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Effects of Continuous Positive Airway Pressure on Pulmonary Function and Exercise Tolerance in Patients With Congestive Heart Failure
CHEST
Original Research HEART FAILURE
Effects of Continuous Positive Airway Pressure on Pulmonary Function and Exercise Tolerance in Patients With Congestive Heart Failure* Veronica L. Wittmer, MSc; Giovana M. S. Simoes, MSc Luciana C. M. Sogame, PhD; and Elisardo C. Vasquez, PhD
Study objectives: Continuous positive airway pressure (CPAP) has been used to improve cardiopulmonary function and reduce pulmonary edema symptoms in patients with congestive heart failure (CHF). The objective of this study was to evaluate the efficacy of CPAP therapy on pulmonary function and exercise tolerance in patients with CHF. Design: Prospective blind randomized clinical study. Participants: Twenty-four patients with class II or III CHF and dilated cardiomyopathy were randomly assigned to 30 min of CPAP therapy and respiratory exercises (CPAP group) or respiratory exercise only (control group) once a day for 14 days. Measurements and results: Evaluation of pulmonary function was performed measuring FEV1 and FVC. Exercise tolerance was assessed measuring the distance walked during the 6-min walking test (6MWT). These parameters were measured before treatment and 4 days, 9 days, and 14 days later. CPAP therapy caused a progressive increase (p < 0.05) in both FVC (maximum of 16% after 9 days) and FEV1 (maximum of 14% after 14 days) compared to basal values, without significant changes in the control group. The 6MWT showed a progressive improvement in the distance walked in the CPAP group, reaching approximately 28% above the basal values in the CPAP group and without significant changes in the control group. Conclusions: These data show that the use of CPAP therapy for 2 weeks on a daily basis is able to enhance pulmonary function and consequently improve the tolerance to physical activities in patients with CHF. The clinical implication of this finding is that CPAP therapy could potentially be used as an adjunct to the treatment of CHF patients. (CHEST 2006; 130:157–163) Key words: continuous positive airway pressure ventilation; exercise tolerance; FVC; heart failure; pulmonary function test Abbreviations: ANOVA ⫽ analysis of variance; 6MWT ⫽ 6-min walk test; CHF ⫽ congestive heart failure; CPAP ⫽ continuous positive airway pressure
heart failure (CHF) resulting from C ongestive dilated cardiomyopathy is a serious disease associated with excessive morbidity and mortality and of elevated costs to health-care plans and the government. Despite advances in the pharmacologic ther*From the Physiological Sciences Graduate Program (Ms. Wittmer and Ms. Simoes), Biomedical Center, Federal University of Espirito Santo; and Emescam College of Health Sciences of Vitoria (Drs. Sogame and Vasquez), Vitoria, Brazil. The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/orgainzations whose products or services may be discussed in this article. Manuscript received October 4, 2005; revision accepted January 11, 2006. www.chestjournal.org
apy for CHF, the mortality from this disease remains very high. A consequence of the CHF is an extensive fluid accumulation in the lungs (pulmonary edema), which results in muscle fatigue or dyspnea symptoms when performing routine activities and progressing to dyspnea at rest.1,2 Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal. org/misc/reprints.shtml). Correspondence to: Elisardo C Vasquez, PhD, Physiological Sciences Graduate Program, Biomedical Center, Federal University of Espirito Santo, Av. Marechal Campos 1468, Vitoria, 29042–755 ES, Brazil; e-mail: [email protected] DOI: 10.1378/chest.130.1.157 CHEST / 130 / 1 / JULY, 2006
157
Oxygen supplementation and administration of drugs are commonly used as an attempt to decrease lung edema and improve myocardial performance in patients with CHF,3 but severe respiratory failure develops in many patients and requires intubation and mechanical ventilation. An additive approach that has long been used to improve pulmonary function in these patients is the use of continuous positive airway pressure (CPAP) delivered through a tight-fitting nasal or oronasal mask.4 The main direct benefits of CPAP include improvement in oxygenation, a decrease in respiratory work, and decrease in left ventricular preload and afterload.3–5 It is reasonable that the increase in cardiac and respiratory function may result in beneficial effects on the exercise capacity in CHF patients, as reported by Nanas et al.6 However, it has not yet been investigated if the improvement of pulmonary function through CPAP therapy affects the tolerance to physical exercise in CHF patients. Considering that any intervention that favorably alters integrated cardiopulmonary function should improve exercise endurance, this study was designed to determine the effects of CPAP therapy on the pulmonary function and its contribution to exercise tolerance in patients with CHF. Materials and Methods
ratio. Measurements were obtained in the sitting position with a closed-circuit spirometer (Respiradyne II Plus; Kendall Healthcare Products Company; Mansfield, MA). Predicted values for FEV1, FVC, and FEV1/FVC ratio were calculated using reference values of Knudson et al.8 Six-Minute Walk Test The 6-min walk test (6MWT) was performed in an indoor, 25-m long corridor, according to the suggestions from Guyatt et al.9 In brief, the patients were asked to walk at their highest rate from one end of the corridor to the other end as many times as possible within the established time of 6 min. The test was performed under the control of a therapist who encouraged the patients with phrases like “you are doing well” or “you are doing a good job; keep going.” At the end of the 6-min period, the therapist measured the distance walked by the patient. Respiratory Exercises Patients in the sitting position were subjected to three different respiratory exercises, each exercise repeated 10 times. First, slow inspiration through the nose was performed up to the maximum to reach total lung capacity, followed by a brief expiration through the mouth and another maximum inspiration followed by a complete expiration. Second, inspiration through the nose was performed up to approximately one half of total lung capacity, followed by a brief expiration through the mouth, another inspiration up to approximately two thirds of the total lung capacity followed by a brief expiration, and finally an inspiration up to the total lung capacity followed by a prolonged expiration. Third, brief and consecutive inspirations were performed through the nose until total lung capacity was reached, followed by a prolonged expiration through the mouth.
Subjects
Walking Exercise
The procedures used in this study were in accordance with the recommendations of the Helsinski Declaration of 1975. All subjects provided written informed consent before entry, and the protocol was approved by the Ethics Committee at the College of Health Sciences of Vitoria. We recruited consecutive patients who were admitted to the hospital for treatment of CHF. Patients were eligible to participate if they had a clinical diagnosis of New York Heart Association class II or III CHF. Patients were excluded from participating in the study if they had one or more of the following conditions: (1) unstable angina; (2) atrial fibrillation or third-degree atrioventricular blockade; (3) myocardial infarction; (4) cardiac surgery within 1 year prior to study entry; (5) pulmonary disease; (6) radiologic signs of pleural effusion; (7) use of bronchodilators; (8) pregnancy; (9) frequent vomiting; (10) smokers; (11) unable to successfully complete the walking test; and (12) ⬍ 30 years old and ⬎ 80 years old. After a clinical examination, which included echocardiography, ECG, and chest radiography by an independent physician who acted on clinical judgment alone, 24 patients were randomly assigned to the CPAP group or the control group. During the study, two patients were excluded: one because angina pectoris developed during the walking test, and the other because of CPAP therapy intolerance.
All patients were asked to walk 100 m/d at a slow pace under the control of a therapist.
Spirometry
Experimental Protocol
Routine spirometry was performed following the standardization of the American Thoracic Society.7 Pulmonary function testing included measurement of FEV1, FVC, and FEV1/FVC
All patients were initially subjected to a physical evaluation and also evaluation of arterial pressure, heart rate, hemogram, respiratory frequency, and peripheral hemoglobin oxygen saturation,
158
CPAP Therapy CPAP was applied through a tight-fitting nasal mask (Sollo; Sao Paulo, Brazil) breathing at pressure of 8 cm H2O with the mouth closed for a 30-min period every morning while awake and in the sitting position. BP, Heart Rate, and Hemoglobin Saturation With Oxygen Measurements Systolic and diastolic arterial BP were measured with a validated automatic sphygmomanometer (model HEM-705CP; Omron; Chicago, IL) with the patient at rest and in a sitting position following the IV Brazilian guidelines in arterial hypertension.10 Heart rate was measured using a portable monitor (model A1; Polar Electro; Lake Success, NY) positioned around the patient’s thorax. Peripheral hemoglobin oxygen saturation was measured through a fingertip pulse oximeter (Onyx; Nonin Medical; Plymouth, MN).
Original Research
After that, patients were allocated to daily CPAP therapy plus respiratory and walking exercises (CPAP group, n ⫽ 12) or respiratory and walking exercises (control group, n ⫽ 10) in a blind randomized, prospective study design. Spirometry and 6MWTs were performed by an independent investigator 1 day before treatment (day 0) and at the fourth, ninth, and 14th days of treatment, and all other parameters were measured every day in both groups. Statistical Analysis All data are expressed as mean ⫾ SEM. Means of groups were compared by two-way analysis of variance (ANOVA) for repeated measurements followed by the post hoc Tukey/Kramer test. A Student t test was used for comparisons of two means when appropriate. The relative changes in the FVC, FEV1, and 6MWT distance were determined as follows: ⌬% ⫽ ([posttreatment value – pretreatment value]/pretreatment value) ⫻ 100; p ⬍ 0.05 was considered significant.
Results Subject Characteristics Eleven patients included in this analysis were in New York Heart Association class II (CPAP group, n ⫽ 5; control group, n ⫽ 6), and 11 patients were in class III (CPAP group, n ⫽ 5; control group, n ⫽ 6). The characteristics of the patients are shown in Table 1. CPAP and control groups were comparable in age, body mass index, heart rate, systolic and diastolic arterial BP, respiratory rate, and hemoglobin saturation with oxygen. Although patients were randomly allocated in each group, the left ventricular ejection fraction was 8% higher in the CPAP group than in the control group. Initial physical examination showed that some patients had a respiratory rate ⬎ 22 breaths/min (CPAP group, n ⫽ 2; control group, n ⫽ 4); lowerextremity edema (CPAP group, n ⫽ 6; control group, n ⫽ 6); abdominal distension suggestive of ascites (CPAP group, n ⫽ 2; control group, n ⫽ 1);
Table 1—Characteristics and Vital Signals of the Patients* Parameters
Control Group
CPAP Group
Female/male gender, No. Body mass index, kg/m2 Age, yr Heart rate, beats/min Systolic arterial BP, mm Hg Diastolic arterial BP, mm Hg Left ventricular ejection fraction, % Respiratory rate, breaths/min Hemoglobin saturation with oxygen, %
4/6 22.6 ⫾ 1.0 52.7 ⫾ 11.4 76 ⫾ 3.1 97 ⫾ 2.9 69 ⫾ 1.8 39.2 ⫾ 0.9 19 ⫾ 0.7 94.9 ⫾ 0.5
6/6 24.9 ⫾ 0.5 59.8 ⫾ 3.7 73 ⫾ 5.1 98 ⫾ 4.8 67 ⫾ 2.8 42.7 ⫾ 1.9† 18 ⫾ 0.9 94.5 ⫾ 0.5
*Data are presented as mean ⫾ SEM unless otherwise indicated. †p ⬍ 0.05 vs control group. www.chestjournal.org
pulmonary crackles (CPAP group, n ⫽ 7; control group, n ⫽ 5); paroxysmal nocturnal dyspnea (CPAP group, n ⫽ 3; control group, n ⫽ 2); jugular vein congestion (CPAP group, n ⫽ 5; control group, n ⫽ 6); and hepatojugular reflux (CPAP group, n ⫽ 5; control group, n ⫽ 5). In addition, the hemogram showed the presence of anemia in some patients (CPAP group, n ⫽ 5; control group, n ⫽ 7). As shown in Table 2, all the patients from CPAP and control groups had a left ventricular ejection fraction ⱕ 45% and dilated cardiomyopathy associated with valvular diseases. All patients from both groups were receiving medication, as shown in Table 3. In the pulmonary function tests, it was observed that FVC was similar in the CPAP and control groups (66 ⫾ 6% vs 69 ⫾ 5% of predicted, respectively; p ⬎ 0.05). FEV1 was also similar in the CPAP and control groups (63 ⫾ 6% vs 67 ⫾ 4% of predicted value; p ⬎ 0.05). Most of the patients in the control group (8 of 10 patients) and CPAP group (9 of 12 patients) showed a restrictive spirometric pattern, ie, a FVC ⬍ 80% of the predicted value and a FEV1/FVC ratio ⬎ 75% of the predicted value, in the pretreatment evaluation (day 0). However, the spirometric parameters were comparable in both groups. One patient of each group presented with obstructive spirometric pattern: FEV1 ⬍ 80% of the predicted value and FEV1/FVC ratio ⬍ 75% of the predicted value. The other three patients (control group, n⫽ 1; CPAP group, n ⫽ 2) showed a normal spirometric pattern. The distance walked in the 6MWT in the pretreatment evaluation was similar in the CPAP group (344 ⫾ 25 m) and the control group (341 ⫾ 16 m). Effects of CPAP The group treated with CPAP showed a progressive increase in FVC, reaching a maximum of 16% of Table 2—Incidence of Cardiac Diseases Evidenced by Echocardiography* Parameters Dilated cardiomyopathy Idiopathic Alcoholic After rheumatic fever Mitral failure Mitral stenosis Tricuspid failure Aortic failure Aortic stenosis Left ventricular ejection fraction ⱕ 45%
Control Group (n ⫽ 10)
CPAP Group (n ⫽ 12)
8 0 4 8 2 2 6 1 10
5 1 4 6 1 1 3 2 12
*Data are presented as No. CHEST / 130 / 1 / JULY, 2006
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Table 3—Frequency of Cardiovascular Medication Used by the Patients* Drugs Diuretic Digitalis glycoside -Blocker Angiotensin-converting enzyme inhibitor Vasodilator Amiodarone Anticlotting
Control Group (n ⫽ 10)
CPAP Group (n ⫽ 12)
8 4 2 3
5 4 1 5
0 2 3
1 1 4
*Data are presented as No.
the basal value on the ninth day of treatment without additional improvement on the 14th day of treatment, in contrast with the control group, which showed no significant improvement at any time point (Fig 1). Similarly, FEV1 values progressively increased and reached a maximum of 14% on the 14th day of CPAP treatment, without any significant change in the control group (Fig 2). At the end of experiments, three patients from CPAP group and one patient from the control group changed from a restrictive to a normal spirometric pattern. However, Figure 2. Time course of relative changes in FEV1. Values are mean ⫾ SEM; *p ⬍ 0.05 vs control group (ANOVA).
no changes of pattern were observed in those patients with a previous diagnosis of airway obstruction. As summarized in Figure 3, the 6MWT showed a progressive improvement in the distance walked in the CPAP group, reaching approximately 28% above basal values at the end of treatment, but no significant changes were observed in the control group. Discussion
Figure 1. Time course of relative changes in FVC. Values are mean ⫾ SEM; *p ⬍ 0.05 vs control group (ANOVA). 160
Reduced exercise capacity is one of the characteristics of patients with CHF and is correlated with abnormal respiratory function, as noted in this study, and involves several other mechanisms, including impaired tissue oxygen extraction11,12; abnormalities in skeletal muscle metabolism and structure,12–14 and reduced skeletal muscle blood flow during exercise12,13; hyperventilation caused by elevated physiologic dead space in the edematous lung12,13; reduced myocardial -adrenoceptor density and sensitivity12,13; chronotropic failure12–15; and diastolic dysfunction.15 It is interesting that CHF patients show persistent physical limitations after heart transplantation, probably due to increased vasoconstriction drive to skeletal muscles.16 In the current study, Original Research
Figure 3. Time course of relative changes in distance walked in 6 min by the patients. Values are mean ⫾ SEM; *p ⬍ 0.05 vs control group (ANOVA).
we have demonstrated that CPAP therapy for 2 weeks increased the pulmonary function of patients with CHF, consequently improving their tolerance to physical activities. Approximately 80% of the patients with CHF showed a restrictive spirometric pattern, which has been mainly attributed to extravascular volume expansion and fluid accumulation in interstitial compartments of the lungs associated with increased heart size, and consequently reduced lung compliance.1,17,18 The accumulation of interstitial fluid leads the alveoli to flood and results in a deficient alveolar gas exchanging of the lungs with several consequences, including the manifestation of muscle weakness and dyspnea.19 Some studies3,4 indicate that the use of CPAP may improve the cardiac and pulmonary function and relieve the symptoms of patients with CHF. In this study, CPAP therapy caused a progressive and significant improvement of the FVC and FEV1 in patients with CHF compared to the control group. The effects of CPAP could be because this therapy increases functional residual capacity and opens collapsed or underventilated alveoli, thus decreasing right-to-left intrapulmonary shunt, improving oxygenation and lung compliance.4 www.chestjournal.org
It is well known that exercise limitation frequently observed in patients with CHF is multifactorial and includes abnormal ventilatory responses.20 The 6MWT has been used to evaluate functional capacity in symptomatic CHF patients.21,22 In a recent systematic review, Olsson et al23 concluded that although there is uncertainty about the utility of this test for the evaluation of pharmacologic therapy, the 6MWT may be of greater value in patients with advanced CHF, in whom it may function as a maximal exercise test. A possible disadvantage of using the 6MWT as an outcome measure in studies of CHF treatment is that the verbal encouragement of the person administering the test could affect the distance walked by the patient.23 The advantages of the 6MWT rather than the bicycle or treadmill exercise are that the test is simple, inexpensive, and easily performed; a more natural form of exercise that may better reflect daily activity; and has important prognostic information.21–23 In this study, the physical limitation in patients with CHF was confirmed through the 6MWT, observing that most patients showed muscle weakness and dyspnea during the test and hardly completed the test. It is reasonable to assume that the improvement of the pulmonary function and associated symptoms caused by the CPAP therapy contributed to the progressive increase in the distance walked in the 6MWT by patients with CHF in our study. However, we may consider that other investigators have shown that the improvement of exercise tolerance in CHF patients could also be due to the beneficial effects of CPAP therapy on other parameters. It has been shown that CPAP application causes significant improvements in cardiac function of CHF patients, including reduction in left ventricular preload24 and afterload,25 augmented left ventricular ejection fraction,26 reduction in mitral regurgitant fraction,26 and in myocardial oxygen consumption plus carbon dioxide production.27 These improvements in cardiovascular function could be as a consequence of the CPAPinduced increase in intrathoracic pressure.24 –26,28 Other beneficial cardiovascular effects of CPAP on CHF patients have been reported, including inhibition of cardiac sympathetic nervous activity,27 and reduction in plasma atrial natriuretic peptide concentration.26 It is interesting that in this study, we observed a substantial improvement in pulmonary function and 6MWT distance even after short-term CPAP therapy. Our findings are in agreement with others24,27,29 showing beneficial effects of short-term CPAP therapy in CHF patients. Based on other studies,27,29,30 we speculate that among possible mechanisms could account for some of the favorable effects of short-term CPAP on pulmonary function and 6MWT distance in CHF patients are decreases CHEST / 130 / 1 / JULY, 2006
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of cardiac sympathetic nervous activity,30 myocardial work and oxygen consumption,27 mitral regurgitation,29 and improvement of ejection fraction.29 Although the patients were randomly allocated in the CPAP or control groups, we cannot rule out the possibility that the pretreatment value of the left ventricular ejection fraction 8% higher in the CPAP group could additionally contributed to the improvement of cardiopulmonary function and tolerance to physical exercise in this group. CHF is commonly treated with pharmacologic approaches, and the drugs used could influence the tolerance to physical exercise.31–34 It is interesting that in this study, most of the patients receiving drug therapy were receiving diuretics, digitalis glycosides, and angiotensin-converting enzyme inhibitors rather than -blockers, which is not considered a standard practice currently. However, we did not interfere with the clinical medications that were prescribed. Based on other studies,32,33,35 we speculate that the beneficial effects of CPAP therapy on tolerance to physical exercise could be exacerbated if the patients were mainly receiving medication with -blockers, which are known to improve cardiac function and exercise tolerance in CHF patients. Although in our study all patients were receiving cardiovascular medication, the class and dosage of medication were not changed during the 14 days of the study. Our study has some limitations. Although our data show that CPAP treatment improved exercise tolerance, we do not know if this was caused only by the improvement of the pulmonary function or/and by hemodynamic changes, since the patients were not submitted to an echocardiographic evaluation at the end of the experiments. Another limitation was the fact that the number of patients with anemia was not exactly the same in both groups, which could have affected the tolerance to physical exercise. In conclusion, these data show that the use of nasal CPAP significantly improves pulmonary function and, consequently, also improved the tolerance to the physical activities of CHF patients. The clinical implication of our findings is that the use of noninvasive CPAP for 30 min/d could potentially be used as an adjunct to the treatment of CHF patients.
References 1 Francis GS. Pathophysiology of chronic heart failure. Am J Med 2001; 110:37– 46 2 Pin˜a IL, Apstein CS, Balady GJ, et al. Exercise and heart failure. Circulation 2003; 107:1210 –1241 3 Yan AT, Bradley D, Liu PP. The role of continuous positive airway pressure in the treatment of congestive heart failure. Chest 2001; 120:1675–1685 4 Mehta S, Hill NS. Noninvasive ventilation. Am J Respir Crit Care Med 2001; 163:540 –577 162
5 Acosta B, DiBenedetto R, Rahimi A, et al. Hemodynamic effects of noninvasive bilevel positive airway pressure on patients with chronic congestive heart failure with systolic dysfunction. Chest 2000; 118:1004 –1009 6 Nanas S, Nanas J, Papazachou O, et al. Resting lung function and hemodynamic parameters as predictors of exercise capacity in patients with chronic heart failure. Chest 2003; 123:1386 –1393 7 American Thoracic Society. Standardization of spirometry: 1994 update. Am J Respir Crit Care Med 1995; 152:1107– 1136 8 Knudson RJ, Lebowitz MD, Holberg CJ, et al. Changes in the normal maximal expiratory flow-volume curve with growth and aging. Am Rev Respir Dis 1983; 127:725–734 9 Guyatt GH, Sullivan MJ, Thompson PJ, et al. The 6-minute walk: a new measure of exercise capacity in patients with chronic heart failure. Can Med Assoc J 1985; 132:919 –923 10 IV Brazilian guidelines in arterial hypertension. Arq Bras Cardiol 2004; 82(suppl IV):7–22 11 Kraemer MD, Kubo SH, Rector TS, et al. Pulmonary and peripheral vascular factors are important determinants of peak exercise oxygen uptake in patients with heart failure. J Am Coll Cardiol 1993; 21:641– 648 12 Pin˜a IL, Daoud S. Exercise and heart failure. Minerva Cardioangiol 2004; 52:537–546 13 Myers J, Froelicher VF. Hemodynamic determinants of exercise capacity in chronic heart failure. Ann Intern Med 1991; 115:377–386 14 Pin˜a IL, Fitzpatrick JT. Exercise and heart failure. Chest 1996; 110:1317–1327 15 Kitzman DW. Exercise intolerance. Prog Cardiovasc Dis 2005; 47:367–369 16 Hognestad A, Holm T, Simonsen S, et al. Serial measurements of peripheral vascular reactivity and exercise capacity in congestive heart failure and after heart transplantation. J Card Fail 2005; 11:447– 454 17 Ulrik CS, Carlsen J, Arendrup H, et al. Pulmonary function in chronic heart failure. Scand Cardiovasc J 1999; 33:131–136 18 Gehlbach B, Geppert E. The pulmonary manifestations of left heart failure. Chest 2004; 125:669 – 682 19 Johnson BD, Beck KC, Olson LJ, et al. Ventilatory constraints during exercise in patients with chronic heart failure. Chest 2000; 117:321–331 20 O’Donnel DE, D’Arsigny C, Raj S, et al. Ventilatory assistance improves exercise endurance in stable congestive heart failure. Am J Respir Crit Care Med 1999; 160:1804 –1811 21 Opasich C, Pinna GD, Mazza A, et al. Reproducibility of the six minutes walking test in patients with chronic congestive heart failure: practical implications. Am J Cardiol 1998; 81:1497–1500 22 Rostagno C, Galanti G, Comeglio M, et al. Comparison of different methods of functional evaluation in patients with chronic heart failure. Eur J Heart Failure 2000; 2:273–280 23 Olsson LG, Swedberg K, Clark AL, et al. Six minute walk test as an outcome measure for the assessment of treatment in randomized, blinded intervention trials of chronic heart failure: a systematic review. Eur Heart J 2005; 26:778 –793 24 Mehta S, Liu PP, Fitzerald FS, et al. Effects of continuous positive airway pressure on cardiac volumes in patients with ischemic and dilated cardiomyopathy. Am J Respir Crit Care Med 2000; 161:128 –134 25 Naughton MT, Rahman MA, Hara K, et al. Effect of continuous positive airway pressure on intrathoracic and left ventricular transmural pressures in patients with congestive heart failure. Circulation 1995; 91:1725–1731 26 Tkacova R, Liu PP, Naughton MT. Effect of continuous Original Research
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positive airway pressure on mitral regurgitant fraction and atrial natriuretic peptide in patients with heart failure. J Am Coll Cardiol 1997; 30:739 –745 Kaye DM, Mansfield D, Naughton MT. Continuous positive airway pressure decreases myocardial oxygen consumption in heart failure. Clin Sci (Lond) 2004; 106:599 – 603 Sin DD, Logan AG, Fitzgerald FS, et al. Effects of continuous positive airway pressure on cardiovascular outcomes in heart failure patients with and without Cheyne-Stokes respiration. Circulation 2000; 102:61– 66 Bellone A, Barbieri A, Ricci C, et al. Acute effects of non-invasive ventilatory support on functional mitral regurgitation in patients with exacerbation of congestive heart failure. Intensive Care Med 2002; 28:1348 –1350 Kaye DM, Mansfield D, Aggarwal A, et al. Acute effects of continuous positive airway pressure on cardiac sympathetic tone in congestive heart failure. Circulation 2001; 103:2336 – 2338
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31 Gomberg-Maitland M, Baran DA, Fuster V. Treatment of congestive heart failure. Arch Intern Med 2001; 161:342–352 32 Metra M, Nardi M, Giubbini R, et al. Effects of short- and long-term carvedilol administration on rest and exercise hemodynamic variables, exercise capacity and clinical conditions in patients with idiopathic dilated cardiomyopathy. J Am Coll Cardiol 1994; 24:1678 –1687 33 Al-Nasser F, Yousufuddin M, Al-Nozha F, et al. Effect of carvedilol on exercise tolerance in patients with chronic heart failure and a restrictive left ventricular filling pattern. Am J Cardiol 2003; 91:1281–1283 34 Wolk R, Johnson BD, Somers VK, et al. Effects of  blocker therapy on ventilatory responses to exercise in patients with heart failure. J Card Fail 2005; 11:333–339 35 Guazzi M, Agostoni P, Matturri M, et al. Pulmonary function, cardiac function, and exercise capacity in a follow-up of patients with congestive heart failure treated with carvediolol. Am Heart J 1999; 138:460 – 467
CHEST / 130 / 1 / JULY, 2006
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Original Research HEART FAILURE
Effects of Continuous Positive Airway Pressure on Pulmonary Function and Exercise Tolerance in Patients With Congestive Heart Failure* Veronica L. Wittmer, MSc; Giovana M. S. Simoes, MSc Luciana C. M. Sogame, PhD; and Elisardo C. Vasquez, PhD
Study objectives: Continuous positive airway pressure (CPAP) has been used to improve cardiopulmonary function and reduce pulmonary edema symptoms in patients with congestive heart failure (CHF). The objective of this study was to evaluate the efficacy of CPAP therapy on pulmonary function and exercise tolerance in patients with CHF. Design: Prospective blind randomized clinical study. Participants: Twenty-four patients with class II or III CHF and dilated cardiomyopathy were randomly assigned to 30 min of CPAP therapy and respiratory exercises (CPAP group) or respiratory exercise only (control group) once a day for 14 days. Measurements and results: Evaluation of pulmonary function was performed measuring FEV1 and FVC. Exercise tolerance was assessed measuring the distance walked during the 6-min walking test (6MWT). These parameters were measured before treatment and 4 days, 9 days, and 14 days later. CPAP therapy caused a progressive increase (p < 0.05) in both FVC (maximum of 16% after 9 days) and FEV1 (maximum of 14% after 14 days) compared to basal values, without significant changes in the control group. The 6MWT showed a progressive improvement in the distance walked in the CPAP group, reaching approximately 28% above the basal values in the CPAP group and without significant changes in the control group. Conclusions: These data show that the use of CPAP therapy for 2 weeks on a daily basis is able to enhance pulmonary function and consequently improve the tolerance to physical activities in patients with CHF. The clinical implication of this finding is that CPAP therapy could potentially be used as an adjunct to the treatment of CHF patients. (CHEST 2006; 130:157–163) Key words: continuous positive airway pressure ventilation; exercise tolerance; FVC; heart failure; pulmonary function test Abbreviations: ANOVA ⫽ analysis of variance; 6MWT ⫽ 6-min walk test; CHF ⫽ congestive heart failure; CPAP ⫽ continuous positive airway pressure
heart failure (CHF) resulting from C ongestive dilated cardiomyopathy is a serious disease associated with excessive morbidity and mortality and of elevated costs to health-care plans and the government. Despite advances in the pharmacologic ther*From the Physiological Sciences Graduate Program (Ms. Wittmer and Ms. Simoes), Biomedical Center, Federal University of Espirito Santo; and Emescam College of Health Sciences of Vitoria (Drs. Sogame and Vasquez), Vitoria, Brazil. The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/orgainzations whose products or services may be discussed in this article. Manuscript received October 4, 2005; revision accepted January 11, 2006. www.chestjournal.org
apy for CHF, the mortality from this disease remains very high. A consequence of the CHF is an extensive fluid accumulation in the lungs (pulmonary edema), which results in muscle fatigue or dyspnea symptoms when performing routine activities and progressing to dyspnea at rest.1,2 Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal. org/misc/reprints.shtml). Correspondence to: Elisardo C Vasquez, PhD, Physiological Sciences Graduate Program, Biomedical Center, Federal University of Espirito Santo, Av. Marechal Campos 1468, Vitoria, 29042–755 ES, Brazil; e-mail: [email protected] DOI: 10.1378/chest.130.1.157 CHEST / 130 / 1 / JULY, 2006
157
Oxygen supplementation and administration of drugs are commonly used as an attempt to decrease lung edema and improve myocardial performance in patients with CHF,3 but severe respiratory failure develops in many patients and requires intubation and mechanical ventilation. An additive approach that has long been used to improve pulmonary function in these patients is the use of continuous positive airway pressure (CPAP) delivered through a tight-fitting nasal or oronasal mask.4 The main direct benefits of CPAP include improvement in oxygenation, a decrease in respiratory work, and decrease in left ventricular preload and afterload.3–5 It is reasonable that the increase in cardiac and respiratory function may result in beneficial effects on the exercise capacity in CHF patients, as reported by Nanas et al.6 However, it has not yet been investigated if the improvement of pulmonary function through CPAP therapy affects the tolerance to physical exercise in CHF patients. Considering that any intervention that favorably alters integrated cardiopulmonary function should improve exercise endurance, this study was designed to determine the effects of CPAP therapy on the pulmonary function and its contribution to exercise tolerance in patients with CHF. Materials and Methods
ratio. Measurements were obtained in the sitting position with a closed-circuit spirometer (Respiradyne II Plus; Kendall Healthcare Products Company; Mansfield, MA). Predicted values for FEV1, FVC, and FEV1/FVC ratio were calculated using reference values of Knudson et al.8 Six-Minute Walk Test The 6-min walk test (6MWT) was performed in an indoor, 25-m long corridor, according to the suggestions from Guyatt et al.9 In brief, the patients were asked to walk at their highest rate from one end of the corridor to the other end as many times as possible within the established time of 6 min. The test was performed under the control of a therapist who encouraged the patients with phrases like “you are doing well” or “you are doing a good job; keep going.” At the end of the 6-min period, the therapist measured the distance walked by the patient. Respiratory Exercises Patients in the sitting position were subjected to three different respiratory exercises, each exercise repeated 10 times. First, slow inspiration through the nose was performed up to the maximum to reach total lung capacity, followed by a brief expiration through the mouth and another maximum inspiration followed by a complete expiration. Second, inspiration through the nose was performed up to approximately one half of total lung capacity, followed by a brief expiration through the mouth, another inspiration up to approximately two thirds of the total lung capacity followed by a brief expiration, and finally an inspiration up to the total lung capacity followed by a prolonged expiration. Third, brief and consecutive inspirations were performed through the nose until total lung capacity was reached, followed by a prolonged expiration through the mouth.
Subjects
Walking Exercise
The procedures used in this study were in accordance with the recommendations of the Helsinski Declaration of 1975. All subjects provided written informed consent before entry, and the protocol was approved by the Ethics Committee at the College of Health Sciences of Vitoria. We recruited consecutive patients who were admitted to the hospital for treatment of CHF. Patients were eligible to participate if they had a clinical diagnosis of New York Heart Association class II or III CHF. Patients were excluded from participating in the study if they had one or more of the following conditions: (1) unstable angina; (2) atrial fibrillation or third-degree atrioventricular blockade; (3) myocardial infarction; (4) cardiac surgery within 1 year prior to study entry; (5) pulmonary disease; (6) radiologic signs of pleural effusion; (7) use of bronchodilators; (8) pregnancy; (9) frequent vomiting; (10) smokers; (11) unable to successfully complete the walking test; and (12) ⬍ 30 years old and ⬎ 80 years old. After a clinical examination, which included echocardiography, ECG, and chest radiography by an independent physician who acted on clinical judgment alone, 24 patients were randomly assigned to the CPAP group or the control group. During the study, two patients were excluded: one because angina pectoris developed during the walking test, and the other because of CPAP therapy intolerance.
All patients were asked to walk 100 m/d at a slow pace under the control of a therapist.
Spirometry
Experimental Protocol
Routine spirometry was performed following the standardization of the American Thoracic Society.7 Pulmonary function testing included measurement of FEV1, FVC, and FEV1/FVC
All patients were initially subjected to a physical evaluation and also evaluation of arterial pressure, heart rate, hemogram, respiratory frequency, and peripheral hemoglobin oxygen saturation,
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CPAP Therapy CPAP was applied through a tight-fitting nasal mask (Sollo; Sao Paulo, Brazil) breathing at pressure of 8 cm H2O with the mouth closed for a 30-min period every morning while awake and in the sitting position. BP, Heart Rate, and Hemoglobin Saturation With Oxygen Measurements Systolic and diastolic arterial BP were measured with a validated automatic sphygmomanometer (model HEM-705CP; Omron; Chicago, IL) with the patient at rest and in a sitting position following the IV Brazilian guidelines in arterial hypertension.10 Heart rate was measured using a portable monitor (model A1; Polar Electro; Lake Success, NY) positioned around the patient’s thorax. Peripheral hemoglobin oxygen saturation was measured through a fingertip pulse oximeter (Onyx; Nonin Medical; Plymouth, MN).
Original Research
After that, patients were allocated to daily CPAP therapy plus respiratory and walking exercises (CPAP group, n ⫽ 12) or respiratory and walking exercises (control group, n ⫽ 10) in a blind randomized, prospective study design. Spirometry and 6MWTs were performed by an independent investigator 1 day before treatment (day 0) and at the fourth, ninth, and 14th days of treatment, and all other parameters were measured every day in both groups. Statistical Analysis All data are expressed as mean ⫾ SEM. Means of groups were compared by two-way analysis of variance (ANOVA) for repeated measurements followed by the post hoc Tukey/Kramer test. A Student t test was used for comparisons of two means when appropriate. The relative changes in the FVC, FEV1, and 6MWT distance were determined as follows: ⌬% ⫽ ([posttreatment value – pretreatment value]/pretreatment value) ⫻ 100; p ⬍ 0.05 was considered significant.
Results Subject Characteristics Eleven patients included in this analysis were in New York Heart Association class II (CPAP group, n ⫽ 5; control group, n ⫽ 6), and 11 patients were in class III (CPAP group, n ⫽ 5; control group, n ⫽ 6). The characteristics of the patients are shown in Table 1. CPAP and control groups were comparable in age, body mass index, heart rate, systolic and diastolic arterial BP, respiratory rate, and hemoglobin saturation with oxygen. Although patients were randomly allocated in each group, the left ventricular ejection fraction was 8% higher in the CPAP group than in the control group. Initial physical examination showed that some patients had a respiratory rate ⬎ 22 breaths/min (CPAP group, n ⫽ 2; control group, n ⫽ 4); lowerextremity edema (CPAP group, n ⫽ 6; control group, n ⫽ 6); abdominal distension suggestive of ascites (CPAP group, n ⫽ 2; control group, n ⫽ 1);
Table 1—Characteristics and Vital Signals of the Patients* Parameters
Control Group
CPAP Group
Female/male gender, No. Body mass index, kg/m2 Age, yr Heart rate, beats/min Systolic arterial BP, mm Hg Diastolic arterial BP, mm Hg Left ventricular ejection fraction, % Respiratory rate, breaths/min Hemoglobin saturation with oxygen, %
4/6 22.6 ⫾ 1.0 52.7 ⫾ 11.4 76 ⫾ 3.1 97 ⫾ 2.9 69 ⫾ 1.8 39.2 ⫾ 0.9 19 ⫾ 0.7 94.9 ⫾ 0.5
6/6 24.9 ⫾ 0.5 59.8 ⫾ 3.7 73 ⫾ 5.1 98 ⫾ 4.8 67 ⫾ 2.8 42.7 ⫾ 1.9† 18 ⫾ 0.9 94.5 ⫾ 0.5
*Data are presented as mean ⫾ SEM unless otherwise indicated. †p ⬍ 0.05 vs control group. www.chestjournal.org
pulmonary crackles (CPAP group, n ⫽ 7; control group, n ⫽ 5); paroxysmal nocturnal dyspnea (CPAP group, n ⫽ 3; control group, n ⫽ 2); jugular vein congestion (CPAP group, n ⫽ 5; control group, n ⫽ 6); and hepatojugular reflux (CPAP group, n ⫽ 5; control group, n ⫽ 5). In addition, the hemogram showed the presence of anemia in some patients (CPAP group, n ⫽ 5; control group, n ⫽ 7). As shown in Table 2, all the patients from CPAP and control groups had a left ventricular ejection fraction ⱕ 45% and dilated cardiomyopathy associated with valvular diseases. All patients from both groups were receiving medication, as shown in Table 3. In the pulmonary function tests, it was observed that FVC was similar in the CPAP and control groups (66 ⫾ 6% vs 69 ⫾ 5% of predicted, respectively; p ⬎ 0.05). FEV1 was also similar in the CPAP and control groups (63 ⫾ 6% vs 67 ⫾ 4% of predicted value; p ⬎ 0.05). Most of the patients in the control group (8 of 10 patients) and CPAP group (9 of 12 patients) showed a restrictive spirometric pattern, ie, a FVC ⬍ 80% of the predicted value and a FEV1/FVC ratio ⬎ 75% of the predicted value, in the pretreatment evaluation (day 0). However, the spirometric parameters were comparable in both groups. One patient of each group presented with obstructive spirometric pattern: FEV1 ⬍ 80% of the predicted value and FEV1/FVC ratio ⬍ 75% of the predicted value. The other three patients (control group, n⫽ 1; CPAP group, n ⫽ 2) showed a normal spirometric pattern. The distance walked in the 6MWT in the pretreatment evaluation was similar in the CPAP group (344 ⫾ 25 m) and the control group (341 ⫾ 16 m). Effects of CPAP The group treated with CPAP showed a progressive increase in FVC, reaching a maximum of 16% of Table 2—Incidence of Cardiac Diseases Evidenced by Echocardiography* Parameters Dilated cardiomyopathy Idiopathic Alcoholic After rheumatic fever Mitral failure Mitral stenosis Tricuspid failure Aortic failure Aortic stenosis Left ventricular ejection fraction ⱕ 45%
Control Group (n ⫽ 10)
CPAP Group (n ⫽ 12)
8 0 4 8 2 2 6 1 10
5 1 4 6 1 1 3 2 12
*Data are presented as No. CHEST / 130 / 1 / JULY, 2006
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Table 3—Frequency of Cardiovascular Medication Used by the Patients* Drugs Diuretic Digitalis glycoside -Blocker Angiotensin-converting enzyme inhibitor Vasodilator Amiodarone Anticlotting
Control Group (n ⫽ 10)
CPAP Group (n ⫽ 12)
8 4 2 3
5 4 1 5
0 2 3
1 1 4
*Data are presented as No.
the basal value on the ninth day of treatment without additional improvement on the 14th day of treatment, in contrast with the control group, which showed no significant improvement at any time point (Fig 1). Similarly, FEV1 values progressively increased and reached a maximum of 14% on the 14th day of CPAP treatment, without any significant change in the control group (Fig 2). At the end of experiments, three patients from CPAP group and one patient from the control group changed from a restrictive to a normal spirometric pattern. However, Figure 2. Time course of relative changes in FEV1. Values are mean ⫾ SEM; *p ⬍ 0.05 vs control group (ANOVA).
no changes of pattern were observed in those patients with a previous diagnosis of airway obstruction. As summarized in Figure 3, the 6MWT showed a progressive improvement in the distance walked in the CPAP group, reaching approximately 28% above basal values at the end of treatment, but no significant changes were observed in the control group. Discussion
Figure 1. Time course of relative changes in FVC. Values are mean ⫾ SEM; *p ⬍ 0.05 vs control group (ANOVA). 160
Reduced exercise capacity is one of the characteristics of patients with CHF and is correlated with abnormal respiratory function, as noted in this study, and involves several other mechanisms, including impaired tissue oxygen extraction11,12; abnormalities in skeletal muscle metabolism and structure,12–14 and reduced skeletal muscle blood flow during exercise12,13; hyperventilation caused by elevated physiologic dead space in the edematous lung12,13; reduced myocardial -adrenoceptor density and sensitivity12,13; chronotropic failure12–15; and diastolic dysfunction.15 It is interesting that CHF patients show persistent physical limitations after heart transplantation, probably due to increased vasoconstriction drive to skeletal muscles.16 In the current study, Original Research
Figure 3. Time course of relative changes in distance walked in 6 min by the patients. Values are mean ⫾ SEM; *p ⬍ 0.05 vs control group (ANOVA).
we have demonstrated that CPAP therapy for 2 weeks increased the pulmonary function of patients with CHF, consequently improving their tolerance to physical activities. Approximately 80% of the patients with CHF showed a restrictive spirometric pattern, which has been mainly attributed to extravascular volume expansion and fluid accumulation in interstitial compartments of the lungs associated with increased heart size, and consequently reduced lung compliance.1,17,18 The accumulation of interstitial fluid leads the alveoli to flood and results in a deficient alveolar gas exchanging of the lungs with several consequences, including the manifestation of muscle weakness and dyspnea.19 Some studies3,4 indicate that the use of CPAP may improve the cardiac and pulmonary function and relieve the symptoms of patients with CHF. In this study, CPAP therapy caused a progressive and significant improvement of the FVC and FEV1 in patients with CHF compared to the control group. The effects of CPAP could be because this therapy increases functional residual capacity and opens collapsed or underventilated alveoli, thus decreasing right-to-left intrapulmonary shunt, improving oxygenation and lung compliance.4 www.chestjournal.org
It is well known that exercise limitation frequently observed in patients with CHF is multifactorial and includes abnormal ventilatory responses.20 The 6MWT has been used to evaluate functional capacity in symptomatic CHF patients.21,22 In a recent systematic review, Olsson et al23 concluded that although there is uncertainty about the utility of this test for the evaluation of pharmacologic therapy, the 6MWT may be of greater value in patients with advanced CHF, in whom it may function as a maximal exercise test. A possible disadvantage of using the 6MWT as an outcome measure in studies of CHF treatment is that the verbal encouragement of the person administering the test could affect the distance walked by the patient.23 The advantages of the 6MWT rather than the bicycle or treadmill exercise are that the test is simple, inexpensive, and easily performed; a more natural form of exercise that may better reflect daily activity; and has important prognostic information.21–23 In this study, the physical limitation in patients with CHF was confirmed through the 6MWT, observing that most patients showed muscle weakness and dyspnea during the test and hardly completed the test. It is reasonable to assume that the improvement of the pulmonary function and associated symptoms caused by the CPAP therapy contributed to the progressive increase in the distance walked in the 6MWT by patients with CHF in our study. However, we may consider that other investigators have shown that the improvement of exercise tolerance in CHF patients could also be due to the beneficial effects of CPAP therapy on other parameters. It has been shown that CPAP application causes significant improvements in cardiac function of CHF patients, including reduction in left ventricular preload24 and afterload,25 augmented left ventricular ejection fraction,26 reduction in mitral regurgitant fraction,26 and in myocardial oxygen consumption plus carbon dioxide production.27 These improvements in cardiovascular function could be as a consequence of the CPAPinduced increase in intrathoracic pressure.24 –26,28 Other beneficial cardiovascular effects of CPAP on CHF patients have been reported, including inhibition of cardiac sympathetic nervous activity,27 and reduction in plasma atrial natriuretic peptide concentration.26 It is interesting that in this study, we observed a substantial improvement in pulmonary function and 6MWT distance even after short-term CPAP therapy. Our findings are in agreement with others24,27,29 showing beneficial effects of short-term CPAP therapy in CHF patients. Based on other studies,27,29,30 we speculate that among possible mechanisms could account for some of the favorable effects of short-term CPAP on pulmonary function and 6MWT distance in CHF patients are decreases CHEST / 130 / 1 / JULY, 2006
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of cardiac sympathetic nervous activity,30 myocardial work and oxygen consumption,27 mitral regurgitation,29 and improvement of ejection fraction.29 Although the patients were randomly allocated in the CPAP or control groups, we cannot rule out the possibility that the pretreatment value of the left ventricular ejection fraction 8% higher in the CPAP group could additionally contributed to the improvement of cardiopulmonary function and tolerance to physical exercise in this group. CHF is commonly treated with pharmacologic approaches, and the drugs used could influence the tolerance to physical exercise.31–34 It is interesting that in this study, most of the patients receiving drug therapy were receiving diuretics, digitalis glycosides, and angiotensin-converting enzyme inhibitors rather than -blockers, which is not considered a standard practice currently. However, we did not interfere with the clinical medications that were prescribed. Based on other studies,32,33,35 we speculate that the beneficial effects of CPAP therapy on tolerance to physical exercise could be exacerbated if the patients were mainly receiving medication with -blockers, which are known to improve cardiac function and exercise tolerance in CHF patients. Although in our study all patients were receiving cardiovascular medication, the class and dosage of medication were not changed during the 14 days of the study. Our study has some limitations. Although our data show that CPAP treatment improved exercise tolerance, we do not know if this was caused only by the improvement of the pulmonary function or/and by hemodynamic changes, since the patients were not submitted to an echocardiographic evaluation at the end of the experiments. Another limitation was the fact that the number of patients with anemia was not exactly the same in both groups, which could have affected the tolerance to physical exercise. In conclusion, these data show that the use of nasal CPAP significantly improves pulmonary function and, consequently, also improved the tolerance to the physical activities of CHF patients. The clinical implication of our findings is that the use of noninvasive CPAP for 30 min/d could potentially be used as an adjunct to the treatment of CHF patients.
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