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Objective Functional Improvement in Chronic Airway Obstruction
CLINICAL INVESTIGATIONS
Obiective Functional Improvement I-n Chronic Airway Obstruction* T. L. Petty, M.D., F.C.C.P., G. A. Brink, M.D., M. W. Miller, M.D., and P. R. Corsello, M.D.
Elgbteen patients witb revenible airway disease judged by an improvement In maximum voluntary ventilation (MVV) of 30 percent or more six months after entry Into a comprebensive, standardized care program for chronic airway obstruction were compared to similar Individuals not equally improved. Patients witb chronic airway obstruction with a wbeezing type onset wbo also demonstrated recurrent bouts of wbeezlng or congestion and those with a relatively sbort duration of disease with a small but definite response to inhaled broncbodilator are candidates for a trial of corticosteroid tberapy guided by pbysiologic tests to measure objective functional improvement. The 18 improved patients bad a statistically significant improvement in vital capacity, maximum voluntary ventilation, resting pO:!, resting oxygen saturation, and a marked improvement in exercise tolerance.
INTRoDucnoN
tive functional improvement compared to patients with lesser or no improvement. The major purpose is to report the observation that patients with apparently irreversible CAO may have some degree of physiologic improvement associated with systematic respiratory care.
Chronic airway obstruction (CAO) refers to a clinical spectrum ranging from relatively pure emphysema to chronic bronchitis.l" When studied at postmortem, the majority of patients with CAO have both elements of disease, ie, emphysema which refers to alveolar wall destruction, and mucous gland hyperplasia, the principal histologic lesion in chronic bronchitis.l! All patients in this spectrum demonstrate obstruction to expiratory air flow which is not significantly reversed by therapeutic measures as judged by pulmonary function tests. 5 •7 In addition, a progressive deterioration of function is expected with time. 5 •8 -11 During the development of a comprehensive care program for patients with severe CAO,12 certain patients demonstrated marked clinical improvement which was accompanied by sustained improvement in various simple pulmonary function tests which indicated a significant degree of reversibility of the airway obstruction. This report represents a retrospective analysis of background factors of patients with CAO and objec-
METHODS
During a two-year period, 182 consecutive patients with CAD have been accepted into a comprehensive care program designed to provide physical rehabilitation for patients with marked disability. These patients have been selected according to specific criteria, including the following: 1. A clinical diagnosis of emphysema and chronic bronchitis or both utilizing the established clinical definitions of the American Thoracic Societyt8 and the Ciba Guest Symposium. 14 Patients were excluded if their primary diagnosis was bronchial asthma (episodic acute wheezing dyspnea), if they had been symptomatic for less than two years, or if they had a symptom free interval within the past two years. Most patients had been symptomatic for many years, in spite of varying therapy, including bronchodilator drugs by referring physicians, prior to evaluation for our study. 2. Maximum voluntary ventilation (MVV) or forced expiratory volume in one second (FEV1) of less than 50 percent of predicted.l 5 •t 6 3. Failure to improve FEV! following inhaled bronchodilator administration (isoproterenol or isoetharene with phenylephrine) by more than 30 percent of the original value. In all cases, the FEV! remained less than 50 percent
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-From the Department of Medicine and the Webb-Waring Institute for Medical Research, University of Colorado School of Medicine, supported by PHS Contract PH 108-66-227.
216
217
FUNCTIONAL IMPROVEMENT IN CHRONIC AIRWAY OBSTRUCTION Table I-Correlation Coefficient of Percent Change in Ventilation Tests (109 PatientsSix Month Interval) VC FEV t MMF MW r r
= .195 = .254
VC
FEV t
MMF
MW
1.00 .467 .361 .528
1.00 .563 .569
1.00 .525
1.00
p p
= .05 = .01
oxygen consumption, and carbon dioxide production were performed on selected patients. An analysis of this data will be the subject of a later report. Patients received a fairly standardized treatment regimen which included the administration of oral bronchodilator drugs (an ephedrine containing drug or a xanthine, ie, choline theophylinate [Choledyl]), antibiotics (eg, tetracycline) in short courses (five to seven days) for specific clinical episodes of deep chest infection, and cardiac glycosides as well as diuretics for congestive heart failure. Patients were individually instructed in bronchial hygiene techniques always employing an inhaled bronchodilator (isoproterenol or isoetharene with phenylephrine) for approximately ten breaths followed by a period of steam inhalation for approximately ten minutes, followed in tum by expulsive coughing maneuvers or postural drainage.t? The bronchial hygiene regimen was performed each morning and evening with the intermittent home supervision of public health nurses. Corticosteroids were employed at the discretion of physicians participating in this study. These drugs were generally instituted for episodes of acute bronchiolitis characterized by sudden decrease in breath sounds and cessation of sputum production. In these instances corticosteroids were oniy used for three to five days (generally prednisone 30 mg per day for a three day period). A "trial" of corticosteroids was also given to selected individuals with intractable symptoms (cough and dyspnea) which persisted in spite of aggressive efforts at bronchial hygiene using both oral and inhaled bronchodilators as listed above. Patients did not receive steroids if clinical improvement was satisfactory by bronchial hygiene alone. The initial dose was prednisone, 30 mg daily, with reduction in dosage after three days to a maintenance daily dose of 5 to 10 mg. No attempt was made to study the efficacy of steroids alone, in a controlled fashion, be-
of predicted after bronchodilator. 4. Absence of other complicating pulmonary disease such as tuberculosis, silicosis, fibrosis, neoplasm, etc. 5. Absence of clinical evidence of cardiac disease except for cor pulmonale. 6. Absence of other complicating systemic illness, such as uncontrolled diabetes, uncompensated hepatic cirrhosis, renal insufficiency, etc. Patients were evaluated in standard fashion using the following tests: 1. Slow and fast vital capacity (VC), FEV t , maximum mid expiratory How (MMEF), and maximum voluntary ventilation (MW), using a Collins 13.5 liter spirometer. 2. Arterial blood analysis for at rest oxygen tension (p02)' oxygen saturation (SA0 2), carbon dioxide tension (pC0 2 ), and pH. o 3. Exercise tolerance on stairs or on treadmill at a pace, rate, and grade commensurate with the patient's exercise tolerance judged clinically by a physical therapist and physician. In addition, steady state diffusion tests, lung volumes, °Radiometer equipment, Westlake, Ohio.
Table 2-Eighteen Patients with 30 Percent Increase in MVV After Six Months Patient CB WV O BN° WA HR CV GR EL FW JM MS GL TJ SB BH OH ED BB Mean
Age
64 66 75 65 57 51 62 65 54 44 59 73 49 57 44 57 49 58 58
Ht.
Wt
Sex
70 66.5 71.5 68.5 68.2 72.5 70 64.2 64 69 66.5 63 74 67.5 63 72 68.5 64.5 68.0
131 157 155 120 121 157 189 132 149 137 148 93 205 131 137 152 169 144 146
M M M M M M M M F M M F M M F M M M
°Expired after six months. A Asthmatic on wheezing onset. T Tussive onset. D Dyspneic onset. X Combined onset. Y: 2 Clinically better. I Clinically same. o Clinically worse.
00
= = = = = = =
CHEST, VOL. 57, NO.3, MARCH 1970
Attacks of Wheeze
Type° ° Onset X A D X A A T D A A T D D X A X A D
Yes Yes Yes Yes
Yes Yes Yes Yes Yes Yes Yes Yes Yes
Clin. Y Chg.
Duration DOE (Yrs)
2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 0 2 1
10 3 3 4 2 3 20 3 4 2 10 15 10 3 7 5 16 13 7.4
Pk. Yrsz Smoke
Steroids?
64.5 (c) -(n)
50 (s) 60 (s) 4 (s) -(n) 44 (c)
16 (s)
Yes Yes Yes Yes Yes
-(n)
26 (s) 90 (s)
Yes
-(n) 52 (s) 20 (s)
Yes
3 (s) 92 (c) -(s) 38 (s)
Yes Yes Yes
43
Z: No. pack years cigarettes only. s Stopped at least one month before six month evaluation. Continued smoking throughout. c n Never smoked regularly.
= = =
PEITY ET AL
218 Table 3-Twenty-otle Patients with Leas Than 30 Percent Improvement in MVV Patient HH CB
WM BL FH IN EEo DR PYo FH CA KVo FCo CDo HL HQo JM RL WCo EEo Lpo Mean
Age 66 66 67 70 58
53 74 68 49 68 72 61
n
68 58 65
59 65
48 62 72 64
Ht.
Wt
Sex
74.0 67.8 68.5 69.0 67.0 71.0 74.8 68.0 69.0 64.2 69.0 68.2 64.0 67.5 66.0 71.5 70.0 70.0 70.0 69.0 70.0 66.0
158 163 135 110 120 170 173 152
M M M M
Attacks of Wheeze
D
T X D
M M M M M M M
265 102 138 123 112 136 113 175 184 202 132 103 142 148
M M M F M M M M M
X Yes
A D T D A
Yes Yes
X
X D D D D
M
Clin. Y Chg. 2 1 1 1 2 2 1 2 2 1 2 2 2 2 2 2 2 2 2 2 0
Duration DOE (Yrs)
Pic.Yrsz Smoke
10 15 7 5 11 10 6 10 4 9 11 19 10 9 10 20 3 10 6 13 17 10
50 (s) 50 (c) 125 (c) 62.5 (s) 76 (s) 34 (s) 55 (c) 45 (s) 13lh (s) 37.5 (c) -(s) 30 (s) 120 (s) 59 (s) 28 (s) 80 (s) 30 (s) 60 (c) -en) 90 (c) 110 (c) 61
Steroids?
Yes Yes
Yes
z: No. pack years cigarettes only.
s = Stopped at least one month before six month evaluation. c = Continued smoking throughout. n = Never smoked regularly.
cause of the other therapeutic measures also being used. Serial pulmonary function tests and arterial blood gas determinations were performed at regular intervals, always in duplicate (initial, one month, and at quarterly intervals thereafter). When it became apparent that certain patients within this series experienced marked symptomatic and functional improvement which was sustained for periods as long as six months, an analysis of background factors was therefore made to compare patients who demonstrated objective ventilatory function improvement of more than 30 percent above the initial value judged by MVV with those of lesser or no improvement. In each case, the clinical chart was reviewed to determine the type of onset of disease-s-dyspnetc" (D), tussive" (T), or asthmatic" (A)--since these initial symptoms represent the most common modes of onset in chronic airway obstruction.P' Mixed onset was designated as "X" (Tables 2 and 3). Background factors including age, sex, height, weight, duration of clinical illness (years of dyspnea on exertion), and smoking history are recorded. A complete review of each patient's chart was made to ascertain which drugs each patient was receiving at the time of the six-month pulmonary function reevaluation. The patients in the "nonsteroid" !{TOUp, at times actually received a three to five day course ----
D D T A A
Yes Yes
°Expired after six months. ° °A = Asthmatic on wheezing onset. T = Tussive onset. D = Dyspneic onset. X = Combined onset. Y: 2 = Clinically better. 1 = Clinically same. o = Clinically worse.
-
TypeoO Onset
---
°D=unrelenting shortness of breath on exertion without relief for at least two years (usually longer). T=chronic cough and expectoration for at least two years before onset of dyspnea. A=episodic wheezing dyspnea occurring usually with cough and progressing to unrelenting dyspnea on exertion for at least two years.
of prednisone within the month of reevaluation but not within ten days of study. The application of "significant steroid therapy" is also recorded in Tables 2 and 3.
In an earlier analysis of 182 patients in this study, we observed that mean ventilatory function parame,ters for the group showed little change throughout a 12-month period of observation.P A slight but statistically insignificant increase in MVV was apparent at six months for the group, however. In order to determine whether or not individual ventilatory function changes tended to correlate with each other and change in the same direction, an analysis was made of the 109 patients available at the six-month point of evaluation. This material is presented in Table 1. (The remaining 73 patients from the original series were unavailable for sixmonth studies for various reasons: in study < six months 34, missed appointment or appointments pending 28, dead 11.) It is apparent that a change in MVV correlates most highly with changes in the other parameters of ventilatory function (eg, FEV1, MMEF; a perfect positive correlation would be r 1; a negative correlation, r -1). Because of this, we employed improvement in MVV as the pri-
=
=
CHEST, VOL. 57, NO.3, MARCH 1970
219
FUNCTIONAL IMPROVEMENT IN CHRONIC AIRWAY OBSTRUCTION Table 4-Background Factors in "Improved" vs "Nonimproved" Patients
Wheezeo
X
D
Onset
T
Less than 5 Year Durationo
A
Steroids°
Smoking S
N
C
(43 Pack Years)OO 18 patients, 30% increase MVV
72%
22%
28%
11%
39%
56%
22%
61%
17%
(61 Pack Years)OO 21 patients without improvement
28%
19%
48%
14%
16%
19%
5%
62%
33%
0p < .05. oORepresents average lifetime cigarette consumption for the group.
mary yardstick of significant evidence of reversal of chronic airway obstruction as judged by ventilation tests and arbitrarily chose a level of > 30 percent improvement in MVV as evidence of significant improvement. Using this measure, we found 18 patients with significant function improvement at the six-month evaluation point. This evaluation point was chosen to rule out early or temporary physiological benefits which mayor may not be sustained. We then compared this improved group with a similar group of 21 contemporary patients not demonstrating this degree of improvement. Since smoking background factors might have an important bearing on reversibility or nonreversibility, smoking histories were analyzed from the carefully taken initial history. Pack years of cigarette smoking and whether or not the patient continued smoking or stopped within one month or more of the six-month evaluation were recorded. Pipe and cigar smokers who consumed no significant number of cigarettes were considered nonsmokers. Table 2 lists the age, height, weight, sex, presence or absence of significant attacks of wheeze superimposed on chronic dyspnea, the type of onset, the subjective clinical change, duration of disease, and background smoking factors for the 18 patients with significant improvement in MVV. The use of corticosteroids is also indicated. These background factors can be compared to the first 21 nonimproved patients in the study who proved to be representative of the entire group of unimproved patients (Table 3). It is apparent, in comparing the two tables, that the improved patients were more apt to have significant attacks of wheeze superimposed on their chronic dyspnea and received corticosteroid drugs more frequently than did those patients in the comparison group. Additional significant findings in Tables 2 and 3 were the subjective impression of clinical improvement" ° which was approximately the same in both CHEST, VOL. 57, NO.3, MARCH 1970
the improved and nonimproved group (p > 50). Also, later death is far more common in the nonimproved vs improved group (p < .05). All of the background factors comparing the improved versus the unimproved patients are summarized in Table 4. Significant differences at the 95 percent confidence level were found in presence or absence of wheeze, duration of disease, and clinical use of corticosteroid drugs. In addition, more patients with an asthmatic type of onset are found in the improved group and more with the dyspneic type of onset in the unimproved group. The unimproved group also included a greater background of cigarette smoking (pack years) and more patients who continued to smoke throughout the study. By contrast, more nonsmokers were found in the improved group. The differences are not statistically significant, however. As noted from Tables 2 and 3, the groups did not differ by height, weight, or sex ratio. Table 5 is an analysis of ventilatory function, blood gases, and walk performance on both stairs and treadmill for all 91 nonimproved patients from the original 109 available for six-month analysis. The only significant changes within this group include a slight decrease in MMEF, a marked improvement in walk tolerance, stairs climbed, calculated work on stairs and reduction in hematocrit. The FEVt/FVC ratio expressed as percent is reduced. For comparison, Table 6 reports more complete data from the 18 improved patients and demonstrates a significant improvement in vital capacity, MVV, resting p02, resting oxygen saturation, as well as a marked improvement in the fast vital °°The subjective evaluation of clinical improvement was recorded at each evaluation point. This was the patient's self-analysis of his daily activity level. In brief, to be "better" a patient had to be more comfortable doing an increased number of tasks at home and demonstrate 75 percent improvement on the treadmill with less dyspnea. If dyspnea remained in spite of improved exercise tolerance, patients were classified as the same; any deterioration in daily activity or treadmill performance classified patients as "worse."
PErrY ET AL
220 Table 5-Pulmona'll Function, Blood Goa, and Walk Performance (91 Patients with '"eversible Chronic Ainvay ObBtroction) Initial Tests
Six-Month Tests
A
Test VC FEV 1 MMEF MVV pH pC0 2 p02 02 saturation Walk tolerance (ft.) No. stairs Work on stairs (kgm) Weight Hct FastVC ~FEVl Broncho.effect(~
increase in MMEF) Age
N
Mean
91 91 91 91 56 55 49 56 81 67 67 66 36 91 91
2.57 .97 .43 37.9 7.40 38.4 59.6 88.8 681. 43. 496. 145. 51.0 2.41 40.6
79 91
49.2 60.2
.77 .37 .24 14.6 .04 6.1 8.2 5.0 614. 27. 345. 30. 5.5 .76 11.6 41.7 8.3
capacity. In sum, it is apparent from Tables 5 and 6 that initial values for ventilatory function tests, blood gases, and exercise tolerance were generally quite similar for both groups. A slightly greater bronchodilator response was evidence in the patients with reversible airway disease. After six months, however, the objectively improved patients also had significant improvement in other physiological parameters and a marked improvement in exercise tolerance. ILLUSTRATIVE CASES 1 A 51-year-old engineer was referred
CASE
to
A
SO
the
PIII-
Mean
SO
2.56 .91 .37 36.7 7.41 38.9 59.4 88.9 1,229. 67. 776. 146. 49.1 2.42 37.6 38.5
.74 .41 .21 16.6 .03 5.5 8.6 4.9 929. 32. 408. 32. 4.7 .79 11.0 35.2
P
.04
.0006 .0008 .001
.05 .03
monary Rehabilitation Program on March 8, 1967. The patient had suffered allergic rhinitis since age 22 with spring attacks. He did not smoke tobacco. At approximately age 32, the patient began having attacks of acute wheezing dyspnea, primarily in the spring time. His early symptomatology was clearly episodic. Six years before entry, acute attacks increased in severity and chronic unrelenting dyspnea occurred. No true symptom-free interval could be recalled since 1961, and the patient had chronic progressive cough and dyspnea on exertion. Four years before entry, following a deep chest infection, an episode of respiratory failure occurred, requiring tracheostomy and ventilatory assistance. He recovered, but with chronic breathlessness. For the two years before entry, the patient followed a systematic therapy program using inhaled isoproterenol by
Table 6-Pulmonary Function, Blood Goa, and Walk Performance (18 Patients with Reversible Chronic Ainvay ObBtruction) Initial Tests
Six-Month Tests
A
Test VC FEV 1 MMEF MVV pH pCO., p02 02 saturation Walk tolerance (ft.) No. stairs Work on stairs (kgrn) Weight Hct Fast VC ~FEVI
Broncho. effect (~ increase in MMEF) Age
_
..
N
Mean
18 18 18 18 18 13 11 13 14 12 12 13 8 18 18
2.72 1.07 .49 39.6 7.40 36.2 57.6 88.9 593. 36. 425. 150. 48.9 2.39 45.4
15 18
84.6 58.3
_ _. _ - -
-
-
A
SO .92 .50 .21 18.0 .02 3.7 8.9 4.9 418. 26. 319. 29. 31. 1.03 9.8 59.6 9.1
Mean 3.45 1.54 .85 65.2 7.43 34.4 67.4 92.3 1,525. 89. 1,063. 151. 46.6 3.36 45.2 49.8
SO 1.07 .87 .77 35.4 .05 6.8 11.7 4.2 1,165. 39. 562. 27. 5.0 1.14 14.1 35.2
P .05 .04 .05
.02 .04 .005 .0004 .001 .05
--------. ---- ----------
CHEST,
VOL. 57, NO. 3,
MARCH 1970
FUNCTIONAL IMPROVEMENT IN CHRONIC AIRWAY OBSTRUCTION nebulizer regularly throughout the day with controlled expulsive coughing which produced profuse secretions. In addition, the patient had received oral bronchodilators (choline salt of theophylline-Choledyl) regularly as well as prednisone in low dosage, usually 5 mg daily on an intermittent basis. In addition, rectal aminophylline was useful for attacks of superimposed choking, cough, and dyspnea. Exercise tolerance at the time of evaluation was fairly good with approximately a half-mile tolerance at a slow speed on the treadmill. Climbing stairs and other acts of exertion, however, caused severe breathlessness each day. On examination, the patient's height was 72.5 inches, weight 157 pounds. Blood pressure was 140/90. Positive physical findings included a well-healed tracheostomy scar, a prominent chest, fair chest expansions, diminished breath sounds at the apices, but fair air entry and exit at the bases as well as prolonged expiration. Deep breathing caused some diffuse wheeze, though the patient denied he was wheezing at the time of evaluation. Precordial activity was normal, and no murmurs were heard. Abdominal and extremity examinations were normal. A diagnosis of chronic bronchial asthma and chronic bronchitis was made. Ventilation tests revealed a vital capacity of 2.36 liters, normal in parentheses (4.86); FEVl 0.75 liters (3.70); MMEF 0.3 liters per second (3.71, standard deviation ± 1.00); MW 30 liters per minute (139). Arterial detenninations revealed a pH of 7.39, pC0 2 35 mm, p02 54 mm, and SA0 2 85 mm. (normal Denver SA0 2 > 92 percent, p02 65 to 75.) Following isoproterenol inhalation, MMEF increased to 0.46 liters per second and FEV l to 0.89 liters per second. Chest x-ray film demontrated moderate hyperinflation of the lung fields with increased anterior-posterior diameter and flat diaphragms. Cardiac silhouette was normal. Routine urinalysis and blood determinations were normal. Electrocardiogram revealed right axis deviation and right ventricular enlargement. Initially, the patient was managed with regular inhalations of isoproterenol, using a powered nebulized and oral ephedrine. After one month, the patient was moderately symptomatically improved; and repeat ventilatory function tests showed modest improvement (Table 7). Because of recurrent exacerbations of cough and unrelenting dyspnea, however, the patient was managed with prednisone, 15 mg daily, reducing to 7.5 mg per day after the first week. Pulmonary function determinations at six months showed
=
Table 7-Physiologic Data from Illustrative Cases Case No. 1-51 W M
Initial VC(L) FEVl (L/sec) MMEF (Lz'sec) MW(Llmin)
2.36 0.75 0.30 30
After One Month Six Months One Year Bronchial (3Mo, Maint. Hygiene Steroids) Steroids 3.15 0.99 0.45 41
3.57 1.35 0.51 61
4.17 1.68 0.60 67
Case No. 2--64 W M Initial VC(L) FEVl (L/sec) MMEF (L/sec) MVV(Llmin)
1.71 0.95 0.43 30
Two Month Bronchial Hygiene Six Months One Year 2.63 0.93 0.31 45
3.48 1.09 0.36
45
CHEST, VOl. 57, NO.3, MARCH 1970
2.88 0.85 0.32
38
221
further improvement; and the values at one year showed continued improvement. At this time, the patient was receiving prednisone, 5 mg daily, along with his bronchial hygiene regimen. The patient appreciated marked symptomatic improvement and was able, after six months, to exercise at high altitude (10,000 feet) and participate in all normal work and pleasurable activities.
Comment This case with chronic airway obstruction and unrelenting symptoms for at least six years, began as seasonal bronchial asthma. Chronic airway obstruction was present on entry to the study in view of the chronicity of symptoms and lack of significant benefit from inhaled bronchodilator drugs. Initial benefit did occur with the systematic use of bronchial hygiene alone, but further improvement occurred coincident with steroid administration and was sustained for up to one year (Table 7). It is likely that a significant degree of chronic reversible asthma was present in this case ofCAO.
2 A 64-year-old retired clerk was evaluated for the Pulmonary Rehabilitation Program because of chronic cough and dyspnea for the previous ten years. The patient's symptoms began with cough and dyspnea; cough was more productive in the past than at the time of evaluation. Shortness of breath became progressively more severe during the eight years before entry; during this period a ten pound weight loss occurred. At the time of evaluation, the patient was limited to walking approximately one block a day. The patient had a heavy smoking history, with a cigarette consumption of 64 pack years over a 3O-year period. During the year before evaluation, the patient smoked one-half pack each day. The patient also had five episodes of bronchitis during the year before entry, usually requiring hospitalization. On these occasions he was treated with oxygen and bronchodilators. On physical examination he was well developed and in no acute distress. Height was 70 inches, weight 131 pounds, and blood pressure 118/78. Accessory muscles of respiration were employed during quiet breathing. No neck vein distension was present. The chest was enlarged in the anteriorposterior diameter. Poor chest expansions were observed. Diaphragms were low and no perceptible movement could be detected. On auscultation, the chest was clear; and breath sounds were markedly decreased throughout; and augmented breathing did not improve the sound of air entry or exit. Cardiac examination was normal as were the abdominal and the extremity examinations. It was our clinical impression that the patient had chronic airway obstruction due to both emphysema and chronic bronchitis. Initial physiologtcal determinations revealed a vital capacity of 1.71 liters (4.14); FEV 1 of 0.95 liters (3.10); MMEF 0.43 liters per second (3.12 with a standard deviation of ± 0.80 liters per second); and an MW of 30 liters per minute (113). Following isoproterenol inhalations, vital capacity was 2.50 liters; FEV l of 1.16 liters; MMEF of 0.59 liters per second; and MW of 26 liters. Chest x-ray picture revealed hyperinflation of lung fields and increase in the retrostemal space with flattening of the diaphragms. Electrocardiogram demonstrated right atrial enlargement and a rightward axis with a small rightward terminal vector consistent with right ventricular enlargement. The patient was managed with a simple hand bulb nebuCASE
222
PETTY ET AL
lizer, using isoproterenol followed by moisture, followed by expulsive coughing twice daily. Cigarette smoking was discontinued. During the course of the first six months of management, the patient experienced marked improvement in exercise tolerance and a relief of symptoms. Exercise tolerance improved from seven stairs to 69 stairs at the end of two weeks of training, and walk tolerance increased from 172 feet to 737 feet. After two months of bronchial hygiene, the patient's improved VC was 2.63 liters, FEV 1 0.93 liters, MMEF 0.31 liters per second, and MVV was 45 liters. The same benefit was maintained at six months (Table 7); and at one year, only slight deterioration was observed compared to the six-month values.
Comment This patient presented typical features of long-standing chronic airway obstruction primarily related to emphysema. It is noteworthy that systematic respiratory care could provide some measurable reversibility of the pulmonary function abnormality. Whether this was due to the bronchial hygiene program or the physical retraining and reconditioning, is not answered by this study. It is also noteworthy that at one year, the patient's measurable pulmonary function was slightly better than his initial values; and the expected deterioration of pulmonary function determinations was not experienced.
DISCUSSION This study does not make a critical inquiry into the relative merits and effectiveness of the various forms of therapy employed. Our objectives were to identify background factors in patients with significant physiological improvement, in patients receiving systematic physiologically oriented therapy. Of particular interest is the possible effectiveness of prednisone in ten of the 18 improved patients. The use of corticosteroid drugs in chronic airway obstruction has been controversial. No clinical or physiological benefit was reported with intravenous methylprednisolone given for a one-week period in emphysema patients. HI By contrast, an FEV I improvement of 25 percent was found in one third of the individuals with chronic bronchitis and emphysema in another study.f" In patients with clinical chronic bronchitis, 15 of 28 patients who also received spasmolytic drugs showed measureable pulmonary function improvement/" and a transient improvement was observed in ten patients in both ventilatory function tests and resting p02 and oxygen saturation during a course of steroid therapy.22 This improvement was lost on reduction to maintenance levels of corticosteroids, however. In a controlled study of the effects of prednisone in ten patients with chronic airway obstruction, it was found that the patients hehaved as two populations with eight patients showing no clinical or physiological benefit; but two demonstrated strik-
ing clinical and functional benefits. 23 The two with benefit in this study also had a background of asthmatic symptoms, and the authors suggested that patients with a wheezing type of onset might well respond to the administration of corticosteroid drugs. Observations made in ten of the 18 improved patients of this study support this conclusion. On the other hand, we found equally Significant improvement in eight of 18 patients without steroids; and we do not know what effect if any, corticosteroids might have produced in 18 of the 21 patients in the unimproved group who did not receive steroids. In addition, the clinical effectiveness of systematic bronchial hygiene in CAO with the use of corticosteroid drugs has been reportedy·24 Bronchial hygiene is probably effective by promoting the clearance of retained secretions and reversal of muscular bronchospastn.F-" It has long been our policy to manage patients with chronic airway obstruction conservatively, employing bronchial hygiene, breathing retraining, physical medicine measures, and graded exercises.P We have reserved corticosteroid drugs for patients with intractable cough and dyspnea when other measures have failed to bring improvement. It is interesting that subjective improvement was similar in both groups at six months (Tables 2 and 3). This is consistent with Burrows'!" observations where clinical improvement was often observed for up to two years in spite of no measureable functional improvement. We have observed this same clinical improvement in our entire series, and this is often accompanied by increased exercise tolerance and work capacity. In spite of the subjective nature of this improvement, reduction in symptoms and ability to function at a higher activity level is greatly appreciated by the patient.P That the early mortality is Significantly lower in the functionally improved groups (Tables 2 and 3) may be highly important. A long-term analysis of survival is needed to strengthen this contention. The reason for the functional improvement in the small group of 18 patients is likely due to some degree of reversal bronchitisv' or an element of bronchial asthma. These patients were specifically selected to exclude reversible asthma, but a companion study in our institute suggests that bronchial asthma may be found post mortem in patients believed to have either emphysema or chronic bronchitis. For example, in a postmortem study conducted by one of our colleagues, exhaustive special postmortem pulmonary evaluations were performed on specimens from patients with criteria almost identical to those described in this paper. In this study, CHEST, VOL. 57, NO.3, MARCH 1970
FUNCTIONAL IMPROVEMENT IN CHRONIC AIRWAY OBSTRUCTION
three patients from a group of 156 thought to have chronic airway obstruction during life were found at autopsy to have no destruction of alveolar walls or mucous gland hyperplasia." These three individuals had the histologic findings consistent with bronchial asthma, ie, mucous plugging, thickening of the basement membrane, hypertrophy to the muscle of the airway walls, dilated submucosal mucous glands, and eosinophilic mucosal cellular infiltrates. 26 It is unlikely that the small and statistically insignificant differences in smoking background factors for the two groups explain the physiological differences observed. Cessation of smoking, however, apparently has a salutory effect on survival in CAO.27 The current study suggests that patients with chronic airway obstruction with an asthmatic type of onset, recurrent bouts of cough and wheeze, a relatively short duration of disease, and a significant bronchodilator response judged by spirometric tests, are good candidates for a "trial" of corticosteroid drugs. ACKNOWLEDGMENT: The technical assistance of Sidney Shelden, BS, is gratefully acknowledged. REFERENCES
I MITCHELL, RS., SILVERS, G.W., DART, G.A., PETTY, T.L., VINCENT, T.N., RYAN, S.F., AND FILLEY, G.F.: Clinical physiologic and morphologic correlations in chronic airway obstruction, Amer. Rev. Resp. Dis., 97:54, 1968. 2 MITCHELL, RS., RYAN, S.F., PETTY, T.L., AND FILLEY, G.F.: The significance of morphologic chronic hyperplastic bronchitis, Amer. Rev. Resp. Dis., 93:720, 1966. 3 THURLBECK, W.M., FRAZER, RG., AND BATES, D.V.: The correlation between pulmonary structure and functions: chronic bronchitis, emphysema, and asthma, Med. Thorac., 22:295, 1965. 4 PETTY, T.L., MIERCORT, R., RYAN, S.F., VINCENT, T.N., FILLEY, G.F., AND MITCHELL, RS.: The functional and bronchographic evaluation of postmortem human lungs (clinical, physiologic, roentgenographic, and pathologic correlations in normal subjects and patients with emphysema and chronic bronchitis), Amer. Rev. Resp. Dis., 92:450, 1965. 5 British Medical Research Council: Value of chemoprophylaxis and chemotherapy in early chronic bronchitis, Brit. Med. ]., 1:1317, 1966. 6 SULCUMALCHANTRO, Y., AND WILLIAMS, M.H.: Serial studies of pulmonary function in patients with chronic obstructive pulmonary disease, Amer. J. Med., 39:941, 1965. 7 SIMPSON, T.: Chronic bronchitis and emphysema with special reference to treatment, Brit. J. Dis. Chest, 62:70, 1968. 8 HOWARD, P.: Evaluation of ventilatory capacity in chronic bronchitis, Brit. Med. t; 3:392, 1967. 9 BOUSHY, S.F., AND COATES, E.O.: The prognostic value of pulmonary function tests in emphysema (with special reference to arterial blood studies), Amer. Rev. Resp. oi«. 90:553, 1964.
CHEST, VOL. 57, NO.3, MARCH 1970
223
10 BURROWS, B., AND EARLE, R.H.: Course and prognosis of chronic obstructive lung disease, New Eng. J. Med., 280:397, 1969. II RENZETTI, D.D., MCCLEMENT, ].H., AND LITT, B.: The Veterans Administration cooperative study of pulmonary function, III. Mortality in relation to respiratory function in chronic obstructive pulmonary disease, Amer. ]. Med., 41:II5, 1966. 12 PETTY, T.L., NETT, L.M., FINIGAN, M.M., BRINK, G.A., AND CoRSELLO, P.R.: A comprehensive care program for chronic airway obstruction, Ann. Intern. Med., 70:II09, 1969. 13 Definitions and classification of chronic bronchitis, asthma, and pulmonary emphysema (a statement of the AMERICAN THORACIC SOCIETY), Amer. Rev. Resp. Dis., 85:762, 1962. 14 CmA SYMPOSIUM: Terminology, definitions and classifications of chronic pulmonary emphysema and related conditions, Thorax, 14:286, 1959. 15 GOLDMAN, H.I., AND BECKLAKE, M.R.: Respiratory function tests (normal values at median altitudes and the prediction of normal results), Amer. Rev. Resp. Dis., 79:457,1959. 16 LINDALL, A., MEDINA, A., AND GRISMER, ].T.: A reevaluation of normal measurements in the adult female, Amer. Rev. Resp. Dis., 95:1061, 1961. 17 NETT, L.M., AND PETTY, T.L.: Effective treatment for emphysema and chronic bronchitis, J. Rehab., 33: 10, 1967. 18 MITCHELL, R.S., AND FILLEY, G.F.: Chronic obstructive bronchopulmonary disease, I. Clinical features, Amer. Rev. Resp. o«; 89:360, 1964. 19 PECORA, L.]., Zoss, A.R., BAUM, G.L., IUIO, W., AND TAN, A.: A study of the physiologic effects of intravenous methylprednisolone in chronic pulmonary emphysema, Amer. Rev. Resp. tn«, 89:528, 1964. 20 FREIDMAN, B.].: Bronchodilators and corticosteroids in chronic bronchitis and emphysema, Brit. Med. J., 2:1509, 1963. 21 CLIFTON, M., AND STUART-HARRIS, C.H.: Steroid therapy in chronic bronchitis, Lancet., 1:13II, 1962. 22 FULEIHAM, F.].D., F'EIsAN, K.A., AND MALOUF, N.W.: Effect of corticosteroids in pulmonary function in chronic bronchitis with airway obstruction, Amer. Rev. Resp. o«, 96:678, 1967. 23 BEEREL, F., ]ICK, H., AND TYLER, ].M.: A controlled study of the effect of prednisone on air Bow obstruction in severe pulmonary emphysema, New Eng. J. Med., 268:226,1963. 24 MILLER, W.F.: Rehabilitation of patients with chronic obstructive lung disease, Med. Clin. N. Amer., 51:349, 1967. 25 MITCHELL, R.S.: Data from emphysema registry, WehhWaring Institute, personal communication. 26 CoHEN, E.P., PETrY, T.L., SZENTIVANYI, A., AND PRIEST, R.E.: Clinical and pathological observations in fatal bronchial asthma, Ann. Intern. Med., 62:103, 1965. 27 PETTY, T.L., RYAN, S.F., AND MITCHELL, R.S.: Cigarette smoking and the lungs, Af'ch. Environ. Health, 14:172, 1967. Reprint requests: Dr. Petty, 4200 East Ninth Avenue, Denver 80220.
Obiective Functional Improvement I-n Chronic Airway Obstruction* T. L. Petty, M.D., F.C.C.P., G. A. Brink, M.D., M. W. Miller, M.D., and P. R. Corsello, M.D.
Elgbteen patients witb revenible airway disease judged by an improvement In maximum voluntary ventilation (MVV) of 30 percent or more six months after entry Into a comprebensive, standardized care program for chronic airway obstruction were compared to similar Individuals not equally improved. Patients witb chronic airway obstruction with a wbeezing type onset wbo also demonstrated recurrent bouts of wbeezlng or congestion and those with a relatively sbort duration of disease with a small but definite response to inhaled broncbodilator are candidates for a trial of corticosteroid tberapy guided by pbysiologic tests to measure objective functional improvement. The 18 improved patients bad a statistically significant improvement in vital capacity, maximum voluntary ventilation, resting pO:!, resting oxygen saturation, and a marked improvement in exercise tolerance.
INTRoDucnoN
tive functional improvement compared to patients with lesser or no improvement. The major purpose is to report the observation that patients with apparently irreversible CAO may have some degree of physiologic improvement associated with systematic respiratory care.
Chronic airway obstruction (CAO) refers to a clinical spectrum ranging from relatively pure emphysema to chronic bronchitis.l" When studied at postmortem, the majority of patients with CAO have both elements of disease, ie, emphysema which refers to alveolar wall destruction, and mucous gland hyperplasia, the principal histologic lesion in chronic bronchitis.l! All patients in this spectrum demonstrate obstruction to expiratory air flow which is not significantly reversed by therapeutic measures as judged by pulmonary function tests. 5 •7 In addition, a progressive deterioration of function is expected with time. 5 •8 -11 During the development of a comprehensive care program for patients with severe CAO,12 certain patients demonstrated marked clinical improvement which was accompanied by sustained improvement in various simple pulmonary function tests which indicated a significant degree of reversibility of the airway obstruction. This report represents a retrospective analysis of background factors of patients with CAO and objec-
METHODS
During a two-year period, 182 consecutive patients with CAD have been accepted into a comprehensive care program designed to provide physical rehabilitation for patients with marked disability. These patients have been selected according to specific criteria, including the following: 1. A clinical diagnosis of emphysema and chronic bronchitis or both utilizing the established clinical definitions of the American Thoracic Societyt8 and the Ciba Guest Symposium. 14 Patients were excluded if their primary diagnosis was bronchial asthma (episodic acute wheezing dyspnea), if they had been symptomatic for less than two years, or if they had a symptom free interval within the past two years. Most patients had been symptomatic for many years, in spite of varying therapy, including bronchodilator drugs by referring physicians, prior to evaluation for our study. 2. Maximum voluntary ventilation (MVV) or forced expiratory volume in one second (FEV1) of less than 50 percent of predicted.l 5 •t 6 3. Failure to improve FEV! following inhaled bronchodilator administration (isoproterenol or isoetharene with phenylephrine) by more than 30 percent of the original value. In all cases, the FEV! remained less than 50 percent
---------
-From the Department of Medicine and the Webb-Waring Institute for Medical Research, University of Colorado School of Medicine, supported by PHS Contract PH 108-66-227.
216
217
FUNCTIONAL IMPROVEMENT IN CHRONIC AIRWAY OBSTRUCTION Table I-Correlation Coefficient of Percent Change in Ventilation Tests (109 PatientsSix Month Interval) VC FEV t MMF MW r r
= .195 = .254
VC
FEV t
MMF
MW
1.00 .467 .361 .528
1.00 .563 .569
1.00 .525
1.00
p p
= .05 = .01
oxygen consumption, and carbon dioxide production were performed on selected patients. An analysis of this data will be the subject of a later report. Patients received a fairly standardized treatment regimen which included the administration of oral bronchodilator drugs (an ephedrine containing drug or a xanthine, ie, choline theophylinate [Choledyl]), antibiotics (eg, tetracycline) in short courses (five to seven days) for specific clinical episodes of deep chest infection, and cardiac glycosides as well as diuretics for congestive heart failure. Patients were individually instructed in bronchial hygiene techniques always employing an inhaled bronchodilator (isoproterenol or isoetharene with phenylephrine) for approximately ten breaths followed by a period of steam inhalation for approximately ten minutes, followed in tum by expulsive coughing maneuvers or postural drainage.t? The bronchial hygiene regimen was performed each morning and evening with the intermittent home supervision of public health nurses. Corticosteroids were employed at the discretion of physicians participating in this study. These drugs were generally instituted for episodes of acute bronchiolitis characterized by sudden decrease in breath sounds and cessation of sputum production. In these instances corticosteroids were oniy used for three to five days (generally prednisone 30 mg per day for a three day period). A "trial" of corticosteroids was also given to selected individuals with intractable symptoms (cough and dyspnea) which persisted in spite of aggressive efforts at bronchial hygiene using both oral and inhaled bronchodilators as listed above. Patients did not receive steroids if clinical improvement was satisfactory by bronchial hygiene alone. The initial dose was prednisone, 30 mg daily, with reduction in dosage after three days to a maintenance daily dose of 5 to 10 mg. No attempt was made to study the efficacy of steroids alone, in a controlled fashion, be-
of predicted after bronchodilator. 4. Absence of other complicating pulmonary disease such as tuberculosis, silicosis, fibrosis, neoplasm, etc. 5. Absence of clinical evidence of cardiac disease except for cor pulmonale. 6. Absence of other complicating systemic illness, such as uncontrolled diabetes, uncompensated hepatic cirrhosis, renal insufficiency, etc. Patients were evaluated in standard fashion using the following tests: 1. Slow and fast vital capacity (VC), FEV t , maximum mid expiratory How (MMEF), and maximum voluntary ventilation (MW), using a Collins 13.5 liter spirometer. 2. Arterial blood analysis for at rest oxygen tension (p02)' oxygen saturation (SA0 2), carbon dioxide tension (pC0 2 ), and pH. o 3. Exercise tolerance on stairs or on treadmill at a pace, rate, and grade commensurate with the patient's exercise tolerance judged clinically by a physical therapist and physician. In addition, steady state diffusion tests, lung volumes, °Radiometer equipment, Westlake, Ohio.
Table 2-Eighteen Patients with 30 Percent Increase in MVV After Six Months Patient CB WV O BN° WA HR CV GR EL FW JM MS GL TJ SB BH OH ED BB Mean
Age
64 66 75 65 57 51 62 65 54 44 59 73 49 57 44 57 49 58 58
Ht.
Wt
Sex
70 66.5 71.5 68.5 68.2 72.5 70 64.2 64 69 66.5 63 74 67.5 63 72 68.5 64.5 68.0
131 157 155 120 121 157 189 132 149 137 148 93 205 131 137 152 169 144 146
M M M M M M M M F M M F M M F M M M
°Expired after six months. A Asthmatic on wheezing onset. T Tussive onset. D Dyspneic onset. X Combined onset. Y: 2 Clinically better. I Clinically same. o Clinically worse.
00
= = = = = = =
CHEST, VOL. 57, NO.3, MARCH 1970
Attacks of Wheeze
Type° ° Onset X A D X A A T D A A T D D X A X A D
Yes Yes Yes Yes
Yes Yes Yes Yes Yes Yes Yes Yes Yes
Clin. Y Chg.
Duration DOE (Yrs)
2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 0 2 1
10 3 3 4 2 3 20 3 4 2 10 15 10 3 7 5 16 13 7.4
Pk. Yrsz Smoke
Steroids?
64.5 (c) -(n)
50 (s) 60 (s) 4 (s) -(n) 44 (c)
16 (s)
Yes Yes Yes Yes Yes
-(n)
26 (s) 90 (s)
Yes
-(n) 52 (s) 20 (s)
Yes
3 (s) 92 (c) -(s) 38 (s)
Yes Yes Yes
43
Z: No. pack years cigarettes only. s Stopped at least one month before six month evaluation. Continued smoking throughout. c n Never smoked regularly.
= = =
PEITY ET AL
218 Table 3-Twenty-otle Patients with Leas Than 30 Percent Improvement in MVV Patient HH CB
WM BL FH IN EEo DR PYo FH CA KVo FCo CDo HL HQo JM RL WCo EEo Lpo Mean
Age 66 66 67 70 58
53 74 68 49 68 72 61
n
68 58 65
59 65
48 62 72 64
Ht.
Wt
Sex
74.0 67.8 68.5 69.0 67.0 71.0 74.8 68.0 69.0 64.2 69.0 68.2 64.0 67.5 66.0 71.5 70.0 70.0 70.0 69.0 70.0 66.0
158 163 135 110 120 170 173 152
M M M M
Attacks of Wheeze
D
T X D
M M M M M M M
265 102 138 123 112 136 113 175 184 202 132 103 142 148
M M M F M M M M M
X Yes
A D T D A
Yes Yes
X
X D D D D
M
Clin. Y Chg. 2 1 1 1 2 2 1 2 2 1 2 2 2 2 2 2 2 2 2 2 0
Duration DOE (Yrs)
Pic.Yrsz Smoke
10 15 7 5 11 10 6 10 4 9 11 19 10 9 10 20 3 10 6 13 17 10
50 (s) 50 (c) 125 (c) 62.5 (s) 76 (s) 34 (s) 55 (c) 45 (s) 13lh (s) 37.5 (c) -(s) 30 (s) 120 (s) 59 (s) 28 (s) 80 (s) 30 (s) 60 (c) -en) 90 (c) 110 (c) 61
Steroids?
Yes Yes
Yes
z: No. pack years cigarettes only.
s = Stopped at least one month before six month evaluation. c = Continued smoking throughout. n = Never smoked regularly.
cause of the other therapeutic measures also being used. Serial pulmonary function tests and arterial blood gas determinations were performed at regular intervals, always in duplicate (initial, one month, and at quarterly intervals thereafter). When it became apparent that certain patients within this series experienced marked symptomatic and functional improvement which was sustained for periods as long as six months, an analysis of background factors was therefore made to compare patients who demonstrated objective ventilatory function improvement of more than 30 percent above the initial value judged by MVV with those of lesser or no improvement. In each case, the clinical chart was reviewed to determine the type of onset of disease-s-dyspnetc" (D), tussive" (T), or asthmatic" (A)--since these initial symptoms represent the most common modes of onset in chronic airway obstruction.P' Mixed onset was designated as "X" (Tables 2 and 3). Background factors including age, sex, height, weight, duration of clinical illness (years of dyspnea on exertion), and smoking history are recorded. A complete review of each patient's chart was made to ascertain which drugs each patient was receiving at the time of the six-month pulmonary function reevaluation. The patients in the "nonsteroid" !{TOUp, at times actually received a three to five day course ----
D D T A A
Yes Yes
°Expired after six months. ° °A = Asthmatic on wheezing onset. T = Tussive onset. D = Dyspneic onset. X = Combined onset. Y: 2 = Clinically better. 1 = Clinically same. o = Clinically worse.
-
TypeoO Onset
---
°D=unrelenting shortness of breath on exertion without relief for at least two years (usually longer). T=chronic cough and expectoration for at least two years before onset of dyspnea. A=episodic wheezing dyspnea occurring usually with cough and progressing to unrelenting dyspnea on exertion for at least two years.
of prednisone within the month of reevaluation but not within ten days of study. The application of "significant steroid therapy" is also recorded in Tables 2 and 3.
In an earlier analysis of 182 patients in this study, we observed that mean ventilatory function parame,ters for the group showed little change throughout a 12-month period of observation.P A slight but statistically insignificant increase in MVV was apparent at six months for the group, however. In order to determine whether or not individual ventilatory function changes tended to correlate with each other and change in the same direction, an analysis was made of the 109 patients available at the six-month point of evaluation. This material is presented in Table 1. (The remaining 73 patients from the original series were unavailable for sixmonth studies for various reasons: in study < six months 34, missed appointment or appointments pending 28, dead 11.) It is apparent that a change in MVV correlates most highly with changes in the other parameters of ventilatory function (eg, FEV1, MMEF; a perfect positive correlation would be r 1; a negative correlation, r -1). Because of this, we employed improvement in MVV as the pri-
=
=
CHEST, VOL. 57, NO.3, MARCH 1970
219
FUNCTIONAL IMPROVEMENT IN CHRONIC AIRWAY OBSTRUCTION Table 4-Background Factors in "Improved" vs "Nonimproved" Patients
Wheezeo
X
D
Onset
T
Less than 5 Year Durationo
A
Steroids°
Smoking S
N
C
(43 Pack Years)OO 18 patients, 30% increase MVV
72%
22%
28%
11%
39%
56%
22%
61%
17%
(61 Pack Years)OO 21 patients without improvement
28%
19%
48%
14%
16%
19%
5%
62%
33%
0p < .05. oORepresents average lifetime cigarette consumption for the group.
mary yardstick of significant evidence of reversal of chronic airway obstruction as judged by ventilation tests and arbitrarily chose a level of > 30 percent improvement in MVV as evidence of significant improvement. Using this measure, we found 18 patients with significant function improvement at the six-month evaluation point. This evaluation point was chosen to rule out early or temporary physiological benefits which mayor may not be sustained. We then compared this improved group with a similar group of 21 contemporary patients not demonstrating this degree of improvement. Since smoking background factors might have an important bearing on reversibility or nonreversibility, smoking histories were analyzed from the carefully taken initial history. Pack years of cigarette smoking and whether or not the patient continued smoking or stopped within one month or more of the six-month evaluation were recorded. Pipe and cigar smokers who consumed no significant number of cigarettes were considered nonsmokers. Table 2 lists the age, height, weight, sex, presence or absence of significant attacks of wheeze superimposed on chronic dyspnea, the type of onset, the subjective clinical change, duration of disease, and background smoking factors for the 18 patients with significant improvement in MVV. The use of corticosteroids is also indicated. These background factors can be compared to the first 21 nonimproved patients in the study who proved to be representative of the entire group of unimproved patients (Table 3). It is apparent, in comparing the two tables, that the improved patients were more apt to have significant attacks of wheeze superimposed on their chronic dyspnea and received corticosteroid drugs more frequently than did those patients in the comparison group. Additional significant findings in Tables 2 and 3 were the subjective impression of clinical improvement" ° which was approximately the same in both CHEST, VOL. 57, NO.3, MARCH 1970
the improved and nonimproved group (p > 50). Also, later death is far more common in the nonimproved vs improved group (p < .05). All of the background factors comparing the improved versus the unimproved patients are summarized in Table 4. Significant differences at the 95 percent confidence level were found in presence or absence of wheeze, duration of disease, and clinical use of corticosteroid drugs. In addition, more patients with an asthmatic type of onset are found in the improved group and more with the dyspneic type of onset in the unimproved group. The unimproved group also included a greater background of cigarette smoking (pack years) and more patients who continued to smoke throughout the study. By contrast, more nonsmokers were found in the improved group. The differences are not statistically significant, however. As noted from Tables 2 and 3, the groups did not differ by height, weight, or sex ratio. Table 5 is an analysis of ventilatory function, blood gases, and walk performance on both stairs and treadmill for all 91 nonimproved patients from the original 109 available for six-month analysis. The only significant changes within this group include a slight decrease in MMEF, a marked improvement in walk tolerance, stairs climbed, calculated work on stairs and reduction in hematocrit. The FEVt/FVC ratio expressed as percent is reduced. For comparison, Table 6 reports more complete data from the 18 improved patients and demonstrates a significant improvement in vital capacity, MVV, resting p02, resting oxygen saturation, as well as a marked improvement in the fast vital °°The subjective evaluation of clinical improvement was recorded at each evaluation point. This was the patient's self-analysis of his daily activity level. In brief, to be "better" a patient had to be more comfortable doing an increased number of tasks at home and demonstrate 75 percent improvement on the treadmill with less dyspnea. If dyspnea remained in spite of improved exercise tolerance, patients were classified as the same; any deterioration in daily activity or treadmill performance classified patients as "worse."
PErrY ET AL
220 Table 5-Pulmona'll Function, Blood Goa, and Walk Performance (91 Patients with '"eversible Chronic Ainvay ObBtroction) Initial Tests
Six-Month Tests
A
Test VC FEV 1 MMEF MVV pH pC0 2 p02 02 saturation Walk tolerance (ft.) No. stairs Work on stairs (kgm) Weight Hct FastVC ~FEVl Broncho.effect(~
increase in MMEF) Age
N
Mean
91 91 91 91 56 55 49 56 81 67 67 66 36 91 91
2.57 .97 .43 37.9 7.40 38.4 59.6 88.8 681. 43. 496. 145. 51.0 2.41 40.6
79 91
49.2 60.2
.77 .37 .24 14.6 .04 6.1 8.2 5.0 614. 27. 345. 30. 5.5 .76 11.6 41.7 8.3
capacity. In sum, it is apparent from Tables 5 and 6 that initial values for ventilatory function tests, blood gases, and exercise tolerance were generally quite similar for both groups. A slightly greater bronchodilator response was evidence in the patients with reversible airway disease. After six months, however, the objectively improved patients also had significant improvement in other physiological parameters and a marked improvement in exercise tolerance. ILLUSTRATIVE CASES 1 A 51-year-old engineer was referred
CASE
to
A
SO
the
PIII-
Mean
SO
2.56 .91 .37 36.7 7.41 38.9 59.4 88.9 1,229. 67. 776. 146. 49.1 2.42 37.6 38.5
.74 .41 .21 16.6 .03 5.5 8.6 4.9 929. 32. 408. 32. 4.7 .79 11.0 35.2
P
.04
.0006 .0008 .001
.05 .03
monary Rehabilitation Program on March 8, 1967. The patient had suffered allergic rhinitis since age 22 with spring attacks. He did not smoke tobacco. At approximately age 32, the patient began having attacks of acute wheezing dyspnea, primarily in the spring time. His early symptomatology was clearly episodic. Six years before entry, acute attacks increased in severity and chronic unrelenting dyspnea occurred. No true symptom-free interval could be recalled since 1961, and the patient had chronic progressive cough and dyspnea on exertion. Four years before entry, following a deep chest infection, an episode of respiratory failure occurred, requiring tracheostomy and ventilatory assistance. He recovered, but with chronic breathlessness. For the two years before entry, the patient followed a systematic therapy program using inhaled isoproterenol by
Table 6-Pulmonary Function, Blood Goa, and Walk Performance (18 Patients with Reversible Chronic Ainvay ObBtruction) Initial Tests
Six-Month Tests
A
Test VC FEV 1 MMEF MVV pH pCO., p02 02 saturation Walk tolerance (ft.) No. stairs Work on stairs (kgrn) Weight Hct Fast VC ~FEVI
Broncho. effect (~ increase in MMEF) Age
_
..
N
Mean
18 18 18 18 18 13 11 13 14 12 12 13 8 18 18
2.72 1.07 .49 39.6 7.40 36.2 57.6 88.9 593. 36. 425. 150. 48.9 2.39 45.4
15 18
84.6 58.3
_ _. _ - -
-
-
A
SO .92 .50 .21 18.0 .02 3.7 8.9 4.9 418. 26. 319. 29. 31. 1.03 9.8 59.6 9.1
Mean 3.45 1.54 .85 65.2 7.43 34.4 67.4 92.3 1,525. 89. 1,063. 151. 46.6 3.36 45.2 49.8
SO 1.07 .87 .77 35.4 .05 6.8 11.7 4.2 1,165. 39. 562. 27. 5.0 1.14 14.1 35.2
P .05 .04 .05
.02 .04 .005 .0004 .001 .05
--------. ---- ----------
CHEST,
VOL. 57, NO. 3,
MARCH 1970
FUNCTIONAL IMPROVEMENT IN CHRONIC AIRWAY OBSTRUCTION nebulizer regularly throughout the day with controlled expulsive coughing which produced profuse secretions. In addition, the patient had received oral bronchodilators (choline salt of theophylline-Choledyl) regularly as well as prednisone in low dosage, usually 5 mg daily on an intermittent basis. In addition, rectal aminophylline was useful for attacks of superimposed choking, cough, and dyspnea. Exercise tolerance at the time of evaluation was fairly good with approximately a half-mile tolerance at a slow speed on the treadmill. Climbing stairs and other acts of exertion, however, caused severe breathlessness each day. On examination, the patient's height was 72.5 inches, weight 157 pounds. Blood pressure was 140/90. Positive physical findings included a well-healed tracheostomy scar, a prominent chest, fair chest expansions, diminished breath sounds at the apices, but fair air entry and exit at the bases as well as prolonged expiration. Deep breathing caused some diffuse wheeze, though the patient denied he was wheezing at the time of evaluation. Precordial activity was normal, and no murmurs were heard. Abdominal and extremity examinations were normal. A diagnosis of chronic bronchial asthma and chronic bronchitis was made. Ventilation tests revealed a vital capacity of 2.36 liters, normal in parentheses (4.86); FEVl 0.75 liters (3.70); MMEF 0.3 liters per second (3.71, standard deviation ± 1.00); MW 30 liters per minute (139). Arterial detenninations revealed a pH of 7.39, pC0 2 35 mm, p02 54 mm, and SA0 2 85 mm. (normal Denver SA0 2 > 92 percent, p02 65 to 75.) Following isoproterenol inhalation, MMEF increased to 0.46 liters per second and FEV l to 0.89 liters per second. Chest x-ray film demontrated moderate hyperinflation of the lung fields with increased anterior-posterior diameter and flat diaphragms. Cardiac silhouette was normal. Routine urinalysis and blood determinations were normal. Electrocardiogram revealed right axis deviation and right ventricular enlargement. Initially, the patient was managed with regular inhalations of isoproterenol, using a powered nebulized and oral ephedrine. After one month, the patient was moderately symptomatically improved; and repeat ventilatory function tests showed modest improvement (Table 7). Because of recurrent exacerbations of cough and unrelenting dyspnea, however, the patient was managed with prednisone, 15 mg daily, reducing to 7.5 mg per day after the first week. Pulmonary function determinations at six months showed
=
Table 7-Physiologic Data from Illustrative Cases Case No. 1-51 W M
Initial VC(L) FEVl (L/sec) MMEF (Lz'sec) MW(Llmin)
2.36 0.75 0.30 30
After One Month Six Months One Year Bronchial (3Mo, Maint. Hygiene Steroids) Steroids 3.15 0.99 0.45 41
3.57 1.35 0.51 61
4.17 1.68 0.60 67
Case No. 2--64 W M Initial VC(L) FEVl (L/sec) MMEF (L/sec) MVV(Llmin)
1.71 0.95 0.43 30
Two Month Bronchial Hygiene Six Months One Year 2.63 0.93 0.31 45
3.48 1.09 0.36
45
CHEST, VOl. 57, NO.3, MARCH 1970
2.88 0.85 0.32
38
221
further improvement; and the values at one year showed continued improvement. At this time, the patient was receiving prednisone, 5 mg daily, along with his bronchial hygiene regimen. The patient appreciated marked symptomatic improvement and was able, after six months, to exercise at high altitude (10,000 feet) and participate in all normal work and pleasurable activities.
Comment This case with chronic airway obstruction and unrelenting symptoms for at least six years, began as seasonal bronchial asthma. Chronic airway obstruction was present on entry to the study in view of the chronicity of symptoms and lack of significant benefit from inhaled bronchodilator drugs. Initial benefit did occur with the systematic use of bronchial hygiene alone, but further improvement occurred coincident with steroid administration and was sustained for up to one year (Table 7). It is likely that a significant degree of chronic reversible asthma was present in this case ofCAO.
2 A 64-year-old retired clerk was evaluated for the Pulmonary Rehabilitation Program because of chronic cough and dyspnea for the previous ten years. The patient's symptoms began with cough and dyspnea; cough was more productive in the past than at the time of evaluation. Shortness of breath became progressively more severe during the eight years before entry; during this period a ten pound weight loss occurred. At the time of evaluation, the patient was limited to walking approximately one block a day. The patient had a heavy smoking history, with a cigarette consumption of 64 pack years over a 3O-year period. During the year before evaluation, the patient smoked one-half pack each day. The patient also had five episodes of bronchitis during the year before entry, usually requiring hospitalization. On these occasions he was treated with oxygen and bronchodilators. On physical examination he was well developed and in no acute distress. Height was 70 inches, weight 131 pounds, and blood pressure 118/78. Accessory muscles of respiration were employed during quiet breathing. No neck vein distension was present. The chest was enlarged in the anteriorposterior diameter. Poor chest expansions were observed. Diaphragms were low and no perceptible movement could be detected. On auscultation, the chest was clear; and breath sounds were markedly decreased throughout; and augmented breathing did not improve the sound of air entry or exit. Cardiac examination was normal as were the abdominal and the extremity examinations. It was our clinical impression that the patient had chronic airway obstruction due to both emphysema and chronic bronchitis. Initial physiologtcal determinations revealed a vital capacity of 1.71 liters (4.14); FEV 1 of 0.95 liters (3.10); MMEF 0.43 liters per second (3.12 with a standard deviation of ± 0.80 liters per second); and an MW of 30 liters per minute (113). Following isoproterenol inhalations, vital capacity was 2.50 liters; FEV l of 1.16 liters; MMEF of 0.59 liters per second; and MW of 26 liters. Chest x-ray picture revealed hyperinflation of lung fields and increase in the retrostemal space with flattening of the diaphragms. Electrocardiogram demonstrated right atrial enlargement and a rightward axis with a small rightward terminal vector consistent with right ventricular enlargement. The patient was managed with a simple hand bulb nebuCASE
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lizer, using isoproterenol followed by moisture, followed by expulsive coughing twice daily. Cigarette smoking was discontinued. During the course of the first six months of management, the patient experienced marked improvement in exercise tolerance and a relief of symptoms. Exercise tolerance improved from seven stairs to 69 stairs at the end of two weeks of training, and walk tolerance increased from 172 feet to 737 feet. After two months of bronchial hygiene, the patient's improved VC was 2.63 liters, FEV 1 0.93 liters, MMEF 0.31 liters per second, and MVV was 45 liters. The same benefit was maintained at six months (Table 7); and at one year, only slight deterioration was observed compared to the six-month values.
Comment This patient presented typical features of long-standing chronic airway obstruction primarily related to emphysema. It is noteworthy that systematic respiratory care could provide some measurable reversibility of the pulmonary function abnormality. Whether this was due to the bronchial hygiene program or the physical retraining and reconditioning, is not answered by this study. It is also noteworthy that at one year, the patient's measurable pulmonary function was slightly better than his initial values; and the expected deterioration of pulmonary function determinations was not experienced.
DISCUSSION This study does not make a critical inquiry into the relative merits and effectiveness of the various forms of therapy employed. Our objectives were to identify background factors in patients with significant physiological improvement, in patients receiving systematic physiologically oriented therapy. Of particular interest is the possible effectiveness of prednisone in ten of the 18 improved patients. The use of corticosteroid drugs in chronic airway obstruction has been controversial. No clinical or physiological benefit was reported with intravenous methylprednisolone given for a one-week period in emphysema patients. HI By contrast, an FEV I improvement of 25 percent was found in one third of the individuals with chronic bronchitis and emphysema in another study.f" In patients with clinical chronic bronchitis, 15 of 28 patients who also received spasmolytic drugs showed measureable pulmonary function improvement/" and a transient improvement was observed in ten patients in both ventilatory function tests and resting p02 and oxygen saturation during a course of steroid therapy.22 This improvement was lost on reduction to maintenance levels of corticosteroids, however. In a controlled study of the effects of prednisone in ten patients with chronic airway obstruction, it was found that the patients hehaved as two populations with eight patients showing no clinical or physiological benefit; but two demonstrated strik-
ing clinical and functional benefits. 23 The two with benefit in this study also had a background of asthmatic symptoms, and the authors suggested that patients with a wheezing type of onset might well respond to the administration of corticosteroid drugs. Observations made in ten of the 18 improved patients of this study support this conclusion. On the other hand, we found equally Significant improvement in eight of 18 patients without steroids; and we do not know what effect if any, corticosteroids might have produced in 18 of the 21 patients in the unimproved group who did not receive steroids. In addition, the clinical effectiveness of systematic bronchial hygiene in CAO with the use of corticosteroid drugs has been reportedy·24 Bronchial hygiene is probably effective by promoting the clearance of retained secretions and reversal of muscular bronchospastn.F-" It has long been our policy to manage patients with chronic airway obstruction conservatively, employing bronchial hygiene, breathing retraining, physical medicine measures, and graded exercises.P We have reserved corticosteroid drugs for patients with intractable cough and dyspnea when other measures have failed to bring improvement. It is interesting that subjective improvement was similar in both groups at six months (Tables 2 and 3). This is consistent with Burrows'!" observations where clinical improvement was often observed for up to two years in spite of no measureable functional improvement. We have observed this same clinical improvement in our entire series, and this is often accompanied by increased exercise tolerance and work capacity. In spite of the subjective nature of this improvement, reduction in symptoms and ability to function at a higher activity level is greatly appreciated by the patient.P That the early mortality is Significantly lower in the functionally improved groups (Tables 2 and 3) may be highly important. A long-term analysis of survival is needed to strengthen this contention. The reason for the functional improvement in the small group of 18 patients is likely due to some degree of reversal bronchitisv' or an element of bronchial asthma. These patients were specifically selected to exclude reversible asthma, but a companion study in our institute suggests that bronchial asthma may be found post mortem in patients believed to have either emphysema or chronic bronchitis. For example, in a postmortem study conducted by one of our colleagues, exhaustive special postmortem pulmonary evaluations were performed on specimens from patients with criteria almost identical to those described in this paper. In this study, CHEST, VOL. 57, NO.3, MARCH 1970
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three patients from a group of 156 thought to have chronic airway obstruction during life were found at autopsy to have no destruction of alveolar walls or mucous gland hyperplasia." These three individuals had the histologic findings consistent with bronchial asthma, ie, mucous plugging, thickening of the basement membrane, hypertrophy to the muscle of the airway walls, dilated submucosal mucous glands, and eosinophilic mucosal cellular infiltrates. 26 It is unlikely that the small and statistically insignificant differences in smoking background factors for the two groups explain the physiological differences observed. Cessation of smoking, however, apparently has a salutory effect on survival in CAO.27 The current study suggests that patients with chronic airway obstruction with an asthmatic type of onset, recurrent bouts of cough and wheeze, a relatively short duration of disease, and a significant bronchodilator response judged by spirometric tests, are good candidates for a "trial" of corticosteroid drugs. ACKNOWLEDGMENT: The technical assistance of Sidney Shelden, BS, is gratefully acknowledged. REFERENCES
I MITCHELL, RS., SILVERS, G.W., DART, G.A., PETTY, T.L., VINCENT, T.N., RYAN, S.F., AND FILLEY, G.F.: Clinical physiologic and morphologic correlations in chronic airway obstruction, Amer. Rev. Resp. Dis., 97:54, 1968. 2 MITCHELL, RS., RYAN, S.F., PETTY, T.L., AND FILLEY, G.F.: The significance of morphologic chronic hyperplastic bronchitis, Amer. Rev. Resp. Dis., 93:720, 1966. 3 THURLBECK, W.M., FRAZER, RG., AND BATES, D.V.: The correlation between pulmonary structure and functions: chronic bronchitis, emphysema, and asthma, Med. Thorac., 22:295, 1965. 4 PETTY, T.L., MIERCORT, R., RYAN, S.F., VINCENT, T.N., FILLEY, G.F., AND MITCHELL, RS.: The functional and bronchographic evaluation of postmortem human lungs (clinical, physiologic, roentgenographic, and pathologic correlations in normal subjects and patients with emphysema and chronic bronchitis), Amer. Rev. Resp. Dis., 92:450, 1965. 5 British Medical Research Council: Value of chemoprophylaxis and chemotherapy in early chronic bronchitis, Brit. Med. ]., 1:1317, 1966. 6 SULCUMALCHANTRO, Y., AND WILLIAMS, M.H.: Serial studies of pulmonary function in patients with chronic obstructive pulmonary disease, Amer. J. Med., 39:941, 1965. 7 SIMPSON, T.: Chronic bronchitis and emphysema with special reference to treatment, Brit. J. Dis. Chest, 62:70, 1968. 8 HOWARD, P.: Evaluation of ventilatory capacity in chronic bronchitis, Brit. Med. t; 3:392, 1967. 9 BOUSHY, S.F., AND COATES, E.O.: The prognostic value of pulmonary function tests in emphysema (with special reference to arterial blood studies), Amer. Rev. Resp. oi«. 90:553, 1964.
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10 BURROWS, B., AND EARLE, R.H.: Course and prognosis of chronic obstructive lung disease, New Eng. J. Med., 280:397, 1969. II RENZETTI, D.D., MCCLEMENT, ].H., AND LITT, B.: The Veterans Administration cooperative study of pulmonary function, III. Mortality in relation to respiratory function in chronic obstructive pulmonary disease, Amer. ]. Med., 41:II5, 1966. 12 PETTY, T.L., NETT, L.M., FINIGAN, M.M., BRINK, G.A., AND CoRSELLO, P.R.: A comprehensive care program for chronic airway obstruction, Ann. Intern. Med., 70:II09, 1969. 13 Definitions and classification of chronic bronchitis, asthma, and pulmonary emphysema (a statement of the AMERICAN THORACIC SOCIETY), Amer. Rev. Resp. Dis., 85:762, 1962. 14 CmA SYMPOSIUM: Terminology, definitions and classifications of chronic pulmonary emphysema and related conditions, Thorax, 14:286, 1959. 15 GOLDMAN, H.I., AND BECKLAKE, M.R.: Respiratory function tests (normal values at median altitudes and the prediction of normal results), Amer. Rev. Resp. Dis., 79:457,1959. 16 LINDALL, A., MEDINA, A., AND GRISMER, ].T.: A reevaluation of normal measurements in the adult female, Amer. Rev. Resp. Dis., 95:1061, 1961. 17 NETT, L.M., AND PETTY, T.L.: Effective treatment for emphysema and chronic bronchitis, J. Rehab., 33: 10, 1967. 18 MITCHELL, R.S., AND FILLEY, G.F.: Chronic obstructive bronchopulmonary disease, I. Clinical features, Amer. Rev. Resp. o«; 89:360, 1964. 19 PECORA, L.]., Zoss, A.R., BAUM, G.L., IUIO, W., AND TAN, A.: A study of the physiologic effects of intravenous methylprednisolone in chronic pulmonary emphysema, Amer. Rev. Resp. tn«, 89:528, 1964. 20 FREIDMAN, B.].: Bronchodilators and corticosteroids in chronic bronchitis and emphysema, Brit. Med. J., 2:1509, 1963. 21 CLIFTON, M., AND STUART-HARRIS, C.H.: Steroid therapy in chronic bronchitis, Lancet., 1:13II, 1962. 22 FULEIHAM, F.].D., F'EIsAN, K.A., AND MALOUF, N.W.: Effect of corticosteroids in pulmonary function in chronic bronchitis with airway obstruction, Amer. Rev. Resp. o«, 96:678, 1967. 23 BEEREL, F., ]ICK, H., AND TYLER, ].M.: A controlled study of the effect of prednisone on air Bow obstruction in severe pulmonary emphysema, New Eng. J. Med., 268:226,1963. 24 MILLER, W.F.: Rehabilitation of patients with chronic obstructive lung disease, Med. Clin. N. Amer., 51:349, 1967. 25 MITCHELL, R.S.: Data from emphysema registry, WehhWaring Institute, personal communication. 26 CoHEN, E.P., PETrY, T.L., SZENTIVANYI, A., AND PRIEST, R.E.: Clinical and pathological observations in fatal bronchial asthma, Ann. Intern. Med., 62:103, 1965. 27 PETTY, T.L., RYAN, S.F., AND MITCHELL, R.S.: Cigarette smoking and the lungs, Af'ch. Environ. Health, 14:172, 1967. Reprint requests: Dr. Petty, 4200 East Ninth Avenue, Denver 80220.