Annals of the American Thoracic Society

Rationale: Obesity hypoventilation syndrome (OHS) is an undesirable consequence of obesity. Weight loss is an important component of management based on clinical rationale, but the evidence supporting weight loss has not been summarized and the optimal approach has not been determined.

Objectives: This systematic review informed an international, multidisciplinary panel of experts who had converged to develop a clinical practice guideline on OHS for the American Thoracic Society. The panel asked, “Should a weight loss intervention be performed in patients with OHS?”

Methods: Medline, the Cochrane Library, and Embase were searched from January 1946 to March 2019 for studies that assessed weight loss interventions in obese adults with confirmed OHS, suspected OHS, or hypercapnia. The quality of the evidence was appraised using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach.

Results: The search identified 2,994 articles. Six studies were selected, including two randomized trials and four nonrandomized studies without a comparator. Sample size ranged from 16 to 63 subjects. The studies found that a comprehensive weight loss program (including motivational counseling, dieting, and exercise) can reduce weight by 6% to 7% but confers no clinically significant effects compared with standard care. Bariatric surgery, on the other hand, is associated with more robust weight loss (15–64.6%, depending on the type of intervention), reduction of obstructive sleep apnea severity (18–44% reduction of the apnea–hypopnea index), and improvement in gas exchange (17–20% reduction in partial pressure of carbon dioxide in the arterial blood), ultimately leading to the resolution of OHS. Moreover, daytime sleepiness and pulmonary artery pressure also improve with significant weight loss. Bariatric surgery is associated with adverse effects in roughly one-fifth of patients, but serious adverse effects are very rare. The level of certainty in the estimated effects was very low for most outcomes.

Conclusions: The guideline panel for which the systematic review was performed made a conditional (i.e., weak) recommendation suggesting a weight loss intervention for patients with OHS, targeting a sustained weight loss of 25% to 30% of actual body weight. This recommendation was based on very low-quality evidence. Although the weight loss target is based on the observation that greater weight loss is associated with better outcomes, there is a need for better-quality studies to ascertain the degree of weight loss necessary to achieve improvement in clinically relevant outcomes in patients with OHS.

Obesity hypoventilation syndrome (OHS) is defined as a combination of obesity (body mass index [BMI] ≥ 30 kg/m2), sleep-disordered breathing, and chronic daytime hypercapnia (partial pressure of carbon dioxide in the arterial blood > 45 mm Hg) in the absence of other known causes of hypercapnia (1). Most patients with OHS present with obstructive sleep apnea (OSA). The conditions frequently coexist, because obesity is the predominant risk factor for both; only 10% of patients with OHS do not have OSA but rather have nonobstructive sleep hypoventilation (24). OHS is prevalent and, if untreated, can lead to significant adverse outcomes. In high-risk groups of individuals, such as patients with obesity and OSA, the prevalence of OHS can range between 17% and 30% (5), leading to increased respiratory and cardiovascular morbidity and mortality (6). The prevalence of OHS is likely to increase globally with the increasing prevalence of severe obesity (79).

Obesity is a critically important risk factor for the development of OHS. Most treatment strategies for patients with OHS focus on treating sleep-disordered breathing (SDB) with positive airway pressure (PAP) therapy during sleep, as opposed to aiming to reduce the cardiovascular risk profile by targeting the underlying severe obesity. Despite adequate adherence to PAP therapy, multiple studies have shown that cardio-metabolic risk factors of severe obesity persist (1012), and cardiovascular morbidity and mortality remain high in patients with OHS (1315).

Weight loss interventions can have several benefits, including improvements in SDB and OHS, as well as improvements in cardiovascular and metabolic outcomes. There are a variety of strategies to achieve weight loss. Commercially available programs designed for weight loss tend not to be effective in the long term (16). Very intensive lifestyle interventions can lead to weight loss of approximately 10 kg in obese patients with type 2 diabetes or prediabetes without improving long-term cardiovascular outcomes, because the lost weight is often regained (17, 18).

Bariatric interventions are more effective than lifestyle interventions in achieving and sustaining significant weight loss that can ultimately improve cardiometabolic outcomes. Three commonly performed bariatric surgery procedures in the United States are sleeve gastrectomy, Roux-en-Y gastric bypass, and laparoscopic adjustable gastric banding (LAGB) (19, 20). Currently, sleeve gastrectomy is the most common bariatric surgical intervention; it was originally considered the first component of a two-stage biliopancreatic diversion with duodenal switch (BPD/DS) procedure, but it has proven to be an effective stand-alone bariatric procedure. The Roux-en-Y gastric bypass is the second most commonly performed bariatric surgery. Laparoscopic gastric banding is the least common; it is associated with lower perioperative morbidity but more modest weight loss at both short- and medium-term follow-up. Biliopancreatic diversion is another bariatric procedure that is reserved for the extremely obese (BMI > 60 kg/m2) and for those who have failed other bariatric operations. The safety profile of bariatric surgery has improved over the last three decades (21). Clinical trials of sleeve gastrectomy or gastric bypass surgery have reported significant improvements in metabolic (2224) and cardiovascular morbidities (25), as well as reductions in all-cause and cardiovascular mortality (26, 27). Given that most studies excluded patients with OHS or simply did not assess whether the enrolled patients had OHS makes it challenging to assess the impact of bariatric surgery on OHS.

The American Thoracic Society (ATS) recently developed clinical practice guidelines on the evaluation and management of OHS (28). The guideline panel asked, “Should a weight loss intervention be performed in patients with OHS?” This systematic review of the literature was performed to inform the recommendation that the guideline panel made to answer the question.

We adhered to standards described in detail in the Cochrane Handbook for Systematic Reviews of Interventions to perform this systematic review (29). The conduct of this systematic review was similar to our prior studies (30, 31). The systematic review was not registered because it was performed as a component of guideline development rather than standalone research. This systematic review and the guidelines on OHS were funded by the ATS.

Research Question

We used the population, intervention, comparator, outcome (PICO) format to address the guideline panel’s question, “Should a weight loss intervention be performed in patients with OHS?” Patients with OHS with or without OSA were defined as the population, the intervention as any type of weight loss intervention (i.e., dietary programs, bariatric surgery, etc.), and the comparator as no weight loss intervention. The guideline panel identified patient-important outcomes, prioritizing them using a 9-point Likert rating scale. Critical outcomes included resolution of OHS, mortality, weight change, and daytime sleepiness. Important outcomes included apnea–hypopnea index (AHI), awake hypoxemia, awake hypercapnia, pulmonary artery pressure, and adverse effects. A patient advocate was consulted regarding the appropriateness of the selected clinical outcomes.

Literature Search

The Cochrane Library and MEDLINE were searched for recently published, relevant systematic reviews. Given the absence of systematic reviews that addressed our question, we developed a search strategy to identify studies that evaluated bariatric surgery as a treatment for OHS (see Table E1 in the online supplement). We used a broad search strategy from January 1946 to June 2017 to identify both direct evidence and indirect evidence in MEDLINE (using the Ovid interface), EMBASE, as well as ClinicalTrials.gov for ongoing trials. Furthermore, the guideline panelists identified additional relevant studies that were not identified in the search.

Study Selection

A priori study selection criteria included 1) enrolled patients with known or suspected OHS with and without OSA, and 2) compared bariatric surgery of any type to no bariatric surgery. The type of studies included were randomized controlled trials (RCTs), nonrandomized comparative studies (i.e., prospective and retrospective cohort, case–control, before–after studies), and nonrandomized studies without a comparator (i.e., single-arm cohorts, case series with more than 20 patients). Case reports, case series with fewer than 20 patients, and animal studies were excluded. Other exclusion criteria were studies that enrolled nonobese patients, receiving invasive mechanical ventilation, patients with tracheostomy, or patients with interstitial lung disease, COPD, neuromuscular disease, and chest wall disorders. Our search included all types of bariatric surgery, including sleeve gastrectomy, Roux-en-Y gastric bypass, laparoscopic gastric banding, and biliopancreatic diversion. The outcomes were not criteria for selecting studies. Two authors selected studies in duplicate, and disagreements were addressed through discussion and consensus.

Data Extraction

We extracted data into a form developed specifically for this systematic review. The extracted information included the study setting and design, patient demographics, baseline characteristics, type of intervention, duration of follow-up, outcomes, and risk of bias on the basis of the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach. Two authors extracted data in duplicate, and disagreements were addressed through discussion and consensus.

Data Synthesis

For dichotomous outcomes, relative effects were reported as a relative risk, and absolute effects were reported as a risk difference. For continuous outcomes, effects were reported as a mean difference (MD) or standardized mean difference. The 95% confidence interval (CI) was provided for all estimates. The initial research plan included meta-analyses of RCTs and nonrandomized comparative studies. However, effects were not pooled for any outcome because of insufficient crude data; the range of effects across studies was reported instead.

Quality of Evidence Appraisal

We used the GRADE approach to assess for risk of bias (internal validity), indirectness (external validity), inconsistency of estimates across studies (increased I2 statistic), imprecision of estimates (wide confidence intervals), and likelihood of publication bias (3237). If a flaw was present in any of these domains, the quality of the evidence was downgraded. The GRADE approach also assesses potential reasons to upgrade quality (38). To assess the risk of bias domain, the Newcastle-Ottawa scale was used for nonrandomized studies and the Cochrane risk of bias tool was used for randomized trials.

Evidence Profile

We developed evidence profiles summarizing the estimated effects on an outcome-by-outcome basis as well as the judgments made during the appraisal of the quality of evidence. During the development of the clinical practice guideline, these evidence profiles were used by the guideline panel to inform its recommendation.

Our literature search identified 2,994 articles after removal of duplicates. We reviewed the full text of 17 articles, then excluded four studies because patients with OHS were a minority of the patients (3942), one study because it used an outdated bariatric procedure (43), three studies because they did not report outcomes of interest (4446), and three studies that were nonrandomized studies without a control group that enrolled fewer than 20 patients (4749). The remaining six studies were selected to inform the guideline committee (42, 5054) (Figure E1).

The selected studies included two RCTs and four nonrandomized studies without a comparator (i.e., case series). One RCT enrolled 37 patients with OHS and randomly assigned them to undergo a comprehensive weight loss program (motivational counseling, close dietary oversight, and an exercise program) or standard care (diet and exercise advice during a routine outpatient visit) (42). The other RCT enrolled 63 morbidly obese patients with OSA who were receiving noninvasive ventilation and compared LAGB to intensive nutritional care alone over 3 years, with additional follow-up 7 years later (50). Three nonrandomized studies collectively enrolled 210 patients with morbid obesity, more than half of whom had OHS, and reported outcomes from gastric bypass (5153). The fourth nonrandomized study enrolled 16 morbidly obese patients and reported outcomes from BPD/DS (54) (Table 1).

Table 1. Characteristics of selected studies

AuthorYearPopulationInterventionComparatorDurationNAge (yr)BMI (kg/m2)PaCO2 (mm Hg)Male (%)Hypertension (%)Diabetes Mellitus (%)
Randomized trials   
 Feigel-Guiller (50)2015OHSAGBINC1-, 3-, 10-yr follow-up63Intervention 46.9 ± 8.6Intervention 48.8 ± 9.9Not reported60/53 (INC/AGB)70/50 (INC/AGB)36/33 (INC/AGB)
Comparator 50.1 ± 7.4Comparator 44.4 ± 9
 Mandal (42)2018OHSNIV + comprehensive weight loss program (intervention)NIV + standard nutritional and exercise advice leaflet (control)3 and 12 mo37Intervention 57.8 ± 12.759.8 ± 7.753.7 ± 6.9735/23 (intervention/control)Not reported40/59 (intervention/control)
Comparator 61.4 ± 12.9
Nonrandomized comparative studies   
 None   
Nonrandomized studies without a comparator group   
 Sugerman (51)1986OHSGastric surgery 3–5 mo and 6–12 mo29 with OHS out of 38 with OHS and/or OSA41 ± 11Mean weight, 155 ± 44 kg (BMI not reported)51 ± 763Not reportedNot reported
 Sugerman (52)1988OHSGastric surgery and RHC 3–9 mo after gastric surgery26 (only 18 had repeat RHC for outcome of the study)44 ± 11Percentage ideal body weight, 225 ± 46 (BMI not reported)51 ± 654Not reportedNot reported
 Sugerman (53)1992OHSGastric surgery 5.8 ± 2.4 yr38 out of 61 had long-term follow-upNot reported56 ± 1353 ± 9Not reportedNot reportedNot reported
 DeCesare (54)2014OHSDerivative biliodigestive surgery 2–7 yr16(Range reported) 19–62(Range reported) 35–70.9 33.343.131.4

Definition of abbreviations: AGB = adjustable gastric banding; BMI = body mass index; INC = intensive nutritional care; NIV = noninvasive ventilation; OHS = obesity hypoventilation syndrome; OSA = obstructive sleep apnea; PaCO2 =  partial pressure of carbon dioxide in the arterial blood; RHC = right heart catheterization.

Weight Loss

Change in body weight was reported by two RCTs and two nonrandomized studies (42, 50, 51, 53). In one RCT, patients had a baseline weight of 140 kg; more weight loss was achieved with a comprehensive weight loss program than standard care at 3 months (MD, −11.8 kg; 95% CI, −22.1 to −1.5 kg) (42) (Table 2). In the other RCT, patients had a baseline weight of 130 kg; there was a trend toward more weight loss with LAGB than intensive nutritional care at 1 year (MD, −12.9 kg; 95% CI, −30.2 to 4.4 kg) and 3 years (MD, −15.7 kg; 95% CI, −36.5 to 5.1 kg) (50) (Table 3). In the two nonrandomized studies, gastric bypass was associated with a mean weight loss of 50 kg (95% CI, −39 to −60 kg) from a baseline of 155 kg in one study (51) and a mean weight loss of 44 kg (95% CI, −33 to −55 kg) from a baseline of 163 kg in the other study (53) (Table 4).

Table 2. Evidence profile for a comprehensive weight loss program

Certainty AssessmentNo. of PatientsEffectCertaintyImportance
No. of StudiesStudy DesignRisk of BiasInconsistencyIndirectnessImprecisionOther ConsiderationsWeight Loss ProgramNutritional and Exercise AdviceRelative (95% CI)Absolute (95% CI)
Death (follow-up: 3 mo)
 1 (42)RCTSerious*Not seriousNot seriousVery seriousNone0/17 (0.0%)1/20 (5.0%)Not estimable ⨁◯◯◯ VERY LOWCRITICAL
Quality of life (follow-up: 3 mo; assessed with: SF-36 mental and physical component scores [scale: 0–100; higher score is better; MID ∼5])
 1 (42)RCTSerious*Not seriousNot seriousVery seriousNoneSF-36 mental: MD, 3.0 (95% CI, −7.67 to 13.66) (baseline: 42 points)⨁◯◯◯ VERY LOWCRITICAL
SF-36 physical: MD, 4.6 (95% CI, −2.28 to 11.55) (baseline: 30 points)
Resolution of hypercapnia: not reported
 —CRITICAL
Awake hypoxemia (follow-up: 3 mo; assessed with: change from baseline in PaO2 of 62 mm Hg)
 1 (42)RCTSerious*Not seriousNot seriousSeriousNone1515MD, 0.38 mm Hg lower (7.5 lower to 6.75 higher)⨁⨁◯◯ LOWIMPORTANT
Awake hypercapnia (PaCO2) (follow-up: 3 mo; assessed with: change from baseline in PaCO2 of 53 mm Hg)
 1 (42)RCTSerious*Not seriousNot seriousSerious§None1515MD, 1.95 mm Hg lower (5.25 lower to 1.2 higher)⨁⨁◯◯ LOWIMPORTANT
Nocturnal oxygen saturation < 90% (% total sleep time) (follow-up: 3 mo; assessed with: change from baseline 52%)
 1 (42)RCTSerious*Not seriousNot seriousSeriousNone1515MD, 3.6% higher (6.9 lower to 14.1 higher)⨁⨁◯◯ LOWIMPORTANT
AHI: not reported
 —IMPORTANT
Motor vehicle accidents: not reported
 —CRITICAL
Daytime sleepiness (follow-up: 3 mo; assessed with: change from baseline in Epworth Sleepiness Scale [lower score is better; MID ∼2–3 points]; scale, 0–24)
 1 (42)RCTSerious*Not seriousNot seriousSerious§None1515MD, 2.1 points lower (4.72 lower to 0.48 higher)||⨁⨁◯◯ LOWCRITICAL
Cardiovascular events: not reported
 —CRITICAL
Exercise and/or functional capacity (follow-up: 3 mo; assessed with: change from baseline in 6-min-walk distance in meters [MID ∼20–40 m])
 1 (42)RCTSerious*Not seriousNot seriousSeriousNone1515MD, 9.3 m higher (0.7 higher to 18 higher)**⨁⨁◯◯ LOWIMPORTANT
Dyspnea (follow-up: 3 mo; assessed with: change from baseline 4 points in Medical Research Council breathlessness scale [range, 1–5; lower score is better])
 1 (42)RCTSerious*Not seriousNot seriousSerious§None1515MD, 0.98 points lower (1.87 lower to 0.08 lower)⨁⨁◯◯ LOWIMPORTANT
Weight (follow-up: 3 mo; assessed with: change from baseline 140 kg)
 1 (42)RCTSerious*Not seriousNot seriousSerious§None1515MD, 11.8 kg lower (22.1 lower to 1.5 lower)⨁⨁◯◯ LOWCRITICAL
Mood (follow-up: 3 mo; assessed with: change from baseline 6 points in Hospital Anxiety and Depression Scale [lower score is better; MID ∼2–2.5]; scale, 0–21)
 1 (42)RCTSeriousNot seriousNot seriousSerious§None1515MD, 1.1 points lower (2.83 lower to 0.63 higher)⨁⨁◯◯ LOWIMPORTANT
Need for daytime supplemental oxygen: not reported
 —IMPORTANT
Hospitalization: not reported
 —CRITICAL
Emergency department visit: not reported
 —IMPORTANT
Adverse effects: not reported
 —IMPORTANT

Definition of abbreviations: AHI = apnea–hypopnea index; CI = confidence interval; MID = minimally important difference; MD = mean difference; PaCO2 =  partial pressure of carbon dioxide in the arterial blood; PaO2 = partial pressure of oxygen in the arterial blood; RCT = randomized controlled trial; SF-36 = 36-Item Short Form Health Survey.

Question: Should adults with obesity hypoventilation syndrome be treated with a comprehensive weight loss program (including motivational counseling, dieting, and exercise)? Weight loss program consisted of motivational session, personalized exercise and dietary plan, monthly review, weekly phone calls/reminders; all patients in both groups received noninvasive ventilation.

*Study was not blinded and stopped early for low accrual, large loss to follow-up, and unavailability of personnel to provide intervention.

Only one event among 37 patients.

Only 30 patients; CIs do not exclude an appreciable benefit with either approach.

§Only 30 patients; CI does not exclude an appreciable benefit or no important difference.

||Baseline 12 points.

Only 30 patients; assuming the MID ∼20 m, the CIs do not exclude an appreciable benefit in some patients.

**Baseline 165–200 m.

Table 3. Evidence profile for laparoscopy adjustable gastric banding

Certainty AssessmentNo. of PatientsEffectCertaintyImportance
No. of StudiesStudy DesignRisk of BiasInconsistencyIndirectnessImprecisionOther ConsiderationsLAGBIntensive Nutritional CareRelative (95% CI)Absolute (95% CI)
Death (follow-up: 3 mo)
 1 (50)RCTSerious*Not seriousSeriousVery seriousNone0/30 (0.0%)0/33 (0.0%)Not estimable ⨁◯◯◯ VERY LOWCRITICAL
Resolution of OHS (follow-up: 3 yr; assessed with: weaning from NIV)
 1 (50)RCTSerious*Not seriousSeriousSerious§||None9/30 (30.0%)4/33 (12.1%)RR, 2.48 (0.85–7.21)179 more per 1,000 (from 18 fewer to 753 more)⨁◯◯◯ VERY LOWCRITICAL
AHI (follow-up: 1 yr; assessed with: change from baseline of 52 episodes/h)
 1 (50)RCTSerious*Not seriousSeriousNot seriousNone2630MD, 22 episodes/h fewer (6 fewer to 39 fewer)⨁⨁◯◯ LOWIMPORTANT
AHI (follow-up: 3 yr; assessed with: change from baseline of 52 episodes/h)
 1 (50)RCTSerious*Not seriousSeriousNot seriousNone2224MD, 13 episodes/h fewer (32 fewer to 6 more)⨁⨁◯◯ LOWIMPORTANT
Weight (follow-up: 1 yr; assessed with: change from baseline 130 kg)
 1 (50)RCTSerious*Not seriousSeriousSerious§**None2630MD, 12.9 kg lower (30.2 lower to 4.4 higher)⨁◯◯◯ VERY LOWCRITICAL
Weight (follow-up: 3 yr; assessed with: change from baseline 130 kg)
 1 (50)RCTSerious*††Not seriousSeriousSerious§‡‡None2224MD, 15.7 kg lower (36.5 lower to 5.1 higher)⨁◯◯◯ VERY LOWCRITICAL
Adverse effects (follow-up: 3 yr)
 1 (50)RCTSerious*Not seriousSeriousSerious§§None6/30 (20.0%)||||0/33 (0.0%)Not estimable ⨁◯◯◯ VERY LOWIMPORTANT

Definition of abbreviations: AHI = apnea–hypopnea index; CI = confidence interval; LABG = laparoscopic adjustable gastric banding; MD = mean difference; NIV = noninvasive ventilation; OHS = obesity hypoventilation syndrome; RCT = randomized controlled trial; RR = risk ratio.

Question: Should adults with OHS undergo LAGB? Components of the nutritional care were not described; all patients received a 1,400 kcal/d diet.

*Study was not blinded; other risk of bias criteria were not adequately described.

The question is about LAGB compared to no LAGB, but the study addressed LAGB compared with intensive nutritional program (indirectness of the comparator).

There were no deaths among only 63 patients.

§CI does not exclude an appreciable benefit or no important difference.

||Only 13 events.

We assumed that even the reduction in 32–39 episodes per hour would still not resolve sleep apnea in patients with a baseline average of 52 apnea episodes per hour.

**Only 56 patients.

††22/66 patients were lost to follow-up at 3 yr.

‡‡Only 46 patients.

§§Only 6 events.

||||All adverse effects were related to the surgery itself: gastric band repositioning because of dysphagia and gastric band replacement, gastric band removal because of gastric band slippage (3, 4, and 9 yr after surgery), gastric ulcer (8 yr after surgery), and discovery of gastric cancer (7 yr after surgery).

Resolution of OHS

Change in the severity of OHS was measured by one RCT and two nonrandomized studies (50, 51, 54). The RCT found a trend toward more resolution of OHS, defined as weaning from noninvasive ventilation, among those who underwent LAGB compared with intensive nutritional care (30% vs. 12.1%; relative risk, 2.48; 95% CI, 0.85–7.21) (51) (Table 3). One nonrandomized study reported resolution of OHS 2 years after gastric bypass in 25 out of 29 patients (86.2%; 95% CI, 69.4–94.5%) (51) (Table 4), and another nonrandomized study reported resolution of OHS 5 to 7 years after BPD/DS in all 16 patients (100%; 95% CI, 80.6–100%) (54) (Table 5).

Table 4. Evidence profile for gastric bypass

Certainty AssessmentNo. of PatientsEffectCertaintyImportance
No. of StudiesStudy DesignRisk of BiasInconsistencyIndirectnessImprecisionOther ConsiderationsGastric BypassNo Bariatric SurgeryRelative (95% CI)Absolute (95% CI)
Death (follow-up: 2 yr)
 1 (51)Observational studiesSerious*Not seriousNot seriousSeriousNone2/29 (6.9%)⨁◯◯◯ VERY LOWCRITICAL
Resolution of OHS (follow-up: 2 yr)
 1 (51)Observational studiesSerious*Not seriousSeriousSerious§None25/29 (86.2%)⨁◯◯◯ VERY LOWCRITICAL
Awake hypoxemia (PaO2) (follow-up: 2 yr)
 2 (51, 52)Observational studiesSerious*Not seriousNot seriousNot seriousNoneMean change from baseline was 15 mm Hg more (95% CI, 9 to 21 more) (51) and 19 mm Hg more (11 to 27 more) (52).⨁◯◯◯ VERY LOWIMPORTANT
Awake hypercapnia (PaCO2) (follow-up: 2 yr)
 2 (51, 52)Observational studiesSerious*Not seriousNot seriousNot seriousNoneMean change from baseline was 10 mm Hg less (95% CI, 7 to 13 less) (51) and 10 mm Hg less (95% CI, 6 to 14 less) (52)⨁◯◯◯ VERY LOWIMPORTANT
Daytime sleepiness (follow-up: 2 yr)
 1 (51)Observational studiesSerious*Not seriousNot seriousSerious§None“Daytime hypersomnolence disappeared”⨁◯◯◯ VERY LOWCRITICAL
Weight (follow-up: 2 yr)
 2 (51, 52)Observational studiesSerious*Not seriousNot seriousSeriousNoneAverage weight loss:⨁◯◯◯ VERY LOWCRITICAL
−50 kg (95% CI, −39 to −60 kg) from baseline 155 kg in 30 patients (51)
−44 kg (95% CI, −33 to −55 kg) from baseline 163 kg in 38 patients (53)
Pulmonary artery pressure (follow-up: 3–6 mo)
 1 (52)Observational studiesSerious*Not seriousNot seriousSeriousNonePulmonary artery pressure fell on average 13 mm Hg (95% CI, 5.8 to 20.2 mm Hg) from baseline 36 mm Hg⨁◯◯◯ VERY LOWIMPORTANT

Definition of abbreviations: CI = confidence interval; OHS = obesity hypoventilation syndrome; PaCO2 =  partial pressure of carbon dioxide in the arterial blood; PaO2 =  partial pressure of oxygen in the arterial blood.

Question: Should adults with OHS undergo gastric bypass?

*Series of cases; no direct comparison with a control group.

Only two events among 29 patients.

Based on “improved or cured,” but definition not provided.

§Only 29 patients.

Table 5. Evidence profile for biliopancreatic diversion with duodenal switch

Certainty AssessmentNo. of PatientsEffectCertaintyImportance
No. of StudiesStudy DesignRisk of BiasInconsistencyIndirectnessImprecisionOther ConsiderationsBPD/DSNo Bariatric SurgeryRelative (95% CI)Absolute (95% CI)
Resolution of OHS (follow-up: 5–7 yr)
 1 (54)Observational studiesSerious*Not seriousNot seriousSeriousNone16/16 (100.0%)⨁◯◯◯ VERY LOWCRITICAL

Definition of abbreviations: BPD/DS = biliopancreatic diversion with duodenal switch; CI = confidence interval; OHS = obesity hypoventilation syndrome.

Question: Should adults with OHS undergo gastric bypass?

*Series of cases; no direct comparison with a control group.

Only 16 cases.

Mortality

Mortality was measured by both RCTs and one of the nonrandomized studies (42, 50, 51). In the RCT that compared a comprehensive weight loss program to standard care, there were no deaths among those in the comprehensive weight loss program and one death among those receiving standard care at 3 months (42) (Table 2). In the other RCT, which compared LAGB to an intensive nutritional program, there were no deaths in either group during the 3-month trial (50) (Table 3). The nonrandomized study reported two deaths (6.9%; 95% CI, 1.9–2.2%) during the 3 years after gastric bypass (51) (Table 4). One death was due to a cardiac arrhythmia 5 weeks after surgery and the other was due to an automobile accident 6 months after surgery.

Gas Exchange

The RCT that compared a comprehensive weight loss program to standard care found no difference in awake hypoxemia (MD, −0.38 mm Hg; 95% CI, −7.5 to 6.75 mm Hg), awake hypercapnia (MD, −1.95 mm Hg; 95% CI, −5.25 to 1.2 mm Hg), or nocturnal oxygen saturation (MD, 3.6%; 95% CI, −6.9% to 14.1%) after 3 months (Table 2) (42). Importantly, the weight loss in this RCT was modest (MD, −11.8 kg; 95% CI, −22.1 to −1.5 kg), which likely explains the lack of significant improvement in gas exchange. Two nonrandomized studies also evaluated awake hypoxemia and awake hypercapnia at 2 years after gastric bypass (50, 52). One reported a mean increase in the partial pressure of oxygen in the arterial blood of 15 mm Hg (95% CI, 9–21 mm Hg) (52), and the other reported a mean increase of 19 mm Hg (95% CI, 11–27 mm Hg) (52). Similarly, one reported a mean decrease in the partial pressure of carbon dioxide in the arterial blood of 10 mm Hg (95% CI, 7–13 mm Hg) (51), and the other reported a mean decrease of 10 mm Hg (95% CI, 6–14 mm Hg) (52) (Table 4). In these two studies of gastric bypass surgery, the mean weight loss was close to 50 kg.

OSA and Daytime Sleepiness

The severity of comorbid OSA was assessed using the AHI in one RCT (50). The trial found that, beginning with a baseline AHI of 52 events/h, LAGB resulted in a reduced AHI at 1 year (MD, −22 events/h; 95% CI, −6 to −39 events/h) and a trend toward a reduced AHI at 3 years (MD, −13 events/h; 95% CI, −32 to 6 events/h) (50) (Table 3). Daytime sleepiness was evaluated by the other RCT and one nonrandomized study. The RCT compared a comprehensive weight loss program to standard care and found no difference in the Epworth Sleepiness Scale (MD, −2.1 points; 95% CI, −4.72 to 0.48 points) (Table 2) (50), and the nonrandomized study reported that “daytime hypersomnolence resolved” after gastric bypass (51) (Table 4).

Dyspnea, Mood, and Quality of Life

Dyspnea, mood, and quality of life were reported by the RCT comparing a comprehensive weight loss program to standard care (42). The comprehensive weight loss program modestly improved dyspnea when measured using the Medical Research Council Breathlessness Scale (MD, −0.98 points; 95% CI, −1.87 to −0.08 points), but there was no difference in mood using the Hospital Anxiety Depression Scale (MD, −1.1 points; 95% CI, −2.83 to 0.63 points) or quality of life using the 36-Item Short Form Health Survey (SF-36) mental scale (MD, +3 points; 95% CI, −7.67 to 13.66 points) and the SF-36 physical scale (MD, +4.6 points; 95% CI, −2.28 to 11.55 points) (Table 2).

Exercise Capacity

Exercise capacity was also measured using the 6-minute-walk test in the RCT comparing a comprehensive weight loss program to standard care (42). After 3 months, exercise capacity was better in the comprehensive weight loss group, but the difference was less that what is considered clinically important (MD, 9.3 m; 95% CI, 0.7–18 m) (Table 2).

Pulmonary Artery Pressure

A single observational study using right heart catheterization assessed pulmonary artery pressure in 18 patients with OHS 3 to 9 months after surgery (52). The mean pulmonary artery pressure decreased by a mean of 13 mm Hg (95% CI, −5.8 to −20.2 mm Hg) from a baseline of 36 mm Hg (52) (Table 4).

Adverse Effects

Only the RCT that compared LAGB to an intensive nutritional program reported the adverse effects of a bariatric surgical procedure (50). Six out of 30 patients (20%; 95% CI 9.5–37.3%) who underwent LAGB experienced a gastric-related adverse event. These included dysphagia requiring gastric band repositioning (n = 1), gastric band slippage requiring removal (n = 3), gastric ulceration (n = 1), and gastric cancer (n = 1) (50) (Table 3).

This is the first systematic review to assess the effects of weight loss interventions in patients with OHS. There is an overall paucity of evidence, with two RCTs, no nonrandomized comparative studies, and four nonrandomized studies without a comparator (42, 5054). The results suggest that a comprehensive weight loss program (including motivational counseling, dieting oversight, and an exercise program) reduces body weight but confers no clinically significant effects compared with standard care (diet and exercise advice during a routine outpatient visit). In contrast, bariatric surgery is associated with more significant weight loss, resolution of OHS, reduction of OSA severity, and improvement in gas exchange, daytime sleepiness, and pulmonary artery pressure. Bariatric surgery in OHS was associated with adverse effects in roughly one-fifth of patients in the only study that reported adverse outcomes published in 1986 (51).

A recently published systematic review and network meta-analysis of randomized controlled trials evaluating effectiveness of bariatric surgical procedures included follow-up evaluation at 1 year of 338 patients after gastric bypass, 240 patients after sleeve gastrectomy, and 153 patients after band procedure (55). The 30-day postoperative complication was 16% after gastric bypass, 10.4% after sleeve gastrectomy, and 3.9% after band procedure, and the late complication rate at 1-year follow-up was 33.1% after gastric bypass, 26.3% after sleeve gastrectomy, and 6.5% after band procedure (55). However, in larger observational multicenter studies, the rate of major adverse events seems to be lower. A prospective observational cohort study of 4,776 patients undergoing bariatric surgery reported a 30-day mortality of 0.3% and incidence of major adverse events of 4.3% (56). A recent retrospective observational cohort study of 65,093 patients undergoing bariatric surgery in the United States between 2005 and 2015 reported a 30-day mortality rate of 0.1% and 30-day adverse event rate of 3.8%. The overall 30-day complication rate by procedures was 5% after gastric bypass, 2.6% after sleeve gastrectomy, and 2.9% after band procedure (57).

The limited articles available on weight loss interventions in patients with OHS are highly noncomparable with one another, thus further limiting the ability to directly compare specific interventions and impacts on specific outcomes. As such, it remains unclear what is the exact magnitude of weight loss necessary to achieve clinically significant improvement in OHS. The degree of weight loss required to improve OSA (i.e., reduction in the AHI) can be much different from the degree needed to normalize gas exchange (i.e., resolution of hypercapnia and hypoxemia). The limited literature suggests that clinically significant improvement in gas exchange can be observed with 30% weight loss (Table 6). This is also consistent with the evidence showing improvement in OSA (58) and overall pulmonary function (59) in patients with severe obesity after bariatric surgery.

Table 6. Outcomes associated with percentage of weight loss

StudyInterventionWeight Loss (%)OutcomeOutcome Difference from Baseline with Weight Loss Intervention (%)Time of Assessment
Mandal (42)Standard of care2.16MWT123 mo
Standard of care plus rehabilitation6.96MWT30 
Feigel-Guiller (50)Intensive nutritional care6AHI−91 yr
Laparoscopic adjustable gastric banding15AHI−44 
Sugerman (51)Gastric Roux-en-Y surgery53PaCO2−203–5 mo
AHI−18 
Sugerman (52)Gastric Roux-en-Y surgery42 (% excess weight loss)PaO2383–9 mo
PaCO2−19
Pulmonary artery pressure−36
Pulmonary artery occlusion pressure−29
Sugerman (53)Gastric Roux-en-Y surgery30PaO2371 yr
PaCO2−17 
DeCesare (54)Derivative biliodigestive surgery58.5–64.6OHS resolution100% resolution2 yr

Definition of abbreviations: 6MWT = 6-minute-walk distance test; AHI = apnea-hypopnea index; OHS = obesity hypoventilation syndrome; PaCO2 = partial pressure of carbon dioxide in the arterial blood; PaO2 = partial pressure of oxygen in the arterial blood.

On the basis of the limited body of evidence, the guideline panel suggested a weight loss intervention for patients with OHS, targeting sustained weight loss of 25% to 30% of actual body weight. However, it is important to point out that in the context of developing a clinical practice guideline, the panel of experts’ recommendation of a target weight loss of 25% to 30% was mostly based on discussion and by weighing the pros/cons of recommending a target weight loss rather than relying on firm evidence. Although the weight loss target is based on the observation that greater weight loss seemed associated with better outcomes, including resolution of OHS, improvement in gas exchange, and reduction in the severity of comorbid OSA, there is a need for better-quality studies to ascertain the degree of weight loss necessary to achieve improvement in clinically relevant outcomes in patients with OHS. Although short-term and long-term lifestyle interventions can induce weight loss, it tends to be modest, and even intensive lifestyle interventions produce 10- to 12-kg weight loss. This degree of weight loss is unlikely to lead to clinically significant improvement in OHS. On the other hand, bariatric interventions such as laparoscopic sleeve gastrectomy, Roux-en-Y gastric bypass or BPD/DS are much more likely to lead to the magnitude of weight loss necessary to lead to the resolution of OHS (58). This is in line with literature demonstrating that bariatric surgery leads to greater weight loss and higher remission rate of type 2 diabetes and metabolic syndrome when compared with lifestyle interventions (60). However, bariatric surgery is costly and not risk free. Therefore, bariatric surgery should be considered the treatment of choice only when the estimated benefit outweighs the risk of postoperative morbidity and mortality.

The strength of this systematic review lies in its conduct within the context of clinical practice guideline development. Panel experts identified relevant studies and ensured that the selected outcomes are important and clinically relevant. Similarly, a patient panelist provided a unique perspective as to the relevance of the selected outcomes to patients. An additional strength was the breadth of the search criteria, making it unlikely that we missed important studies.

The main limitation of the systematic review is the quality of the evidence (i.e., the certainty of the estimated effects). There was a paucity of evidence, with only two RCTs and no nonrandomized comparative studies. The evidence was estimated to be low or very low quality, mostly due to study design, small study size, and indirectness when the population included obese patients without OHS. There is a need for high-quality, adequately powered randomized trials with long observation periods to confirm the effectiveness of various weight loss interventions in patients with OHS. Moreover, it remains unclear what degree of weight loss is necessary to diminish cardiometabolic risk in patients with OHS. Trials should include subgroup analyses of patients with different degrees of obesity and severities of SDB. As such, revised guideline recommendations will be necessary when such studies are completed.

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Correspondence and requests for reprints should be addressed to Babak Mokhlesi, M.D., M.Sc., University of Chicago, 5841 South Maryland Avenue, MC6076/Room M630, Chicago, IL 60637. E-mail: .

Supported by the American Thoracic Society.

Author Contributions: M.T.K.—contribution to conception and design of the project and participation in acquisition and analysis of data: preparing and validation of search strategy, searching bibliographic databases, title abstract screening, full text screening, data extraction, and drafting of manuscript. I.S.—contribution to conception and design of the project and participation in acquisition: preparing and validation of search strategy, searching bibliographic databases, title abstract screening, full text screening, data extraction, and drafting of manuscript. M.A.—contribution to conception and design of the project and participation in acquisition: preparing and validation of search strategy, searching bibliographic databases, title abstract screening, full text screening, data extraction, and drafting of manuscript. J.L.B.—contribution to conception and design of the project, verification and supervision over of all parts of the project, and drafting of manuscript. K.C.W.—contribution to conception and design of the project and drafting of manuscript. J.F.M.—contribution to conception and design of the project, participation in analysis of data, and drafting of manuscript. B.M.—contribution to conception and design of the project, participation in analysis of data, and drafting of manuscript.

This article has an online supplement, which is accessible from this issue’s table of contents at www.atsjournals.org.

Author disclosures are available with the text of this article at www.atsjournals.org.

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