Nocturnal Positive-Pressure Ventilation via Nasal Mask in Patients with Severe Chronic Obstructive Pulmonary Disease 1- 3
DAVID A. STRUMPF, RICHARD P. MILLMAN, CAROL C. CARLISLE, LYNN M. GRATTAN, SUSAN M. RYAN, ALLAN D. ERICKSON, and NICHOLAS S. HILL
Introduction
Numerous studies have reported improvement in daytime symptoms and gas exchange after use of nocturnal ventilatory assistance using noninvasive ventilators in patients with hypoventilation caused by restrictive pulmonary diseases (1-4). However, the efficacy of intermittent ventilatory assistance in patients with severechronic obstructive pulmonary disease (COPD) remains controversial. Several studies have demonstrated improvements in gas exchange and pulmonary function after use of negative pressure ventilators in patients with COPD (5-7), but these have either been uncontrolled or very short-term. Twolonger controlled studies using negative pressure ventilators in patients with severe COPD reported no improvements in gas exchange or pulmonary function after a period of intermittent ventilatory assistance (8, 9). One, a 6-month outpatient study (8), encountered very poor patient tolerance of the negative pressure device. More recently, nocturnal intermittent positive pressure ventilation administered via a nasal mask has been reported to improve symptoms of hypoventilation and gas exchange abnormalities in patients with restrictive pulmonary diseases (10-14). In the present study, wehypothesized that nocturnal nasal ventilation (NNV) would bring about significant improvements in gas exchange and pulmonary function in patients with severe COPD because it would be better tolerated than negative pressure ventilation and would be more effective at overcoming the sleep disturbances associated with COPD (15-18). Using a randomized, crossover design, we assessed the effects of 3 months ofNNV versus standard care on pulmonary functions, gas exchange, dyspnea ratings, sleep and neuropsychological function in seven patients with severe COPD. 1234
SUMMARY Intermittent positive pressure ventilation administered nocturnally via a nasal mask has been associated with Improvements In pUlmonary function and symptoms In patients with restrictive ventilatory disorders. We hypothesized that nocturnal nasal ventilation (NNV) would bring about similar Improvements In patients with severe chronic obstructive pUlmonary disease (COPO). The atudy used a randomized, crossover design, with subjects undergoing NNV or "standard care" for sequentlal3-month periods. Of 23 patients with obstructive lung disease and a FEV, < 1 L who were Initially enrolled, 4 were excluded because of obstructive sleep apnea prior to randomization. Among the remaining 19 patients, 7 withdrew because of Intolerance of the nose mask, 5 were withdrawn because of Intercurrent Illnesses, and 7 completed both arms of the protocol. These latter 7 patients used the ventilator for an average of 6.7 h/nlght, and 3 of the 7 had partial relief of dyspnea during ventilator use. However, In comparison with atudles performed upon Initiation or after the standard care arm of the study, atudles performed after 3 months of NNV revealed no Improvements In pulmonary function, respiratory muscle strength, gas exchange, exercise endurance, sleep efficiency, quality or oxygenation, or dyspnea ratings. The only Improvements observed were In neuropsychological function, possibly related to a placebo effect or another unknown mechanism. Despite the smsll sample size, our study Indicates that NNV Is not well tolerated by and brings sbout minimal Improvements In stsble outpatients with savere COPO. AM REV RESPIR DIS 1991; 144:1234-1239
Methods Patient Selection Patients with severe COPD were recruited from the pulmonary clinics at the Rhode Island Hospital and the Providence Veterans Administration Medical Center. The study was approved by the Institutional Review Boards at both hospitals, and informed consent was obtained from all patients. Entry criteria included a FEV, of < I L, a FEV,! FVC ratio of < 0.75, and a TLC of> 80070 predicted. Patients were excluded if they had > 15% increase in FEV, after administration of an inhaled bronchodilator, an exacerbation of their airway disease within the previous month, obstructive sleep apnea, coexisting medical conditions such as uncontrolled coronary heart disease, malignancy, or cardiac failure, or any condition that might hamper their ability to participate in a long-term trial. Patients continued on all standard medication, including theophylline, steroids, and 0, throughout the study. Initial Evaluation Patients admitted to the study underwent baseline pulmonary function testing including routine spirometry (Eagle I Spirometer; Warren E. Collins, Inc., Braintree, MA), de-
termination of lung volumes by variable pressure plethysmography (Collins, Inc.), and measurement of maximal inspiratory and expiratory pressures (MIP, MEP) using a precalibrated handheld manometer (Boehringer, Inc., Wynnewood, PA) as described by Black and Hyatt (19). Arterial blood gases were obtained in the sitting position with the patient breathing room air. Treadmill walking time (TWT) was determined as the amount of time required by the patient to reach exhaustion walking at a speed of 1.2 miles/h, 0% grade. The test was terminated early if oxygen saturation (Received in original form October 29. 1990 and in revised form March 18, 1991) , From the Division of Pulmonary and Critical Care Medicine and the Department of Psychiatry, Rhode Island Hospital, the Providence Veterans Administration Medical Center, and BrownUniversity, Providence, Rhode Island. , Supported in part by a grant from Respironics, Inc., Monroeville, Pennsylvania. 3 Correspondence and requests for reprints should be addressed to Nicholas S. Hill, M.D., Division of Pulmonary and Critical Care Medicine, Rhode Island Hospital, 593 Eddy Street, Providence, RI 02903.
NASAL VENTILATION IN COPO
dropped below 85% or systolic blood pressure fell by more than 20 mm Hg, Dyspnea was assessed using the dyspnea scale of Mahler, which rates dyspnea on three scales graded from zero to 4, higher numbers indicating superior function (20). The magnitude of task scale reflects the most strenuous task the patient can perform without dyspnea, the magnitude of effort scale assesses the patient's ability to perform the task without rest periods, and the functional impairment scale estimates the degree to which dyspnea has affected the patient's daily activities. Neuropsychologic function was examined using 10 measures that were administered to each patient by a clinical psychologist (LMG) who was blinded to the experimental condition. These measures assessed a wide range of neurobehavioral functions including attention and concentration (Digit Symbol Substitution subset of the Weschler Adult Intelligence Scale-Revised) (WAIS-R); attention and flexibility (Trails B); psychomotor speed and coordination (Grooved Pegboard); verbal memory (Rey Auditory Verbal Learning 'lest scored for total numbers of words recalled in Trial S and delayed recall); visual memory (Benton Visual Retention Testscored for number of errors); construction praxis (Block Design subset to the WAIS-R); verbal associative fluency (Controlled Oral Word Association lest); self-regulation (Stroop 'Irial J); and depression (BeckDepression Inventory). Standard administration and scoring procedures were utilized for all neuropsychological measures as previously described (21). Two all-night polysomnography studies were performed during the initial evaluation, consisting of continuous monitoring of nasal and oral airflow, chest wall and abdominal movement, oxygen saturation, electrocardiogram, and anterior tibialis electromyograms (EMG). Sleep stages were determined from electroencephalograms, electrooculograms, and submental EMGs recorded on a polygraph (Nihon-Kohden, Irvine, CA). Patients ordinarily receivingO 2supplementation remained on O 2 during the polysomnographic studies. The first study was to allow adaptation to the sleep laboratory and to screen out those with unsuspected sleep apnea. The second and subsequent studies were used for data analysis. The following sleep parameters were determined using the method of Rechtschaffen and Kales (22); total sleep time (TST); sleep efficiency defined as TST divided by time in bed; percent REM defined as the total time spent in rapid-eye movement sleep divided by TSl; and sleep latency to the first epoch of sleep. In addition, mean and lowest O 2 saturation, apneas (cessation of airflow for 10 s or longer), and hypopneas (500/0 decrease in airflow for 10 s or longer associated with an arousal and 4% fall in oxygen saturation) were noted. Patients with obstructive sleep apnea, defined as more than five apneas or hypopneas per hour, were excluded from the study.
1235
Introduction to the Ventilator Nasal ventilation was initiated in outpatients and was administered via a standard nasal continuous positive airway pressure mask (Respironics, Inc., Monroeville, PA) using a BiPAP ventilator (Respironics, Inc.) (23). After measurement of resting minute ventilation using a portable flow meter (No. 5420; Ohmeda, Englewood, CO) and proper fitting and adjustment of the nasal mask, BiPAP settings were adjusted to match the patient's spontaneous breathing rate and to provide a 20 to 50% augmentation of resting minute ventilation and reduction of at least 5 mm Hg in end-tidal Pco, (PETeo2) (Engstrom Eliza CO 2analyzer; Gambro-Engstrom, Bromma, Sweden). Tidal volume was augmented by increasing the inspiratory positive airway pressure (IPAP) setting on the BiPAP device. Expiratory positive airway pressure (EPAP) was kept at the lowest setting (2 em H 20 ), and percent inspiratory time (%IPAP) was set at 40%. Patients were observed using the nasal ventilator for an initial 2 to 3 h period, and further adjustments were made as necessary. Patients were then asked to use the device at home every evening and to gradually extend periods ofuse until they could sleep using it throughout the night. Ventilator use by patients was verified using an electronic timer. Patients receiving O 2 supplementation continued to receive it at the usual flow rate via a cannula attached to a port on the nasal mask during NNV. A respiratory therapist (SR) skilled in the use of NNV visited the home three times weekly until the patient had successfully adapted to the device, and visits were less frequent thereafter. Investigators were in frequent telephone contact with patients and made periodic home visits as necessary to obtain arterial blood gas and PETe02 measurements during the initial adjustment period. Further upward adjustments in IPAP were made if necessary to maintain PETeo2at least 5 mm Hg below the spontaneous resting level. Spot readings ofFETe02 were also obtained during follow-up sleep studies during ventilator use. Study Design After initial studies, patients were randomized to receive NNV during the initial 3-month period or to continue their standard COPD therapy. They were then crossed over to the other arm of the study for a final 3-month peiod. Studies were repeated after each 3-month period. No adaptation night was used for follow-up sleep studies, and polysomnography after the NNV arm was performed during ventilator use. Comparisons were made between initial measurements and those obtained at the completion of NNV and standard care (control) arms. Standard Care During the "standard care" period, patients were seen by one of the investigators on a monthly basis, or more frequently if clinical-
ly indicated. Bronchodilator medications were adjusted to achieve optimal doses, and antibiotics and corticosteroids were administered during acute exacerbations. Oxygen supplementation was administered to patients with severehypoxemia, and hospitalization was advised for those suffering severeexacerbations. Pulmonary function studies and arterial blood determinations were obtained as per the protocol or more frequently if clinically indicated. Patients were encouraged to remain active, but no specific rehabilitation program was offered to them.
Statistics Data are shown as mean ± SE. Comparisons between initial and follow-up measurements were made using analysis of variance for repeated measures. When significant F ratios wereobtained, the Student Newman Keulstest (24) was used to test for significance between individual group means. Analysis of variance was also performed to test for sequence effects related to the crossover design (25). To better demonstrate the magnitude of detectable differences given our small sample size, confidence intervals werecalculated for differences between mean values during the control and NNV periods. Differences were considered statistically significant at p < 0.05. Results
Patient Characteristics Thirty-nine patients meeting the pulmonary function criteria for entry into the study were recruited, but 11 declined to participate. Five had recent exacerbations ofCOPD or unstable cardiac disease and wererejected. Twenty-threepatients were initially enrolled in the study, including 19men and 4 women (table 1). Mean age of the patients upon entry was 66 ± 1 yr, and pulmonary function studies showed severe airway obstruction with moderate hyperinflation. Most patients had CO 2 retention and moderate to severe hypoxemia.
Patient Withdrawal Of the 23 patients initially entered into the study, 16 failed to complete the pro-
TABLE 1 CHARACTERISTICS OF PATIENTS' INITIALLY ENROLLED INTO THE STUDY Mean ± SE Age, yr
FEV,. L FEV" % TLC, % pred Paeo" mm Hg Pao" room air • n
= 23 (19 men;
66 0.56 33 133 49 59 4 women).
± 1
± 0.03 ± 2
± 5 ± 2 ± 2
Range
57-76 0.46-0.88 20-64 100-168 35-67 44-76
1236
STRUMPF, MILLMAN, CARLISLE, GRATTAN, RYAN, ERICKSON, AND HILL
TABLE 2
TABLE 3
VENTILATOR SETTINGS FOR PATIENTS COMPLETING THE STUDY'
PULMONARY FUNCTIONS, EXERCISE TOLERANCE, AND ARTERIAL BLOOD GAS DETERMINATION IN PATIENTS COMPLETING THE STUDY'
-----
Spontaneous RR, breaths/min VT, ml YE, Umin IPAP, em H,O PETeo" mm Hg
16.6± 1.3 347 ± 66 5.5 ± 0.9 40 ± 1
Initial
Ventilator 16.6 523 8.4 15 35
± ± ± ± ±
1.1 61 0.7 1 2
Definitionof abbreviations: RR = respiratory rate; VT = tidal volume; \IE = expired minute ventilation; IPAP = inspiratory positive airway pressure; PETCO, = end·tidal Peo,. • All values are mean ± SE; n = 7.
tocol. Four were found to have obstructive sleep apnea during the initial adaptation polysomnogram and were withdrawn prior to randomization. Despite every effort to alleviate discomfort and to encourage patients to continue the protocol, including multiple home visits by therapist and physicians, 7 patients withdrew because they could not tolerate the mask. Complaints included intolerable nasal mucosal irritation unresponsive to nasal corticosteroids or humidification in 4 patients, inability to sleep using the ventilator in 2, and excessive anxiety associated with ventilator use in 1. Five patients were withdrawn because of intercurrent illnessesthat disrupted the protocol; three during the NNV arm of the protocol and two during the control phase. Four had repeated hospitalizations, one for an auto accident that caused complicated recurrent pneumothoraces, one for repeated exacerbations of COPD, one for treatment of bladder cancer, and the other for unstable coronary artery disease. The fifth patient became depressed and requested withdrawal after his wife died unexpectedly.
Effect of NNV in Patients Completing the Protocol Baseline pulmonary functions for the seven patients who completed both arms of the study did not differ significantly from those of the initial 23 patients. Six ofthe seven patients used supplemental O 2, four at 1 L/min, and two at 2 L/min. Among these patients, breathing rate during ventilation use was the same as during spontaneous breathing (table 2). Tidal and minute volumes wereincreased by roughly 50010 during ventilator use. This augmentation was achieved by using a mean IPAP setting of 15 em H 20 , resulting in a drop of 5 mm Hg in PETC02 (table 2). Weobserved no improvements in FVC, FEV l , or FEV t% in the seven patients after a 3-month period of NNV com-
FVC, L FEV" L FEV" % TLC, % pred MIP, em H2O MEP, em H2O MVV, Umin TWT, min Pao" mm Hg Paco 2 , mm Hg pH
1.71 ± 0.54 ± 32 ± 133 ± -52 ± 92 ± 25 ± 4.3 ± 64 ± 46 ± 7.42 ±
0.23 0.03 1 7 8 10 2 1.6 3 2 0.01
Control 1.57 0.53 33 125 -50 91 24 3.8 60 47 7.42
± ± ± ± ± ± ± ± ± ± ±
NNV
0.31 0.06 2 5 6 9 2 1.8 4 3 0.01
Definitionof abbreviations: NNV = nocturnal nasal ventilation; MIP pressure; TWT = treadmill walking time. • Data are mean ± SE; n = 7.
pared with initial studies or the standard care (control) period (table 3). Likewise, the degree of hyperinflation as indicated by the TLC was unchanged, and indices of respiratory muscle strength (MIP and MEP) and endurance (MVV) were unchanged. Room air arterial blood gases and walking endurance on a treadmill (TWT) were also not improved by NNV. Daytime Paco2 failed to drop despite demonstrations that PETC02 was consistently reduced in all patients during ventilator use. Values for MVV, MIP, and Pac02 in individual subjects (figure 1) revealed no trends for improvement during NNV. Mean total sleep time and sleep efficiency were slightly lower during NNV than during the initial and control periods, but differences were not statistically significant (table 4). There was also a trend toward prolongation of sleep latency, and reduction in %REM, mean O 2 saturation, and lowest O2 saturation during NNV, but once again, differences were not statistically significant. Examination of the polysomnogram to assess synchrony of the patient's breathing with the ventilator revealed synchrony during 78% of non-REM and 76% of REM sleep, and spot readings of PETC02 during NNV demonstrated that the reduction shown in table 2 was sustained nocturnally. As expected, patients were severely limited by dyspnea and were capable of only minimal exertion, as reflected in the dyspnea ratings (table 5). No improvements wereobserved in the ability to perform tasks or in functional activity, nor did a reduction occur in the amount of effort required to perform a given task after use of NNV. In contrast to the above results, neuropsychologic performance was signifi-
1.60 0.55 34 133 -47 102 25 3.9 62 50 7.40
= maximal
± ± ± ± ± ± ± ± ± ± ±
NNV-Control (95% CI) 0.20 0.05 2 9 8 13 2 1.8 4 2 0.01
0.03 (- 0.23 to 0.29) 0.02 (- 0.07 to 0.11) 1 (-2to 4) 8 (-14 to 30) 3 (-3to 10) 11 (-6to 27) 1 (-1 to 4) 0.10 (- 0.4 to 0.6) 2(-4to7) 3 (-1 to 6) -0.01(-0.03 to 0.01)
inspiratory pressure; MEP
= maximal expiratory
candy improved after NNV in five of the measures administered (table 6). Higher mean scores were obtained after NNV in measures that assessedattention and flexibility, verbal and visual memory, constructional praxis, and self-regulation abilities. On the other hand, score on tasks of attention and concentration, psychomotor speed, abstraction, and verbal fluency were unchanged, and the depression score failed to improve. Analysis of variance performed on the above studies to determine whether re-
35
30
MW
Vrnin
2.S 20 15 10 ·20 -30
MIP anH~
-40 -50 ·60 -70
-80 -90 65
-
PaC02
60 55 50 45 40 35 30
INITIAL
CONTROL
NNV
Fig. 1. Individual values are shown for maximal voluntary ventilation (MW), maximal inspiratory pressure (MIP),and Paco 2 during initialstudiesand afterthe eontrol and NNV arms of the study. Different symbols correspond to the seven individual patients who completed the protocol. The value for the initial MIP was missing for one patient.
1237
NASAL VENTILATION IN COPO
TABLE 4 POLYSOMNOGRAM RESULTS IN PATIENTS COMPLETING THE STUDY' Initial Total sleep time, min Sleep efficiency, % Sleep latency, min REM,% Mean O. sat, oAJ O. sat nadir, % • Data are mean ± SE; n
229 59 39 14
± ± ± ± 96 ± 94 ±
z
NNV
Control
32 8 19 1 1 1
254 67 21 12 96 90
± ± ± ± ± ±
189 53 55 11 92 89
27 5 5 2 1 2
NNV-Control (95% CI)
39 10 30 2 2 ± 2
-65 (-142 to 12) -14(-36to7) 34 (-43 to 110) -1(-7t05) -4(-7tol) -1 (-3 to 1)
± ± ± ± ±
7.
TABLE 5 DYSPNEA RATINGS IN PATIENTS COMPLETING THE STUDY'
Magnitude of task Magnitude of effort Functional impairment
Initial
Control
NNV
NNV-Control (950AJ CI)
0.9 ± 0.3 2.3 ± 0.3 0.6 ± 0.4
0.9 ± 0.1 1.9 ± 0.3 0.0 ± 0.0
0.9 ± 0.1 2.3 ± 0.4 0.3 ± 0.3
o 0.4 (-0.8 to 1.6) 0.3 ( - 0.4 to 1.0)
• Data are mean ± SE; n = 7. TABLE 6 PERFORMANCE IN NEUROPSYCHOLOGICAL MEASURES IN PATIENTS COMPLETING THE STUDY' Neuropsychological Measure Attention and concentration Attention and flexibility Psychomotor speed Verbal memory Visual memory Constructional praxis Abstraction Verbal associative fluency Self-regulation Depression
Initial 10 112 176 18 6 11 11 44 32 12
± ± ± :t ± ± ± ± ± ±
2 25 10 2 1 1 1 5 4 1
Control 11 133 178 19 8 11 12 47 27 11
± ± ± ± ± ± ± ± ± ±
2 19 9 2 2 1 1 4 4 2
NNV 11 84 215 21 4 13 12 47 41 8
± ± ± ± ± ± ± ± ± ±
NNV-Control (95% CI) 2 13t 30
ar It It 1 6
rt 1
0(-1 to 2) - 49 (- 87 to - 10) 36 (-28 to 100) 3 (0.5 to 5) -4 (-7to -1) 2 (0.2 to 3.6) 2(-2t06) o (-8 to 8) 14 (3 to 24) -3 (-8to 2)
• Data are mean ± SE; n = 7. with control values.
t p < 0.05 compared
sults may have been affected by sequence effects (25)revealed no significant trends. Also because of the small number of subjects who completed the study, confidence intervals for the differences between mean values obtained during the control and NNV periods are given in tables 3 to 6.
Acceptance of the Ventilator All of the seven patients who completed the study protocol were able to sleep through the night using the ventilator within 2 wk of initiating ventilator use. Average duration of use was 6.7 ± 0.6 h per night. Three of the seven patients felt better overall and experienced relief of dyspnea while using the ventilator. One of these subjects requested continued use of NNV after completion of study. The other four had no subjective improvement during ventilator use. Among the patients who completed the trial, no complications related to the ventilator occurred during the study. One patient required two brief hospitalizations for ex-
acerbations of COPD, one during the control phase and the other during the NNV phase. None of the other seven patients required hospitalization, nor did any interrupt use of the ventilator for more than three consecutive nights. Discussion
Using a randomized, crossover design, our study detected no improvements in daytime pulmonary function, indices of respiratory muscle function, arterial blood gases, dyspnea ratings, sleep quality, or nocturnal oxygenation in patients with severe COPD after a 3-month trial of NNV. Improvements did occur, however, in certain aspects of neuropsychologic function. In addition, tolerance of the nasal mask was limited, with 7 of 17 patients who were initially introduced to NNV withdrawing from the study because of intolerance of the mask. These results fail to confirm our initial hypotheses. On the basis of observations suggesting that respiratory muscle fatigue and weakness contribute to exer-
cise limitation and respiratory failure in patients with COPD (26, 27), we and others (5-9) have hypothesized that intermittent rest of the respiratory muscles would improve their strength and function. Others (28) have proposed that respiratory muscle weakness in patients with COPD also contributes to the sensation of dyspnea, and we hypothesized that improvements in respiratory muscle function associated with use of NNV would alleviate daytime dyspnea. Sleep disturbances are also common in patients with severe COPD. Unsuspected sleep apnea is commonly found when normal sleep studies are performed in patients with severe COPD (15, 16), as was the case in 4 of the 23 patients initially enrolled in our study. However, even in the absence of frank sleepapnea, patients with severe COPD have more frequent sleep disturbances, longer sleep latencies, less total sleep time, and higher degrees of sleep fragmentation than do control populations (17, 18). Oxygen desaturation is common, particularly during REM sleep (15). Thus, we hypothesized that NNV would prevent nocturnal oxygen desaturation and improve sleep quality in our patients. We further hypothesized that these improvements would translate into improved cognitive functioning as assessed by neuropsychologic studies. An earlier study by Zibrak and coworkers (8) that was similar in design to the present one demonstrated no favorable effects of intermittent long-term ventilatory assistance using a poncho wrap negative-pressure ventilator in patients with severe COPD. However, patients in that study tolerated the poncho wrap poorly, using it for an average of only 4.1 h per day, and none were able to sleep with it. The proportion of patients in our study who failed to tolerate NNV (7 of 19) was slightly less than that of patients who failed to tolerate the poncho wrap in the study of Zibrak and coworkers (11 of 20), and those who completed the present study averaged 6.7 h of use per night during sleep. Despite the improvedtolerance, however, NNV proved to be no more efficacious than the poncho wrap ventilator. Our findings are particularly disappointing in view of the favorable results reported for NNV in patients with restrictive pulmonary disease (10-14).
Although we did not detect anticipated improvements in most of our clinical measures, we did encounter improvements in tests of neuropsychologic func-
1238
tion. In the absence of any demonstrable improvement in total sleep time, sleep efficiency, 070REM sleep, or nocturnal oxygen saturation, we are at a loss to explain the physiologic basis for these improvements. We did not use a sham ventilator during the control arm of our study, and it is possible that use of the device elicited a placebo effect. On the other hand, a placebo effect would have been expected to influence most of the neuropsychologic tests, not just a few. Furthermore, the neuropsychologic tests that improved attention and flexibility, verbal and visual memory, constructional praxis, and self-regulation, fit a pattern that is thought to reflect cerebral function in "watershed areas" (21, 29, 30). These areas are supplied by terminal branches of the cerebral arteries and are particularly vulnerable to insults resulting from reduced blood flow such as hypotension, anoxia, or carbon monoxide. Thus, the improvements in neuropsychologic function could reflect enhancements of cerebral perfusion or oxygenation related to NNV that were not measured. Results from other studies on the efficiency of long-term noninvasive ventilatory assistance in patients with severe COPD are conflicting. Short-term studies using either poncho wrap or nasal ventilators have demonstrated that respiratory muscle function and gas exchange improve (6) in patients with COPD after brief periods of ventilatory assistance. In longer uncontrolled studies using negative pressure ventilators, Braun and Marino (5) observed improvements in respiratory muscle strength and gas exchange after 5 months of daily ventilatory assistance, and Gutierrez and coworkers (7) observed sustained improvements in inspiratory muscle strength, gas exchange, and functional scores when ventilatory assistance was given for 8 h once weekly for 4 months. No long-term controlled study has yet demonstrated the efficacy of intermittent noninvasive ventilatory assistance in patients with severe COPD. In addition to the previously cited 6-month trial of Zibrak and coworkers (8), Celli and colleagues (9) found no differences in pulmonary function, respiratory muscle strength, or exercise tolerance in a randomized parallel-group inpatient study comparing the effects of 3 wk of daily poncho wrap ventilation and pulmonary rehabilitation with rehabilitation alone. Differences in the severity of illness of the patients studied may explain some
STRUMPF, MILLMAN, CARLISLE, GRATTAN, RYAN, ERICKSON, AND HILL
ofthe conflicting results cited above. The present study and those of Zibrak and coworkers (8) and Celli and colleagues (9)examined patients with severebut clinically stable COPD with had mild CO 2 retention. Cropp and Dimarco (6) investigated patients with more severe CO 2 retention, and found that patients with the greatest CO 2retention tended to benefit most from assisted ventilation. Thus, it remains possible that patients with more severegas exchange derangements and who are less clinically stable than those in the present study might benefit from NNV. Further support for this possibility derives from preliminary, uncontrolled investigations demonstrating a tendencytoward fewer intubations in patients with acute exacerbations of COPD given assisted ventilation via a nose or face mask upon admission to the hospital (31, 32). Another preliminary evaluation of NNV showed ameliorations of nocturnal hypoventilation and oxygen desaturation in patients with more severe sleep desaturations than those encountered in our study (33). 1\\'0 caveats must be considered in interpreting our results. First, only a small number of subjects completed our trial, raising the likelihood of type II error. Every effort was made to minimize dropouts, but the severely ill nature of our patient population made a high dropout rate inevitable. The crossover design enhanced the statistical power of our results, but we cannot exclude the possibility that a small effect of NNV was missed that would have been detected in a larger study. For this reason, we have included 95070 confidence intervals for the mean differences between NNV and control values in tables 3 through 6. The individual variability for a number of key variables such as MVV, MIP, and Pac02 was quite small (figure 1). The 95% confidence intervals for these variables were likewise quite narrow. Therefore, despite the small number of subjects, our study demonstrated no favorableeffect of NNV on pulmonary functions, sleep, or dyspnea scores with a fairly high level of certainty. The second caveat is that we cannot be certain that adequate rest of the ventilatory muscles was achieved in our study. Before initiating the present study, we demonstrated that the BiPAP device functions effectivelyas a ventilator using an artificial lung model and compares favorably with standard portable positive pressure volume ventilators in pa-
tients with restrictive pulmonary diseases (23). Our subsequent experience shows that NNV administered using the BiPAP device reverses nocturnal hypoventilation and oxygen desaturation in patients with restrictive pulmonary diseases (Hill NS, unpublished observations). During overnight polysomnography, subjects in the present study breathed in synchrony with the ventilator for at least three quarters of their time asleep using a controlled ventilator rate, a mode that may rest inspiratory muscles more than patientinitiated modes (34, 35). Furthermore, repeated measurements of PETC02 showed sustained reductions of at least 5 mm Hg below levels obtained during spontaneous breathing, reductions similar to those shown to eliminate diaphragmatic EMG activity in normal subjects (36). Thus, at least some resting of respiratory muscles was likely achieved in our study, as has been reported by others in patients with COPD using nasal ventilation (34). However, lacking direct measurements of diaphragm electromyographic activity or transdiaphragmatic pressure, we cannot objectively assess resting of the ventilatory muscles. Despite these caveats, our data indicate that NNV administered to stable outpatients with severe COPD using a timecycled BiPAP ventilator is of minimal benefit. Further studies will be necessary to determine whether administration of NNV to a different population of patients with COPD or using a different ventilator technique will result in more benefit. Acknowledgment The writers thank Susan Beadles, RRT, and Stephanie Goff, RRT, of Amcare, Inc., for their kind assistance,and John Pezzullo, PhD, for helping with statistical analysis. References 1. Weirs PWJ, Le Coultre R, Dallinga OT, Van Dijl W, Meinesz AF, Sluiter HJ. Cuirass respirator of chronic respiratory failure in scoliotic patients. Thorax 1977; 32:221-8. 2. Garay SM, Turino GM, Goldring RM. Sustained reversal of chronic hypercapnia in patients with alveolar hypoventilation syndromes: long-term maintenance with non-invasive mechanical ventilation. Am J Med 1981; 70:269-74. 3. Curran Fl. Night ventilation by body respirators for patients in chronic respiratory failure due to late stage Duchenne muscular dystrophy. Arch Phys Med Rehabil 1981; 62:270-4. 4. Strumpf DA, Millman RP, Hill NS. Management of chronic hypoventilation. Chest 1990; 98: 474-80. 5. Braun NMT, Marino WD. Effect of daily intermittent rest of respiratory muscles in patients
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NASAL VENTILATION IN COPD
with severe chronic airflow limitation (CAL). Chest 1984; 85:59S-60S. 6. Cropp A, DiMarco AF. Effects of intermittent negative pressure ventilation on respiratory muscle function in patients with severe chronic obstructive pulmonary disease. Am Rev Respir Dis 1987; 136:1056-61. 7. Gutierrez M, Beroiza T, Contreras G, et 01. Weekly cuirass ventilation improves blood gases and inspiratory muscle strength in patients with chronic airflow limitation and hypercarbia. Am Rev Respir Dis 1988; 138:617-23. 8. Zibrak JD, Hill NS, Federman ED, Kwa SL, O'Donnell C. Evaluation of intermittent long-term negative-pressure ventilation in patients with severe chronic obstructive pulmonary disease. Am Rev Respir Dis 1988; 138:1515-2528. 9. Celli B, Lee H, Criner G, et 01. Controlled trial of external negative pressure ventilation in patients with severe chronic airflow obstruction. Am Rev Respir Dis 1989; 140:1251-6. 10. Kerby GR, Mayer LS, Pingleton SK. Nocturnal positive pressure ventilation via nasal mask. Am Rev Respir Dis 1987; 135:738-40. II. Ellis ER, Bye PTP, Bruderer JW, Sullivan CEo 'Ireatment of respiratory failure during sleep in patients with neuromuscular disease: positive-pressure ventilation through a nose mask. Am Rev Respir Dis 1987; 135:148-52. 12. Ellis ER, Grunstein RR, Chan S,· Bye PTP, Sullivan CEo Noninvasive ventilatory support during sleep improves respiratory failure in kyphoscoliosis. Chest 1988; 94:811-5. 13. Heckmatt JZ, Loh L, Dubowitz V. Night-time nasal ventilation in neuromuscular disease. Lancet 1990; 335:579-82. 14. Bach JR, Alba AS. Management of chronic alveolar hypoventilation by nasal ventilation. Chest 1990; 97:52-7. 15. Wynne JW, Block AJ, Hemenway J, Hunt LA, Flick MR. Disordered breathing and oxygen de-
saturation during sleep in patients with chronic ob~ structive lung disease (COLD). Am J Med 1979; 66:573-9. 16. Kearley R, Wynne JW, Block AJ, Boysen PG, Lindsey S, Martin C. The effect of low flow oxygen on sleep-disordered breathing and oxygen desaturation: a study of patients with chronic obstructive lung disease. Chest 1980; 78:682-5. 17. Caterall JR, Douglas NJ, Calvery PMA, et 01. Transient hypoxemia during sleep in chronic obstructive pulmonary disease is not a sleep apnea syndrome. Am Rev Respir Dis 1983; 128:24-9. 18. Klink M, Quan SF. Prevalence of reported sleep disturbances in a general adult population and their relationship to obstructive airways diseases. Chest 1987; 91:540-6. 19. Black LF, Hyatt RE. Maximal respiratory pressures: Normal values and relationship to age and sex. Am Rev Respir Dis 1969; 99:696-702. 20. Mahler DA, Weinberg DH, Wells CK, Feinstein AR. The measurement of dyspnea: contents, interobserver agreement, and physiologic correlates of two new clinical indexes. Chest 1984; 85:751-8. 21. Grattan LM, Eslinger P, Faust D. Reversible neuropsychological impairment after severe carbon monoxide poisoning in a child. Dev Neuropsychol 1988; 4:37-46. 22. Rechtschaffen A, Kales A, eds. A manual of standardized techniques and scoring system for sleep stages of human subjects. Los Angeles: Brain Information Service and Brain Research Institute, 1968. 23. Strumpf DA, Carlisle CC, Millman RP, Smith KW, Hill NS. An evaluation of the Respironics BiPAP bi-Ievel CPAP device for delivery of assisted ventilation. Respir Care 1990; 35:415-22. 24. Steel ReD, Torrie JH. Principles and procedures of statistics. New York: McGraw-Hill, 1960. 25. Woods JR, Williams JG, Tavel M. The twoperiod crossover design in medical research. Ann Intern Med 1989; 220:560-6.
26. Bellemare F, Grassino A. Force reserve of the diaphragm in patients with chronic obstructive pulmonary disease. J Appl Physiol 1983; 55:8-15. 27. Rochester DF, Braun NMT, Arora NS. Respiratory muscle strength in chronic obstructive pulmonary disease. Am Rev Respir Dis 1979; 119:151-4. 28. Murciano D, Auclair M·H, Parienti R, Aubier M. A randomized, controlled trial of theophylline in patients with severe chronic obstructive pulmonary disease. N Engl J Med 1989; 320:1521-5. 29. Prigatano GP, Parsons 0, Wright E, Levin DC, Hawryluk G. Neurophysiological test performance in mildly hypoxemic patients with chronic obstructive pulmonary disease. J Clin Consult Psychol 1983; 51:108-16. 30. Wood JH. Cerebral blood flow: physiologic and clinical aspects. New York: McGraw-Hill, 1987. 31. Benhamore MJF, Heliot P, Girault C, Callonec F, Portier F. Management of acute respiratory failure (ARF) in elderly patients with nasal intermittent positive pressure ventilation (NIPPV) (abstract). Am Rev Respir Dis 1990; 141:A237. 32. Meduri GU, Abor-Shala N, Jones CJ, Fox R, Leeper KV, Wunderink RG. Noninvasive face mask mechanical ventilation in patients with respiratory failure (abstract). Am Rev Respir Dis 1990; 141: A238. 33. Elliott M, Carroll M, Wedzicha J, Branthwaite M. Nasal positive pressure ventilation can be used successfully at home to control nocturnal hypoventilation in COPD (abstract). Am Rev Respir Dis 1990; 141:A322. 34. Carrey Z, Gottfried SB, Levy RD. Ventilatory muscle support in respiratory failure with nasal positive pressure ventilation. Chest 1990; 97:322-7. 35. Marini JJ, Rodriguez RM, Lamb V. The inspiratory work load of patient-initiated mechanical ventilation. Am Rev Respir Dis 1986; 134:902-9. 36. Henke KG, Arias A, Skatrud JB, Demsey JA. The inhibition of inspiratory muscle during sleep. Am Rev Respir Dis 1988; 138:8-15.
DAVID A. STRUMPF, RICHARD P. MILLMAN, CAROL C. CARLISLE, LYNN M. GRATTAN, SUSAN M. RYAN, ALLAN D. ERICKSON, and NICHOLAS S. HILL
Introduction
Numerous studies have reported improvement in daytime symptoms and gas exchange after use of nocturnal ventilatory assistance using noninvasive ventilators in patients with hypoventilation caused by restrictive pulmonary diseases (1-4). However, the efficacy of intermittent ventilatory assistance in patients with severechronic obstructive pulmonary disease (COPD) remains controversial. Several studies have demonstrated improvements in gas exchange and pulmonary function after use of negative pressure ventilators in patients with COPD (5-7), but these have either been uncontrolled or very short-term. Twolonger controlled studies using negative pressure ventilators in patients with severe COPD reported no improvements in gas exchange or pulmonary function after a period of intermittent ventilatory assistance (8, 9). One, a 6-month outpatient study (8), encountered very poor patient tolerance of the negative pressure device. More recently, nocturnal intermittent positive pressure ventilation administered via a nasal mask has been reported to improve symptoms of hypoventilation and gas exchange abnormalities in patients with restrictive pulmonary diseases (10-14). In the present study, wehypothesized that nocturnal nasal ventilation (NNV) would bring about significant improvements in gas exchange and pulmonary function in patients with severe COPD because it would be better tolerated than negative pressure ventilation and would be more effective at overcoming the sleep disturbances associated with COPD (15-18). Using a randomized, crossover design, we assessed the effects of 3 months ofNNV versus standard care on pulmonary functions, gas exchange, dyspnea ratings, sleep and neuropsychological function in seven patients with severe COPD. 1234
SUMMARY Intermittent positive pressure ventilation administered nocturnally via a nasal mask has been associated with Improvements In pUlmonary function and symptoms In patients with restrictive ventilatory disorders. We hypothesized that nocturnal nasal ventilation (NNV) would bring about similar Improvements In patients with severe chronic obstructive pUlmonary disease (COPO). The atudy used a randomized, crossover design, with subjects undergoing NNV or "standard care" for sequentlal3-month periods. Of 23 patients with obstructive lung disease and a FEV, < 1 L who were Initially enrolled, 4 were excluded because of obstructive sleep apnea prior to randomization. Among the remaining 19 patients, 7 withdrew because of Intolerance of the nose mask, 5 were withdrawn because of Intercurrent Illnesses, and 7 completed both arms of the protocol. These latter 7 patients used the ventilator for an average of 6.7 h/nlght, and 3 of the 7 had partial relief of dyspnea during ventilator use. However, In comparison with atudles performed upon Initiation or after the standard care arm of the study, atudles performed after 3 months of NNV revealed no Improvements In pulmonary function, respiratory muscle strength, gas exchange, exercise endurance, sleep efficiency, quality or oxygenation, or dyspnea ratings. The only Improvements observed were In neuropsychological function, possibly related to a placebo effect or another unknown mechanism. Despite the smsll sample size, our study Indicates that NNV Is not well tolerated by and brings sbout minimal Improvements In stsble outpatients with savere COPO. AM REV RESPIR DIS 1991; 144:1234-1239
Methods Patient Selection Patients with severe COPD were recruited from the pulmonary clinics at the Rhode Island Hospital and the Providence Veterans Administration Medical Center. The study was approved by the Institutional Review Boards at both hospitals, and informed consent was obtained from all patients. Entry criteria included a FEV, of < I L, a FEV,! FVC ratio of < 0.75, and a TLC of> 80070 predicted. Patients were excluded if they had > 15% increase in FEV, after administration of an inhaled bronchodilator, an exacerbation of their airway disease within the previous month, obstructive sleep apnea, coexisting medical conditions such as uncontrolled coronary heart disease, malignancy, or cardiac failure, or any condition that might hamper their ability to participate in a long-term trial. Patients continued on all standard medication, including theophylline, steroids, and 0, throughout the study. Initial Evaluation Patients admitted to the study underwent baseline pulmonary function testing including routine spirometry (Eagle I Spirometer; Warren E. Collins, Inc., Braintree, MA), de-
termination of lung volumes by variable pressure plethysmography (Collins, Inc.), and measurement of maximal inspiratory and expiratory pressures (MIP, MEP) using a precalibrated handheld manometer (Boehringer, Inc., Wynnewood, PA) as described by Black and Hyatt (19). Arterial blood gases were obtained in the sitting position with the patient breathing room air. Treadmill walking time (TWT) was determined as the amount of time required by the patient to reach exhaustion walking at a speed of 1.2 miles/h, 0% grade. The test was terminated early if oxygen saturation (Received in original form October 29. 1990 and in revised form March 18, 1991) , From the Division of Pulmonary and Critical Care Medicine and the Department of Psychiatry, Rhode Island Hospital, the Providence Veterans Administration Medical Center, and BrownUniversity, Providence, Rhode Island. , Supported in part by a grant from Respironics, Inc., Monroeville, Pennsylvania. 3 Correspondence and requests for reprints should be addressed to Nicholas S. Hill, M.D., Division of Pulmonary and Critical Care Medicine, Rhode Island Hospital, 593 Eddy Street, Providence, RI 02903.
NASAL VENTILATION IN COPO
dropped below 85% or systolic blood pressure fell by more than 20 mm Hg, Dyspnea was assessed using the dyspnea scale of Mahler, which rates dyspnea on three scales graded from zero to 4, higher numbers indicating superior function (20). The magnitude of task scale reflects the most strenuous task the patient can perform without dyspnea, the magnitude of effort scale assesses the patient's ability to perform the task without rest periods, and the functional impairment scale estimates the degree to which dyspnea has affected the patient's daily activities. Neuropsychologic function was examined using 10 measures that were administered to each patient by a clinical psychologist (LMG) who was blinded to the experimental condition. These measures assessed a wide range of neurobehavioral functions including attention and concentration (Digit Symbol Substitution subset of the Weschler Adult Intelligence Scale-Revised) (WAIS-R); attention and flexibility (Trails B); psychomotor speed and coordination (Grooved Pegboard); verbal memory (Rey Auditory Verbal Learning 'lest scored for total numbers of words recalled in Trial S and delayed recall); visual memory (Benton Visual Retention Testscored for number of errors); construction praxis (Block Design subset to the WAIS-R); verbal associative fluency (Controlled Oral Word Association lest); self-regulation (Stroop 'Irial J); and depression (BeckDepression Inventory). Standard administration and scoring procedures were utilized for all neuropsychological measures as previously described (21). Two all-night polysomnography studies were performed during the initial evaluation, consisting of continuous monitoring of nasal and oral airflow, chest wall and abdominal movement, oxygen saturation, electrocardiogram, and anterior tibialis electromyograms (EMG). Sleep stages were determined from electroencephalograms, electrooculograms, and submental EMGs recorded on a polygraph (Nihon-Kohden, Irvine, CA). Patients ordinarily receivingO 2supplementation remained on O 2 during the polysomnographic studies. The first study was to allow adaptation to the sleep laboratory and to screen out those with unsuspected sleep apnea. The second and subsequent studies were used for data analysis. The following sleep parameters were determined using the method of Rechtschaffen and Kales (22); total sleep time (TST); sleep efficiency defined as TST divided by time in bed; percent REM defined as the total time spent in rapid-eye movement sleep divided by TSl; and sleep latency to the first epoch of sleep. In addition, mean and lowest O 2 saturation, apneas (cessation of airflow for 10 s or longer), and hypopneas (500/0 decrease in airflow for 10 s or longer associated with an arousal and 4% fall in oxygen saturation) were noted. Patients with obstructive sleep apnea, defined as more than five apneas or hypopneas per hour, were excluded from the study.
1235
Introduction to the Ventilator Nasal ventilation was initiated in outpatients and was administered via a standard nasal continuous positive airway pressure mask (Respironics, Inc., Monroeville, PA) using a BiPAP ventilator (Respironics, Inc.) (23). After measurement of resting minute ventilation using a portable flow meter (No. 5420; Ohmeda, Englewood, CO) and proper fitting and adjustment of the nasal mask, BiPAP settings were adjusted to match the patient's spontaneous breathing rate and to provide a 20 to 50% augmentation of resting minute ventilation and reduction of at least 5 mm Hg in end-tidal Pco, (PETeo2) (Engstrom Eliza CO 2analyzer; Gambro-Engstrom, Bromma, Sweden). Tidal volume was augmented by increasing the inspiratory positive airway pressure (IPAP) setting on the BiPAP device. Expiratory positive airway pressure (EPAP) was kept at the lowest setting (2 em H 20 ), and percent inspiratory time (%IPAP) was set at 40%. Patients were observed using the nasal ventilator for an initial 2 to 3 h period, and further adjustments were made as necessary. Patients were then asked to use the device at home every evening and to gradually extend periods ofuse until they could sleep using it throughout the night. Ventilator use by patients was verified using an electronic timer. Patients receiving O 2 supplementation continued to receive it at the usual flow rate via a cannula attached to a port on the nasal mask during NNV. A respiratory therapist (SR) skilled in the use of NNV visited the home three times weekly until the patient had successfully adapted to the device, and visits were less frequent thereafter. Investigators were in frequent telephone contact with patients and made periodic home visits as necessary to obtain arterial blood gas and PETe02 measurements during the initial adjustment period. Further upward adjustments in IPAP were made if necessary to maintain PETeo2at least 5 mm Hg below the spontaneous resting level. Spot readings ofFETe02 were also obtained during follow-up sleep studies during ventilator use. Study Design After initial studies, patients were randomized to receive NNV during the initial 3-month period or to continue their standard COPD therapy. They were then crossed over to the other arm of the study for a final 3-month peiod. Studies were repeated after each 3-month period. No adaptation night was used for follow-up sleep studies, and polysomnography after the NNV arm was performed during ventilator use. Comparisons were made between initial measurements and those obtained at the completion of NNV and standard care (control) arms. Standard Care During the "standard care" period, patients were seen by one of the investigators on a monthly basis, or more frequently if clinical-
ly indicated. Bronchodilator medications were adjusted to achieve optimal doses, and antibiotics and corticosteroids were administered during acute exacerbations. Oxygen supplementation was administered to patients with severehypoxemia, and hospitalization was advised for those suffering severeexacerbations. Pulmonary function studies and arterial blood determinations were obtained as per the protocol or more frequently if clinically indicated. Patients were encouraged to remain active, but no specific rehabilitation program was offered to them.
Statistics Data are shown as mean ± SE. Comparisons between initial and follow-up measurements were made using analysis of variance for repeated measures. When significant F ratios wereobtained, the Student Newman Keulstest (24) was used to test for significance between individual group means. Analysis of variance was also performed to test for sequence effects related to the crossover design (25). To better demonstrate the magnitude of detectable differences given our small sample size, confidence intervals werecalculated for differences between mean values during the control and NNV periods. Differences were considered statistically significant at p < 0.05. Results
Patient Characteristics Thirty-nine patients meeting the pulmonary function criteria for entry into the study were recruited, but 11 declined to participate. Five had recent exacerbations ofCOPD or unstable cardiac disease and wererejected. Twenty-threepatients were initially enrolled in the study, including 19men and 4 women (table 1). Mean age of the patients upon entry was 66 ± 1 yr, and pulmonary function studies showed severe airway obstruction with moderate hyperinflation. Most patients had CO 2 retention and moderate to severe hypoxemia.
Patient Withdrawal Of the 23 patients initially entered into the study, 16 failed to complete the pro-
TABLE 1 CHARACTERISTICS OF PATIENTS' INITIALLY ENROLLED INTO THE STUDY Mean ± SE Age, yr
FEV,. L FEV" % TLC, % pred Paeo" mm Hg Pao" room air • n
= 23 (19 men;
66 0.56 33 133 49 59 4 women).
± 1
± 0.03 ± 2
± 5 ± 2 ± 2
Range
57-76 0.46-0.88 20-64 100-168 35-67 44-76
1236
STRUMPF, MILLMAN, CARLISLE, GRATTAN, RYAN, ERICKSON, AND HILL
TABLE 2
TABLE 3
VENTILATOR SETTINGS FOR PATIENTS COMPLETING THE STUDY'
PULMONARY FUNCTIONS, EXERCISE TOLERANCE, AND ARTERIAL BLOOD GAS DETERMINATION IN PATIENTS COMPLETING THE STUDY'
-----
Spontaneous RR, breaths/min VT, ml YE, Umin IPAP, em H,O PETeo" mm Hg
16.6± 1.3 347 ± 66 5.5 ± 0.9 40 ± 1
Initial
Ventilator 16.6 523 8.4 15 35
± ± ± ± ±
1.1 61 0.7 1 2
Definitionof abbreviations: RR = respiratory rate; VT = tidal volume; \IE = expired minute ventilation; IPAP = inspiratory positive airway pressure; PETCO, = end·tidal Peo,. • All values are mean ± SE; n = 7.
tocol. Four were found to have obstructive sleep apnea during the initial adaptation polysomnogram and were withdrawn prior to randomization. Despite every effort to alleviate discomfort and to encourage patients to continue the protocol, including multiple home visits by therapist and physicians, 7 patients withdrew because they could not tolerate the mask. Complaints included intolerable nasal mucosal irritation unresponsive to nasal corticosteroids or humidification in 4 patients, inability to sleep using the ventilator in 2, and excessive anxiety associated with ventilator use in 1. Five patients were withdrawn because of intercurrent illnessesthat disrupted the protocol; three during the NNV arm of the protocol and two during the control phase. Four had repeated hospitalizations, one for an auto accident that caused complicated recurrent pneumothoraces, one for repeated exacerbations of COPD, one for treatment of bladder cancer, and the other for unstable coronary artery disease. The fifth patient became depressed and requested withdrawal after his wife died unexpectedly.
Effect of NNV in Patients Completing the Protocol Baseline pulmonary functions for the seven patients who completed both arms of the study did not differ significantly from those of the initial 23 patients. Six ofthe seven patients used supplemental O 2, four at 1 L/min, and two at 2 L/min. Among these patients, breathing rate during ventilation use was the same as during spontaneous breathing (table 2). Tidal and minute volumes wereincreased by roughly 50010 during ventilator use. This augmentation was achieved by using a mean IPAP setting of 15 em H 20 , resulting in a drop of 5 mm Hg in PETC02 (table 2). Weobserved no improvements in FVC, FEV l , or FEV t% in the seven patients after a 3-month period of NNV com-
FVC, L FEV" L FEV" % TLC, % pred MIP, em H2O MEP, em H2O MVV, Umin TWT, min Pao" mm Hg Paco 2 , mm Hg pH
1.71 ± 0.54 ± 32 ± 133 ± -52 ± 92 ± 25 ± 4.3 ± 64 ± 46 ± 7.42 ±
0.23 0.03 1 7 8 10 2 1.6 3 2 0.01
Control 1.57 0.53 33 125 -50 91 24 3.8 60 47 7.42
± ± ± ± ± ± ± ± ± ± ±
NNV
0.31 0.06 2 5 6 9 2 1.8 4 3 0.01
Definitionof abbreviations: NNV = nocturnal nasal ventilation; MIP pressure; TWT = treadmill walking time. • Data are mean ± SE; n = 7.
pared with initial studies or the standard care (control) period (table 3). Likewise, the degree of hyperinflation as indicated by the TLC was unchanged, and indices of respiratory muscle strength (MIP and MEP) and endurance (MVV) were unchanged. Room air arterial blood gases and walking endurance on a treadmill (TWT) were also not improved by NNV. Daytime Paco2 failed to drop despite demonstrations that PETC02 was consistently reduced in all patients during ventilator use. Values for MVV, MIP, and Pac02 in individual subjects (figure 1) revealed no trends for improvement during NNV. Mean total sleep time and sleep efficiency were slightly lower during NNV than during the initial and control periods, but differences were not statistically significant (table 4). There was also a trend toward prolongation of sleep latency, and reduction in %REM, mean O 2 saturation, and lowest O2 saturation during NNV, but once again, differences were not statistically significant. Examination of the polysomnogram to assess synchrony of the patient's breathing with the ventilator revealed synchrony during 78% of non-REM and 76% of REM sleep, and spot readings of PETC02 during NNV demonstrated that the reduction shown in table 2 was sustained nocturnally. As expected, patients were severely limited by dyspnea and were capable of only minimal exertion, as reflected in the dyspnea ratings (table 5). No improvements wereobserved in the ability to perform tasks or in functional activity, nor did a reduction occur in the amount of effort required to perform a given task after use of NNV. In contrast to the above results, neuropsychologic performance was signifi-
1.60 0.55 34 133 -47 102 25 3.9 62 50 7.40
= maximal
± ± ± ± ± ± ± ± ± ± ±
NNV-Control (95% CI) 0.20 0.05 2 9 8 13 2 1.8 4 2 0.01
0.03 (- 0.23 to 0.29) 0.02 (- 0.07 to 0.11) 1 (-2to 4) 8 (-14 to 30) 3 (-3to 10) 11 (-6to 27) 1 (-1 to 4) 0.10 (- 0.4 to 0.6) 2(-4to7) 3 (-1 to 6) -0.01(-0.03 to 0.01)
inspiratory pressure; MEP
= maximal expiratory
candy improved after NNV in five of the measures administered (table 6). Higher mean scores were obtained after NNV in measures that assessedattention and flexibility, verbal and visual memory, constructional praxis, and self-regulation abilities. On the other hand, score on tasks of attention and concentration, psychomotor speed, abstraction, and verbal fluency were unchanged, and the depression score failed to improve. Analysis of variance performed on the above studies to determine whether re-
35
30
MW
Vrnin
2.S 20 15 10 ·20 -30
MIP anH~
-40 -50 ·60 -70
-80 -90 65
-
PaC02
60 55 50 45 40 35 30
INITIAL
CONTROL
NNV
Fig. 1. Individual values are shown for maximal voluntary ventilation (MW), maximal inspiratory pressure (MIP),and Paco 2 during initialstudiesand afterthe eontrol and NNV arms of the study. Different symbols correspond to the seven individual patients who completed the protocol. The value for the initial MIP was missing for one patient.
1237
NASAL VENTILATION IN COPO
TABLE 4 POLYSOMNOGRAM RESULTS IN PATIENTS COMPLETING THE STUDY' Initial Total sleep time, min Sleep efficiency, % Sleep latency, min REM,% Mean O. sat, oAJ O. sat nadir, % • Data are mean ± SE; n
229 59 39 14
± ± ± ± 96 ± 94 ±
z
NNV
Control
32 8 19 1 1 1
254 67 21 12 96 90
± ± ± ± ± ±
189 53 55 11 92 89
27 5 5 2 1 2
NNV-Control (95% CI)
39 10 30 2 2 ± 2
-65 (-142 to 12) -14(-36to7) 34 (-43 to 110) -1(-7t05) -4(-7tol) -1 (-3 to 1)
± ± ± ± ±
7.
TABLE 5 DYSPNEA RATINGS IN PATIENTS COMPLETING THE STUDY'
Magnitude of task Magnitude of effort Functional impairment
Initial
Control
NNV
NNV-Control (950AJ CI)
0.9 ± 0.3 2.3 ± 0.3 0.6 ± 0.4
0.9 ± 0.1 1.9 ± 0.3 0.0 ± 0.0
0.9 ± 0.1 2.3 ± 0.4 0.3 ± 0.3
o 0.4 (-0.8 to 1.6) 0.3 ( - 0.4 to 1.0)
• Data are mean ± SE; n = 7. TABLE 6 PERFORMANCE IN NEUROPSYCHOLOGICAL MEASURES IN PATIENTS COMPLETING THE STUDY' Neuropsychological Measure Attention and concentration Attention and flexibility Psychomotor speed Verbal memory Visual memory Constructional praxis Abstraction Verbal associative fluency Self-regulation Depression
Initial 10 112 176 18 6 11 11 44 32 12
± ± ± :t ± ± ± ± ± ±
2 25 10 2 1 1 1 5 4 1
Control 11 133 178 19 8 11 12 47 27 11
± ± ± ± ± ± ± ± ± ±
2 19 9 2 2 1 1 4 4 2
NNV 11 84 215 21 4 13 12 47 41 8
± ± ± ± ± ± ± ± ± ±
NNV-Control (95% CI) 2 13t 30
ar It It 1 6
rt 1
0(-1 to 2) - 49 (- 87 to - 10) 36 (-28 to 100) 3 (0.5 to 5) -4 (-7to -1) 2 (0.2 to 3.6) 2(-2t06) o (-8 to 8) 14 (3 to 24) -3 (-8to 2)
• Data are mean ± SE; n = 7. with control values.
t p < 0.05 compared
sults may have been affected by sequence effects (25)revealed no significant trends. Also because of the small number of subjects who completed the study, confidence intervals for the differences between mean values obtained during the control and NNV periods are given in tables 3 to 6.
Acceptance of the Ventilator All of the seven patients who completed the study protocol were able to sleep through the night using the ventilator within 2 wk of initiating ventilator use. Average duration of use was 6.7 ± 0.6 h per night. Three of the seven patients felt better overall and experienced relief of dyspnea while using the ventilator. One of these subjects requested continued use of NNV after completion of study. The other four had no subjective improvement during ventilator use. Among the patients who completed the trial, no complications related to the ventilator occurred during the study. One patient required two brief hospitalizations for ex-
acerbations of COPD, one during the control phase and the other during the NNV phase. None of the other seven patients required hospitalization, nor did any interrupt use of the ventilator for more than three consecutive nights. Discussion
Using a randomized, crossover design, our study detected no improvements in daytime pulmonary function, indices of respiratory muscle function, arterial blood gases, dyspnea ratings, sleep quality, or nocturnal oxygenation in patients with severe COPD after a 3-month trial of NNV. Improvements did occur, however, in certain aspects of neuropsychologic function. In addition, tolerance of the nasal mask was limited, with 7 of 17 patients who were initially introduced to NNV withdrawing from the study because of intolerance of the mask. These results fail to confirm our initial hypotheses. On the basis of observations suggesting that respiratory muscle fatigue and weakness contribute to exer-
cise limitation and respiratory failure in patients with COPD (26, 27), we and others (5-9) have hypothesized that intermittent rest of the respiratory muscles would improve their strength and function. Others (28) have proposed that respiratory muscle weakness in patients with COPD also contributes to the sensation of dyspnea, and we hypothesized that improvements in respiratory muscle function associated with use of NNV would alleviate daytime dyspnea. Sleep disturbances are also common in patients with severe COPD. Unsuspected sleep apnea is commonly found when normal sleep studies are performed in patients with severe COPD (15, 16), as was the case in 4 of the 23 patients initially enrolled in our study. However, even in the absence of frank sleepapnea, patients with severe COPD have more frequent sleep disturbances, longer sleep latencies, less total sleep time, and higher degrees of sleep fragmentation than do control populations (17, 18). Oxygen desaturation is common, particularly during REM sleep (15). Thus, we hypothesized that NNV would prevent nocturnal oxygen desaturation and improve sleep quality in our patients. We further hypothesized that these improvements would translate into improved cognitive functioning as assessed by neuropsychologic studies. An earlier study by Zibrak and coworkers (8) that was similar in design to the present one demonstrated no favorable effects of intermittent long-term ventilatory assistance using a poncho wrap negative-pressure ventilator in patients with severe COPD. However, patients in that study tolerated the poncho wrap poorly, using it for an average of only 4.1 h per day, and none were able to sleep with it. The proportion of patients in our study who failed to tolerate NNV (7 of 19) was slightly less than that of patients who failed to tolerate the poncho wrap in the study of Zibrak and coworkers (11 of 20), and those who completed the present study averaged 6.7 h of use per night during sleep. Despite the improvedtolerance, however, NNV proved to be no more efficacious than the poncho wrap ventilator. Our findings are particularly disappointing in view of the favorable results reported for NNV in patients with restrictive pulmonary disease (10-14).
Although we did not detect anticipated improvements in most of our clinical measures, we did encounter improvements in tests of neuropsychologic func-
1238
tion. In the absence of any demonstrable improvement in total sleep time, sleep efficiency, 070REM sleep, or nocturnal oxygen saturation, we are at a loss to explain the physiologic basis for these improvements. We did not use a sham ventilator during the control arm of our study, and it is possible that use of the device elicited a placebo effect. On the other hand, a placebo effect would have been expected to influence most of the neuropsychologic tests, not just a few. Furthermore, the neuropsychologic tests that improved attention and flexibility, verbal and visual memory, constructional praxis, and self-regulation, fit a pattern that is thought to reflect cerebral function in "watershed areas" (21, 29, 30). These areas are supplied by terminal branches of the cerebral arteries and are particularly vulnerable to insults resulting from reduced blood flow such as hypotension, anoxia, or carbon monoxide. Thus, the improvements in neuropsychologic function could reflect enhancements of cerebral perfusion or oxygenation related to NNV that were not measured. Results from other studies on the efficiency of long-term noninvasive ventilatory assistance in patients with severe COPD are conflicting. Short-term studies using either poncho wrap or nasal ventilators have demonstrated that respiratory muscle function and gas exchange improve (6) in patients with COPD after brief periods of ventilatory assistance. In longer uncontrolled studies using negative pressure ventilators, Braun and Marino (5) observed improvements in respiratory muscle strength and gas exchange after 5 months of daily ventilatory assistance, and Gutierrez and coworkers (7) observed sustained improvements in inspiratory muscle strength, gas exchange, and functional scores when ventilatory assistance was given for 8 h once weekly for 4 months. No long-term controlled study has yet demonstrated the efficacy of intermittent noninvasive ventilatory assistance in patients with severe COPD. In addition to the previously cited 6-month trial of Zibrak and coworkers (8), Celli and colleagues (9) found no differences in pulmonary function, respiratory muscle strength, or exercise tolerance in a randomized parallel-group inpatient study comparing the effects of 3 wk of daily poncho wrap ventilation and pulmonary rehabilitation with rehabilitation alone. Differences in the severity of illness of the patients studied may explain some
STRUMPF, MILLMAN, CARLISLE, GRATTAN, RYAN, ERICKSON, AND HILL
ofthe conflicting results cited above. The present study and those of Zibrak and coworkers (8) and Celli and colleagues (9)examined patients with severebut clinically stable COPD with had mild CO 2 retention. Cropp and Dimarco (6) investigated patients with more severe CO 2 retention, and found that patients with the greatest CO 2retention tended to benefit most from assisted ventilation. Thus, it remains possible that patients with more severegas exchange derangements and who are less clinically stable than those in the present study might benefit from NNV. Further support for this possibility derives from preliminary, uncontrolled investigations demonstrating a tendencytoward fewer intubations in patients with acute exacerbations of COPD given assisted ventilation via a nose or face mask upon admission to the hospital (31, 32). Another preliminary evaluation of NNV showed ameliorations of nocturnal hypoventilation and oxygen desaturation in patients with more severe sleep desaturations than those encountered in our study (33). 1\\'0 caveats must be considered in interpreting our results. First, only a small number of subjects completed our trial, raising the likelihood of type II error. Every effort was made to minimize dropouts, but the severely ill nature of our patient population made a high dropout rate inevitable. The crossover design enhanced the statistical power of our results, but we cannot exclude the possibility that a small effect of NNV was missed that would have been detected in a larger study. For this reason, we have included 95070 confidence intervals for the mean differences between NNV and control values in tables 3 through 6. The individual variability for a number of key variables such as MVV, MIP, and Pac02 was quite small (figure 1). The 95% confidence intervals for these variables were likewise quite narrow. Therefore, despite the small number of subjects, our study demonstrated no favorableeffect of NNV on pulmonary functions, sleep, or dyspnea scores with a fairly high level of certainty. The second caveat is that we cannot be certain that adequate rest of the ventilatory muscles was achieved in our study. Before initiating the present study, we demonstrated that the BiPAP device functions effectivelyas a ventilator using an artificial lung model and compares favorably with standard portable positive pressure volume ventilators in pa-
tients with restrictive pulmonary diseases (23). Our subsequent experience shows that NNV administered using the BiPAP device reverses nocturnal hypoventilation and oxygen desaturation in patients with restrictive pulmonary diseases (Hill NS, unpublished observations). During overnight polysomnography, subjects in the present study breathed in synchrony with the ventilator for at least three quarters of their time asleep using a controlled ventilator rate, a mode that may rest inspiratory muscles more than patientinitiated modes (34, 35). Furthermore, repeated measurements of PETC02 showed sustained reductions of at least 5 mm Hg below levels obtained during spontaneous breathing, reductions similar to those shown to eliminate diaphragmatic EMG activity in normal subjects (36). Thus, at least some resting of respiratory muscles was likely achieved in our study, as has been reported by others in patients with COPD using nasal ventilation (34). However, lacking direct measurements of diaphragm electromyographic activity or transdiaphragmatic pressure, we cannot objectively assess resting of the ventilatory muscles. Despite these caveats, our data indicate that NNV administered to stable outpatients with severe COPD using a timecycled BiPAP ventilator is of minimal benefit. Further studies will be necessary to determine whether administration of NNV to a different population of patients with COPD or using a different ventilator technique will result in more benefit. Acknowledgment The writers thank Susan Beadles, RRT, and Stephanie Goff, RRT, of Amcare, Inc., for their kind assistance,and John Pezzullo, PhD, for helping with statistical analysis. References 1. Weirs PWJ, Le Coultre R, Dallinga OT, Van Dijl W, Meinesz AF, Sluiter HJ. Cuirass respirator of chronic respiratory failure in scoliotic patients. Thorax 1977; 32:221-8. 2. Garay SM, Turino GM, Goldring RM. Sustained reversal of chronic hypercapnia in patients with alveolar hypoventilation syndromes: long-term maintenance with non-invasive mechanical ventilation. Am J Med 1981; 70:269-74. 3. Curran Fl. Night ventilation by body respirators for patients in chronic respiratory failure due to late stage Duchenne muscular dystrophy. Arch Phys Med Rehabil 1981; 62:270-4. 4. Strumpf DA, Millman RP, Hill NS. Management of chronic hypoventilation. Chest 1990; 98: 474-80. 5. Braun NMT, Marino WD. Effect of daily intermittent rest of respiratory muscles in patients
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26. Bellemare F, Grassino A. Force reserve of the diaphragm in patients with chronic obstructive pulmonary disease. J Appl Physiol 1983; 55:8-15. 27. Rochester DF, Braun NMT, Arora NS. Respiratory muscle strength in chronic obstructive pulmonary disease. Am Rev Respir Dis 1979; 119:151-4. 28. Murciano D, Auclair M·H, Parienti R, Aubier M. A randomized, controlled trial of theophylline in patients with severe chronic obstructive pulmonary disease. N Engl J Med 1989; 320:1521-5. 29. Prigatano GP, Parsons 0, Wright E, Levin DC, Hawryluk G. Neurophysiological test performance in mildly hypoxemic patients with chronic obstructive pulmonary disease. J Clin Consult Psychol 1983; 51:108-16. 30. Wood JH. Cerebral blood flow: physiologic and clinical aspects. New York: McGraw-Hill, 1987. 31. Benhamore MJF, Heliot P, Girault C, Callonec F, Portier F. Management of acute respiratory failure (ARF) in elderly patients with nasal intermittent positive pressure ventilation (NIPPV) (abstract). Am Rev Respir Dis 1990; 141:A237. 32. Meduri GU, Abor-Shala N, Jones CJ, Fox R, Leeper KV, Wunderink RG. Noninvasive face mask mechanical ventilation in patients with respiratory failure (abstract). Am Rev Respir Dis 1990; 141: A238. 33. Elliott M, Carroll M, Wedzicha J, Branthwaite M. Nasal positive pressure ventilation can be used successfully at home to control nocturnal hypoventilation in COPD (abstract). Am Rev Respir Dis 1990; 141:A322. 34. Carrey Z, Gottfried SB, Levy RD. Ventilatory muscle support in respiratory failure with nasal positive pressure ventilation. Chest 1990; 97:322-7. 35. Marini JJ, Rodriguez RM, Lamb V. The inspiratory work load of patient-initiated mechanical ventilation. Am Rev Respir Dis 1986; 134:902-9. 36. Henke KG, Arias A, Skatrud JB, Demsey JA. The inhibition of inspiratory muscle during sleep. Am Rev Respir Dis 1988; 138:8-15.
