Sleeping on a Royal Flush

A 40-year-old Caucasian man presents to sleep disorders clinic for significant daytime sleepiness. He reports fatigue and inability to concentrate at work during the day even after adequate overnight sleep. He takes frequent naps during the day. He recently fell asleep while playing poker with his friends despite having a royal flush, which prompted him to seek medical attention. His wife reports loud snoring and periods of choking during sleep. He reports mild dyspnea with exertion, which has been stable for many years. His review of systems is remarkable for daily morning headaches. He also complains of bilateral leg swelling, which has been gradually worsening for past year. His medical history is significant for poorly controlled hypertension and insulin-requiring diabetes mellitus. His medications include metoprolol 100 mg twice a day, lisinopril 20 mg once a day, amlodipine 10 mg once a day, glargine insulin 20 units once a day, metformin 1000 mg twice a day, and aspirin 81 mg once a day. He never smoked. He drinks 1 glass of red wine a few times a week but denies alcohol abuse. On examination, he is obese, with a BMI of 40 kg/m2. His blood pressure is 150/96 mm Hg, pulse rate 72 bpm, respiratory rate 16 bpm, and oxygen saturation is 90% on room air. He has a thick neck and a small and crowded oropharynx and bilateral pitting edema in the lower extremities. The remainder of physical examination is normal. His laboratory studies are remarkable for hemoglobin 19 g/dL and serum bicarbonate of 35 mg/dL. The chest radiograph reveals elevated hemidiaphragms with no pulmonary parenchymal abnormalities. The arterial blood gas on room air shows pH = 7.35, PCO2 = 55 mm Hg, and PO2 = 61 mm Hg. His overnight polysomnography is consistent with moderate obstructive sleep apnea, with an apnea-hypopnea index (AHI) 28/hour. He had low oxygen levels throughout the duration of sleep, with significant desaturations during REM sleep. WHICH OF THE FOLLOWING IS MOST LIKELY TO BE ASSOCIATED WITH THIS DISORDER? Increased expiratory reserve volume (ERV) Increased serum leptin level Restless legs syndrome Cheyne Stokes Breathing CORRECT ANSWER: b. Increased serum leptin level The clinical scenario is consistent with obesity hypoventilation syndrome (OHS). This disorder was originally coined as Pickwickian syndrome by Burwell and his colleagues in 1956.1 OHS is defined as a combination of obesity (i.e., BMI ≥ 30 kg/m2) and awake chronic hypercapnia (i.e., PaCO2 ≥ 45 mm Hg) accompanied by sleep disordered breathing (SDB).2 The majority of patients with OHS have obstructive sleep apnea (OSA), while a small percentage have sleep hypoventilation. Restless legs syndrome (choice C) is not a typical feature of OHS. OHS should be differentiated from other conditions such as obstructive lung disease, interstitial lung disease, and neuromuscular disorders, which may be associated with hypercapnia. The OHS patients usually provide a history that includes symptoms of OSA and CO2 retention, such as snoring, witnessed apnea, excessive daytime sleepiness, and morning headaches. The physical examination, in addition to obesity, may reveal large neck circumference, crowded oropharynx and signs of right heart failure (i.e., elevated jugular venous pressure and lower extremities edema). Cheyne Stokes breathing (Choice D) is usually seen in association with congestive heart failure and is not a common feature of OHS. The laboratory studies in OHS are remarkable for polycythemia (secondary to hypoxemia) and elevated bicarbonate (due to metabolic compensation). Arterial blood gas usually shows hypercapnia and hypoxemia with normal alveolar-arterial gradient. Pulmonary function tests frequently reveal a low vital capacity, a normal ratio of forced expiratory volume in one second to forced vital capacity (FEV1/FVC), and a markedly reduced expiratory reserve volume (Choice A). Total lung capacity may be low or normal.2 Endothelial function is significantly impaired in OHS patients compared with age- and BMI-matched controls.3 The rates of poorly controlled hypertension, diabetes mellitus, coronary artery disease and congestive heart failure as well as healthcare utilization are also higher in OHS.4,5 One small study followed OHS patients for 50 ± 25 months and showed a higher mortality in a group that refused therapy compared to the group managed with positive pressure therapy. 6 Leptin is a hormone produced primarily by adipose tissue. It interacts with hypothalamic receptors to inhibit eating and stimulate respiratory drive. Increased adiposity is associated with increased serum leptin levels. Plasma leptin levels are even higher in OHS than in weight-matched controls without OHS (Choice B).7–9 A relative central leptin deficiency or leptin resistance, and consequent reduction in ventilatory drive, may represent the primary mechanism underlying daytime hypercapnia in patients who develop OHS.2 Notably, leptin deficiency in a mouse model leads to features of OHS, which reverse with leptin replacement. Recombinant leptin may reverse leptin resistance and may represent a future therapeutic option for OHS.10 Positive pressure therapy is the primary medical management for OHS patients. Continuous positive airway pressure therapy (CPAP) will correct SDB in a significant proportion of patients. Bilevel positive airway pressure (BPAP) therapy can be used if awake hypercapnia or overnight oxygen desaturation persist despite elimination of obstructive events, or if the patient is intolerant to CPAP owing to the high pressures that may be required to alleviate SDB.2 Supplemental oxygen may be required to maintain oxygen saturation at acceptable levels. Surgical options include tracheostomy for patients intolerant to PAP therapy and bariatric surgery in selected patients to achieve substantial weight loss.