The Effect of Obliterative Bronchiolitis on Breathing Pattern during Exercise in Recipients of Heart-Lung Transplants1- 3
FRANK c. SCIURBA, GREGORY R. OWENS, MARK H. SANDERS, JOSEPH P. COSTANTINO, IRVIN L. PARADIS, and BARTLEY R GRIFFITH
T he
Introduction
SUMMARY The more r.pld .nd sh.llow ventll.tlon pettern _n during exerel.. In patients with normal ventilatory response to obstructive .nd/or restrictive lung dl_ _ h.s been .ttrlbuted by some Investigators to the effecta moderate exercise is made up predomiof vag.1 .fferents from Intrapulmonary receptors. Recipients of he.rt-Iung transpl.nts (HLTR)offer nantly of an increase in tidal volume ac• unique opportunity to test this hypothesis since they have denervated lungs .nd may develop companied by a relatively small increase obllter.tlve bronchiolitis .fter org.n reJection. We thus compered the ventll.tlon re&pOn.. to Inin respiratory rate. Patients with obstruccremental bicycle ergometry of five HLTRwith relatively norm.1 pUlmonary function (HLTR-N) .nd four with bronchiolitis obllter.ns (HLTR-O). We comp.red the .Iopes of the Ilne.r portion of the tive or restrictive lung disease, however, tld.1 volume versus Inspired minute "ventilation rel.tlonshlp of both groupe. The rate of rI.. of tld.1 respond to exertion with a slower rise in volume (VT) (slope of VT versus VI) was greater In HLTR-N (0.031 ± 0.004) th.n In HLTR-O (0.023 tidal volume and a more rapid increase ± 0.007) (p < 0.05). This corresponded to ••Iower Incre... In respiratory r.te (RR) (slope of RR in respiratory rate than do normal subveraus VI/em) In HLTR-N (0.055 ± 0.005) th.n In HLTR-O (0.083 ± 0.019) (p < 0.01). Furthermore, jects (1-3). This altered respiratory patvalu.. for VT, Inspiratory time (TI), .nd duty cycle (TlI11ot)meuured during exerel. . at the VTbreak tern may serve to decrease the work of point were .11 significantly lower In the HLTR-O th.n In HLTR-N. We .Iso evaluated the ability of breathing in patients with noncompliant HLTRwith lung dl..... to regul.te their ultimate level of ventilation during maxlm.lexerel... Yentlor hyperinflated lungs, although the latlon . . . proportion of maxlm.1 voluntary ventilation was slgn"lcantly greater In HLTR-O (0.90 precise mechanism for this altered ven± 0.11) th.n In HLTR-N (0.50 ± 0.11). Arterl.1 pH .nd PC0 2 at maxlm.lexercl.e In HLTR-O were tilatory pattern is not known. Some in.pproprlately regUlated. In conclusion, HLTR-Ohave. more rapid rise In RR .nd slower Incre... In VTth.n do HLTR-N. This respon.. pattern, In the .b..nce of pUlmon.ry Innervation, auggeata vestigators have speculated that the unth.t mech.nlsms outside of pulmon.ry vag.l.fferentB contribute to regulation of breathing pattern derlying disease process or concomitant In patients with lung dl...... Also, HLTR-Odemonstr.te .pproprl.te regulation of ventll.tlon duralterations in pulmonary mechanics reAM REV RESPIR DIS 1111; 144:131-135 Ing m.xlmal exerel... sult in stimulation of pulmonary J- or stretch receptors resulting in a vagally mediated alteration in respiratory pattern (2, 4-6). Alternative mechanisms not mediated through pulmonary vagal af- (HLTR-O) in order to gain insight into lung disease, then HLTR with lung disferent pathways have been shown to in- the contribution of pulmonary vagal and ease should have a ventilatory pattern fluence respiratory pattern in experimen- nonvagal mechanisms to the regulation during exercise that is similar to that of tal animals (7) and must also be consid- of respiratory pattern in patients with HLTR with normal pulmonary function (HLTR-N). Specifically, they should not ered as possible effectors of respiratory lung disease. Wehave also evaluated the capacity of develop high respiratory rates and relapattern in these patients. Stimulation of chest wall proprioceptors or upper air- HLTR-O to regulate overall ventilation tively small tidal volumes. way receptors has been shown to in- and gas exchange during maximal exerfluence respiratory pattern in normal cise.Previous reports of exercise response subjects (8, 9). How and to what extent in HLTR have dealt only with subjects these factors influence the respiratory with relatively normal pulmonary func- (Received in original form March 8, 1990 and in pattern of patients with lung disease is tion (10, 11, 13). These studies demon- revised form October 8, 1990) not known. strated levels of exercise ventilation and 1 From the Division of Pulmonary Medicine, Heart-lungtransplant recipients (HLTR) gas exchange that were essentially withare a unique population of patients who in normal limits. However, because pa- Departments of Medicine and Surgery,Presbyterian University Hospital, The University of Pittsburgh have had complete disruption of the pul- tients with lung disease, but not normal School of Medicine, and the Department of Biomonary vagal afferents below the trache- subjects, may approach their limits of statistics, University of Pittsburgh Graduate School al anastomosis of the transplanted lungs. maximal ventilation during exertion, we of Public Health, Pittsburgh, Pennsylvania. 1 Supported in part by Grant no. N-129 from the These patients can thus be evaluated to investigated the ability of these pulmoLung Association of Western Pennsylassess the effects of denervation of the nary denervated patients to regulate ven- American vania, by Training Grant IT32 HL-07563 from the human lung on the regulation of breath- tilation and gas exchange during the National Institutes of Health, and by the Research ing (10-13). The patients in this group stress of maximal exercise. Fund, Department of Medicine, University of Pittssometimes develop obliterative bronchioOur study was designed to test the fol- burgh School of Medicine. 3 Correspondence and requests for reprints litis after chronic lung rejection. Wehave lowing principal hypothesis: if vagal afshould be addressed to Frank C. Sciurba, M.D., analyzed the exercise breathing pattern ferents are primarily responsible for the Division of Pulmonary Medicine, University of in a group of heart-lung recipients with generation of the altered respiratory Pittsburgh, 3550 Terrace Street, 440 Scaife Hall, biopsy-proved obliterative bronchiolitis pattern during exercise in patients with Pittsburgh, PA 15261.
131
132
Methods Subjects The study participants werenine patients who had undergone heart-lung transplantation. Subjects were studied during routine followup evaluations or during evaluations for symptoms suggestiveof chronic rejection. All consecutive patients were included who met the following pulmonary function criteria. Five had normal pulmonary function (HLTRN). Patients were excluded from this group if their forced vital capacity was lessthan 70010 predicted, if their FEVt/FVC was < 0.7, or if deterioration in pulmonary function had occurred during the preceding 3 months. Subjects with erratic ventilatory pattern responses that could not be represented by simple algebraic pattern were excluded from the analysis (6). The responses of two such HLTR-N were described in a previous report (10).Subjects wereincluded in the study group HLTRN only if clinically stable without current or past evidence of rejection and without infection for at least 6 wk. The second group included four HLTR-O documented by transbronchial biopsy. All patients in this group had experienced recent clinical deterioration associated with worsening of FEV t/FVC to < 0.7.
Protocol Symptom-limited incremental exercise was performed on an electronically braked cycle ergometer (Godart Lanooy, Utrecht, Holland), at a patient-selected pedaling frequency between 55 and 70 rpm. All patients began the test with unloaded pedaling. The power output was then increased each minute by 10 to 15 watts. Exercise tests were ended at the point of exhaustion or upon the appearance of signs or symptoms of exertional intolerance (14). No training period was provided before testing. However, all patients had used the bicycle ergometer during rehabilitation therapy. The subjects breathed through a low resistance unidirectional valve (Hans Rudolph, Kansas City, MO) containing 75 ml of dead space. Ventilatory flow was measured using a pneumotachograph (Fleisch No.3), transducer (Validyne MP-45; Validyne Corp., Northridge, CA) and carrier demodulator (ValidyneCDI3) placed in the inspiratory side of the valve. Inspiratory volume was determined by electrical integration of the flow signal. Flow and volume signals were displayed on a strip chart recorder (Gould 24OOS; Gould Instruments, Cleveland, OH) providing a breath-by-breath analog representation of the ventilation parameters. No adjustment was made for valve dead space in these calculations. Arterial blood was sampled from a radial artery catheter at rest and during the final minute of exertion. Automated arterial blood gas analysis was performed (Radiometer ABU; Radiometer, Copenhagen, Denmark). Spirometry was performed with an automated system (Gould 5000IV) using a dry rolling-seal spirometer. The maximal volun-
SCIURBA, OWENS, SANDERS, COSTANTINO, PARADIS, AND GRIFFITH
tary ventilation (MVV) was measured in all subjects. Functional residual capacity was assessed using body plethysmography (Model 2000B Cardio-Pulmonary Instruments, Houston, TX). The predicted normal values for spirometry were those of Morris and coworkers (15), and the values for lung volume were those of Goldman and Becklake (16). These values were based on the age, sex, and height of the recipient.
Data Analysis The inspired minute ventilation (VI),tidal volume (VT), respiratory rate (RR), inspiratory time (II), expiratory time (IE), and total breath cycle time (not) were calculated on a breathby-breath basis from the flow and inspired volume (expressedin BTPS) signal of the pneumotachograph. All breaths were included in the analysis. In order to minimize the effects of random variation of individual breaths of the analysis, sequential values of groups of fivebreaths wereaveraged.The VT and VIwere divided by patient height in order to standardize for patient size in comparing the breathing patterns of patients (2, 17). These values will be referred to as adjusted VTand adjusted VI, respectively. It has previously been shown that VTand VI increase linearly up to a break point (2, 18, 19). Beyond this point, VT does not increase substantially, and further increases in VI are due predominantly to an increase in respiratory rate. Our method for determining the break point of VT is demonstrated in figure 1. The VT break point is defined as the point at which linear regressions formed by points above and below yield a maximal sum of correlation coefficients. This analysis was performed using a standard algorithm outlined prior to data inspection so as to eliminate investigator bias. The slopes of the lines formed by all points prior to the break point in each patient were determined for both adjusted VT and RR as a function of adjusted VI. These values werethen compared between study groups. In order to confirm that these relationships were well represented by a linear model, we fit both a straight line and a second-order polynomial to each data set through a computer-generated least-squares regression analysis. Comparison of the betacoefficients using a t test confirmed that the
12
E ~
10
~ c w
8
quadratic model did not provide a significantly better fit than a linear model. The mean correlation coefficient for the regression lines representing the VT relationship was 0.93 and for the RR relationship it was 0.82. 'It, Ts, not, duty cycle (Tt/Ttot), and VT determined at rest and during exercise were compared between study groups. The mean valuesof all individual breaths occurring within 15s of the break point were used to evaluate exercise response. All values were represented as a mean ± 1SD. Student's one-tailed t test was used to compare groups with regard to measurements of respiratory pattern. Weconsidered a one-tailed analysis to be appropriate because our hypothesis was clearly stated prior to analysis, and it was illogical to expect the study group to be significantly different in the direction opposite of that tested. Student's two-tailed t test was used to compare groups with regard to ventilation and gas exchange at maximal exercise. Differences were considered significant if the p value was < 0.05.
Results
Subject characteristics are shown in table 1. There were no significant differences between groups with regard to patient height, age, time post-transplant, or sex proportion. The individual pulmonary function data are shown in table 2. By definition, the HLTR-N group had a significantly higher FVC percent predicted and FEV1/ FVC than did the HLTR-O group. The FEF2 5 - 75 was also significantly greater in the HLTR-N group. 1\vo subjects in the HLTR-N group had a decreased FEF25 - 75 ; however, both subjects' values were substantially higher than any in the HLTR-O group. Both of these subjects had stable pulmonary function for at least 12months after completion of data collection, confirming the absence of active obliterative bronchiolitis. The relationship between the VT and the VI through maximal exercise for subjects in both the HLTR-N and the HLTR-O groups using a quadratic mod-
a a
:§. ~
en :::;)
BREAK POINT:
6
.., c
ct
4
SLOPE= 0.025
2
0
100
200
300
Adjusted VI (ml/mln/cm)
400
500
Fig. 1. Sampleanalysisof an individual respiratory response. Thetidalvolume break point is defined as the point at which linear regressions formed by points above andbelowyielda maximal sum of correlation coefficients. The closed squares(pointsbelowthe break point)are usedto calculatethe slopeof the linearportionof the VTversusventilationrelationship (0.025 in thisSUbject).
133
BRONCHIOLITIS DURING EXERCISE IN HEART-WNG TRANSPLANT RECIPIENTS
TABLE 1
12
CHARACTERISTICS OF THE STUDY SUBJECTS· 10
HLTR-N HLTR-Q
Sex
Height (em)
Age (yr)
Time Post-Tx (month)
Female
172 ± 5
36 ± 6 35 ± 8
15 ± 14 18 ± 12
4 3
vrt
± 4
Male
Definition of abbreviations: Tx • transplant; HLTR-N - heart-lung transplant recipients with relatively normal pulmonary function; HLTR-o • heart-lung transplant recipients with bronchiolitis obliterans. • Values are mean ± SO.
E o
2 +--~---r-----r---,...-----. o 100 200 300 "00 500
...>
TABLE 2
Adjusted VI ( mil min I cm )
'C
Q)
PULMONARY FUNCTION INDICES IN THE STUDY SUBJECTS
7ii
::J
Patient No.
FEF 25- 75
FRC
FEV 1/FVC
(% pred)
(% pred)
76 76 74 71 87 ± 6
0.92 0.80 0.73 0.88 0.93 0.85 ± 0.09
110
66
64
84
55 80 123 86 ± 29
43 66 67 54 58 ± 1
0.54 0.46 0.62 0.55 0.56 ± 0.09
11 13 21 16 15 ± 4
FVC
(0/0 pred)
HLTR-N 1 2
3 4 5 Mean ± SO HLTR-O 1 2 3 4 Mean ± SO
n
~
HLTR-O 10
96 82 80 82 ± 11 2 +-----,..---r---~--_-_
81
o
84
100
200
n 88 ± 14
However, when expressed as a proportion of MVV, HLTR-O had a significantly higher value than did HLTR-N. Significant differences were not found between arterial pH and Peol at maximal exercise. HLTR-O had a significantly higher arterial POl at maximal exercise than did HLTR-N; however, no individual in either group had a POl value lower than 84 mm Hg. Discussion
The differences in ventilatory pattern between normal subjects and patients with either obstructive or restrictive lung disease have been characterized by several investigators. Kaltreider and McCann (1) showed that patients with both emphysema and pulmonary fibrosis have higher respiratory rates and smaller tidal volumes at all work levels than do normal subjects. Bradley and Crawford (2) confirmed these results and noted that men with chronic lung disease have a slower increment in VT and more rapid increase in RR for a given increase in ventilation during exercise. The increased respiratory frequency was associated with a shortening of 'It in the subjects with lung disease. These investigators suggested that increased vagal feedback may shorten 'Ir, thus producing smaller tidal volumes at higher respiratory rates in
300
"00
500
Adjusted VI ( mil min I em )
108
For definition of abbreviations, see table 1.
el is illustrated in figure 2. The slope of the linear portion of the VT versus the VI response was significantly lower in HLTR-O than in HLTR-N (0.023 ± 0.007 versus 0.031 ± 0.004, p < 0.05). The slope of the RR versus the adjusted VI was also compared between the two groups (figure 3). HLTR-O had a significantly greater slope for this relationship than did HLTR-N (0.083 ± 0.014 versus 0.055 ± .005, p < 0.01). Thus, when increasing VI during exercise, HLTR-O utilize a greater RR response and a more gradual increase in VT than do HLTR-N. No significant differences were found at rest between HLTR-N and HLTR-O with respect to 'It, Ts, not, Ti/Ttot, or VT. Measurement of these parameters during exercise at the break point revealed that Tt, Ti/Ttot, and VTwere significantly less in the HLTR-O than in the HLTR-N, but no significant differences existed between the groups with respect to Th or not. Results of n, Th, nlnot, and VT both at rest and as measured at the VT break point during exercise are shown in figure 4. Ventilation and blood gas parameters at maximal exercise are shown in table 3. HLTR-O had a significantly higher RR at maximal exercise than did HLTR-N. Maximal levels of ventilation were not significantly different between the groups.
12
Fig. 2. Comparison of the adjusted tidal volume (Vr/height) and adjusted minute ventilation (VI) in recipients of heart-Iu ng transplants with obliterative bronchiolitis (HLTR-Q) with those of recipients having normal pulmonary function (HLTR-N). The lines represent the best-fit second-order polynomial for each patient. The slope of the early linear portion of each curve prior to the break point (see figure 1) was significantly less in HLTR-Q. 40
HLTR-N
30
20
'2
~
i
iI!
..
a. !
10 0
100
200
300
.. 00
Adjusted VI (ml/mln/cm) 40
HLTR-o
30
20
10
+------r------r----,...-------,
o
100
200
300
.. 00
Adjusted VI (ml/mln/cm)
Fig. 3. Comparison of the respiratory rate and adjusted minute ventilation (VI)in recipients of heart-lung transplants with obliterative bronchiolitis (HLTR-Q)with those of recipients having normal pulmonary function (HLTRN). The lines represent the early portion of the response used in the analysis as defined in METHODS. The slopes were significantly greater in HLTR-Q.
134
SCIURBA, OWENS, SANDERS, COSTANnNO, PARADIS, AND GRIFFITH
TE
TI 4.0
_4.0 U)
Ui
Q
~3.0
~3.0
0
0
0 ~2.0
w
~2.0
w :IE
w :IE 1.0
i= 1.0
i= 0.0
0.0
REST
EXERCISE
REST
TV
TIITTOT 0.6
12
*
0.5
10
0.4
E
0
~
~ 0.3
E
~
a:
EXERCISE
8
6
0.2
4
0.1
2
0.0 REST
0
EXERCISE
REST
EXERCISE
Fig. 4. Comparison of inspiratory time (11), expiratory time ~), duty cycle (11/Ttot), and adjusted tidal volume (TV) at ~e~~ and during e~ercise at the ti~a! volume break point in heart-lung transplent recipients with obliterative bronchlontls (HLTR-Q) with those of recipients with normal pulmonary function (HLTR-N)(*p < 0.05; #p < 0.005). Solid bars = HLTR-N; hatched bars = HLTR-Q. '
these subjects. It was thought that decreased lung compliance or increased airway resistance in these patients induced greater transpulmonary pressures for a given volume change, thus resulting in an increased activity of intrapulmonary receptors. Sorli and coworkers (4) also hypothesized that increased activity of pulmonary stretch or irritant receptors explained the significant relationship between FEV 1 and Tr/Ttot in patients with obstructive lung disease. Schaanning (5) confirmed the results of previous investigators and suggested further that the altered respiratory pattern in patients with airflow obstruction is due to ventilation at higher than normal lung volumes resulting in increased activity of pulmonary stretch receptors. Although the alteration in breathing pattern in these subjects may be vagally
mediated, alternative mechanisms may include feedback from chest wall (7, 9) or upper airway (8) receptors or intrinsic changes in central respiratory output. However,direct experimental evidence in humans is scarce. Guz and Widdicombe (20)described a lowerRR for a givenlevel of ventilation during exercise in two patients with pulmonary fibrosis and asthma after anesthesia of the vagus and glossopharyngeal nerves. In contrast, Savoy and coworkers (21) and Winning and colleagues (22) found no difference in the breathing pattern of patients with pulmonary fibrosis after local airway anesthesia during rest and during exertion, respectively. We have chosen to study the exercise response in HLTR in order to further elucidate the role of pulmonary vagal afferents on the control of respiration. This is a unique group of sub-
TABLE 3 INDICES OF VENTILATION AND GAS EXCHANGE AT MAXIMAL EXERCISE*
HLTR-N HLTR-O
VT*
RRt (min-')
(mUcm)
VI (mUmin/cm)
VI/MW§
pH
PC02 (mm Hg)
29 ± 7 44 ± 13
9.45 ± 1.11 6.36 ± 0.93
277 ± 92 273 ± 71
0.50 ± 0.11 0.90 ± 0.11
7.39 ± 0.03 7.35 ± 0.09
24 ± 9 30 ± 4
Definitionof abbreviations: RR • respiratoryrate.VT = tidal volume; VI tary ventilation. For other definitions, see table 1. * Values are mean ± SO. t p < 0.05. t p < 0.005. § p < 0.001.
-
111 ± 8 97 ± 13
inspiratoryminuteventilation; MVV • maximalvolun-
jects with denervated lungs. No previous study has addressed the pattern of breathing in heart-lung recipients with significant lung disease. Our study shows that HLTR-O increase VI utilizing a greater increase in RR and a slower increment in VT when compared with HLTR-N. Further, nand Tr/Ttot at the break point were less in HLTR-O. These differences in breathing pattern seen in our denervated patients with obliterative bronchiolitis are similar to those changes reported in patients with lung disease who have normal pulmonary innervation. This finding suggests that mechanisms outside of pulmonary vagal afferents are responsible for the altered respiratory pattern seen in patients with lung disease. Another significant difference between the two groups was the level of VT at the break point, which was significantly lower in HLTR-O than in HLTR-N. The break point or VT plateau has been discussed by many investigators (18, 19,23). Beyond this point, ventilation increases predominantly by a shortening of nand Th (i.e., increasing RR) whereas VT remains relatively constant. Possible reasons for this phenomenon include pulmonary vagal feedback, chest wall receptor feedback, and intrinsic properties of the patient's central respiratory center. The identification of a break point in both of our denervated groups in the absence of pulmonary vagal feedback implies that vagal afferents are not necessary for this response. Also, the fact that the level of VT at which the break point occurred was lower in our subjects with lung disease implies that mechanisms outside of pulmonary vagal afferents have significant influence over this event. Our study cannot entirely exclude an influence of vagal mechanisms on regulation of respiratory pattern in patients with lung disease. Rather, it confirms the presence of nonvagal mechanisms that operate in the absence of pulmonary receptor feedback. Studies in experimental animals, in fact, support a role for both vagal and nonvagal influences over breathing pattern in dogs with lung disease (7). HLTR with normal lung function do have a slower RR rate and greater VT response to exercise than does a group of heart transplant recipients with normal pulmonary function, suggesting an impact of vagal afferents on breathing pattern in subjects without substantial pulmonary function abnormalities (10). It would have been useful to compare our study group with a second control group with lung disease but intact
BRONCHIOLITIS DURING EXERCISE IN HEART-WNG TRANSPLANT RECIPIENTS
pulmonary vagal pathways in order to further clarify the role of pulmonary vagal feedback. This third control group, however, would have required similarity to our study group with regard to the many characteristics that could independently influence breathing pattern such as previous surgery on the chest, chronic steroid therapy, chronic deconditioning, and cardiac denervation. These conditions would not be met by a group of otherwise normal patients with restrictive or obstructive lung disease; heart transplant recipients with lung disease were not available to study. In this study we have not attempted to sort out the possible roles of other nonvagal mediators that may be influencing the breathing pattern in these patients. The most likely mechanism involveschest wall receptors, including costovertebral joint proprioceptors (24) and diaphragmatic or skeletal muscle proprioceptors. Another less commonly discussed mechanism potentially involves receptors that sense pressure changes in the upper airway (8, 25). In patients with obstructive airway disease, perhaps an altered respiratory pattern may result from a discordance between central respiratory output and feedback from pressure changes sensed in the upper airway. Studies to further assess the influence of nonvagal mechanism on respiratory pattern may include assessment of the effects of upper airway anesthesia, chest wall compression, or rib vibration in a group of HLTR-O. The HLTR-O had lower arterial POl values during exercise than did the HLTR-N. The lowest POl value of 84 mm Hg in the HLTR-O, however, was not in a range that was low enough to have influenced the VI caused by an increased hypoxic drive (26, 27). Furthermore, although hypoxemia can increase VI, it has not been shown to cause a change in respiratory pattern. Although this study was designed to assess the control of ventilation in patients with lung disease in general, several observations have particular clinical importance relating to the regulation of breathing in HLTR with superimposed lung disease. It has previously been' shown that HLTR with normal pulmonary function have normal regulation of ventilation and gas exchange at maximal exercise despite the absence of pulmonary vagal pathways (10). This, however, is the first report to document normal regulation of ventilation and arterial carbon dioxide levels at maximal exercise in
HLTR with obliterative bronchiolitis. Arterial Pco, and pH at maximal exercise were not significantly different in HLTR-O from those in HLTR-N (table 3). The ventilation at maximal exercise for HLTR-O was 90070 of the MVV, which is in the usual range for patients with pulmonary disease who are ventilatorylimited during exercise (28-30). This normal response in this group of patients with lung disease who have undergone a maximal stress to their ventilatory system substantiates previous findings that pulmonary vagal afferents are not essential for the regulation of the ultimate level of ventilation in humans. In summary, HLTR-O have a more' rapid and shallow breathing pattern than do HLTR-N, which is the usual response of patients with restrictive or obstructive lung disease who have normal pulmonary innervation. This finding suggests that mechanisms outside of the lung contribute significantly to this respiratory pattern response. Also, recipients of heartlung transplants, who have obliterative bronchiolitis, have appropriate regulation of the level of ventilation and gas exchange at maximal exercise. Acknowledgment The writers thank Drs. Robert Rogers and James Dauber for their constructive comments throughout the study. References 1. Kaltreider NL, McCann WS. Respiratory response during exercise in pulmonary fibrosis and emphysema. J Clin Invest 1937; 16:23-40. 2. BradleyGW, Crawford R. Regulation of breathing during exercisein normal subjects and in chronic lung disease. Clin Sci Mol Med 1976; 51:575-82. 3. Spiro SG, Hahn HL, Edwards HT, Pride NB. An analysis of the physiological strain of submaximal exercise in patients with chronic obstructive bronchitis. Thorax 1975; 30:415-25. 4. Sorli J, Grassino A, Lorange G, Milic-Emili J. Control of breathing in patients with chronic obstructive lung disease. Clin Sci Mol Med 1978; 54:295-304. 5. Schaanning J. Respiratory cycletime duration during exercise in patients with chronic obstructive lung disease. Scand J Respir Dis 1979;59:313-8. 6. Gautier H. Control of the pattern of breathing. Clin Sci 1980; 58:343-8. 7. Phillipson EA, Murphy E, Kozar LF, Schultze RK. Role of vagal stimuli in exercise ventilation in dogs with experimental pneumonitis: J Appl Physiol 1975; 39:76-85. 8. Mathew OP, Abu-Osba YK, Thach BT. Influence of upper airway pressure changes on respiratory frequency. Respir Physiol1982; 49:223-33. 9. Remmers JE. Inhibition of inspiratory activity by intercostal muscle afferents. Respir Physiol1970; 10:358-83. 10. Sciurba FC, Owens GR, Sanders MH, et ale Evidence of an altered pattern of breathing during exercise in recipients of heart-lung transplants. N Engl J Med 1988; 319:1186-92.
135 11. Theodore J, Morris AJ, Burke CM, et ale Cardiopulmonary function at maximum tolerable constant work rate exercisefollowing human heartlung transplantation. Chest 1987; 92:433-9. 12. Sanders MH, Owens GR, Sciurba FC, et ale Ventilation and breathing pattern during progressive hypercapnia and hypoxia after human heartlung transplantation. Am Rev Respir Dis 1989; 140:38-44. 13. Banner NB, Lloyd MH, Hamilton RD, Innes JA, Guz A, Yacoub MH. Cardiopulmonary response to dynamic exercise after heart and combined heart-lung transplantation. Br Heart J 1989; 61:215-23. 14. American College of Sports Medicine. Guidelines for exercise testing and prescription. 3rd ed. Philadelphia: Lea & Febiger, 1986; 21. 15. Morris JF, Koski A, Johnson Le. Spirometric standards for healthy nonsmoking adults. Am Rev Respir Dis 1971; 103:57-67. 16. Goldman HI, BecklakeMR. Respiratory function tests: normal values at median altitudes and the prediction of normal results. Am Rev Tuberc 1959; 79:457-67. 17. Cerny FJ. Breathing pattern during exercise in young black and caucasian subjects. J Appl Physiol 1987; 62:2220-3. 18. Hey EN, Lloyd BB, Cunningham DJ, Jukes MG, Bolton OP. Effects of various respiratory stimuli on the depth and frequency of breathing in man. Respir Physiol 1966; 1:193-205. 19. Gardner WN. The relation between tidal volume and inspiratory and expiratory times during steady-state carbon dioxide inhalation in man. J Physiol (Lond) 1977; 272:591-611. 20. Guz A, Widdicombe JG. Pattern of breathing during hypercapnia before and after vagalblockade in man. In: Porter R, ed. Breathing. HeringBreuer Centenary Symposium. London: Churchill, 1970; 41-52. 21. Savoy J, Dhingra S, Anthonisen R. Role of vagal airway reflexes in control of ventilation in pulmonary fibrosis. Clin Sci 1981; 61:781-4. 22. Winning AJ, Hamilton RD, Guz A. Ventilation and breathlessness on maximal exercisein patients with interstitial lung disease after local anaesthetic aerosol inhalation. Clin Sci 1988; 74:275-81. 23. Gallagher CG, Younes M. Breathing pattern during and after maximal exercisein patients with chronic obstructive lung disease, interstitial lung disease, and cardiac disease, and in normal subjects. Am Rev Respir Dis 1986; 133:581-6. 24. Shannon R. Respiratory pattern changes during costovertebral joint movement. J Appl Physiol 1980; 48:862-7. 25. Hammouda M, Wilson WHo Influences that affect the form of respiratory cycle in particular that of the expiratory phase. J Physiol (Lond) 1933; 80:261-84. 26. WeilJV, Byrne Quinn E, Sodal IE, et ale Hypoxic ventilatory drive in normal man. J Clin Invest 1970; 49:1061-72. 27. Kelsen S,Fishman A. In: Fishman AP, 00. Pulmonary diseasesand disorders. NewYork:McGrawHill, 1980; 1787-94. 28. Clark TJ, Freedman S, Campbell EJ, Winn RR. The ventilatory capacity of patients with chronic airways obstruction. Clin Sci 1969; 36:307-16. 29. Potter WA, Olafson S, Hyatt RE. Ventilatory mechanics and expiratory flow limitations during exercise in patients with obstructive lung disease. J Clin Invest 1971; 50:910-9. 30. Pierce AK, Luterman D, Loundermilk J, Blomquist G, Johnson RL Jr. Exercise ventilatory patterns in normal subjects and patients with airway obstruction. J Appl Physiol 25:249-54.
FRANK c. SCIURBA, GREGORY R. OWENS, MARK H. SANDERS, JOSEPH P. COSTANTINO, IRVIN L. PARADIS, and BARTLEY R GRIFFITH
T he
Introduction
SUMMARY The more r.pld .nd sh.llow ventll.tlon pettern _n during exerel.. In patients with normal ventilatory response to obstructive .nd/or restrictive lung dl_ _ h.s been .ttrlbuted by some Investigators to the effecta moderate exercise is made up predomiof vag.1 .fferents from Intrapulmonary receptors. Recipients of he.rt-Iung transpl.nts (HLTR)offer nantly of an increase in tidal volume ac• unique opportunity to test this hypothesis since they have denervated lungs .nd may develop companied by a relatively small increase obllter.tlve bronchiolitis .fter org.n reJection. We thus compered the ventll.tlon re&pOn.. to Inin respiratory rate. Patients with obstruccremental bicycle ergometry of five HLTRwith relatively norm.1 pUlmonary function (HLTR-N) .nd four with bronchiolitis obllter.ns (HLTR-O). We comp.red the .Iopes of the Ilne.r portion of the tive or restrictive lung disease, however, tld.1 volume versus Inspired minute "ventilation rel.tlonshlp of both groupe. The rate of rI.. of tld.1 respond to exertion with a slower rise in volume (VT) (slope of VT versus VI) was greater In HLTR-N (0.031 ± 0.004) th.n In HLTR-O (0.023 tidal volume and a more rapid increase ± 0.007) (p < 0.05). This corresponded to ••Iower Incre... In respiratory r.te (RR) (slope of RR in respiratory rate than do normal subveraus VI/em) In HLTR-N (0.055 ± 0.005) th.n In HLTR-O (0.083 ± 0.019) (p < 0.01). Furthermore, jects (1-3). This altered respiratory patvalu.. for VT, Inspiratory time (TI), .nd duty cycle (TlI11ot)meuured during exerel. . at the VTbreak tern may serve to decrease the work of point were .11 significantly lower In the HLTR-O th.n In HLTR-N. We .Iso evaluated the ability of breathing in patients with noncompliant HLTRwith lung dl..... to regul.te their ultimate level of ventilation during maxlm.lexerel... Yentlor hyperinflated lungs, although the latlon . . . proportion of maxlm.1 voluntary ventilation was slgn"lcantly greater In HLTR-O (0.90 precise mechanism for this altered ven± 0.11) th.n In HLTR-N (0.50 ± 0.11). Arterl.1 pH .nd PC0 2 at maxlm.lexercl.e In HLTR-O were tilatory pattern is not known. Some in.pproprlately regUlated. In conclusion, HLTR-Ohave. more rapid rise In RR .nd slower Incre... In VTth.n do HLTR-N. This respon.. pattern, In the .b..nce of pUlmon.ry Innervation, auggeata vestigators have speculated that the unth.t mech.nlsms outside of pulmon.ry vag.l.fferentB contribute to regulation of breathing pattern derlying disease process or concomitant In patients with lung dl...... Also, HLTR-Odemonstr.te .pproprl.te regulation of ventll.tlon duralterations in pulmonary mechanics reAM REV RESPIR DIS 1111; 144:131-135 Ing m.xlmal exerel... sult in stimulation of pulmonary J- or stretch receptors resulting in a vagally mediated alteration in respiratory pattern (2, 4-6). Alternative mechanisms not mediated through pulmonary vagal af- (HLTR-O) in order to gain insight into lung disease, then HLTR with lung disferent pathways have been shown to in- the contribution of pulmonary vagal and ease should have a ventilatory pattern fluence respiratory pattern in experimen- nonvagal mechanisms to the regulation during exercise that is similar to that of tal animals (7) and must also be consid- of respiratory pattern in patients with HLTR with normal pulmonary function (HLTR-N). Specifically, they should not ered as possible effectors of respiratory lung disease. Wehave also evaluated the capacity of develop high respiratory rates and relapattern in these patients. Stimulation of chest wall proprioceptors or upper air- HLTR-O to regulate overall ventilation tively small tidal volumes. way receptors has been shown to in- and gas exchange during maximal exerfluence respiratory pattern in normal cise.Previous reports of exercise response subjects (8, 9). How and to what extent in HLTR have dealt only with subjects these factors influence the respiratory with relatively normal pulmonary func- (Received in original form March 8, 1990 and in pattern of patients with lung disease is tion (10, 11, 13). These studies demon- revised form October 8, 1990) not known. strated levels of exercise ventilation and 1 From the Division of Pulmonary Medicine, Heart-lungtransplant recipients (HLTR) gas exchange that were essentially withare a unique population of patients who in normal limits. However, because pa- Departments of Medicine and Surgery,Presbyterian University Hospital, The University of Pittsburgh have had complete disruption of the pul- tients with lung disease, but not normal School of Medicine, and the Department of Biomonary vagal afferents below the trache- subjects, may approach their limits of statistics, University of Pittsburgh Graduate School al anastomosis of the transplanted lungs. maximal ventilation during exertion, we of Public Health, Pittsburgh, Pennsylvania. 1 Supported in part by Grant no. N-129 from the These patients can thus be evaluated to investigated the ability of these pulmoLung Association of Western Pennsylassess the effects of denervation of the nary denervated patients to regulate ven- American vania, by Training Grant IT32 HL-07563 from the human lung on the regulation of breath- tilation and gas exchange during the National Institutes of Health, and by the Research ing (10-13). The patients in this group stress of maximal exercise. Fund, Department of Medicine, University of Pittssometimes develop obliterative bronchioOur study was designed to test the fol- burgh School of Medicine. 3 Correspondence and requests for reprints litis after chronic lung rejection. Wehave lowing principal hypothesis: if vagal afshould be addressed to Frank C. Sciurba, M.D., analyzed the exercise breathing pattern ferents are primarily responsible for the Division of Pulmonary Medicine, University of in a group of heart-lung recipients with generation of the altered respiratory Pittsburgh, 3550 Terrace Street, 440 Scaife Hall, biopsy-proved obliterative bronchiolitis pattern during exercise in patients with Pittsburgh, PA 15261.
131
132
Methods Subjects The study participants werenine patients who had undergone heart-lung transplantation. Subjects were studied during routine followup evaluations or during evaluations for symptoms suggestiveof chronic rejection. All consecutive patients were included who met the following pulmonary function criteria. Five had normal pulmonary function (HLTRN). Patients were excluded from this group if their forced vital capacity was lessthan 70010 predicted, if their FEVt/FVC was < 0.7, or if deterioration in pulmonary function had occurred during the preceding 3 months. Subjects with erratic ventilatory pattern responses that could not be represented by simple algebraic pattern were excluded from the analysis (6). The responses of two such HLTR-N were described in a previous report (10).Subjects wereincluded in the study group HLTRN only if clinically stable without current or past evidence of rejection and without infection for at least 6 wk. The second group included four HLTR-O documented by transbronchial biopsy. All patients in this group had experienced recent clinical deterioration associated with worsening of FEV t/FVC to < 0.7.
Protocol Symptom-limited incremental exercise was performed on an electronically braked cycle ergometer (Godart Lanooy, Utrecht, Holland), at a patient-selected pedaling frequency between 55 and 70 rpm. All patients began the test with unloaded pedaling. The power output was then increased each minute by 10 to 15 watts. Exercise tests were ended at the point of exhaustion or upon the appearance of signs or symptoms of exertional intolerance (14). No training period was provided before testing. However, all patients had used the bicycle ergometer during rehabilitation therapy. The subjects breathed through a low resistance unidirectional valve (Hans Rudolph, Kansas City, MO) containing 75 ml of dead space. Ventilatory flow was measured using a pneumotachograph (Fleisch No.3), transducer (Validyne MP-45; Validyne Corp., Northridge, CA) and carrier demodulator (ValidyneCDI3) placed in the inspiratory side of the valve. Inspiratory volume was determined by electrical integration of the flow signal. Flow and volume signals were displayed on a strip chart recorder (Gould 24OOS; Gould Instruments, Cleveland, OH) providing a breath-by-breath analog representation of the ventilation parameters. No adjustment was made for valve dead space in these calculations. Arterial blood was sampled from a radial artery catheter at rest and during the final minute of exertion. Automated arterial blood gas analysis was performed (Radiometer ABU; Radiometer, Copenhagen, Denmark). Spirometry was performed with an automated system (Gould 5000IV) using a dry rolling-seal spirometer. The maximal volun-
SCIURBA, OWENS, SANDERS, COSTANTINO, PARADIS, AND GRIFFITH
tary ventilation (MVV) was measured in all subjects. Functional residual capacity was assessed using body plethysmography (Model 2000B Cardio-Pulmonary Instruments, Houston, TX). The predicted normal values for spirometry were those of Morris and coworkers (15), and the values for lung volume were those of Goldman and Becklake (16). These values were based on the age, sex, and height of the recipient.
Data Analysis The inspired minute ventilation (VI),tidal volume (VT), respiratory rate (RR), inspiratory time (II), expiratory time (IE), and total breath cycle time (not) were calculated on a breathby-breath basis from the flow and inspired volume (expressedin BTPS) signal of the pneumotachograph. All breaths were included in the analysis. In order to minimize the effects of random variation of individual breaths of the analysis, sequential values of groups of fivebreaths wereaveraged.The VT and VIwere divided by patient height in order to standardize for patient size in comparing the breathing patterns of patients (2, 17). These values will be referred to as adjusted VTand adjusted VI, respectively. It has previously been shown that VTand VI increase linearly up to a break point (2, 18, 19). Beyond this point, VT does not increase substantially, and further increases in VI are due predominantly to an increase in respiratory rate. Our method for determining the break point of VT is demonstrated in figure 1. The VT break point is defined as the point at which linear regressions formed by points above and below yield a maximal sum of correlation coefficients. This analysis was performed using a standard algorithm outlined prior to data inspection so as to eliminate investigator bias. The slopes of the lines formed by all points prior to the break point in each patient were determined for both adjusted VT and RR as a function of adjusted VI. These values werethen compared between study groups. In order to confirm that these relationships were well represented by a linear model, we fit both a straight line and a second-order polynomial to each data set through a computer-generated least-squares regression analysis. Comparison of the betacoefficients using a t test confirmed that the
12
E ~
10
~ c w
8
quadratic model did not provide a significantly better fit than a linear model. The mean correlation coefficient for the regression lines representing the VT relationship was 0.93 and for the RR relationship it was 0.82. 'It, Ts, not, duty cycle (Tt/Ttot), and VT determined at rest and during exercise were compared between study groups. The mean valuesof all individual breaths occurring within 15s of the break point were used to evaluate exercise response. All values were represented as a mean ± 1SD. Student's one-tailed t test was used to compare groups with regard to measurements of respiratory pattern. Weconsidered a one-tailed analysis to be appropriate because our hypothesis was clearly stated prior to analysis, and it was illogical to expect the study group to be significantly different in the direction opposite of that tested. Student's two-tailed t test was used to compare groups with regard to ventilation and gas exchange at maximal exercise. Differences were considered significant if the p value was < 0.05.
Results
Subject characteristics are shown in table 1. There were no significant differences between groups with regard to patient height, age, time post-transplant, or sex proportion. The individual pulmonary function data are shown in table 2. By definition, the HLTR-N group had a significantly higher FVC percent predicted and FEV1/ FVC than did the HLTR-O group. The FEF2 5 - 75 was also significantly greater in the HLTR-N group. 1\vo subjects in the HLTR-N group had a decreased FEF25 - 75 ; however, both subjects' values were substantially higher than any in the HLTR-O group. Both of these subjects had stable pulmonary function for at least 12months after completion of data collection, confirming the absence of active obliterative bronchiolitis. The relationship between the VT and the VI through maximal exercise for subjects in both the HLTR-N and the HLTR-O groups using a quadratic mod-
a a
:§. ~
en :::;)
BREAK POINT:
6
.., c
ct
4
SLOPE= 0.025
2
0
100
200
300
Adjusted VI (ml/mln/cm)
400
500
Fig. 1. Sampleanalysisof an individual respiratory response. Thetidalvolume break point is defined as the point at which linear regressions formed by points above andbelowyielda maximal sum of correlation coefficients. The closed squares(pointsbelowthe break point)are usedto calculatethe slopeof the linearportionof the VTversusventilationrelationship (0.025 in thisSUbject).
133
BRONCHIOLITIS DURING EXERCISE IN HEART-WNG TRANSPLANT RECIPIENTS
TABLE 1
12
CHARACTERISTICS OF THE STUDY SUBJECTS· 10
HLTR-N HLTR-Q
Sex
Height (em)
Age (yr)
Time Post-Tx (month)
Female
172 ± 5
36 ± 6 35 ± 8
15 ± 14 18 ± 12
4 3
vrt
± 4
Male
Definition of abbreviations: Tx • transplant; HLTR-N - heart-lung transplant recipients with relatively normal pulmonary function; HLTR-o • heart-lung transplant recipients with bronchiolitis obliterans. • Values are mean ± SO.
E o
2 +--~---r-----r---,...-----. o 100 200 300 "00 500
...>
TABLE 2
Adjusted VI ( mil min I cm )
'C
Q)
PULMONARY FUNCTION INDICES IN THE STUDY SUBJECTS
7ii
::J
Patient No.
FEF 25- 75
FRC
FEV 1/FVC
(% pred)
(% pred)
76 76 74 71 87 ± 6
0.92 0.80 0.73 0.88 0.93 0.85 ± 0.09
110
66
64
84
55 80 123 86 ± 29
43 66 67 54 58 ± 1
0.54 0.46 0.62 0.55 0.56 ± 0.09
11 13 21 16 15 ± 4
FVC
(0/0 pred)
HLTR-N 1 2
3 4 5 Mean ± SO HLTR-O 1 2 3 4 Mean ± SO
n
~
HLTR-O 10
96 82 80 82 ± 11 2 +-----,..---r---~--_-_
81
o
84
100
200
n 88 ± 14
However, when expressed as a proportion of MVV, HLTR-O had a significantly higher value than did HLTR-N. Significant differences were not found between arterial pH and Peol at maximal exercise. HLTR-O had a significantly higher arterial POl at maximal exercise than did HLTR-N; however, no individual in either group had a POl value lower than 84 mm Hg. Discussion
The differences in ventilatory pattern between normal subjects and patients with either obstructive or restrictive lung disease have been characterized by several investigators. Kaltreider and McCann (1) showed that patients with both emphysema and pulmonary fibrosis have higher respiratory rates and smaller tidal volumes at all work levels than do normal subjects. Bradley and Crawford (2) confirmed these results and noted that men with chronic lung disease have a slower increment in VT and more rapid increase in RR for a given increase in ventilation during exercise. The increased respiratory frequency was associated with a shortening of 'It in the subjects with lung disease. These investigators suggested that increased vagal feedback may shorten 'Ir, thus producing smaller tidal volumes at higher respiratory rates in
300
"00
500
Adjusted VI ( mil min I em )
108
For definition of abbreviations, see table 1.
el is illustrated in figure 2. The slope of the linear portion of the VT versus the VI response was significantly lower in HLTR-O than in HLTR-N (0.023 ± 0.007 versus 0.031 ± 0.004, p < 0.05). The slope of the RR versus the adjusted VI was also compared between the two groups (figure 3). HLTR-O had a significantly greater slope for this relationship than did HLTR-N (0.083 ± 0.014 versus 0.055 ± .005, p < 0.01). Thus, when increasing VI during exercise, HLTR-O utilize a greater RR response and a more gradual increase in VT than do HLTR-N. No significant differences were found at rest between HLTR-N and HLTR-O with respect to 'It, Ts, not, Ti/Ttot, or VT. Measurement of these parameters during exercise at the break point revealed that Tt, Ti/Ttot, and VTwere significantly less in the HLTR-O than in the HLTR-N, but no significant differences existed between the groups with respect to Th or not. Results of n, Th, nlnot, and VT both at rest and as measured at the VT break point during exercise are shown in figure 4. Ventilation and blood gas parameters at maximal exercise are shown in table 3. HLTR-O had a significantly higher RR at maximal exercise than did HLTR-N. Maximal levels of ventilation were not significantly different between the groups.
12
Fig. 2. Comparison of the adjusted tidal volume (Vr/height) and adjusted minute ventilation (VI) in recipients of heart-Iu ng transplants with obliterative bronchiolitis (HLTR-Q) with those of recipients having normal pulmonary function (HLTR-N). The lines represent the best-fit second-order polynomial for each patient. The slope of the early linear portion of each curve prior to the break point (see figure 1) was significantly less in HLTR-Q. 40
HLTR-N
30
20
'2
~
i
iI!
..
a. !
10 0
100
200
300
.. 00
Adjusted VI (ml/mln/cm) 40
HLTR-o
30
20
10
+------r------r----,...-------,
o
100
200
300
.. 00
Adjusted VI (ml/mln/cm)
Fig. 3. Comparison of the respiratory rate and adjusted minute ventilation (VI)in recipients of heart-lung transplants with obliterative bronchiolitis (HLTR-Q)with those of recipients having normal pulmonary function (HLTRN). The lines represent the early portion of the response used in the analysis as defined in METHODS. The slopes were significantly greater in HLTR-Q.
134
SCIURBA, OWENS, SANDERS, COSTANnNO, PARADIS, AND GRIFFITH
TE
TI 4.0
_4.0 U)
Ui
Q
~3.0
~3.0
0
0
0 ~2.0
w
~2.0
w :IE
w :IE 1.0
i= 1.0
i= 0.0
0.0
REST
EXERCISE
REST
TV
TIITTOT 0.6
12
*
0.5
10
0.4
E
0
~
~ 0.3
E
~
a:
EXERCISE
8
6
0.2
4
0.1
2
0.0 REST
0
EXERCISE
REST
EXERCISE
Fig. 4. Comparison of inspiratory time (11), expiratory time ~), duty cycle (11/Ttot), and adjusted tidal volume (TV) at ~e~~ and during e~ercise at the ti~a! volume break point in heart-lung transplent recipients with obliterative bronchlontls (HLTR-Q) with those of recipients with normal pulmonary function (HLTR-N)(*p < 0.05; #p < 0.005). Solid bars = HLTR-N; hatched bars = HLTR-Q. '
these subjects. It was thought that decreased lung compliance or increased airway resistance in these patients induced greater transpulmonary pressures for a given volume change, thus resulting in an increased activity of intrapulmonary receptors. Sorli and coworkers (4) also hypothesized that increased activity of pulmonary stretch or irritant receptors explained the significant relationship between FEV 1 and Tr/Ttot in patients with obstructive lung disease. Schaanning (5) confirmed the results of previous investigators and suggested further that the altered respiratory pattern in patients with airflow obstruction is due to ventilation at higher than normal lung volumes resulting in increased activity of pulmonary stretch receptors. Although the alteration in breathing pattern in these subjects may be vagally
mediated, alternative mechanisms may include feedback from chest wall (7, 9) or upper airway (8) receptors or intrinsic changes in central respiratory output. However,direct experimental evidence in humans is scarce. Guz and Widdicombe (20)described a lowerRR for a givenlevel of ventilation during exercise in two patients with pulmonary fibrosis and asthma after anesthesia of the vagus and glossopharyngeal nerves. In contrast, Savoy and coworkers (21) and Winning and colleagues (22) found no difference in the breathing pattern of patients with pulmonary fibrosis after local airway anesthesia during rest and during exertion, respectively. We have chosen to study the exercise response in HLTR in order to further elucidate the role of pulmonary vagal afferents on the control of respiration. This is a unique group of sub-
TABLE 3 INDICES OF VENTILATION AND GAS EXCHANGE AT MAXIMAL EXERCISE*
HLTR-N HLTR-O
VT*
RRt (min-')
(mUcm)
VI (mUmin/cm)
VI/MW§
pH
PC02 (mm Hg)
29 ± 7 44 ± 13
9.45 ± 1.11 6.36 ± 0.93
277 ± 92 273 ± 71
0.50 ± 0.11 0.90 ± 0.11
7.39 ± 0.03 7.35 ± 0.09
24 ± 9 30 ± 4
Definitionof abbreviations: RR • respiratoryrate.VT = tidal volume; VI tary ventilation. For other definitions, see table 1. * Values are mean ± SO. t p < 0.05. t p < 0.005. § p < 0.001.
-
111 ± 8 97 ± 13
inspiratoryminuteventilation; MVV • maximalvolun-
jects with denervated lungs. No previous study has addressed the pattern of breathing in heart-lung recipients with significant lung disease. Our study shows that HLTR-O increase VI utilizing a greater increase in RR and a slower increment in VT when compared with HLTR-N. Further, nand Tr/Ttot at the break point were less in HLTR-O. These differences in breathing pattern seen in our denervated patients with obliterative bronchiolitis are similar to those changes reported in patients with lung disease who have normal pulmonary innervation. This finding suggests that mechanisms outside of pulmonary vagal afferents are responsible for the altered respiratory pattern seen in patients with lung disease. Another significant difference between the two groups was the level of VT at the break point, which was significantly lower in HLTR-O than in HLTR-N. The break point or VT plateau has been discussed by many investigators (18, 19,23). Beyond this point, ventilation increases predominantly by a shortening of nand Th (i.e., increasing RR) whereas VT remains relatively constant. Possible reasons for this phenomenon include pulmonary vagal feedback, chest wall receptor feedback, and intrinsic properties of the patient's central respiratory center. The identification of a break point in both of our denervated groups in the absence of pulmonary vagal feedback implies that vagal afferents are not necessary for this response. Also, the fact that the level of VT at which the break point occurred was lower in our subjects with lung disease implies that mechanisms outside of pulmonary vagal afferents have significant influence over this event. Our study cannot entirely exclude an influence of vagal mechanisms on regulation of respiratory pattern in patients with lung disease. Rather, it confirms the presence of nonvagal mechanisms that operate in the absence of pulmonary receptor feedback. Studies in experimental animals, in fact, support a role for both vagal and nonvagal influences over breathing pattern in dogs with lung disease (7). HLTR with normal lung function do have a slower RR rate and greater VT response to exercise than does a group of heart transplant recipients with normal pulmonary function, suggesting an impact of vagal afferents on breathing pattern in subjects without substantial pulmonary function abnormalities (10). It would have been useful to compare our study group with a second control group with lung disease but intact
BRONCHIOLITIS DURING EXERCISE IN HEART-WNG TRANSPLANT RECIPIENTS
pulmonary vagal pathways in order to further clarify the role of pulmonary vagal feedback. This third control group, however, would have required similarity to our study group with regard to the many characteristics that could independently influence breathing pattern such as previous surgery on the chest, chronic steroid therapy, chronic deconditioning, and cardiac denervation. These conditions would not be met by a group of otherwise normal patients with restrictive or obstructive lung disease; heart transplant recipients with lung disease were not available to study. In this study we have not attempted to sort out the possible roles of other nonvagal mediators that may be influencing the breathing pattern in these patients. The most likely mechanism involveschest wall receptors, including costovertebral joint proprioceptors (24) and diaphragmatic or skeletal muscle proprioceptors. Another less commonly discussed mechanism potentially involves receptors that sense pressure changes in the upper airway (8, 25). In patients with obstructive airway disease, perhaps an altered respiratory pattern may result from a discordance between central respiratory output and feedback from pressure changes sensed in the upper airway. Studies to further assess the influence of nonvagal mechanism on respiratory pattern may include assessment of the effects of upper airway anesthesia, chest wall compression, or rib vibration in a group of HLTR-O. The HLTR-O had lower arterial POl values during exercise than did the HLTR-N. The lowest POl value of 84 mm Hg in the HLTR-O, however, was not in a range that was low enough to have influenced the VI caused by an increased hypoxic drive (26, 27). Furthermore, although hypoxemia can increase VI, it has not been shown to cause a change in respiratory pattern. Although this study was designed to assess the control of ventilation in patients with lung disease in general, several observations have particular clinical importance relating to the regulation of breathing in HLTR with superimposed lung disease. It has previously been' shown that HLTR with normal pulmonary function have normal regulation of ventilation and gas exchange at maximal exercise despite the absence of pulmonary vagal pathways (10). This, however, is the first report to document normal regulation of ventilation and arterial carbon dioxide levels at maximal exercise in
HLTR with obliterative bronchiolitis. Arterial Pco, and pH at maximal exercise were not significantly different in HLTR-O from those in HLTR-N (table 3). The ventilation at maximal exercise for HLTR-O was 90070 of the MVV, which is in the usual range for patients with pulmonary disease who are ventilatorylimited during exercise (28-30). This normal response in this group of patients with lung disease who have undergone a maximal stress to their ventilatory system substantiates previous findings that pulmonary vagal afferents are not essential for the regulation of the ultimate level of ventilation in humans. In summary, HLTR-O have a more' rapid and shallow breathing pattern than do HLTR-N, which is the usual response of patients with restrictive or obstructive lung disease who have normal pulmonary innervation. This finding suggests that mechanisms outside of the lung contribute significantly to this respiratory pattern response. Also, recipients of heartlung transplants, who have obliterative bronchiolitis, have appropriate regulation of the level of ventilation and gas exchange at maximal exercise. Acknowledgment The writers thank Drs. Robert Rogers and James Dauber for their constructive comments throughout the study. References 1. Kaltreider NL, McCann WS. Respiratory response during exercise in pulmonary fibrosis and emphysema. J Clin Invest 1937; 16:23-40. 2. BradleyGW, Crawford R. Regulation of breathing during exercisein normal subjects and in chronic lung disease. Clin Sci Mol Med 1976; 51:575-82. 3. Spiro SG, Hahn HL, Edwards HT, Pride NB. An analysis of the physiological strain of submaximal exercise in patients with chronic obstructive bronchitis. Thorax 1975; 30:415-25. 4. Sorli J, Grassino A, Lorange G, Milic-Emili J. Control of breathing in patients with chronic obstructive lung disease. Clin Sci Mol Med 1978; 54:295-304. 5. Schaanning J. Respiratory cycletime duration during exercise in patients with chronic obstructive lung disease. Scand J Respir Dis 1979;59:313-8. 6. Gautier H. Control of the pattern of breathing. Clin Sci 1980; 58:343-8. 7. Phillipson EA, Murphy E, Kozar LF, Schultze RK. Role of vagal stimuli in exercise ventilation in dogs with experimental pneumonitis: J Appl Physiol 1975; 39:76-85. 8. Mathew OP, Abu-Osba YK, Thach BT. Influence of upper airway pressure changes on respiratory frequency. Respir Physiol1982; 49:223-33. 9. Remmers JE. Inhibition of inspiratory activity by intercostal muscle afferents. Respir Physiol1970; 10:358-83. 10. Sciurba FC, Owens GR, Sanders MH, et ale Evidence of an altered pattern of breathing during exercise in recipients of heart-lung transplants. N Engl J Med 1988; 319:1186-92.
135 11. Theodore J, Morris AJ, Burke CM, et ale Cardiopulmonary function at maximum tolerable constant work rate exercisefollowing human heartlung transplantation. Chest 1987; 92:433-9. 12. Sanders MH, Owens GR, Sciurba FC, et ale Ventilation and breathing pattern during progressive hypercapnia and hypoxia after human heartlung transplantation. Am Rev Respir Dis 1989; 140:38-44. 13. Banner NB, Lloyd MH, Hamilton RD, Innes JA, Guz A, Yacoub MH. Cardiopulmonary response to dynamic exercise after heart and combined heart-lung transplantation. Br Heart J 1989; 61:215-23. 14. American College of Sports Medicine. Guidelines for exercise testing and prescription. 3rd ed. Philadelphia: Lea & Febiger, 1986; 21. 15. Morris JF, Koski A, Johnson Le. Spirometric standards for healthy nonsmoking adults. Am Rev Respir Dis 1971; 103:57-67. 16. Goldman HI, BecklakeMR. Respiratory function tests: normal values at median altitudes and the prediction of normal results. Am Rev Tuberc 1959; 79:457-67. 17. Cerny FJ. Breathing pattern during exercise in young black and caucasian subjects. J Appl Physiol 1987; 62:2220-3. 18. Hey EN, Lloyd BB, Cunningham DJ, Jukes MG, Bolton OP. Effects of various respiratory stimuli on the depth and frequency of breathing in man. Respir Physiol 1966; 1:193-205. 19. Gardner WN. The relation between tidal volume and inspiratory and expiratory times during steady-state carbon dioxide inhalation in man. J Physiol (Lond) 1977; 272:591-611. 20. Guz A, Widdicombe JG. Pattern of breathing during hypercapnia before and after vagalblockade in man. In: Porter R, ed. Breathing. HeringBreuer Centenary Symposium. London: Churchill, 1970; 41-52. 21. Savoy J, Dhingra S, Anthonisen R. Role of vagal airway reflexes in control of ventilation in pulmonary fibrosis. Clin Sci 1981; 61:781-4. 22. Winning AJ, Hamilton RD, Guz A. Ventilation and breathlessness on maximal exercisein patients with interstitial lung disease after local anaesthetic aerosol inhalation. Clin Sci 1988; 74:275-81. 23. Gallagher CG, Younes M. Breathing pattern during and after maximal exercisein patients with chronic obstructive lung disease, interstitial lung disease, and cardiac disease, and in normal subjects. Am Rev Respir Dis 1986; 133:581-6. 24. Shannon R. Respiratory pattern changes during costovertebral joint movement. J Appl Physiol 1980; 48:862-7. 25. Hammouda M, Wilson WHo Influences that affect the form of respiratory cycle in particular that of the expiratory phase. J Physiol (Lond) 1933; 80:261-84. 26. WeilJV, Byrne Quinn E, Sodal IE, et ale Hypoxic ventilatory drive in normal man. J Clin Invest 1970; 49:1061-72. 27. Kelsen S,Fishman A. In: Fishman AP, 00. Pulmonary diseasesand disorders. NewYork:McGrawHill, 1980; 1787-94. 28. Clark TJ, Freedman S, Campbell EJ, Winn RR. The ventilatory capacity of patients with chronic airways obstruction. Clin Sci 1969; 36:307-16. 29. Potter WA, Olafson S, Hyatt RE. Ventilatory mechanics and expiratory flow limitations during exercise in patients with obstructive lung disease. J Clin Invest 1971; 50:910-9. 30. Pierce AK, Luterman D, Loundermilk J, Blomquist G, Johnson RL Jr. Exercise ventilatory patterns in normal subjects and patients with airway obstruction. J Appl Physiol 25:249-54.
