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Reversible severe pulmonary hypertension in obesity hypoventilation and Mohr syndrome
Respiratory Medicine CME 4 (2011) 30–32
Contents lists available at ScienceDirect
Respiratory Medicine CME journal homepage: www.elsevier.com/locate/rmedc
Case Report
Reversible severe pulmonary hypertension in obesity hypoventilation and Mohr syndromeq Johannes E.S. Nolte*, Ulrich Koehler, Ali Keywan Sohrabi, Sebastian Canisius, Stephan Baumann, Claus Franz Vogelmeier University Hospital Giessen and Marburg, Department of Internal Medicine, Division of Pneumology, Baldingerstr. 1, 35033 Marburg, Germany
a r t i c l e i n f o
a b s t r a c t
Article history: Received 18 November 2009 Accepted 23 November 2009
A young overweight patient with Mohr–Claussen Syndrome was admitted to our department with the clinical diagnosis of pulmonary hypertension complaining about dyspnea at rest and excessive daytime sleepiness. Pulmonary function testing indicated severe airflow limitation and respiratory insufficiency. Pulmonary artery (PA) pressure was markedly increased. Pulmonary embolism, Alpha-1-antitrypsindeficiency, emphysema and anatomical obstructions were excluded. Polysomnography showed recurrent oxygen desaturations compatible with alveolar hypoventilations. Hypercapnic ventilatory response testing (HCVR) indicated a missing increase in minute ventilation when exposed to hypercapnia. After 6 weeks of nocturnal non-invasive ventilation therapy, her clinical condition markedly improved. Furthermore, PA pressure returned to normal values. HCVR testing showed an adequate response to hypercapnia. Mohr–Claussen syndrome is a rare genetic disease affecting the mouth, face and digits. Adult patients are usually very obese; exposing them at risk for obesity hypoventilation syndrome (OHS). OHS is described as a combination of obesity and awake arterial hypercapnia (PaCO2 > 45 mmHg) in the absence of other known causes of chronic alveolar hypoventilation. Unclear pulmonary hypertension in overweight patients should raise the suspicion for OHS. Ó 2009 Published by Elsevier Ltd.
Keywords: PAH Pulmonary hypertension Mohr–Claussen Syndrome CPAP Non-invasive ventilation Hypercapnic ventilatory response HCVR Chemoreception
1. Case presentation A 32 year-old overweight female patient was admitted to the department of cardiology with the clinical diagnosis of pulmonary hypertension. The patient complained about exercise intolerance, dyspnea at rest and intractable headache. Two weeks before initial presentation, her dyspnea progressively worsened and was accompanied by severe pedal edema. Besides, she mentioned increased daytime sleepiness (Epworth sleepiness scale (ESS): 18/24) and severe problems maintaining sleep including recurrent nightmares, which raised the suspicion for sleep-disordered breathing (Fig. 1). Her past medical history is significant for oro-facial-digitalsyndrome Type II (Mohr Syndrome) which was diagnosed in childhood. Medications included salbutamol bid, Tiotropium
q Financial support: University hospital Giessen and Marburg, Germany, Dept. of Internal Medicine, Division of Pneumology. * Corresponding author. Tel.: þ49 6421 586 2717. E-mail addresses: [email protected] (J.E.S. Nolte), koehleru@med. uni-marburg.de (U. Koehler), [email protected] (A.K. Sohrabi), canisius@med. uni-marburg.de (S. Canisius), [email protected] (S. Baumann), claus.vogelmeier@med. uni-marburg.de (C.F. Vogelmeier). 1755-0017/$36.00 Ó 2009 Published by Elsevier Ltd. doi:10.1016/j.rmedc.2009.11.008
bromide qd, an aldosterone antagonist qd (25 mg/day) and furosemide qd (20 mg/day). She smokes half a pack of cigarettes per day and has done so for the previous 12 years. At time of admission, her height was 148 cm with a body weight of 95 kg, corresponding to a body-mass index of 44 kg/m2. Blood pressure was 140/85 mmHg, heart rate 90 beats per minute. Aside from her obesity, nodules of the tongue, polydactyly, midline cleft of the lip, cyanosis of her hands as well as ankle edema were observed during physical examination. Both lungs were clear on auscultation; the remainder of the physical exam revealed no additional significant findings. Blood gas analysis showed a carbon dioxide pressure of 63.2 mmHg, an oxygen partial pressure of 38.3 mmHg and an oxygen saturation at room air of 77%, compatible with respiratory insufficiency. Pulmonary function testing (PFT) indicated severe airflow limitation (FEV1: 28% predicted, FEV1/FVC ratio: 48% predicted, airway resistance R: 281% predicted) and hyperinflation (residual volume 193% predicted). Furthermore, diffusion capacity of the lungs was impaired (transfer factor for carbon monoxide (DLCO): 62% predicted). Significant findings in the blood were a sodium level of 124 mEq, a potassium level of 2.9 mEq and a C-reactive protein of 28 mg/dl. Alpha-1-antitrypsin level was within normal range.
J.E.S. Nolte et al. / Respiratory Medicine CME 4 (2011) 30–32
31
Fig. 1. Oxygen saturation and heart rate during seven hours of sleep.
Chest X-ray demonstrated prominent interstitial markings with enlargement of the right and left ventricle and the right atrium. Cardiac ultrasound revealed a massively dilated right atrium and ventricle. The estimated systolic pulmonary artery pressure was 83 mmHg. A subsequently performed right heart catheterisation confirmed a systolic pulmonary arterial pressure of 82 mmHg, a diastolic pressure of 36 mmHg and a mean pressure of 51 mmHg. The mean pulmocapillary wedge pressure (PCWP) was 18 mmHg. Polysomnography showed recurrent oxygen desaturations down to 48% compatible with alveolar hypoventilations without any signs of obstructive or central sleep-disordered breathing (Fig. 1). Pulmonary embolism was excluded by a spiral chest CAT scan. In High-Resolution CT (HRCT) scan, no signs of parenchymal damage, emphysema or anatomical obstructions were found. Hypercapnic ventilatory response (HCVR) testing was initiated (Fig. 2, label ‘day1’), showing a very shallow rise in her minute ventilation when exposed to increasing levels of carbon dioxide. Testing was stopped when endexpiratory carbon dioxide values exceeded 100 mmHg. The patient was subsequently treated with nocturnal nasal continuous positive bilevel (nBiPAPÓ) ventilation (ventilator settings: inspiratory positive airway pressure: 19 cm H2O, expiratory pressure: 10 cm H2O, spontaneous/timed mode (‘‘ST’’), respiratory rate: 15/min). She returned 4 weeks later for follow-up. Her general clinical condition had improved markedly, she was able to walk two flights of stairs without any signs of dyspnea; her sleeping problems had vanished (ESS: 4/24). HCVR testing was repeated (Fig. 2, label ‘day30’), now illustrating a sharp rise in minute ventilation. Testing was stopped by the patient because of dyspnea. During a second follow-up 8 weeks after treatment initiation, her pulmonary artery pressure was measured again using ultrasound
Fig. 2. The hypercapnic ventilatory response (HCVR) on three different occasions.
yielding a complete resolution of her PH with an estimated mean systolic pressure of 12 mmHg. The HCVR (Fig. 2, label ‘day60’) showed a parallel line as compared to day 30, with a further left shift to normocapnic values. Moreover, we were able to stop her diuretic medications. 2. Discussion Mohr–Claussen syndrome or oro-facial-digital-syndrome type II is a rare autosomal recessive genetic disease characterised by tongue lobulation, midline cleft lip, high arched or cleft palate, broad nasal root with wide bifid nasal tip, hypertelorism, micrognathia, brachydactyly, syndactyly and polydactyly, bilateral reduplicated hallux, conductive hearing loss and normal intelligence.1 We suggest that pulmonary complications may be part of Mohr Syndrome. Our suspicion is supported by the fact that the patient’s 27 year-old sister who suffers from the same genetic disease was admitted to our department 6 weeks later. PFT showed similar changes as in her sister’s case with severe airway obstruction, hyperinflation and respiratory insufficiency. Adult patients with Mohr’s Syndrome share features with Obesity Hypoventilation Syndrome (OHS), including obesity. OHS is described as a combination of obesity and awake arterial hypercapnia (PaCO2 > 45 mmHg) in the absence of other known causes of chronic alveolar hypoventilation.2 OHS is thought to be the consequence of increased work of breathing due to obesity, normal or diminished respiratory drive, other associated sleep related breathing disorders such as obstructive sleep apnea, as well as endocrinological alterations like increased leptin resistance.3 These patients commonly experience a reduced electromyographic neuromuscular and ventilatory response to hypercapnia.4 Non-invasive mechanical ventilation (NIMV) can effectively improve clinical symptoms and daytime respiratory failure and can enhance the responsiveness to carbon dioxide. It has been suggested that an increase in leptin levels may reverse the blunted responsiveness to CO2 in OHS patients during NIMV.5,6 Another significant finding is the association between OHS and pulmonary hypertension (PH): In a large French trial investigating patients with OHS, more than 50% of these had PH, a much higher percentage than the 9% observed in patients with obstructive sleep apnea.7 Pulmonary hypertension is defined as a mean pulmonary artery pressure greater than 25 mmHg at rest or 30 mmHg with exercise.8 According to the Dana Point classification from 2008, PH is divided into six subgroups, namely pulmonary artery hypertension, pulmonary veno-occlusive diseases and/or pulmonary capillary hemangiomatosis, PH owing to left heart disease, PH owing to lung diseases and/or hypoxia (including OHS), chronic thromboembolic PH, and PH with unclear multifactorial mechanisms.9 The complex
32
J.E.S. Nolte et al. / Respiratory Medicine CME 4 (2011) 30–32
pathogenesis implies an imbalance of vascular effectors leading to vasoconstriction, endothelial cell proliferation and thrombosis.10 PH in patients with OHS may be either caused by chronic left heart failure following left ventricular hypertrophy (which is a common finding in severe obesity) or directly by alveolar hypoxia.11 To date, there is no reported data regarding the alterations in PH after initiation of NIMV in OHS patients. We are aware that the PH in our patient may also be secondary to her obstructive lung pattern. Nevertheless, it would be very unlikely that this form of PH would respond to NIMV. Moreover, PFT in morbid obese patients usually shows a restrictive pattern owing to increased chest wall impedance. The Hypercapnic Ventilatory Response (HCVR) testing was performed using a modified Read rebreathing device. Our setup adjusts automatically the fractions of oxygen, carbon dioxide and nitrogen in a closed loop system. The distinct changes in her minute ventilation when exposed to increasing levels of carbon dioxide with a sharp increase within 60 days of NIMV show impressively the dynamic properties of pulmonary chemoreceptors maintaining their full potential for recovery over a long time. Unclear pulmonary hypertension in overweight patients should raise the suspicion for obesity hypoventilation syndrome, particularly because early recognition and treatment improves outcome. We emphasize the importance of arterial blood gas testing in these patients to evaluate for daytime hypercapnia. Additionally, nocturnal
transcutaneous capnography may be a helpful tool establishing a diagnosis. References 1. Biswas A, Ghosh JK, Sinha MK, Basu K, Chatterjee S. Mohr–Claussen syndrome or oro-facial-digital syndrome (OFDS) type-II. J Pak Med Assoc. 2009 Jul;59(7): 484–6. 2. Subramanian S, Strohl KP. A management guideline for obesity-hypoventilation syndromes. Sleep Breath 1999;3(4):131–8. 3. Olson AL, Zwillich C. The obesity hypoventilation syndrome. Am J Med 2005 Sep;118(9):948–56. 4. Sampson MG, Grassino K. Neuromechanical properties in obese patients during carbon dioxide rebreathing. Am J Med 1983 Jul;75(1):81–90. 5. Masa JF, Celli BR, Riesco JA, Herna´ndez M, Sa´nchez De Cos J, Disdier C. The obesity hypoventilation syndrome can be treated with noninvasive mechanical ventilation. Chest 2001 Apr;119(4):1102–7. 6. Redolfi S, Corda L, La Piana G, Spandrio S, Prometti P, Tantucci C. Long-term non-invasive ventilation increases chemosensitivity and leptin in obesityhypoventilation syndrome. Respir Med 2007 Jun;101(6):1191–5. 7. Kessler R, Chaouat A, Schinkewitch P, Faller M, Casel S, Krieger J, et al. The obesityhypoventilation syndrome revisited: a prospective study of 34 consecutive cases. Chest 2001 Aug;120(2):369–76. 8. Barst RJ, McGoon M, Torbicki A, Sitbon O, Krowka MJ, Olschewski H, et al. Diagnosis and differential assessment of pulmonary arterial hypertension. J Am Coll Cardiol 2004 Jun 16;43(12 Suppl. S):40S–47S. 9. Simonneau G, Robbins IM, Beghetti M, Channick RN, Delcroix M, Denton CP, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 2009 Jun 30;54(1 Suppl):S43–S54. 10. Rubin LJ. Primary pulmonary hypertension. N Engl J Med 1997 Jan 9;336(2):111–7. 11. Weitzenblum E, Chaouat A, Charpentier C, Ehrhart M, Kessler R, Schinkewitch P, et al. Sleep-related hypoxaemia in chronic obstructive pulmonary disease: causes, consequences and treatment. Respiration 1997;64(3):187–93.
Contents lists available at ScienceDirect
Respiratory Medicine CME journal homepage: www.elsevier.com/locate/rmedc
Case Report
Reversible severe pulmonary hypertension in obesity hypoventilation and Mohr syndromeq Johannes E.S. Nolte*, Ulrich Koehler, Ali Keywan Sohrabi, Sebastian Canisius, Stephan Baumann, Claus Franz Vogelmeier University Hospital Giessen and Marburg, Department of Internal Medicine, Division of Pneumology, Baldingerstr. 1, 35033 Marburg, Germany
a r t i c l e i n f o
a b s t r a c t
Article history: Received 18 November 2009 Accepted 23 November 2009
A young overweight patient with Mohr–Claussen Syndrome was admitted to our department with the clinical diagnosis of pulmonary hypertension complaining about dyspnea at rest and excessive daytime sleepiness. Pulmonary function testing indicated severe airflow limitation and respiratory insufficiency. Pulmonary artery (PA) pressure was markedly increased. Pulmonary embolism, Alpha-1-antitrypsindeficiency, emphysema and anatomical obstructions were excluded. Polysomnography showed recurrent oxygen desaturations compatible with alveolar hypoventilations. Hypercapnic ventilatory response testing (HCVR) indicated a missing increase in minute ventilation when exposed to hypercapnia. After 6 weeks of nocturnal non-invasive ventilation therapy, her clinical condition markedly improved. Furthermore, PA pressure returned to normal values. HCVR testing showed an adequate response to hypercapnia. Mohr–Claussen syndrome is a rare genetic disease affecting the mouth, face and digits. Adult patients are usually very obese; exposing them at risk for obesity hypoventilation syndrome (OHS). OHS is described as a combination of obesity and awake arterial hypercapnia (PaCO2 > 45 mmHg) in the absence of other known causes of chronic alveolar hypoventilation. Unclear pulmonary hypertension in overweight patients should raise the suspicion for OHS. Ó 2009 Published by Elsevier Ltd.
Keywords: PAH Pulmonary hypertension Mohr–Claussen Syndrome CPAP Non-invasive ventilation Hypercapnic ventilatory response HCVR Chemoreception
1. Case presentation A 32 year-old overweight female patient was admitted to the department of cardiology with the clinical diagnosis of pulmonary hypertension. The patient complained about exercise intolerance, dyspnea at rest and intractable headache. Two weeks before initial presentation, her dyspnea progressively worsened and was accompanied by severe pedal edema. Besides, she mentioned increased daytime sleepiness (Epworth sleepiness scale (ESS): 18/24) and severe problems maintaining sleep including recurrent nightmares, which raised the suspicion for sleep-disordered breathing (Fig. 1). Her past medical history is significant for oro-facial-digitalsyndrome Type II (Mohr Syndrome) which was diagnosed in childhood. Medications included salbutamol bid, Tiotropium
q Financial support: University hospital Giessen and Marburg, Germany, Dept. of Internal Medicine, Division of Pneumology. * Corresponding author. Tel.: þ49 6421 586 2717. E-mail addresses: [email protected] (J.E.S. Nolte), koehleru@med. uni-marburg.de (U. Koehler), [email protected] (A.K. Sohrabi), canisius@med. uni-marburg.de (S. Canisius), [email protected] (S. Baumann), claus.vogelmeier@med. uni-marburg.de (C.F. Vogelmeier). 1755-0017/$36.00 Ó 2009 Published by Elsevier Ltd. doi:10.1016/j.rmedc.2009.11.008
bromide qd, an aldosterone antagonist qd (25 mg/day) and furosemide qd (20 mg/day). She smokes half a pack of cigarettes per day and has done so for the previous 12 years. At time of admission, her height was 148 cm with a body weight of 95 kg, corresponding to a body-mass index of 44 kg/m2. Blood pressure was 140/85 mmHg, heart rate 90 beats per minute. Aside from her obesity, nodules of the tongue, polydactyly, midline cleft of the lip, cyanosis of her hands as well as ankle edema were observed during physical examination. Both lungs were clear on auscultation; the remainder of the physical exam revealed no additional significant findings. Blood gas analysis showed a carbon dioxide pressure of 63.2 mmHg, an oxygen partial pressure of 38.3 mmHg and an oxygen saturation at room air of 77%, compatible with respiratory insufficiency. Pulmonary function testing (PFT) indicated severe airflow limitation (FEV1: 28% predicted, FEV1/FVC ratio: 48% predicted, airway resistance R: 281% predicted) and hyperinflation (residual volume 193% predicted). Furthermore, diffusion capacity of the lungs was impaired (transfer factor for carbon monoxide (DLCO): 62% predicted). Significant findings in the blood were a sodium level of 124 mEq, a potassium level of 2.9 mEq and a C-reactive protein of 28 mg/dl. Alpha-1-antitrypsin level was within normal range.
J.E.S. Nolte et al. / Respiratory Medicine CME 4 (2011) 30–32
31
Fig. 1. Oxygen saturation and heart rate during seven hours of sleep.
Chest X-ray demonstrated prominent interstitial markings with enlargement of the right and left ventricle and the right atrium. Cardiac ultrasound revealed a massively dilated right atrium and ventricle. The estimated systolic pulmonary artery pressure was 83 mmHg. A subsequently performed right heart catheterisation confirmed a systolic pulmonary arterial pressure of 82 mmHg, a diastolic pressure of 36 mmHg and a mean pressure of 51 mmHg. The mean pulmocapillary wedge pressure (PCWP) was 18 mmHg. Polysomnography showed recurrent oxygen desaturations down to 48% compatible with alveolar hypoventilations without any signs of obstructive or central sleep-disordered breathing (Fig. 1). Pulmonary embolism was excluded by a spiral chest CAT scan. In High-Resolution CT (HRCT) scan, no signs of parenchymal damage, emphysema or anatomical obstructions were found. Hypercapnic ventilatory response (HCVR) testing was initiated (Fig. 2, label ‘day1’), showing a very shallow rise in her minute ventilation when exposed to increasing levels of carbon dioxide. Testing was stopped when endexpiratory carbon dioxide values exceeded 100 mmHg. The patient was subsequently treated with nocturnal nasal continuous positive bilevel (nBiPAPÓ) ventilation (ventilator settings: inspiratory positive airway pressure: 19 cm H2O, expiratory pressure: 10 cm H2O, spontaneous/timed mode (‘‘ST’’), respiratory rate: 15/min). She returned 4 weeks later for follow-up. Her general clinical condition had improved markedly, she was able to walk two flights of stairs without any signs of dyspnea; her sleeping problems had vanished (ESS: 4/24). HCVR testing was repeated (Fig. 2, label ‘day30’), now illustrating a sharp rise in minute ventilation. Testing was stopped by the patient because of dyspnea. During a second follow-up 8 weeks after treatment initiation, her pulmonary artery pressure was measured again using ultrasound
Fig. 2. The hypercapnic ventilatory response (HCVR) on three different occasions.
yielding a complete resolution of her PH with an estimated mean systolic pressure of 12 mmHg. The HCVR (Fig. 2, label ‘day60’) showed a parallel line as compared to day 30, with a further left shift to normocapnic values. Moreover, we were able to stop her diuretic medications. 2. Discussion Mohr–Claussen syndrome or oro-facial-digital-syndrome type II is a rare autosomal recessive genetic disease characterised by tongue lobulation, midline cleft lip, high arched or cleft palate, broad nasal root with wide bifid nasal tip, hypertelorism, micrognathia, brachydactyly, syndactyly and polydactyly, bilateral reduplicated hallux, conductive hearing loss and normal intelligence.1 We suggest that pulmonary complications may be part of Mohr Syndrome. Our suspicion is supported by the fact that the patient’s 27 year-old sister who suffers from the same genetic disease was admitted to our department 6 weeks later. PFT showed similar changes as in her sister’s case with severe airway obstruction, hyperinflation and respiratory insufficiency. Adult patients with Mohr’s Syndrome share features with Obesity Hypoventilation Syndrome (OHS), including obesity. OHS is described as a combination of obesity and awake arterial hypercapnia (PaCO2 > 45 mmHg) in the absence of other known causes of chronic alveolar hypoventilation.2 OHS is thought to be the consequence of increased work of breathing due to obesity, normal or diminished respiratory drive, other associated sleep related breathing disorders such as obstructive sleep apnea, as well as endocrinological alterations like increased leptin resistance.3 These patients commonly experience a reduced electromyographic neuromuscular and ventilatory response to hypercapnia.4 Non-invasive mechanical ventilation (NIMV) can effectively improve clinical symptoms and daytime respiratory failure and can enhance the responsiveness to carbon dioxide. It has been suggested that an increase in leptin levels may reverse the blunted responsiveness to CO2 in OHS patients during NIMV.5,6 Another significant finding is the association between OHS and pulmonary hypertension (PH): In a large French trial investigating patients with OHS, more than 50% of these had PH, a much higher percentage than the 9% observed in patients with obstructive sleep apnea.7 Pulmonary hypertension is defined as a mean pulmonary artery pressure greater than 25 mmHg at rest or 30 mmHg with exercise.8 According to the Dana Point classification from 2008, PH is divided into six subgroups, namely pulmonary artery hypertension, pulmonary veno-occlusive diseases and/or pulmonary capillary hemangiomatosis, PH owing to left heart disease, PH owing to lung diseases and/or hypoxia (including OHS), chronic thromboembolic PH, and PH with unclear multifactorial mechanisms.9 The complex
32
J.E.S. Nolte et al. / Respiratory Medicine CME 4 (2011) 30–32
pathogenesis implies an imbalance of vascular effectors leading to vasoconstriction, endothelial cell proliferation and thrombosis.10 PH in patients with OHS may be either caused by chronic left heart failure following left ventricular hypertrophy (which is a common finding in severe obesity) or directly by alveolar hypoxia.11 To date, there is no reported data regarding the alterations in PH after initiation of NIMV in OHS patients. We are aware that the PH in our patient may also be secondary to her obstructive lung pattern. Nevertheless, it would be very unlikely that this form of PH would respond to NIMV. Moreover, PFT in morbid obese patients usually shows a restrictive pattern owing to increased chest wall impedance. The Hypercapnic Ventilatory Response (HCVR) testing was performed using a modified Read rebreathing device. Our setup adjusts automatically the fractions of oxygen, carbon dioxide and nitrogen in a closed loop system. The distinct changes in her minute ventilation when exposed to increasing levels of carbon dioxide with a sharp increase within 60 days of NIMV show impressively the dynamic properties of pulmonary chemoreceptors maintaining their full potential for recovery over a long time. Unclear pulmonary hypertension in overweight patients should raise the suspicion for obesity hypoventilation syndrome, particularly because early recognition and treatment improves outcome. We emphasize the importance of arterial blood gas testing in these patients to evaluate for daytime hypercapnia. Additionally, nocturnal
transcutaneous capnography may be a helpful tool establishing a diagnosis. References 1. Biswas A, Ghosh JK, Sinha MK, Basu K, Chatterjee S. Mohr–Claussen syndrome or oro-facial-digital syndrome (OFDS) type-II. J Pak Med Assoc. 2009 Jul;59(7): 484–6. 2. Subramanian S, Strohl KP. A management guideline for obesity-hypoventilation syndromes. Sleep Breath 1999;3(4):131–8. 3. Olson AL, Zwillich C. The obesity hypoventilation syndrome. Am J Med 2005 Sep;118(9):948–56. 4. Sampson MG, Grassino K. Neuromechanical properties in obese patients during carbon dioxide rebreathing. Am J Med 1983 Jul;75(1):81–90. 5. Masa JF, Celli BR, Riesco JA, Herna´ndez M, Sa´nchez De Cos J, Disdier C. The obesity hypoventilation syndrome can be treated with noninvasive mechanical ventilation. Chest 2001 Apr;119(4):1102–7. 6. Redolfi S, Corda L, La Piana G, Spandrio S, Prometti P, Tantucci C. Long-term non-invasive ventilation increases chemosensitivity and leptin in obesityhypoventilation syndrome. Respir Med 2007 Jun;101(6):1191–5. 7. Kessler R, Chaouat A, Schinkewitch P, Faller M, Casel S, Krieger J, et al. The obesityhypoventilation syndrome revisited: a prospective study of 34 consecutive cases. Chest 2001 Aug;120(2):369–76. 8. Barst RJ, McGoon M, Torbicki A, Sitbon O, Krowka MJ, Olschewski H, et al. Diagnosis and differential assessment of pulmonary arterial hypertension. J Am Coll Cardiol 2004 Jun 16;43(12 Suppl. S):40S–47S. 9. Simonneau G, Robbins IM, Beghetti M, Channick RN, Delcroix M, Denton CP, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 2009 Jun 30;54(1 Suppl):S43–S54. 10. Rubin LJ. Primary pulmonary hypertension. N Engl J Med 1997 Jan 9;336(2):111–7. 11. Weitzenblum E, Chaouat A, Charpentier C, Ehrhart M, Kessler R, Schinkewitch P, et al. Sleep-related hypoxaemia in chronic obstructive pulmonary disease: causes, consequences and treatment. Respiration 1997;64(3):187–93.