use of these high inspiratory pressures.

Fig. 1. Management of patients prior to inclusion in the study protocol. PSG = Polysomnography.

To be included in the study, patients had to be clinically stable for at least 4 weeks prior to the enrollment in the protocol. We selected the last 11 patients diagnosed as having OHS who were being treated with CPAP and the last 13 diagnosed cases who were receiving treatment with NIPPV, after polysomnographic titration. Mean time between the second polysomnographic recording study and the inclusion in the study was 572.7 (349.9) days. Written informed consent was obtained from all study participants.

 Measurements

Daytime sleepiness was evaluated according to the ESS questionnaire. Dyspnea was evaluated using the modified Medical Research Council dyspnea scale. We performed conventional spirometry with a 10-liter, closed-circuit spirograph, according to the American Thoracic Society/European Respiratory Society consensus [8]. The predicted values used were those of the European Respiratory Society [9]. Arterial blood samples were taken for gas level measurements with patients awake, seated and breathing environmental air in their rooms, and specimens were analyzed immediately (Ciba-Corning Diagnostics, Dietlikon, Switzerland). Transcutaneous oxygen saturation was measured with a pulse oximeter (Pulsox 3i; Minolta, Ramsey, N.J., USA). Mean nighttime and daytime SaO₂, percentage of recording time with SaO₂ <90% (CT90%) and the nocturnal desaturation index, defined as the number of dips in SaO₂ 4% per hour of recording time, were calculated using computer software (Pulsox SaO₂ analysis software DS-3; Minolta). All measurements were performed both at the time of initial diagnosis (prior to start of NIPPV) and at inclusion in the present study protocol, except for spirometry, performed only atdiagnosis, and daytime oximetry, which was only carried out at inclusion in the study protocol.

 Study Protocol

Patients were admitted to hospital for 24 h. Baseline characteristics (those observed at the moment of diagnosis, prior to treatment with NIPPV) were collected by reviewing the patients' Xeral-Calde Hospital charts. Current demographic data, respiratory symptoms and BMI were recorded prospectively. Arterial blood samples were drawn early in the morning (30 min after CPAP or NIPPV was removed) and again in the evening, just prior to initiating ventilatory support. Patients underwent 2 oximetric studies: during the night, while on the positive pressure device, and again during the day (10:00 to 22:00 h). Patients were encouraged to stroll for 3 h in the morning and evening and to climb stairs without becoming exhausted; participants were not allowed to sleep during the day. 'Suboptimal control' was arbitrarily defined as presenting CT90% during 15% of the recording time.

 Statistical Analysis

Unless otherwise indicated, all data are expressed as means with SD in parentheses or as percentages. Proportions were compared by Fisher's exact test. The average values of the 2 groups were compared using Student's ttest for unpaired data and, when applicable, 95% confidence intervals were calculated for descriptive analysis of the data. Comparisons between baseline and posttreatment data, and between daytime and nocturnal measurements were made by means of Student's ttest for paired data. Spearman correlation coefficients were used to assess the strength of associations with suboptimal control, and PaO₂, PaCO₂ and mean nighttime SaO₂ were used for each subject. A p value of 0.05 indicated significance for all statistical tests. These analyses were carried out using the statistical software package SPSS, version 10.0 for Windows (SPSS Inc., Chicago, Ill., USA).

 Results

 Baseline Characteristics

A total of 24 subjects participated in the study. Baseline data (at the time of diagnosis) for both groups of patients (those who could be switched to CPAP alone and those who required NIPPV) are shown in table 1.

Table 1. Comparison of baseline data between the NIPPV and CPAP groups

As expected in light of the inclusion criteria, hypoxemia was severe with a mean PaO₂ of 50.6 (7.1) mm Hg and all patients were hypercapnic, with a mean PaCO₂ of 58.8 (8.6) mmHg. There were no intergroup differences with respect to clinical characteristics such as age, BMI, ESS, PaO₂ and PaCO₂ prior to treatment. However, FVC and FEV₁ were lower in the NIPPV group (p = 0.014 and p = 0.017, respectively). Whereas baseline nocturnal mean SaO₂ was similar in the 2 groups, CT90% was significantly higher in the NIPPV group (p = 0.05). In contrast, AHI was significantly higher in the CPAP group (p = 0.049). None of the patients included in the study had a significant number of central apneas during sleep.

 Results of the NIPPV Group

Thirteen patients treated with NIPPV after polysomnographic titration agreed to participate. The mean age was 61 (14) years (range 31-79 years). Prior to polysomnographic titration, the most commonly used NIPPV modality was bi-level positive pressure ventilation (12 patients). After titration, 11 patients were treated with a bi-level device, while the remaining 2 required volume-cycled ventilation. Supplemental oxygen was needed in 8 patients.

We detected no significant change in current versus baseline BMI, with values of 43.2 (7) and 43.6 (9), respectively (p = 0.85). There were no significant differences between morning and evening gas exchange parameters, specifically, morning PaO₂ was 66.3 (10.6) mm Hg and evening PaO₂ 65.7 (8.5) mm Hg (p = 0.87) and morning PaCO₂ was 44.3 (5.5) mm Hg and evening PaCO₂ 45.7 (2.6) mm Hg (p = 0.41). Overnight oximetric measurements, performed while the patient was on the positive pressure device, revealed a mean SaO₂ of 92.3% (2) and a CT90% of 14.8% (14.4). Daytime oximetries demonstrated a mean SaO₂ of 91.7% (1.7) and a CT90% of 18.2% (19.8). Eight patients presented either nocturnal or daytime CT90% 15% (table 2).

Table 2. Comparison of current data between the NIPPV and CPAP groups

None of the variables were seen to correlate significantly with daytime or nocturnal suboptimal control (CT90% 15%) and patients labeled as presenting suboptimal control did not differ significantly from those who exhibited CT90% <15% values in terms of dyspnea or daytime sleepiness.

 Results of the CPAP Group

Eleven patients treated with CPAP following polysomnographic titration were admitted to the study. The mean age was 63 (11) years (range 40-76 years). The mean pressure was 10.4 cm H₂O and none of the patients in this group required supplemental oxygen. Changing from NIPPV to CPAP did not imply deterioration of arterial blood gas values: PaO₂ shifted from 72.6 (6.9) to 68.9 (3.8) mm Hg (p = 0.6) and PaCO₂ went from 41.7 (2.2) to 41.6 (4.5) mm Hg (p = 0.8).

There was a significant decrease in current versus baseline BMI, with values of 40.7 (7.7) and 44.1 (8), respectively (p = 0.002). It must be noted, however, that BMI of patients in the CPAP group did not differ significantly from that of patients in the NIPPV group (p = 0.41). PaO₂ did not differ between morning and evening measurements, at 68.9 (3.8) and 69.1 (4.4) mm Hg, respectively (p = 0.4), nor did PaCO₂, at 41.6 (4.5) and 40.7 (5.1) mm Hg, respectively (p = 0.36). Overnight oximetric measurements, performed while the patient was using the CPAP device, exhibited a mean SaO₂ of 92.4% (1.2) and a CT90% of 5.2% (4.6). Daytime oximetries demonstrated a mean SaO₂ of 94.1% (1.2) and a CT90% of 1.7% (2.4). No cases of suboptimal control were found in this group.

As can be seen in table 2, patients in the CPAP group had significantly better results in several nocturnal/diurnal oximetry and gasometric parameters.

 Discussion

Relatively few articles have focused on the efficacy of NIPPV for patients with respiratory failure due to OHS [10,11,12,13,14,15,16,17]. Recently, we have demonstrated that this treatment is effective in both the acute and chronic treatment setting, providing sustained improvement of PaO₂ and PaCO₂. We have also found that a simple CPAP device is sufficient to achieve good clinical and gasometric control in a significant proportion of patients [6]. In the present study, we divided the patients with OHS into 2 groups with different severity of illness: those who could be switched to CPAP alone and those who continued to need NIPPV after polysomnographic titration. The objective was to assess the degree of control of the disease in each group. The results revealed that nighttime treatment with CPAP or NIPPV allows OHS patients to maintain adequate spontaneous ventilation throughout the day, as quantified by arterial blood gas values measured 12 h apart, immediately on awakening and just prior to onset of sleep. We have also determined nocturnal and daytime oxygen saturation and arbitrarily set a cutoff value for CT90% in order to assess the risk associated with significant desaturation. In the United Kingdom and Europe, desaturation below 90% for 30% of the nighttime has gained widespread acceptance as defining significant nocturnal desaturation in COPD research [18, 19]. However, in the United States, nighttime oxygen therapy is advocated for nocturnal desaturation that is less rigidly defined [20]. In the present study, patients with nocturnal or daytime CT90% >15% despite NIPPV treatment were classified as suboptimal control. We found that 8 patients in the NIPPV group (none in the CPAP group) had either a daytime or nocturnal CT90% >15%. Given that daytime PaO₂ was the best predictor of nocturnal hypoxemia in COPD [21] patients, we have attempted to identify gasometric predictors of suboptimal control; however, neither morning nor evening arterial blood gas values correlated with CT90%. Thus, direct assessment of nocturnal and daytime saturation by pulse oximetry is needed to identify suboptimal control cases.

It must be noted that the finding of suboptimal control did not imply greater dyspnea or daytime sleepiness in our patients. Certainly, the clinical implications of detecting significant desaturation in patients with OHS has yet to be elucidated. Future studies should address this question.

We do not know why some obese subjects develop respiratory failure while others do not, nor do we fully understand the pathogenesis of OHS, although it is almost certainly multifactorial. Ventilatory muscle dysfunction, abnormal load responsiveness, increased respiratory work and CO₂ production, impaired central respiratory drive and repeated airway occlusion during sleep are all possible pathophysiological components in this entity, but the precise contribution of each remains to be fully clarified [22,23,24]. Interestingly, we noticed that patients in the NIPPV group had significantly lower baseline FVC and FEV₁, but higher CT90% compared to patients from the CPAP group. In contrast, AHI in the CPAP group was significantly higher than in the NIPPV group. These results might reflect an intriguing possibility: the weight of the different pathophysiological mechanisms may vary in individuals with OHS. It seems that in some patients, severe obstructive sleep apnea syndrome might be a major contributor to OHS pathophysiology, with respiratory system mechanics playing only a minor role. These patients could be successfully treated with long-term CPAP. On the other hand, other patients might stand out as having moderate or severe restrictive pulmonary defects and considerable nocturnal desaturation with low AHI values. These patients would require long-term NIPPV. We admit that the sample size is small and conventional spirometry might not be the best way to explore the consequences of obesity on the respiratory system. Moreover, as a finding in a post hoc analysis, this hypothesis warrants additional investigation, and further systematic study of subjects with OHS, before and after treatment, will help to determine the contribution of each factor to respiratory failure in an individual patient.

Certain limitations of the present study must be addressed. One of them is the small patient cohort, too small to enable definitive conclusions to be drawn. However, the strict criteria used in recruiting patients for the study made it possible to include a homogeneous sample covering a wide range of obesity-induced respiratory disturbances. Our intention was to avoid confounding effects related to other respiratory disorders (like COPD) capable of producing gas exchange alterations; the obvious consequence was that fewer patients were admitted to the study. Another limitation is the theoretical variability in nocturnal desaturation between nights. This variability was demonstrated in COPD patients, both night-to-night and over a 3-week period of clinical stability [25]. However, in most obstructive sleep apnea syndrome patients, oxygen desaturation index variability is rather modest and screening can be reliably based on a single, 1-night recording [26].

Several conclusions can be drawn from this study. The group of patients treated with NIPPV exhibited worse pulmonary function and nocturnal saturation than patients who could be treated with CPAP after polysomnographic titration. In contrast, the latter group showed significantly higher AHI. Results of arterial blood pressures showed no deterioration during the day in both groups of OHS patients. Patients in the CPAP group are well controlled and do not need further testing. A proportion of patients from the NIPPV group showed suboptimal control, but the clinical importance of this condition is not clear.

  References

1.

Kessler R, Chaouat A, Schinkewitch P, et al: The obesity-hypoventilation syndrome revisited: a prospective study of 34 consecutive cases. Chest 2001;120:369-376.

2.

Nowbar S, Burkart KM, Gonzales R, et al: Obesity-associated hypoventilation in hospitalized patients: prevalence, effects, and outcome. Am J Med 2004;116:1-7.

3.

Pepin JL, Chouri-Pontarollo N, Orliaguet O, et al: Alveolar hypoventilation during sleep and domiciliary assisted ventilation. Rev Mal Respir 2005;22(1 Pt 1):113-125.

4.

Rabec CA: Obesity hypoventilation syndrome. What's in a name? (letter). Chest 2002;122:1498.

5.

Bandyopadhyay T: Obesity-hypoventilation syndrome: the name game continues. Chest 2004;125:352.

6.

Perez de Llano LA, Golpe R, Ortiz Piquer M, et al: Short-term and long-term effects of nasal intermittent positive pressure ventilation in patients with obesity-hypoventilation syndrome. Chest 2005;128:587-594.

7.

Christensen CC, Ryg MS, Edvardsen A, et al: Relationship between exercise desaturation and pulmonary haemodynamics in COPD patients. Eur Respir J 2004;24:580-586.

8.

Miller MR, Hankinson J, Brusasco V, et al: Standardisation of spirometry. Eur Respir J 2005;26:319-338.

9.

Quanjer PH, Tammeling GJ, Cotes JE, et al: Lung volumes and forced expiratory flows. Eur Respir J 1993;6(suppl):15-40.

10.

Shivaram U, Cash ME, Beal A: Nasal continuous positive airway pressure in decompensated hypercapnic respiratory failure as a complication of sleep apnea. Chest 1993;104:770-774.

11.

Waldhorn RE: Nocturnal nasal intermittent positive pressure ventilation with bi-level positive airway pressure (BiPAP) in respiratory failure. Chest 1992;101:516-521.

12.

Schafer H, Ewig S, Hasper E, et al: Failure of CPAP therapy in obstructive sleep apnoea syndrome: predictive factors and treatment with bilevel-positive airway pressure. Respir Med 1998;92:208-215.

13.

Piper AJ, Sullivan CE: Effects of short-term NIPPV in the treatment of patients with severe obstructive sleep apnea and hypercapnia. Chest 1994;105:434-440.

14.

Rabec C, Merati M, Baudouin N, et al: Prise en charge de l'obèse en dècompensation respiratoire: intérêt de la ventilation nasale à double niveau de pression. Rev Mal Respir 1998;15:269-278.

15.

Masa JF, Celli BR, Riesco JA, et al: The obesity hypoventilation syndrome can be treated with noninvasive mechanical ventilation. Chest 2001;119:1102-1107.

16.

De Lucas-Ramos P, de Miguel-Diez J, Santacruz-Siminiani A, et al: Benefits at 1 year of nocturnal intermittent positive pressure ventilation in patients with obesity-hypoventilation syndrome. Respir Med 2004;98:961-967.

17.

De Miguel Diez J, De Lucas Ramos P, Perez Parra JJ, et al: Analysis of withdrawal from noninvasive mechanical ventilation in patients with obesity-hypoventilation syndrome: medium term results. Arch Bronconeumol 2003;39:292-297.

18.

Chaouat A, Weitzenblum E, Kessler R, et al: Sleep-related O₂ desaturation and daytime pulmonary haemodynamics in COPD patients with mild hypoxaemia. Eur Respir J 1997;10:1730-1735.

19.

Chaouat A, Weitzenblum E, Kessler R, et al: A randomized trial of nocturnal oxygen therapy in chronic obstructive pulmonary disease patients. Eur Respir J 1999;14:1002-1008.

20.

Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease. American Thoracic Society. Am J Respir Crit Care Med 1995;152(suppl):S77-S120.

21.

Vos PJ, Folgering HT, van Herwaarden CL: Predictors for nocturnal hypoxaemia (mean SaO₂ < 90%) in normoxic and mildly hypoxic patients with COPD. Eur Respir J 1995;8:74-77.

22.

Berger KI, Ayappa I, Chatr-Amontri B, et al: Obesity hypoventilation syndrome as a spectrum of respiratory disturbances during sleep. Chest 2001;120:1231-1238.

23.

Leech J, Onal E, Aronson R, et al: Voluntary hyperventilation in obesity hypoventilation. Chest 1991;100:1334-1338.

24.

Yee BJ, Cheung J, Phipps P, et al: Treatment of obesity hypoventilation syndrome and serum leptin. Respiration 2006;73:209-212.

25.

Lewis CA, Eaton TE, Fergusson W, et al: Home overnight pulse oximetry in patients with COPD: more than one recording may be needed. Chest 2003;123:1127-1133.

26.

Fietze I, Dingli K, Diefenbach K, et al: Night-to-night variation of the oxygen desaturation index in sleep apnoea syndrome. Eur Respir J 2004;24:987-993.

  Author Contacts

Luis A. Pérez de Llano, MD
Respiratory Division, Hospital Xeral-Calde
c/Dr Ochoa, s/n
ES-27004 Lugo (Spain)
Tel. +34 982 246 852, Fax +34 982 296 281, E-Mail luis@ciberque.com

  Article Information

Received: November 3, 2006
Accepted after revision: April 26, 2007
Published online: July 6, 2007
Number of Print Pages : 6
Number of Figures : 1, Number of Tables : 2, Number of References : 26

  Publication Details

Respiration (International Journal of Thoracic Medicine)

Vol. 75, No. 1, Year 2008 (Cover Date: January 2008)

Journal Editor: Bolliger, C.T. (Cape Town)
ISSN: 0025-7931 (print), 1423-0356 (Online)

For additional information: http://www.karger.com/RES

  Drug Dosage / Copyright

Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.