Alan T. Mulgrew

Diagnosis and Initial Management of Obstructive Sleep Apnea without Polysomnography: A Randomized Validation Study

Context Overnight polysomnography in a sleep laboratory is normal practice for diagnosing obstructive sleep apnea (OSA) but it is expensive and can delay diagnosis. Contribution The authors combined standard clinical scales and overnight home oximetry to ensure a pretest probability of OSA of 90% or greater. Sixty-eight patients were randomly assigned to usual care (polysomnography obtained before continuous positive airway pressure [CPAP]) or ambulatory management (start CPAP without doing polysomnography). After 3 months, the 2 groups had the same results on overnight polysomnography. Cautions The study was done in a single tertiary care center. Implications Most patients with a probability of OSA of 90% or greater do not require polysomnography before starting CPAP. The Editors Symptomatic obstructive sleep apnea is a common, underdiagnosed condition that occurs in 4% of men and in 2% of women (1). Patients with obstructive sleep apnea have considerable comorbid conditions, including excessive daytime sleepiness; concentration difficulties; and an increased risk for motor vehicle accidents, hypertension (2), coronary artery disease, and strokes. Obstructive sleep apnea may result in a systemic inflammatory state that predisposes the patient to cardiac and cerebrovascular conditions (3). Continuous positive airway pressure (CPAP) is an effective treatment that is commonly prescribed for symptomatic patients with obstructive sleep apnea: It is cost-effective (4) and reduces daytime sleepiness, rates of motor vehicle accidents, and blood pressure. The American Thoracic Society (5) and the American Academy of Sleep Medicine (6) recommend supervised polysomnography (PSG) in the sleep laboratory over 2 nights for diagnosis of obstructive sleep apnea and initiation of CPAP. This approach to a highly prevalent condition results in inevitable discrepancies between the demand for services and the current capacity of sleep laboratories (7). Various strategies have been proposed to expedite diagnosis and treatment for obstructive sleep apnea (8). Predictive algorithms (915) and widespread use of overnight home monitoring, such as oximetry, have improved access to diagnostic testing (1622). Several algorithms have been used to determine optimal CPAP (23, 24). Ambulatory use of autotitrating CPAP machines is effective in determining therapeutic CPAP (25) and as a treatment method. To our knowledge, this is the first study to examine a combined ambulatory diagnostic and treatment algorithm without PSG in initial management of obstructive sleep apnea. To do so, we performed 2 parallel validation studies: 1) a cross-sectional study in patients screened by the diagnostic algorithm to test its use in identifying high-probability patients using PSG as the gold standard, and 2) a randomized trial of PSG versus ambulatory CPAP titration in high-probability patients identified by the diagnostic algorithm. Our study asked whether the conventional PSG approach was superior to the ambulatory approach in terms of controlling obstructive sleep apnea as measured by the apneahypopnea index (AHI) on CPAP after 3 months of treatment. We also wanted to determine whether there was any difference between the 2 management strategies in terms of sleepiness, quality of life, treatment adherence, and CPAP after 3 months of treatment. Methods Study Design We designed a randomized, controlled, open-label clinical trial to compare PSG with an ambulatory algorithm for titration of effective CPAP in patients with a high probability of moderate to severe obstructive sleep apnea. Patient Selection Participants were recruited from among adult patients referred from the catchment area of the Sleep Disorders Program at University of British Columbia Hospital, Vancouver, British Columbia, Canada, between May 2004 and November 2005, for assessment of suspected obstructive sleep apnea. Consecutive patients who, on the basis of a routine clinical evaluation by their sleep physician, were suspected of having moderate to severe obstructive sleep apnea, met the inclusion criteria, and were referred for possible participation in the trial, were considered for recruitment. Eligible patients had a high pretest probability of moderate to severe obstructive sleep apnea, were medically stable, and were not taking any sedative medications. We excluded patients who were pregnant or who had abnormal results on spirometry (predicted forced vital capacity or FEV1 <70%); a known cause of daytime sleepiness; a major psychiatric disorder; a life-threatening comorbid illness, such as unstable coronary artery disease or chronic lung disease; a motor vehicle accident attributable to hypersomnolence in the preceding 5 years; previous treatment for obstructive sleep apnea; a contraindication to nasal CPAP therapy; or the inability to provide informed consent. Each eligible patient provided written informed consent, and our institutional ethics review committees approved the protocol. Patients were enrolled by the research coordinator who collected the baseline data. Determining Pretest Probability High-probability patients were identified by sequential application of the Epworth Sleepiness Scale (ESS), Sleep Apnea Clinical Score (SACS) (11), and overnight oximetry in the home. The range of possible scores on the ESS is 0 to 24. In a retrospective case series of all patients (n= 798) referred to our sleep clinic with suspected obstructive sleep apnea who had a full diagnostic overnight PSG between 1 January 2001 and 31 December 2001 (26), the prevalence of moderate to severe obstructive sleep apnea (AHI >15/h) was 49% among patients with an ESS score of 10 or greater. The SACS is a screening tool based on snoring, witnessed episodes of apnea, neck circumference, and systemic hypertension that can be used to calculate likelihood ratios for the presence of obstructive sleep apnea (11). A score of 15 or greater gives a likelihood ratio of 4.45 of having moderate to severe sleep apnea (11). The Remmers Sleep Recorder (SagaTech Electronics Inc., Calgary, Alberta, Canada) is an easy-to-use, multichannel portable device that measures oxygen saturation, respiratory effort, airflow, snoring, and leg movements. This device calculates a respiratory disturbance index (RDI) on the basis of oxygen desaturation events. An RDI of 15/h or greater measured by the Remmers Sleep Recorder has a sensitivity of 98% and a specificity of 88% for diagnosis of moderate to severe obstructive sleep apnea, giving a likelihood ratio of 8.1 (18). Starting with pretest odds of approximately 1:1 on the basis of an ESS score of 10 or greater, we used Bayes theorem and assumed no interaction between components of the algorithm. The combined likelihood ratio conditional on a SACS of 15 or greater and an oximetry RDI of 15/h or greater yielded an estimated pretest probability of moderate to severe obstructive sleep apnea greater than 95%. Protocol Before randomization, all recruited patients completed the Sleep Apnea Quality of Life Index (SAQLI)a comprehensive survey with a high degree of internal consistency, face validity, and construct validity designed to measure outcomes of clinical trials in sleep apnea (27, 28). All patients received a one-on-one orientation and education session from a dedicated CPAP coordinator who provided information in a standardized fashion regarding nasal CPAP therapy. This session included mask fitting and a trial of CPAP while the patient was awake to ensure that he or she could tolerate the device (Appendix). The CPAP coordinator randomly assigned patients to standard PSG or the ambulatory algorithm (Figure 1), using a stratified block randomization with a block size of 20. The stratification factors were an ESS score less than 15 versus an ESS score 15 or greater and oximetry RDI less than 30 episodes per hour versus RDI 30 episodes per hour or greater. Four large envelopes were prepared, 1 for each block. There were 20 folded cards in each envelope, 10 for the PSG group and 10 for the ambulatory group. Patients who consented to participate were assigned to a block according to their ESS and RDI scores. Each patient picked 1 card from the designated envelope; the CPAP coordinator noted the treatment allocation and destroyed the card. Blinding patients to their treatment allocation was not possible, but all patients were treated in an identical manner, including follow-up, aside from the interventions being studied. The ResMed AutoSet Spirit (ResMed Inc., Sydney, Australia) autotitrating CPAP machine was used in all patients. Together with the ResMed Autoscan software, this device is capable of storing and downloading data on compliance; mask leak; and CPAP, including the 95th percentile pressure (29)the pressure at or below which the patient spent 95% of the time. Final CPAP was determined according to treatment group. Figure 1. Design of the clinical study. CPAP = continuous positive airway pressure; ESS = Epworth Sleepiness Scale; PSG = polysomnography; SAQLI = Sleep Apnea Quality of Life Index. Polysomnography Group A trained technologist supervised PSG. Obstructive sleep apnea was confirmed during a regularly scheduled overnight PSG in the sleep laboratory at our hospital. Final CPAP was determined according to a standard protocol during a CPAP titration PSG performed on the following night (Appendix). There was no subsequent adjustment to the fixed CPAP in the PSG group. Ambulatory Group The AutoSet Spirit was set to autotitrate at pressures between 4 and 20 cm H2O. After being used for 1 week, the ResMed Autoscan software was interrogated for efficacy data, including CPAP, mask leak, residual respiratory events, and use. The 95th percentile pressure was taken as the initial effective pressure if no residual sleep-disordered breathing was identified. The patient continued treatment at this pressure in fixed CPAP mode for another week. On days 6 and 13, overnight oximetry using

Activation of Endoplasmic Reticulum-Specific Stress Responses Associated with the Conformational Disease Z α1-Antitrypsin Deficiency

Conformational diseases are a class of disorders associated with aberrant protein accumulation in tissues and cellular compartments. Z α1-antitrypsin (A1AT) deficiency is a genetic disease associated with accumulation of misfolded A1AT in the endoplasmic reticulum (ER) of hepatocytes. We sought to identify intracellular events involved in the molecular pathogenesis of Z A1AT-induced liver disease using an in vitro model system of Z A1AT ER accumulation. We investigated ER stress signals induced by Z A1AT and demonstrated that both the ER overload response and the unfolded protein response were activated by mutant Z A1AT, but not wild-type M A1AT. Interestingly, activation of the unfolded protein response pathway required an additional insult, whereas NF-κB activation, a hallmark of the ER overload response, was constitutive. These findings have important implications for the design of future therapeutics for Z A1AT liver disease and may also impact on drug design for other conformational diseases.

Risk and severity of motor vehicle crashes in patients with obstructive sleep apnoea/hypopnoea

Background: Obstructive sleep apnoea/hypopnoea (OSAH) appears to be associated with an increased risk of motor vehicle crashes (MVCs). However, its impact on crash patterns, particularly the severity of crashes, has not been well described. A study was undertaken to determine whether OSAH severity influenced crash severity in patients referred for investigation of suspected sleep-disordered breathing. Methods: Objective crash data (including the nature of crashes) for 783 patients with suspected OSAH for the 3 years prior to polysomnography were obtained from provincial insurance records and compared with data for 783 age- and sex-matched controls. The patient group was 71% male with a mean age of 50 years, a mean apnoea-hypopnoea index (AHI) of 22 events/h and a mean Epworth Sleepiness Scale score of 10. Results: There were 375 crashes in the 3-year period, 252 in patients and 123 in controls. Compared with controls, patients with mild, moderate and severe OSAH had an increased rate of MVCs with relative risks of 2.6 (95% CI 1.7 to 3.9), 1.9 (95% CI 1.2 to 2.8) and 2.0 (95% CI 1.4 to 3.0), respectively. Patients with suspected OSAH and normal polysomnography (AHI 0–5) did not have an increased rate of MVC (relative risk 1.5 (95% CI 0.9 to 2.5), p = 0.21). When the impact of OSAH on MVC associated with personal injury was examined, patients with mild, moderate and severe OSAH had a substantially higher rate of MVCs than controls with relative risks of 4.8 (95% CI 1.8 to 12.4), 3.0 (95% CI 1.3 to 7.0) and 4.3 (95% CI 1.8 to 8.9), respectively, whereas patients without OSAH had similar crash rates to controls with a relative risk of 0.6 (95% CI 0.2 to 2.5). Very severe MVCs (head-on collisions or those involving pedestrians or cyclists) were rare, but 80% of these occurred in patients with OSAH (p = 0.06). Conclusion: Patients with OSAH have increased rates of MVCs, and disproportionately increased rates of MVCs are associated with personal injury.

Residual sleep apnea on polysomnography after 3 months of CPAP therapy: Clinical implications, predictors and patterns

OBJECTIVE We sought to determine the clinical implications, predictors and patterns of residual sleep apnea on continuous positive airway pressure (CPAP) treatment in patients with moderate-to-severe obstructive sleep apnea (OSA). METHODS We performed a post hoc secondary analysis of data from a previously reported randomized trial. Sleepy patients with a high risk of moderate-to-severe OSA identified by a diagnostic algorithm were randomly assigned to standard CPAP titration during polysomnography (PSG) or ambulatory titration using auto-CPAP and home sleep testing. We observed them for 3 months and measured apnea-hypopnea index (AHI) on CPAP, Epworth sleepiness scale (ESS), sleep apnea quality of life index (SAQLI), CPAP pressure and objective CPAP compliance. RESULTS Sixty-one patients were randomized, 30 to the PSG group and 31 to the ambulatory group. Fifteen patients (25%) had residual sleep apnea (AHI > 10/h on CPAP) with similar proportions in the PSG (7/30) and ambulatory (8/31) groups. Baseline variables including age, body mass index (BMI), ESS, SAQLI, respiratory disturbance index (RDI) and CPAP pressure did not differ between the groups. Outcomes including compliance were worse in patients with residual sleep apnea. Periodic breathing was prevalent among patients with residual sleep apnea. CONCLUSIONS Residual sleep apnea is common in patients with moderate-to-severe OSA, despite careful CPAP titration, and is associated with worse outcomes.

Cost-effectiveness of continuous positive airway pressure therapy in patients with obstructive sleep apnea-hypopnea in British Columbia.

BACKGROUND Obstructive sleep apnea-hypopnea (OSAH) is a common disorder characterized by recurrent collapse of the upper airway during sleep. Patients experience a reduced quality of life and an increased risk of motor vehicle crashes (MVCs). Continuous positive airway pressure (CPAP), which is the first-line therapy for OSAH, improves sleepiness, vigilance and quality of life. OBJECTIVE To assess the cost-effectiveness of CPAP therapy versus no treatment for OSAH patients who are drivers. METHODS A Markov decision analytical model with a five-year time horizon was used. The study population consisted of male and female patients, between 30 and 59 years of age, who were newly diagnosed with moderate to severe OSAH. The model evaluated the cost-effectiveness of CPAP therapy in reducing rates of MVCs and improving quality of life. Utility values were obtained from previously published studies. Rates of MVCs under the CPAP and no CPAP scenarios were calculated from Insurance Corporation of British Columbia data and a systematic review of published studies. MVCs, equipment and physician costs were obtained from the British Columbia Medical Association, published cost-of-illness studies and the price lists of established vendors of CPAP equipment in British Columbia. Findings were examined from the perspectives of a third-party payer and society. RESULTS From the third-party payer perspective, CPAP therapy was more effective but more costly than no CPAP (incremental cost-effectiveness ratio [ICER] of

Alpha-1-Antitrypsin Deficiency: Current Concepts

3,626 per quality-adjusted life year). From the societal perspective, the ICER was similar (

How best to determine optimal nasal CPAP in patients with OSAH

2,979 per quality-adjusted life year). The ICER was most dependent on preference elicitation method used to obtain utility values, varying almost sixfold under alternative assumptions from the base-case analysis. CONCLUSION After considering costs and impact on quality of life, as well as the risk of MVCs in individuals with OSAH, CPAP therapy for OSAH patients is a highly efficient use of health care resources. Provincial governments who do not provide funding for CPAP therapy should reconsider.

Impact of Continuous Positive Airway Pressure Therapy on Blood Pressure in Patients with Obstructive Sleep Apnea Hypopnea: A Meta-analysis of Randomized Controlled Trials

Since the condition was first described four decades ago, alpha-1-antitrypsin (A1AT) deficiency has served as a model for other disease processes. A1AT is the archetypal serpin designed to ensnare proteases, a process that involves significant conformational change within the molecule. Mutations in the A1AT gene lead to misfolding of the protein and accumulation within the endoplasmic reticulum of hepatocytes resulting in two different pathologic processes. First, the accumulation of mutant A1AT protein has a directly toxic effect on the liver, resulting in hepatitis and cirrhosis. Second, the resultant decrease in circulating A1AT results in protease-antiprotease imbalance at the lung surface and emphysema ensues. A1AT deficiency therefore can be seen as two distinct disease processes: a conformational disease of the liver and a protease-antiprotease imbalance of the lung. This two-stage model of disease in A1AT deficiency is elegant in its simplicity and goes a long way to explaining the clinical manifestations that occur in patients with the condition. However, some aspects of the disease are not readily explained. Recent findings suggest that there is more to the lung damage in A1AT deficiency than simple proteolytic insult and that the presence of the mutant protein itself is proinflammatory and may indeed cause chronic injury to the cells that produce it. This review discusses some of the emerging concepts in alpha-1-antitrypsin research and outlines the implications these new ideas may have for treatment of this condition.

Cathepsin B, L, and S Cleave and Inactivate Secretory Leucoprotease Inhibitor

Optimal CPAP pressure can be determined without in‐laboratory CPAP titration. Doubt remains as to whether long term CPAP treatment reduces blood pressure in patients with OSAH