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Importance of Respiratory Rate as an Indicator of Respiratory Dysfunction in Patients with Cystic Fibrosis
Importance of Respiratory Rate as an Indicator of Respiratory Dysfunction in Patients with Cystic Fibrosis· lley B. Browning, M.D.; Gilbert E. D'Alonzo, o.a, F.C.C.R; and MartinJ Tobin, M.D., F.C.C.P.
Bedside measurement of respiratory frequency is commonly performed in a cursory manner and judged to be of little clinical importance. However, in a recent study of patients being weaned from mechanical ventilation, we found that tachypnea was quite accurate in predicting an unsuccessful weaning outcome. The present study was undertaken to examine the relationship between nonobtrusive measurements of respiratory frequency, using a calibrated inductive plethysmograph, and detailed measurements of pulmonary function in 11 adult patients with cystic 6brosis of varying severity. Respiratory frequency was increased in the patients with cystic 6brosis compared with a group oEhealthy control subjects, as was minute ventilation and mean inspiratory Bow. Respiratory frequency was a
examination of the respiratory system traC linical ditionally consists of inspection, palpation, per-
cussion, and auscultation. In general, physicians place greatest emphasis on auscultation, and relatively little attention is paid to the pattern of breathing. In particular, respiratory frequency is often measured in a cursory manner, although it is one of the four vital signs. Indeed, Kory! considered that measurements of respiratory frequency were frequently of little value and recommended that they should not be routinely obtained. However, bedside measurements of respiratory frequency are frequently quite inaccurate, and in one stud)'; 34 percent of nurses' recordings of respiratory frequency deviated by more than 20 percent from the true value." Thus, the poor reputation of respiratory frequency may be partly due to the inaccuracies in its measurement. In a recent study of patients being weaned from mechanical ventilation, we found that careful measurements of respiratory frequency were helpful in predicting weaning outcomer' patients who failed a weaning trial had a higher respiratory frequency than the patients who were successfully weaned. In that study, we were unable to determine the mechanisms responsible for the in*From the Pulmonary Division, Department of Medicine, University of Texas Health Science Center at Houston, and the Pulmonary Division, Department of Pediatrics, Baylor College of Medicine, Houston. Supported in part by a Fellowship Grant from the American Lung Association/San Jacinto Chapter. Manuscript received July 20; revision accepted October 5. Reprint requests: Dr. Browning, Duke University, Box 31197, Durham 27710
sensitive predictor of respiratory dysfunction, being significantly (p<0.05) correlated with airway obstruction (r = 0.76), hyperin8ation (r = 0.52), arterial oxygenation (r= -0.59), rib cage-abdominal discoordination (r=O.54), and maximum ventilation during exercise (r = 0.66). Despite the presence of tachypnea, the patients did not display shallow breathing; indeed, tidal volume was not correlated with any of the above abnormalities. In conclusion, respiratory rate was a useful indicator of respiratory dysfunction in this group of patients with cystic fibrosis. (Chat 1990; 97:1317-21) RIP
=respiratory inductive plethysmograph
I
creased respiratory frequency in patients who failed the weaning trial. In the present study, we investigate the relationship between respiratory frequency and traditional indices of respiratory function in a group of patients with cystic fibrosis of varying severity. METHODS
Subjects Eleven patients from the Cystic Fibrosis Center at Baylor College of Medicine volunteered for the study. Seven of the patients were men, and four were women. Their ages ranged from 17 to 29 years (mean ± SE, 21 ± 1 year). The studies in the patients were conducted in a sequential manner: resting breathing pattern, followed by pulmonary function testing, and then exercise testing. All but one of the patients completed all portions of the study, and the remaining patient underwent spirometry and assessment of the resting breathing pattern. In addition, the resting breathing pattern was measured in 11 healthy subjects who were matched for age and sex with the patients.
Resting Breathing Iuttem Breathing pattern was monitored with a respiratory inductive plethysmograph. The least-squares method was used to calibrate the RIP against simultaneous spirometry.' Validation was aeeomplished by checking RIP against spirometry during tidal breathing in two different postures. Data were considered unacceptable if the validation procedure indicated that RIP measurements displayed a greater than 10 percent difJeren<.'e from spirometry in any posture. Validation of the RIP against spirometry in the horizontal and semirecumbent position revealed mean arithmetic differences of 4.5 ± 0.8 and 3.5 ± 0.7 percent, respectively, before the experiment, and 5.3±0.7 and 4.1 ± 1.0 percent, respectively, after the experiment. The signals from the RIP were recorded on a breath-by-breath basis by a Z-80A based microprocessor system which sampled the CHEST I 97 I 6 I JUNE. 1990
1317
data at 20 points per second. The microprocessor continuously calculated respiratory frequency (f), tidal volume (VT), minute ventilation (VI), inspiratory time (TI), fractional inspiratory time (TIl TToT), and mean inspiratory flow rate (Vr/Tr). In addition, the degree of abnormal rib cage-abdominal motion was quantiated by measuring the phase angle. 5 Calculation was based on the analysis of sinusoidal phase shifts, according to the equation 00 = sin - 1 (MIS), where 00 is the phase angle, M is the distance between the intercepts of the rib cage-abdominal loop on a line drawn parallel to the X-axis which is placed at one-half the distance between the maximum and minimum rib cage excursion, and S is the maximal abdominal excursion. ~ After calibration of the RIP against spirometry, the subjects rested in the supine position for a minimum of 15 minutes before the breathing pattern was recorded for 15 minutes. The subjects were instructed not to move while the breathing pattern was being recorded, and they were encouraged to watch television in order to distract their attention from the procedure.
Pulmonary Function Measurements Measurements of lung volumes and flow rates were made using a dry rolling seal spirometer, and functional residual capacity and airway resistance were measured by a body plethysmograph. The normal values used to calculate percent predicted for forced vital capacity and the forced expiratory volume in 1 s (FEV I) are from Kory et aI,6 and those for total lung capacity and residual volume are from Goldman and Becklake."
Arterial Blood Gases Resting arterial blood gases were drawn while the subjects rested in a semirecumbent position. The blood was analyzed using an automated blood gas machine. The oxygen (OJ saturation was measured with a co-oximeter.
Exercise Study Exercise studies were conducted at least 2 hours after a light meal. A cycle ergometer was used, and a progressive, J-minute incremental workload test to symptom limited maximum was performed. Each individual was instructed to exercise as long as possible, until a specific symptom (usually marked dyspnea or weakness) limited further performance. Work was begun and increased in 10-W increments following a 1 minute period of unloaded cycling. The electrocardiogram, oxygen saturation, and blood pressure were monitored at rest and throughout exercise. Room air was breathed through a mouthpiece and a low resistance valve connected to a volume turbine coupled in series. All gas and flow measurements were corrected for ambient temperature, barometric pressure, and water vapor. From the expired gas, O 2 tension, carbon dioxide (COJ tension, minute ventilation, O 2 consumption, and CO 2 production were derived. Predicted maximal O 2 consumption and heart rate were determined for each patient by standard equations. R
Data Analysis Two-tailed unpaired Student's t-test was used to compare differences in resting breathing pattern parameters between patients with cystic fibrosis and the healthy subjects. Linear regression analysis was used to correlate parameters. All results are expressed as mean ± standard error unless otherwise noted. We accepted p<0.05 to indicate a significant difference. RESULTS
In the patients with cystic fibrosis, the National Institutes of Health score of clinical severity ranged from 46 to 89 (mean, 62 ± 4); a score of 100 was 1318
Table 1- The Pattern of Breathing in Patients with Cystic FibroBis and Healthy SubjectB*
Respiratory frequency, breaths/min VT,ml Minute ventilation, Umin Inspiratory time, s Fractional inspiratory time Mean inspiratory How, mils Phase angle, degrees
Cystic Fibrosis Patients
Healthy Subjects
26.4±2.0
17.1 ± l.lt
403±28
9.87±O.99
1.04 ± 0.08 0.403±0.140 409±36 18.7±3.4
410±38
6.49±O.42t
l.54±0.09§ 0.411 ±0.010 268± 16* 10.3± l.8t
*Values are means ± SEe Statistical comparisons between the cystic fibrosis patients and healthy subjects: tp<0.05. *p
excellent, and a score of 0, death." Forced expiratory volume in 1 second was 1.73±0.28 L (47.2±7.4 percent predicted), forced vital capacity was 2.87±0.28 L (67.6±6.5 percent predicted), and the ratio of these volumes was 60.2 ± 3.7 percent. Airway resistance was 5.10±0.67 em H20lUs. Total lung capacity was 6.01 ± 0.36 L (116.9 ± 4.5 percent predicted), and the ratio of functional residual capacity to total lung capacity was 66.6±3.4 percent. Arterial O 2 tension was 73 ± 3 mm Hg, arterial CO 2 tension was 43.9±0.9 mm Hg, and pH was 7.40±0.01. The breathing pattern in the patients with cystic fibrosis and the control subjects is shown in Table 1. The patients had an increased respiratory frequency (p<0.OO2)and minute ventilation (p<0.01), while tidal volume was similar in the patients and in the control subjects. Inspiratory time was decreased in the patients (p<0.001), TIffTOT was similar in the two groups, and VTlfI, an index of respiratory drive, was increased in the patients (p<0.005). The phase angle, a measure of the degree of rib cage-abdominal asynchrony, was increased in the patients (p<0.05). During exercise, the maximum O2 consumption was 1.42±0.17 Umin (47±4.2 percent of predicted normal), maximum minute ventilation was 52.3±6.9 Umin, the ratio of maximum minute ventilation to maximum voluntary ventilation was 0.92±0.08, and maximum heart rate was 171 ± 6.0 beats per minute (87 ± 3.0 percent of predicted normal). Respiratory frequency was related to a number of indices of respiratory function. Figure 1 shows the relationships between frequency and airway resistance (r = 0.76, p
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FIGURE 1. Respiratory frequency in the patients with cystic fibrosis was significantly related to airway resistance, (y = 14.1 + 2.3x), hyperinflation (FRC/fLC), (y = 6.2 + O.3x), and forced expiratory volume in 1 second (FEV.) (y=33.6-4.2x).
matic patients breathe against external How resistive
DISCUSSION
loads." However, internal resistive loading, such as
In this study, we found that patients with cystic fibrosis demonstrated a number of differences in breathing pattern compared with healthy control subjects. In addition, we noted that respiratory frequency appeared to be a useful indicator of respiratory dysfunction, in that it displayed a relationship with airway obstruction, hyperinflation, rib cage-abdominal discoordination, arterial oxygenation, and maximum ventilation during exercise. Respiratory frequency is controlled by a complex balance of many modulating factors, including pulmonary mechanics, pulmonary afferent activity, dead space ventilation, and respiratory center output. Based on the hypotheses ofCCleast average force" or "minimal respiratory work," our patients should have responded to the increased airway obstruction by decreasing their respiratory frequency 10,11 Slowing of the respiratory frequency occurs when healthy individuals and asth-
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occurs with the inhalation of methacholine or histamine, causes respiratory frequency to actually increase l 2 , 13 or show no change.t 4 •15 Dogs also develop bronchoconstriction and an increase in respiratory frequency following the inhalation of histamine or antigen.P-'? However, the tachypnea in these dogs is not primarily dependent on the development ofbronchoconstriction, since it occurs even when the bronchoconstriction is prevented by the prior administration of a bronchodilator. 16,17 Another potential cause of tachypnea is the stimulation of pulmonary sensory receptors by the excessive lung inHammation and mucus production which are characteristically observed in patients with cystic fibrosis. The observation that selective vagal blockade can prevent the tachypnea associated with histamine inhalation in dogs 16 , 17 indicates that activation of pulmonary afferents alone
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FIGURE 2. Respiratory frequency in the patients with cystic fibrosis was significantly related to phase angle (quantified in degrees), (y = 21 + O.3x), arterial oxygen tension (PaOJ, (y = 54 - O.4x), and maximum ventilation during exercise (Vamax) (y = 33.8 - O.2x).
CHEST I 97 I 6 I JUNE. 1990
1319
can induce tachypnea. Another factor that may contribute to the development of tachypnea is the presence of hyperinflation, as suggested by the correlation between respiratory frequency and the ratio of functional residual capacity to total lung capacity (r = 0.55). At a high lung volume, breathing takes place on the upper, less compliant portion of the pulmonary pressure-volume curve. Consequently, hyperinflation acts like an elastic load, which is known to predispose to tachypnea." Hyperinflation also causes activation of pulmonary stretch receptors'? and chest wall aflerents.P' which may lead to tachypnea. Furthermore, tachypnea predisposes to dynamic hyperinflation in patients with airway obstruction, because the associated shortening of expiration provides insufficient time for the complete emptying of lung units with long time constants, with the result that the end-expiratory lung volume increases. Thus, a vicious circle may develop whereby hyperinflation predisposes to tachypnea, and tachypnea may lead to further hyperinflation. The correlation between respiratory frequency and the phase-angle of rib cage-abdominal motion is probably a reflection of the association between both frequency and abnormal motion with the severity of the underlying disease. 5,21 An increase in phase angle is known to be related to worsening airway obstruction," and it is also possible that tachypnea may; in itself, lead to discoordination between rib cage and abdominal movement. Resting respiratory frequency was inversely correlated with the maximum minute ventilation achieved during progressive exercise, although this relationship is less striking than those observed with other variables (Fig 1 and 2). The relationship between resting respiratory frequency and maximum minute ventilation is not surprising, as both are probably reflective of the severity of the underlying lung disease. Patients with either obstructive or restrictive lung disease have higher than normal resting" and exercise23,24 respiratory frequencies and they also have a reduced maximum ventilatory capacity during exercise.P Such a reduction in maximum ventilatory capacity is generally manifested by a minute ventilation during exercise that is equal to the maximum voluntary ventilation measured at rest." Normally, the relationship between maximum minute ventilation during exercise and maximum voluntary ventilation during rest is between 0.5 and 0.7. 26 The patients with cystic fibrosis displayed a remarkably close relationship between maximum minute ventilation during exercise and maximum voluntary ventilation during rest (ratio 0.92 ± 0.08), indicating that exercise was chiefly limited by pulmonary factors. The association between respiratory frequency and arterial O2 tension is of interest, and such an associa1320
tion has also been shown to exist in other disease states. On reanalysis of data obtained by Rees et al27 in patients with severe acute asthma, Saclmer and Krieger" noted a significant correlation between respiratory frequency and arterial O 2 tension (r = - 0.61, p<0.OO2). Similarly, reanalysis of the data obtained by Binger and Davis'" in patients with acute pneumonia reveals a significant correlation between respiratory frequency and arterial O 2 saturation (r = 0.77, p
Although the mechanism for tachypnea in patients with cystic fibrosis is unknown, it is clear that respiratory frequency is a useful indicator of respiratory dysfunction being significantly correlated with the degree of airway obstruction, hyperinflation, rib cageabdominal discoordination, arterial oxygenation, and maximum ventilation during exercise. These findings complement the observations of McFadden et al30 and Gravelyn and WegU who showed that tachypnea commonly antedates all other clinical evidence of respiratory compromise. However, careful attention to detail is required when measuring respiratory frequency at the bedside. Every effort should be made to obtain the measurement in a nonobtrusive manner. In addition, the usual method of counting chest wall excursions over a IS-second period and multiplying the result by four can be very inaccurate. For example, an error of one breath per minute during counting causes a true frequency of 20 breaths per minute to be miscalculated as 16 or 24 breaths per minute. Furthermore, there is considerable breath-to-breath variability in respiratory frequency (coefficient of variation of 20 to 30 percent'"), with the result that a sampling period longer than 15 seconds is desirable. Based on these factors, we recommend that bedside measurements of respiratory frequency should be made over a period of 1 minute. In conclusion, respiratory rate, when carefully measured, appears to be a useful indicator of respiratory dysfunction in patients with cystic fibrosis. REFERENCES 1 Kory RC. Routine measurement of respiratory rate: an expensive tribute to tradition. JAMA 1957; 165:448-50 2 Krieger B, Feinennan 0, Zaron A, Bizousky F. Continuous noninvasive monitoring of respiratory rate in critically ill patients. Chest 1986; 90:632-34 3 Tobin MJ, Perez w Guenther SM, Semmes BJ, Mador MJ, Allen SJ, et al. The pattern of breathing during successful and unsuccessful trials of weaning from mechanical ventilation. Am Rev Respir Dis 1986; 134:1111-18 4 Tobin MJ, Jenouri G, Lind B, Watson H, Schneider A, Sackner MA. Validation of respiratory inductive plethysmography in patients with pulmonary disease. Chest 1983; 83:615-20 5 Tobin MJ, Perez w Guenther SM, Lodato RF, Dantzker DR. Does rib cage-abdominal paradox signify respiratory muscle fatigue? J Appl Physioll987; 63:851-60 6 Kory RC, Callahan R, Boren HG, Syner IC. The Veterans Administration-Army Cooperative Study of pulmonary function: RespiratoryDysfunctionin CF (Browning, D'Alonzo, Tobin)
7
8 9
10 11 12
13 14 15
16
17
18
19
1. Clinical spirometry in normal men. Am J Med 1961; 30:24358 Goldman HI, Becklake MR. Respiratory function tests: normal values at median altitudes and the prediction of normal results. Am Rev Tuberc 1959; 79:457-67 Jones NL, Campbell EJM. Clinical exercise testing. Philadelphia: WB Saunders Co, 1982 Taussig LM, Kattwinkel J, Friedewald wr; di Sant'Agnese PA. A new prognostic and clinical evaluation system for cystic fibrosis. J Pediatr 1973; 82:380 409 Otis AB, Fenn WO, Hahn H. Mechanics of breathing in man. J Appl Physiol 1950; 2:592-607 Mead J. Control of respiratory frequency. J Appl Physiol 1960; 15:325-36 Kelsen SG, Prestel TF, Chemiack NS, Chester EH, Deal EC. Comparison of the respiratory responses to external resistive loading and bronchoconstriction. J Clin Invest 1981; 67:1761-68 Mann J, Bradley CA, Anthonisen NR. Occlusion pressure in acute bronchospasm induced by methylcholine. Resp Physiol 1978; 33:339-47 Chadha TS, Schneider AW, Birch S, Jenouri G, Sackner MA. Breathing pattern during induced bronchoconstriction. J Appl Physiol 1984; 56: 1053-59 Savoy J, Louis M, Kryger MH, Forster A. Respiratory response to histamine- and methacholine-induced bronchospasm in nonsmokers and asymptomatic smokers. Eur Respir J 1988; 1:20916 Cotton OJ, Bleecker ER, Fischer S~ Graf PO, Gold WM, Nadel JA. Rapid, shallow breathing after Ascaris suum antigen inhalation: role of vagus nerves. J Appl Physiol Respirat Environ Exercise PhysioI1977; 42:101-06 Bleecker ER, Cotton OJ, Fischer S~ Graf PO, Gold WM, Nadel JA. The mechanism of rapid, shallow breathing after inhaling histamine aerosol in exercising dogs. Am Rev Respir Dis 1976; 114:909-16 Shekelton M, Lopato M, Evanich MJ, Lourenco R~ Effect of elastic loading on mouth occlusion pressure during CO 2 rebreathing in man. Am Rev Respir Dis 1976; 114:341-46 Muza SR, Lee LY, Pan C~ Zechman Fw, Frazier D1: Respiratory volume-timing relationship during sustained elevation of functional residual capacity. Respir Physioll984; 58:77-86
20 Remmers JE, Martina I. Action of intercostal muscle afferents on the respiratory rhythm of anesthetized cats. Respir Physiol 1975; 24:31-41 21 Tobin MJ, Guenther SM, Perez w Lodato RF, Mador MJ, Allen Sj, et aI. Konno-Mead analysis of rib cage-abdominal motion during successful and unsuccessful trials of weaning from mechanical ventilation. Am Rev Respir Dis 1987; 135:1320-28 22 lhhin MJ, Chadha TS, jenouri G. Birch SJ. Cazeroglu BS, Sackner MA. Breathing patterns: 2. Diseased subjects, Chest 1983; 84:286-94
23 Spiro SG, Hahn HL, Edwards RHT, Pride NB. An analysis of the physiological strain of submaximal exercise in patients with chronic obstructive bronchitis, Thorax 1975; 30:415-25 24 Spiro SG, Oowdeswell IRG, Clark TJH. An analysis of suhmaximal exercise responses in patients with sarcoidosis and fibrosing alveolitis, Br J Dis Chest 1981; 75:169-80 25 Clark TJH, Freedman S, Campbell EJM, Winn RR. The ventilatory capacity of patients with chronic airways obstruction. Clin Sci 1969; 36:307-16 26 Pierce AK, Luterman D, Loudermilk J, Blomquist G, Johnson RL Jr. Exercise ventilatory patterns in normal subjects and patients with airway obstruction. J Appl Physiol 1968; 25:24954 27 Rees HA, Miller JS, Donald K\\Z A study of the clinical course and arterial blood gas tension of patients in status asthmaticus. Q J Med 1968; 37:541-61 28 Sackner MA, Krieger B~ Noninvasive respiratory monitoring, In: Scharf SM, Cassidy SS, eds. Heart-lung interactions in health and disease. New \hrk: Marcel Dekker, Inc, 1989:663805 29 Binger CAL, Davis JS. The relation of anoxemia to the type of breathing in pneumonia: a study of respiration by means of a body plethysmograph. J Clin Invest 1928; 6:171-85 RS. Raised 30 McFadden J~ Price RC, Eastwood HO, Bri~s respiratory rate in elderly patients: a valuable physical sign, Br Med J 1982; 284:626-27 31 Gravelyn TR, \Veg JG. Respiratory rate as an indicator of acute respiratory dysfunction. JAMA 1980; 244:1123-25 32 Tobin MJ, Mador MJ, Guenther SM, Lodato RF, Sackner MA. Variability of resting respiratory drive and timing in healthy subjects. J Appl Physioll988; 65:309-17
CHEST I 97 I 6 I JUNE. 1990
1321
Bedside measurement of respiratory frequency is commonly performed in a cursory manner and judged to be of little clinical importance. However, in a recent study of patients being weaned from mechanical ventilation, we found that tachypnea was quite accurate in predicting an unsuccessful weaning outcome. The present study was undertaken to examine the relationship between nonobtrusive measurements of respiratory frequency, using a calibrated inductive plethysmograph, and detailed measurements of pulmonary function in 11 adult patients with cystic 6brosis of varying severity. Respiratory frequency was increased in the patients with cystic 6brosis compared with a group oEhealthy control subjects, as was minute ventilation and mean inspiratory Bow. Respiratory frequency was a
examination of the respiratory system traC linical ditionally consists of inspection, palpation, per-
cussion, and auscultation. In general, physicians place greatest emphasis on auscultation, and relatively little attention is paid to the pattern of breathing. In particular, respiratory frequency is often measured in a cursory manner, although it is one of the four vital signs. Indeed, Kory! considered that measurements of respiratory frequency were frequently of little value and recommended that they should not be routinely obtained. However, bedside measurements of respiratory frequency are frequently quite inaccurate, and in one stud)'; 34 percent of nurses' recordings of respiratory frequency deviated by more than 20 percent from the true value." Thus, the poor reputation of respiratory frequency may be partly due to the inaccuracies in its measurement. In a recent study of patients being weaned from mechanical ventilation, we found that careful measurements of respiratory frequency were helpful in predicting weaning outcomer' patients who failed a weaning trial had a higher respiratory frequency than the patients who were successfully weaned. In that study, we were unable to determine the mechanisms responsible for the in*From the Pulmonary Division, Department of Medicine, University of Texas Health Science Center at Houston, and the Pulmonary Division, Department of Pediatrics, Baylor College of Medicine, Houston. Supported in part by a Fellowship Grant from the American Lung Association/San Jacinto Chapter. Manuscript received July 20; revision accepted October 5. Reprint requests: Dr. Browning, Duke University, Box 31197, Durham 27710
sensitive predictor of respiratory dysfunction, being significantly (p<0.05) correlated with airway obstruction (r = 0.76), hyperin8ation (r = 0.52), arterial oxygenation (r= -0.59), rib cage-abdominal discoordination (r=O.54), and maximum ventilation during exercise (r = 0.66). Despite the presence of tachypnea, the patients did not display shallow breathing; indeed, tidal volume was not correlated with any of the above abnormalities. In conclusion, respiratory rate was a useful indicator of respiratory dysfunction in this group of patients with cystic fibrosis. (Chat 1990; 97:1317-21) RIP
=respiratory inductive plethysmograph
I
creased respiratory frequency in patients who failed the weaning trial. In the present study, we investigate the relationship between respiratory frequency and traditional indices of respiratory function in a group of patients with cystic fibrosis of varying severity. METHODS
Subjects Eleven patients from the Cystic Fibrosis Center at Baylor College of Medicine volunteered for the study. Seven of the patients were men, and four were women. Their ages ranged from 17 to 29 years (mean ± SE, 21 ± 1 year). The studies in the patients were conducted in a sequential manner: resting breathing pattern, followed by pulmonary function testing, and then exercise testing. All but one of the patients completed all portions of the study, and the remaining patient underwent spirometry and assessment of the resting breathing pattern. In addition, the resting breathing pattern was measured in 11 healthy subjects who were matched for age and sex with the patients.
Resting Breathing Iuttem Breathing pattern was monitored with a respiratory inductive plethysmograph. The least-squares method was used to calibrate the RIP against simultaneous spirometry.' Validation was aeeomplished by checking RIP against spirometry during tidal breathing in two different postures. Data were considered unacceptable if the validation procedure indicated that RIP measurements displayed a greater than 10 percent difJeren<.'e from spirometry in any posture. Validation of the RIP against spirometry in the horizontal and semirecumbent position revealed mean arithmetic differences of 4.5 ± 0.8 and 3.5 ± 0.7 percent, respectively, before the experiment, and 5.3±0.7 and 4.1 ± 1.0 percent, respectively, after the experiment. The signals from the RIP were recorded on a breath-by-breath basis by a Z-80A based microprocessor system which sampled the CHEST I 97 I 6 I JUNE. 1990
1317
data at 20 points per second. The microprocessor continuously calculated respiratory frequency (f), tidal volume (VT), minute ventilation (VI), inspiratory time (TI), fractional inspiratory time (TIl TToT), and mean inspiratory flow rate (Vr/Tr). In addition, the degree of abnormal rib cage-abdominal motion was quantiated by measuring the phase angle. 5 Calculation was based on the analysis of sinusoidal phase shifts, according to the equation 00 = sin - 1 (MIS), where 00 is the phase angle, M is the distance between the intercepts of the rib cage-abdominal loop on a line drawn parallel to the X-axis which is placed at one-half the distance between the maximum and minimum rib cage excursion, and S is the maximal abdominal excursion. ~ After calibration of the RIP against spirometry, the subjects rested in the supine position for a minimum of 15 minutes before the breathing pattern was recorded for 15 minutes. The subjects were instructed not to move while the breathing pattern was being recorded, and they were encouraged to watch television in order to distract their attention from the procedure.
Pulmonary Function Measurements Measurements of lung volumes and flow rates were made using a dry rolling seal spirometer, and functional residual capacity and airway resistance were measured by a body plethysmograph. The normal values used to calculate percent predicted for forced vital capacity and the forced expiratory volume in 1 s (FEV I) are from Kory et aI,6 and those for total lung capacity and residual volume are from Goldman and Becklake."
Arterial Blood Gases Resting arterial blood gases were drawn while the subjects rested in a semirecumbent position. The blood was analyzed using an automated blood gas machine. The oxygen (OJ saturation was measured with a co-oximeter.
Exercise Study Exercise studies were conducted at least 2 hours after a light meal. A cycle ergometer was used, and a progressive, J-minute incremental workload test to symptom limited maximum was performed. Each individual was instructed to exercise as long as possible, until a specific symptom (usually marked dyspnea or weakness) limited further performance. Work was begun and increased in 10-W increments following a 1 minute period of unloaded cycling. The electrocardiogram, oxygen saturation, and blood pressure were monitored at rest and throughout exercise. Room air was breathed through a mouthpiece and a low resistance valve connected to a volume turbine coupled in series. All gas and flow measurements were corrected for ambient temperature, barometric pressure, and water vapor. From the expired gas, O 2 tension, carbon dioxide (COJ tension, minute ventilation, O 2 consumption, and CO 2 production were derived. Predicted maximal O 2 consumption and heart rate were determined for each patient by standard equations. R
Data Analysis Two-tailed unpaired Student's t-test was used to compare differences in resting breathing pattern parameters between patients with cystic fibrosis and the healthy subjects. Linear regression analysis was used to correlate parameters. All results are expressed as mean ± standard error unless otherwise noted. We accepted p<0.05 to indicate a significant difference. RESULTS
In the patients with cystic fibrosis, the National Institutes of Health score of clinical severity ranged from 46 to 89 (mean, 62 ± 4); a score of 100 was 1318
Table 1- The Pattern of Breathing in Patients with Cystic FibroBis and Healthy SubjectB*
Respiratory frequency, breaths/min VT,ml Minute ventilation, Umin Inspiratory time, s Fractional inspiratory time Mean inspiratory How, mils Phase angle, degrees
Cystic Fibrosis Patients
Healthy Subjects
26.4±2.0
17.1 ± l.lt
403±28
9.87±O.99
1.04 ± 0.08 0.403±0.140 409±36 18.7±3.4
410±38
6.49±O.42t
l.54±0.09§ 0.411 ±0.010 268± 16* 10.3± l.8t
*Values are means ± SEe Statistical comparisons between the cystic fibrosis patients and healthy subjects: tp<0.05. *p
excellent, and a score of 0, death." Forced expiratory volume in 1 second was 1.73±0.28 L (47.2±7.4 percent predicted), forced vital capacity was 2.87±0.28 L (67.6±6.5 percent predicted), and the ratio of these volumes was 60.2 ± 3.7 percent. Airway resistance was 5.10±0.67 em H20lUs. Total lung capacity was 6.01 ± 0.36 L (116.9 ± 4.5 percent predicted), and the ratio of functional residual capacity to total lung capacity was 66.6±3.4 percent. Arterial O 2 tension was 73 ± 3 mm Hg, arterial CO 2 tension was 43.9±0.9 mm Hg, and pH was 7.40±0.01. The breathing pattern in the patients with cystic fibrosis and the control subjects is shown in Table 1. The patients had an increased respiratory frequency (p<0.OO2)and minute ventilation (p<0.01), while tidal volume was similar in the patients and in the control subjects. Inspiratory time was decreased in the patients (p<0.001), TIffTOT was similar in the two groups, and VTlfI, an index of respiratory drive, was increased in the patients (p<0.005). The phase angle, a measure of the degree of rib cage-abdominal asynchrony, was increased in the patients (p<0.05). During exercise, the maximum O2 consumption was 1.42±0.17 Umin (47±4.2 percent of predicted normal), maximum minute ventilation was 52.3±6.9 Umin, the ratio of maximum minute ventilation to maximum voluntary ventilation was 0.92±0.08, and maximum heart rate was 171 ± 6.0 beats per minute (87 ± 3.0 percent of predicted normal). Respiratory frequency was related to a number of indices of respiratory function. Figure 1 shows the relationships between frequency and airway resistance (r = 0.76, p
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FIGURE 1. Respiratory frequency in the patients with cystic fibrosis was significantly related to airway resistance, (y = 14.1 + 2.3x), hyperinflation (FRC/fLC), (y = 6.2 + O.3x), and forced expiratory volume in 1 second (FEV.) (y=33.6-4.2x).
matic patients breathe against external How resistive
DISCUSSION
loads." However, internal resistive loading, such as
In this study, we found that patients with cystic fibrosis demonstrated a number of differences in breathing pattern compared with healthy control subjects. In addition, we noted that respiratory frequency appeared to be a useful indicator of respiratory dysfunction, in that it displayed a relationship with airway obstruction, hyperinflation, rib cage-abdominal discoordination, arterial oxygenation, and maximum ventilation during exercise. Respiratory frequency is controlled by a complex balance of many modulating factors, including pulmonary mechanics, pulmonary afferent activity, dead space ventilation, and respiratory center output. Based on the hypotheses ofCCleast average force" or "minimal respiratory work," our patients should have responded to the increased airway obstruction by decreasing their respiratory frequency 10,11 Slowing of the respiratory frequency occurs when healthy individuals and asth-
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occurs with the inhalation of methacholine or histamine, causes respiratory frequency to actually increase l 2 , 13 or show no change.t 4 •15 Dogs also develop bronchoconstriction and an increase in respiratory frequency following the inhalation of histamine or antigen.P-'? However, the tachypnea in these dogs is not primarily dependent on the development ofbronchoconstriction, since it occurs even when the bronchoconstriction is prevented by the prior administration of a bronchodilator. 16,17 Another potential cause of tachypnea is the stimulation of pulmonary sensory receptors by the excessive lung inHammation and mucus production which are characteristically observed in patients with cystic fibrosis. The observation that selective vagal blockade can prevent the tachypnea associated with histamine inhalation in dogs 16 , 17 indicates that activation of pulmonary afferents alone
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FIGURE 2. Respiratory frequency in the patients with cystic fibrosis was significantly related to phase angle (quantified in degrees), (y = 21 + O.3x), arterial oxygen tension (PaOJ, (y = 54 - O.4x), and maximum ventilation during exercise (Vamax) (y = 33.8 - O.2x).
CHEST I 97 I 6 I JUNE. 1990
1319
can induce tachypnea. Another factor that may contribute to the development of tachypnea is the presence of hyperinflation, as suggested by the correlation between respiratory frequency and the ratio of functional residual capacity to total lung capacity (r = 0.55). At a high lung volume, breathing takes place on the upper, less compliant portion of the pulmonary pressure-volume curve. Consequently, hyperinflation acts like an elastic load, which is known to predispose to tachypnea." Hyperinflation also causes activation of pulmonary stretch receptors'? and chest wall aflerents.P' which may lead to tachypnea. Furthermore, tachypnea predisposes to dynamic hyperinflation in patients with airway obstruction, because the associated shortening of expiration provides insufficient time for the complete emptying of lung units with long time constants, with the result that the end-expiratory lung volume increases. Thus, a vicious circle may develop whereby hyperinflation predisposes to tachypnea, and tachypnea may lead to further hyperinflation. The correlation between respiratory frequency and the phase-angle of rib cage-abdominal motion is probably a reflection of the association between both frequency and abnormal motion with the severity of the underlying disease. 5,21 An increase in phase angle is known to be related to worsening airway obstruction," and it is also possible that tachypnea may; in itself, lead to discoordination between rib cage and abdominal movement. Resting respiratory frequency was inversely correlated with the maximum minute ventilation achieved during progressive exercise, although this relationship is less striking than those observed with other variables (Fig 1 and 2). The relationship between resting respiratory frequency and maximum minute ventilation is not surprising, as both are probably reflective of the severity of the underlying lung disease. Patients with either obstructive or restrictive lung disease have higher than normal resting" and exercise23,24 respiratory frequencies and they also have a reduced maximum ventilatory capacity during exercise.P Such a reduction in maximum ventilatory capacity is generally manifested by a minute ventilation during exercise that is equal to the maximum voluntary ventilation measured at rest." Normally, the relationship between maximum minute ventilation during exercise and maximum voluntary ventilation during rest is between 0.5 and 0.7. 26 The patients with cystic fibrosis displayed a remarkably close relationship between maximum minute ventilation during exercise and maximum voluntary ventilation during rest (ratio 0.92 ± 0.08), indicating that exercise was chiefly limited by pulmonary factors. The association between respiratory frequency and arterial O2 tension is of interest, and such an associa1320
tion has also been shown to exist in other disease states. On reanalysis of data obtained by Rees et al27 in patients with severe acute asthma, Saclmer and Krieger" noted a significant correlation between respiratory frequency and arterial O 2 tension (r = - 0.61, p<0.OO2). Similarly, reanalysis of the data obtained by Binger and Davis'" in patients with acute pneumonia reveals a significant correlation between respiratory frequency and arterial O 2 saturation (r = 0.77, p
Although the mechanism for tachypnea in patients with cystic fibrosis is unknown, it is clear that respiratory frequency is a useful indicator of respiratory dysfunction being significantly correlated with the degree of airway obstruction, hyperinflation, rib cageabdominal discoordination, arterial oxygenation, and maximum ventilation during exercise. These findings complement the observations of McFadden et al30 and Gravelyn and WegU who showed that tachypnea commonly antedates all other clinical evidence of respiratory compromise. However, careful attention to detail is required when measuring respiratory frequency at the bedside. Every effort should be made to obtain the measurement in a nonobtrusive manner. In addition, the usual method of counting chest wall excursions over a IS-second period and multiplying the result by four can be very inaccurate. For example, an error of one breath per minute during counting causes a true frequency of 20 breaths per minute to be miscalculated as 16 or 24 breaths per minute. Furthermore, there is considerable breath-to-breath variability in respiratory frequency (coefficient of variation of 20 to 30 percent'"), with the result that a sampling period longer than 15 seconds is desirable. Based on these factors, we recommend that bedside measurements of respiratory frequency should be made over a period of 1 minute. In conclusion, respiratory rate, when carefully measured, appears to be a useful indicator of respiratory dysfunction in patients with cystic fibrosis. REFERENCES 1 Kory RC. Routine measurement of respiratory rate: an expensive tribute to tradition. JAMA 1957; 165:448-50 2 Krieger B, Feinennan 0, Zaron A, Bizousky F. Continuous noninvasive monitoring of respiratory rate in critically ill patients. Chest 1986; 90:632-34 3 Tobin MJ, Perez w Guenther SM, Semmes BJ, Mador MJ, Allen SJ, et al. The pattern of breathing during successful and unsuccessful trials of weaning from mechanical ventilation. Am Rev Respir Dis 1986; 134:1111-18 4 Tobin MJ, Jenouri G, Lind B, Watson H, Schneider A, Sackner MA. Validation of respiratory inductive plethysmography in patients with pulmonary disease. Chest 1983; 83:615-20 5 Tobin MJ, Perez w Guenther SM, Lodato RF, Dantzker DR. Does rib cage-abdominal paradox signify respiratory muscle fatigue? J Appl Physioll987; 63:851-60 6 Kory RC, Callahan R, Boren HG, Syner IC. The Veterans Administration-Army Cooperative Study of pulmonary function: RespiratoryDysfunctionin CF (Browning, D'Alonzo, Tobin)
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