Pulmonary Hypertension and Cardiac Function in Adult Cystic Fibrosis*

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1 Pulmonary Hypertension and Cardiac Function in Adult Cystic Fibrosis* Role of Hypoxemia Kristin L. Fraser; D. Elizabeth Tullis, MD, FCCP; Zion Sasson, MD; Robert H. Hyland, MD, FCCP; Kristine S. Thornley, BSc; and Patrick J. Hanly, MD, FCCP Study objectives: To determine (1) the prevalence of pulmonary hypertension and cardiac dysfunction in adult cystic fibrosis (CF) patients with severe lung disease, (2) the relationship between these cardiovascular abnormalities and hypoxemia, and (3) the impact of subclinical pulmonary hypertension on survival. Design: Single-blind, cross-sectional study. Setting: Ambulatory clinic of the Adult CF program at a tertiary-level hospital. Patients: Clinically stable patients with severe lung disease (FEV 1 < 40% of predicted normal value) who were not receiving supplemental oxygen. A second cohort of patients in stable condition with less severe lung disease (FEV 1 40 to 65% predicted) was also recruited to enable multivariate analysis for the determinants of pulmonary hypertension. Measurements and results: Eighteen patients with severe lung disease (FEV % of predicted normal value) were initially studied. Each patient had overnight polysomnography, pulmonary function tests, and Doppler echocardiography. Arterial oxygen saturation (SaO 2 ) was reduced during wakefulness ( %) and fell during sleep ( %) while transcutaneous PCO 2 was normal during wakefulness ( mm Hg) and increased during sleep ( mm Hg). Left ventricular size, systolic function, and diastolic function were normal except in one patient who had had a previous silent myocardial infarction due to coronary artery disease. Qualitative assessment of right ventricular function was normal in all patients. Pulmonary artery systolic pressure (PASP) was increased (> 35 mm Hg) in seven patients without clinical evidence of cor pulmonale. Regression analysis was performed by combining these data with data from an additional 15 CF patients with moderately severe lung disease (FEV % predicted normal) who were recruited to a modified study protocol that included overnight oximetry, pulmonary function tests, and Doppler echocardiography. None of these patients had evidence of hypoxemia and only three had mild elevation of PASP (36, 37, and 39 mm Hg). Linear regression analysis revealed that PASP was significantly correlated with FEV 1 (r 0.44; p 0.013), and SaO 2 during wakefulness (r 0.60; p ), during sleep (r 0.56; p ), and after 6 min of exercise (r 0.75; p < ). Multivariate analysis revealed that awake SaO 2 was a significantly better predictor of PASP than FEV 1 (p ). Clinical follow-up of the original cohort for up to 5 years revealed that mortality was significantly higher in those with pulmonary hypertension than those without pulmonary hypertension (p ). Conclusions: In adult CF patients with severe stable lung disease, left and right ventricular function is well maintained in the absence of significant coronary artery disease; pulmonary hypertension develops in a significant proportion of patients and is strongly correlated with oxygen status, independent of lung function; and subclinical pulmonary hypertension is associated with an increased mortality. (CHEST 1999; 115: ) Key words: cystic fibrosis; nocturnal hypoxemia; polysomnography; pulmonary hypertension; sleep Abbreviations: BMI body mass index; CF cystic fibrosis; LV left ventricle, ventricular; LVD left ventricular dimension; LVM left ventricular mass; LVW left ventricular wall thickness; NREM nonrapid eye movement; PASP pulmonary artery systolic pressure; REM rapid eye movement; RV right ventricle, ventricular; RVW right ventricular wall thickness; Sao 2 arterial oxygen saturation; tco 2 transcutaneous Pco 2 CHEST / 115 / 5/ MAY,

2 Cystic fibrosis (CF) is the most common lethal genetic disease in white persons and occurs in approximately 1 of every 2,000 live births. 1 Advances in medical therapy have resulted in a dramatic improvement in survival such that many patients are living well into adulthood. Almost 50% of the 550 CF patients currently attending the University of Toronto CF clinic are 18 years of age. As the disease progresses, these patients develop disabling lung disease and eventually respiratory failure, pulmonary hypertension, and cor pulmonale. Although clinically apparent cor pulmonale is a preterminal event in many patients, 2 the prevalence of subclinical pulmonary hypertension and cardiac dysfunction in patients with severe lung disease and their influence on survival are not known. The pathophysiology of pulmonary hypertension and cor pulmonale in CF is thought to be related to progressive destruction of the lung parenchyma and pulmonary vasculature, and to pulmonary vasoconstriction secondary to hypoxemia. 3 Although both awake and sleep-related hypoxemia have been well documented in patients with CF, 4 8 its role in the development of pulmonary hypertension and cor pulmonale has not been conclusively demonstrated. The objectives of this study were (1) to determine the prevalence of subclinical pulmonary hypertension and cardiac dysfunction in adult CF patients with severe lung disease; (2) to examine the relationship between these cardiovascular abnormalities and hypoxemia; and (3) to evaluate the impact of subclinical pulmonary hypertension on survival. Patient Population Materials and Methods Adult patients ( 18 years old) with CF confirmed by an abnormal sweat test result were recruited from the Adult CF program at the Wellesley Hospital in Toronto. We recruited 18 patients with severe lung disease (FEV 1 40% of the predicted normal value) and 15 patients with moderately severe lung disease (FEV 1 40 to 65% predicted). All patients were in clinically stable condition over the month prior to the study with no exacerbations requiring antibiotic therapy or hospitalization. Patients were excluded if they had known primary cardiac disease (such as congenital heart disease, rheumatic valve disease, or pericarditis), significant respiratory disease that was not related to CF, or if they had received domiciliary oxygen therapy. *From St. Michael s Hospital, Wellesley Central Site, University of Toronto, Ontario, Canada. Supported by the Canadian Cystic Fibrosis Foundation and the Ontario Thoracic Society. Manuscript received June 25, 1997; revision accepted December 10, Correspondence to: Patrick J. Hanly, MD, FCCP, Room 6015, Bond Wing, St. Michael s Hospital, 300 Bond Street, Toronto, Ontario, Canada M5B1W8 Study Design Each patient with severe lung disease had a comprehensive overnight sleep study as described below. Patients with moderately severe lung disease had overnight oximetry alone. The next day, a Doppler echocardiographic study, an assessment of clinical stability, and pulmonary function studies were performed in all patients. Functional capacity was assessed by a 6-min walk test as previously described. 9 The technicians who performed the daytime investigations and the cardiologist who interpreted echo- Doppler studies were blinded to the patient s clinical status and the overnight sleep study results. The protocol was approved by the Wellesley Hospital Ethics Committee and informed consent was obtained from each patient. Sleep Studies The following variables were monitored during overnight polysomnography: two-channel EEG (C3 A2, C4 A1), electrooculogram, and submental electromyogram using surface electrodes. Airflow was detected by monitoring expired CO 2 at the nose and mouth through nasal cannulae adapted for this purpose and attached to a CO 2 analyzer (PB 223; Puritan-Bennett Corp; Lawrenceville, GA). Respiratory effort was monitored by respiratory plethysmography with transducers placed around the chest and abdomen (Respitrace; Ambulatory Monitoring, Inc; Ardsley, NY). Arterial oxygen saturation (Sao 2 ) was recorded with a pulse oximeter (Biox 3740; Ohmeda; Boulder, CO) set at its fastest response. Transcutaneous Pco 2 (tco 2 ) was recorded by a Pco 2 sensor placed on the anterior chest wall and attached to a CO 2 monitor (Micro Gas 7640; Kontron Instruments; Watford, UK). The ECG and heart rate were recorded from standard limb leads. All variables were continuously recorded on a computerized data acquisition system (Sandman; Melville Diagnostics; Ottawa, Canada) at a speed of 10 mm/s. tco 2 was displayed on a slow recorder (paper speed, 20 cm/h) synchronized with the polysomnograph. We used tco 2 monitoring to estimate changes in arterial Pco 2. The limitations of tco 2 monitoring include the time required for calibration, initial stabilization of the recording, and delayed response of the electrodes to a change in Pco 2. These factors were not major limitations to our overnight monitoring, where the trend over many hours was more important than instantaneous changes in Pco 2. Reduced skin perfusion, acidosis, and severe hypoxemia can also decrease the accuracy of these instruments. However, none of these factors were present in our outpatients who were in stable condition. All polysomnograms were scored manually and sleep stage and arousals were determined by established criteria using the EEG, electro-oculogram, and electromyogram. 10 Mean Sao 2 was calculated by averaging the high and low Sao 2 for each 30-s epoch. Mean tco 2 during sleep was calculated from the average tco 2 over 36-s intervals. Awake Sao 2 and tco 2 were similarly estimated by calculating mean Sao 2 and tco 2 at rest, during a 5-min period of wakefulness at the beginning of the sleep study. Echo-Doppler Studies M-mode, two-dimensional, and Doppler echocardiography were performed from the standard parasternal, apical, and subcostal views in the resting state, in the supine or left lateral position. The standard M-mode measurements of left atrium, left and right ventricular wall thickness (LVW, RVW), and internal left ventricular dimension (LVD) and right ventricular (RV) dimension at end-diastole were made from the parasternal long-axis view as recommended by the American Society of Echocardiography. 11 Whenever possible, M-mode measures of end-diastolic RV free wall thickness were made from the 1322 Clinical Investigations

3 parasternal views. When there was uncertainty of the anterior border in the M-mode tracings, RV free wall thickness was obtained from the two-dimensional images in the subcostal view. Left ventricular mass (LVM) was calculated using the following formula 12 : LVM 0.8 (1.04 [LVD LVW] 3 LVS 3 ) 0.6 where LVS is left ventricular systolic. The LVM index was calculated by dividing LVM by body surface area (in m 2 ) as derived from the patient s height and weight. RV function was qualitatively assessed in the apical four-chamber and subcostal views of the transthoracic echo study, and graded as normal, mildly impaired, or severely impaired. Left ventricular (LV) systolic function was assessed by a semiquantitative two-dimensional echocardiographic scale of 1 to 4, where grade 1 is normal (ejection fraction 60%) and grade 4 indicates severe ventricular dysfunction (ejection fraction 20%). 13,14 LV systolic function was also assessed by M-mode measurements of fractional shortening 15,16 as follows: fractional shortening (%) LVD (end-diastole) LVD (end-systole) LVD (end-diastole) In patients without segmental wall motion abnormalities, LV ejection fraction was derived from M-mode measurements of ventricular dimensions 16,17 as follows: ejection fraction (%) [LVD (end-diastole)]3 [LVD (end-systole)] 3 [LVD (end-diastole)] 3 Ejection time was defined as the time from aortic valve opening to aortic valve closure and was measured from Doppler recordings of aortic valve opening and closure clicks. It was then corrected for resting heart rate. 18 LV diastolic function was assessed by pulsed Doppler echocardiography 19,20 using ultrasound systems (Sonos 1000 and 2500; Hewlett-Packard; Andover, MA). This method of assessing LV filling is well established and has been validated against contrast and radionuclide angiography. 21,22 The variables measured included isovolumic relaxation time, defined as the time between aortic valve closure and mitral valve opening; peak early filling velocity; peak late filling velocity; the ratio of the latter two variables, a measure of LV filling in early vs late diastole; and mitral pressure half-time, a measure of the rate of deceleration of early diastolic flow. Transmitral flow was analyzed from the apical view, with a sample volume at the mitral leaflet tips level so as to obtain the highest E point velocity as well as the mitral opening and closure sounds. Isovolumic relaxation time was measured with the sample volume at the LV outflow tract, closer to the aortic valve so as to record both aortic closure and mitral opening sounds. Each parameter was measured at end-expiration as judged by an experienced cardiac sonographer and averaged over at least three consecutive analyzable beats. Pulmonary artery systolic pressure (PASP) was measured from the continuous-wave Doppler signal of the tricuspid regurgitation gradient by the simplified Bernoulli equation (Dp 4v 2, where Dp is the peak pressure difference between RV and right atrium, and v is the peak flow velocity of the tricuspid regurgitant jet) and added to the right atrial pressure, which was assumed to be 10 mm Hg. All measurements were made by a single observer blinded to the clinical status of the patients. The interobserver and intraobserver variabilities of these parameters from this laboratory are 6% and 3%, respectively, which are small and similar to the variabilities in other published reports. 23 All echo-doppler studies were done in the resting state on the day after the overnight sleep study, before the 6-min walk test. Pulmonary Function Studies Vital capacity and flow rates were measured by spirometry. Blood gas analysis was performed on blood drawn from the radial artery while the patient was at rest and breathing room air. The functional capacity of subjects was quantitatively measured by perfoming the 6-min walk test, which has been reported to correlate with conventional measures of functional status and exercise capacity. 9 The test was administered by a single supervisor, and standardized instructions were given to each patient. The total distance walked and the initial and final Sao 2 were recorded by pulse oximetry. Statistical Analysis Data are expressed as mean SD. 24 Student s two-sided t test was used to analyze changes in oxygen saturation and tco 2 between sleep stages and wake. Linear and multivariate regression analyses were used to determine the relationship of pulmonary artery pressure to pulmonary function and oxygen status. Survival differences between patients with and without pulmonary hypertension were assessed using a log rank test Ap value of 0.05 was considered significant. Results Patients With Severe Lung Disease Four of the 18 patients studied were female and 14 were male. The average age was 30.2 years (range, 21 to 40) and the mean body mass index (BMI) was 21.9 kg/m 2 (range, 18.3 to 31.2). Indices of pulmonary function are summarized in Table 1. All patients had severe, stable lung disease. Mild hypoxemia was present at rest, and two of our patients had evidence of CO 2 retention with arterial Pco 2 of 66 and 53 mm Hg. Mean Sao 2 and tco 2 during wakefulness and sleep are summarized in Table 2. Mild hypoxemia was present while patients were awake and Sao 2 fell during sleep, although the degree of desaturation was not statistically significant. The observed fall in Sao 2 was greater during rapid eye movement (REM) sleep than during nonrapid eye movement (NREM) sleep and was accompanied by a significant increase in tco 2, which was also greater during REM than NREM sleep. During the 6-min walk test, subjects walked a mean distance of m (range, 90 to 578). Mean Sao 2 fell significantly from % at rest to % at the end of 6 min (p 0.001), indicating that some of our patients experienced significant hypoxemia during routine exertion. Oxygen saturation fell from 89 to 64% in one patient, while all of the other patients demonstrated only CHEST / 115 / 5/ MAY,

4 Table 1 Spirometry and Arterial Blood Gases in Patients With and Without Pulmonary Hypertension* PH No PH Measurement % Predicted Measurement % Predicted Spirometry FEV 1, L FVC, L FEV 1 /FVC, L Arterial blood gases Po 2, mm Hg Pco 2, mm Hg ph Serum bicarbonate, meq/l *Data are presented as mean SD. PH pulmonary hypertension. small degrees of desaturation. A comparative group of eight healthy control subjects aged years also performed this test in our laboratory and walked a significantly greater distance, m (p vs CF patients), and the Sao 2 at the end of 6 min was significantly higher at % (p vs CF patients). Table 3 summarizes the echo-doppler results in our patients. The PASP could be obtained in only 17 patients because hyperinflation of the chest limited visualization of the Doppler signal of tricuspid regurgitation in one patient. PASP was elevated in seven patients (range, 37 to 71 mm Hg), RVW was increased in seven patients (range, 5.1 to 6.1 mm), and both were increased in four patients. One 40-yearold man was found to have segmental hypokinesis and dyssynergy of the LV with grade 2 systolic function and an accompanying reduction in fractional shortening and calculated ejection fraction. This was investigated and found to be due to a previous silent myocardial infarction associated with coronary artery disease, confirmed by a thallium perfusion scan. Remaining ventricular dimensions, qualitative assessment of LV and RV function, and specific indexes of LV systolic function were normal in 17 of 18 patients. LV diastolic function was normal in all subjects. Patients With Moderately Severe Lung Disease Characteristics of this group are summarized in Table 4. None of these patients had hypoxemia while awake or during sleep or exercise, and only three patients had evidence of mildly elevated PASP (36, 37, and 39 mm Hg). Determinants of Pulmonary Hypertension Linear regression analysis (Fig 1) revealed that PASP was significantly correlated with FEV 1 (r 0.44; p 0.013), mean oxygen saturation during wakefulness (r 0.60; p ), mean oxygen saturation during sleep (r 0.56; p ), and mean oxygen saturation at the end of the 6-min walk test (r 0.75; p ). PASP was not significantly correlated with BMI, daytime arterial Pco 2,tco 2 during sleep, or the distance walked in 6 min. Multivariate regression analysis revealed that awake Sao 2 was the single best predictor of PASP and that this effect was independent of the relationship between oxygen status and FEV 1 (p 0.014). Clinical Follow-up of Patients With Severe Lung Disease The mean duration of enrollment in the study was 47 months. Clinical follow-up ranged from 21 to 66 Table 2 Mean SaO 2 and tco 2 During Wakefulness and Sleep in Patients With and Without Pulmonary Hypertension* Sleep Awake TST NREM REM Pulmonary hypertension Sao 2, % tco 2, mm Hg No pulmonary hypertension Sao 2, % tco 2, mm Hg *Data are presented as mean SD. TST total sleep time. p 0.05 vs awake Clinical Investigations

5 Table 3 Echo-Doppler Data in Patients With Severe Lung Disease* Echo-Doppler Data Normal Value Patient Data PASP, mm Hg (n 17) BP, mm Hg (n 18) 118/75 12/8 Ventricular size RV dimension, mm (n 16) RVW, mm (n 16) LVD, mm (n 18) LVW, mm (n 18) LVM index, g/m 2 (n 18) Systolic function (LV) FS,%(n 16) EF,%(n 16) ET, ms (n 16) Diastolic function (LV) IVRT, ms (n 16) E/A (n 16) T 2, ms(n 15) *FS fractional shortening; EF ejection fraction; ET ejection time; IVRT isovolumic relaxation time; E/A ratio of early to late diastolic filling velocity; T 1 2 mitral pressure half-time. Normal values for our laboratory are displayed. Data are presented as mean SD. See text for details. months. In order to examine the impact of pulmonary hypertension on clinical outcome, we divided patients into two groups those with PASP 35 mm Hg and those with PASP 35 mm Hg and compared their cumulative survival (Fig 2 and Table 5). Mortality was significantly higher (p ) in patients with pulmonary hypertension (defined as PASP 35 mm Hg) as seen in Figure 2, which illustrates the number of survivors within each group expressed as a percentage of the number of patients who were followed up at that time. In the group with pulmonary hypertension (seven patients), two died of respiratory failure and four received a lung transplant (three of whom subsequently died). The patients who received a lung transplant were also classified as respiratory deaths because they had Figure 1. Correlation between PASP and FEV 1 (top left), mean oxygen saturation during wakefulness (Sao 2 W; top right), mean oxygen saturation during sleep (Sao 2 S; bottom left), and mean oxygen saturation at the end of the 6-min walk test (Sao 2 WT; bottom right). severe respiratory failure and a lung transplant was done as a life-saving measure. One of the selection criteria for placement on the lung transplant list at our institution is the clinical prediction of death within 12 months without this intervention. Since the transplants were performed 10, 18, 19, and 30 months before the end of the follow-up period, we believe that it is appropriate to classify these patients outcomes as respiratory deaths. Of the 10 patients without pulmonary hypertension, seven died or received a lung transplant. Interestingly, two of the three patients within this group who received a lung transplant are still alive. Table 4 Characteristics of Patients With Moderate and Severe Lung Disease* Patient Characteristics Moderate Lung Disease (n 15) Severe Lung Disease (n 18) Age, yr Male female ratio FEV 1, % predicted FVC, % predicted Sao 2 during wakefulness Sao 2 during sleep Sao 2 at end of 6-min walk test PASP, mm Hg *Data are presented as mean SD. Discussion Clinical cor pulmonale occurs in the terminal stages of CF and its onset carries a grave prognosis. 28 The mean survival time from the onset of clinically apparent cor pulmonale has been reported to be as short as 8 months. 2 The nearly universal finding of severe hypoxemia in association with clinical cor pulmonale is, therefore, not surprising. We chose to study patients with severe CF (FEV 1 40% predicted) prior to the development of hypoxemia or clinically apparent cor pulmonale to investigate the prevalence of pulmonary hypertension and cardiac dysfunction at this stage of the disease and to CHEST / 115 / 5/ MAY,

6 Figure 2. Cumulative survival in two groups of patients with severe lung disease: those with pulmonary hypertension (PASP 35 mm Hg) and those without pulmonary hypertension (PASP 35 mm Hg). Survival was significantly lower in those with pulmonary hypertension (p ) determine the contribution of hypoxemia to the development and progression of cor pulmonale. We found no significant RV dysfunction in 18 CF patients with severe lung disease. Previous investigators have reported RV dysfunction in 0 to 72% of subjects with CF, but all of these groups studied heterogeneous populations. When patients were stratified according to disease severity, RV ejection fraction was abnormal in all six patients with severe disease (including four with clinical cor pulmonale), three of six patients with moderate disease, and none of the 10 patients with mild disease. 31 Although we found evidence of RV hypertrophy, RV function was normal in our population of patients with severe, stable disease without clinical cor pulmonale. This suggests that Table 5 Mortality in CF Patients With and Without Pulmonary Hypertension* Patient Characteristics PH No PH No. of patients 7 10 Respiratory deaths 6 7 Respiratory failure 2 4 Lung transplantation 4 3 Nonrespiratory deaths 0 0 *PH pulmonary hypertension. RV hypertrophy may be a precursor to ventricular failure that is delayed until the terminal stages of disease. LV dysfunction was seen in one of our subjects. This was an unexpected finding of regional myocardial ischemia in a 40-year-old man with CF-induced diabetes mellitus. LV dysfunction in CF may be due to myocardial fibrosis, hypoxemia, or abnormal septal motion due to a markedly dilated RV. 29 Coronary artery disease is not a well-documented cause of impaired LV function in patients with CF, but as the CF population ages, complications of diabetes are increasingly being reported. Microvascular complications have been reported in as many as 21% of diabetic CF patients. 33 Several studies have documented preserved LV function in the presence of normal or severely impaired RV function. 29,31 However, one group reported a reduced LV ejection fraction with a diffusely hypokinetic ventricle in 19% of CF patients (4 of 17). 30 None of these previous studies have focused on subjects with severe stable disease before the development of clinical cor pulmonale, which may account for the inconsistent results. Our findings are in agreement with most previous reports that LV dysfunction is rare even in patients with severe pulmonary disease. 29,31 The prevalence of coronary artery disease in adults with CF, particularly those with diabetes mellitus, may increase as life expectancy continues to improve and the population ages. LV diastolic filling patterns have been found to be significantly different in patients with CF than in normal subjects, and were found to correlate with worsening pulmonary disease. 34 However, overt diastolic dysfunction was not demonstrated, and we also found diastolic filling to be within the normal range. Subtle changes in the diastolic filling patterns likely occur prior to the development of overt heart failure but diastolic dysfunction per se is uncommon. Pulmonary hypertension (PASP 35 mm Hg) was found in 7 of 17 subjects (41%) with severe stable disease without clinical signs of cor pulmonale. Only 3 of 15 subjects (20%) with moderate lung disease had mild elevation of PASP (36, 37, and 39 mm Hg). Although the prevalence of cardiac dysfunction has been studied in this population, to our knowledge, the prevalence of pulmonary hypertension has not been previously reported. PASP was significantly correlated with declining pulmonary function (FEV 1 ). Previous studies have also found that abnormalities of RV structure or function correlate with pulmonary function and/or clinical status. 28,30,31,35,36 In our study, PASP correlated significantly with awake and nocturnal oxygen saturation as well as with the degree of oxygen desaturation on exercise. Matthay and colleagues Clinical Investigations

7 also noted that arterial oxygen tension was lower in those CF patients with a reduced RV ejection fraction (using radionuclide angiocardiography). One group has previously studied the relationship between oxygen status and cardiac function in 11 CF patients and found no significant correlation between RV function and awake or nocturnal Sao 2 ; however, pulmonary artery pressures were not measured. 3 Awake and asleep oxygen saturations decline with increasing respiratory impairment as reflected by a reduction in FEV 1 ; consequently, the correlation of these measurements with PASP may simply reflect parallel changes in coexisting indexes of disease severity. However, both intermittent and sustained hypoxemia have been implicated in the pathogenesis of pulmonary hypertension in animal models 37,38 and in humans with obstructive sleep apnea and COPD. 39 Furthermore, correction of hypoxemia with supplemental oxygen therapy has been shown to reverse the progression of pulmonary hypertension in COPD. 40 Other indexes of advanced disease in our patients, such as arterial Pco 2, BMI, and the distance walked in 6 min, did not correlate with PASP. This suggests that pulmonary hypertension is not just a marker of lung damage; rather, hypoxemia contributes to the development of pulmonary hypertension in adults with CF. Finally, our multivariate analysis lends further support to the notion that hypoxemia contributes to the development of pulmonary hypertension; oxygen saturation was predictive of pulmonary hypertension, independent of lung function (FEV 1 ). The use of supplemental oxygen in CF has been studied by Zinman et al 41 in a randomized controlled clinical trial. Twenty-eight CF patients with an awake Pao 2 65 mm Hg were given nocturnal O 2 or compressed air (control group). After 1 year of treatment, there were no differences in mortality, frequency of hospitalizations, or progression of disease, although school or work attendance was better in the treated group. However, the sample size was small (14 patients in each group) and the duration of treatment (7 h/d for 12 months) was brief, which may have precluded a positive result. In the Nocturnal Oxygen Therapy Trial, which demonstrated that supplemental oxygen improved survival in patients with COPD, the sample size was larger (101 subjects in each group), the duration of therapy longer (12 to 18 h/d for a mean of 19.3 months), and improved survival was not apparent until 500 days after oxygen therapy was started. 42 Our patients were observed for up to 59 months (mean, 47 months from enrollment). In our analysis, death and lung transplantation were considered end points for survival because lung transplantation is considered a life-saving measure. Of the seven patients with evidence of pulmonary hypertension, two died and four received a lung transplant. The mean survival or time until transplant in this group was months. Of the 10 patients with normal pulmonary artery pressures, 3 are alive without lung transplant and 2 are alive after lung transplantation. The mean survival or time until transplant was months. The survival rates in subjects with and without pulmonary hypertension were significantly different (p ), indicating that subclinical pulmonary hypertension is an important predictor of mortality. Interestingly, the time until death or transplantation in patients with pulmonary hypertension was longer than the survival previously described in patients with clinical cor pulmonale 2,28 ; and we attribute this to the detection of disease in these patients at an earlier stage of their disease. Therefore, patients with echocardiographic evidence of pulmonary hypertension have a poorer prognosis than those with normal pulmonary pressures but may survive for many months. We suggest that patients with severe lung disease (arbitrarily defined as FEV 1 40% predicted) undergo overnight and exercise oximetry and Doppler echocardiography. We estimate that up to 40% of this population has pulmonary hypertension without clinical evidence of cor pulmonale. Patients with better pulmonary function (FEV 1 40% predicted) have a much lower incidence of pulmonary hypertension. We further recommend that transplantation be considered in patients with an elevated PASP because we have described a reduced survival in this population. The effect of such screening and intervention will require further study before definitive guidelines can be made. In summary, pulmonary hypertension was found in 41% of patients with advanced, stable CF without clinical evidence of cor pulmonale and was associated with a reduced survival. Our findings suggest that oxygen desaturation at rest and during sleep and exercise contribute to the development of pulmonary hypertension. Further studies are required to determine whether supplemental oxygen therapy delays the development of pulmonary hypertension and improves the associated morbidity and mortality. References 1 di Sant Agnese PA, Talamo RC. 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