Bronchial Responsiveness after Human Heart-Lung Transplantation

Bronchial Responsiveness after Human Heart-Lung Transplantation* Allan R. Glanville, M.B., B.S., F.R.A.C.R; ]ames Theodore, M.D., F.C.C.:e;t John C. Baldwin, M.D., F.C.C.:e;+ and Eugene D. Robin, M.D.§

We evaluated bronchial responsiveness to inhaled albuterol (salbutamol), ipratropium bromide, methacholine, and propranolol in eight heart-lung transplant (HLT) recipients 2.3± 1.5 months (mean±SD) (range, 1 to 4.5 months) after HLT. All patients had a restrictive ventilatory defect but none had airRow limitation (FEV/FVC = 0.93 ± 0.05) (range, 0.86 to 0.97). Speci6c airway conductance (sGaw) improved signi6cantly with both albuterol (p
H

eart-lung transplant (ULT) recipients often exhibit marked bronchial hyperresponsiveness (BUR) to inhaled methacholine,':" possibly due to denervation hypersensitivity of muscarinic receptors. 1 Of note, BUR to methacholine is seen in uncomplicated HLT recipients who have stable lung function

and in the absence of airway infection or lung rejection," whereas BHR to exercise is not." Conversely, BHR to ultrasonically nebulized distilled water has been found in the presence of lung rejection," but reports of BHR to inhaled histamine are limited." Selective pulmonary reinnervation by preganglionic vagal efferents as described in dogs" is not excluded by these studies, but the absence of inspirationinduced bronchodilatation in most long-term HLT recipients? and the absence of a cough reflex" are in keeping with the loss of normal neural pathways. *From the Departments of Medicine and Cardiovascular Surgery, Stanford University School of Medicine, Stanford, Calif. f Associate Professor of Medicine. :l:Professor and Chief, Division of Cardiothoracic Surgery, Yale University, New Haven, Conn. §Professor of Medicine and Physiology. This study was supported by grant HL-131OB from the National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md. Dr. Glanville holds a travel grant from the University of Sydney (Australia) Postgraduate Committee in Medicine. Presently Thoracic Physician, Concord Hospital, Sydney, Australia. Manuscript received October 18; revision accepted January 19. Reprint requests: Dr. Theodore, Division of Respiratory Medicine, Stanford University Medical Center, Stanford 94305-5236

1380

airway narrowing to methacholine was seen in 6ve HLT recipients who showed a 29±4 percent (range, 23 to 35 percent) fall in FEV. compared with two patients who did not achieve a plateau with a 47 percent and 63 percent fall in FEV., respectively. These results further our understanding of bronchial responsiveness in the denervated transplanted lung. The 6ndings of stable hyperresponsiveness to methacholine over a prolonged time interval, limited maximal airway narrowing to methacholine, and blockade of methacholine hyperresponsiveness by ipratropium bromide support the concept of denervation hypersensitivity (Chest 1990; 91:1360-66) of muscarinic receptors. ULT = heart-lung transplant; BUR = bronchial hyperresponsiveness; PPU primary pulmonary hypertension; ES = Eisenmenger s syndrome; CMV = cytomegalovirus; ITGV intrathoracic gas volume; sGaw speci6c airway CODductance

=

=

=

Whether neural components regenerate or not, the totally denervated transplanted lungs function adequately in the early postoperative period.v'" To further understand the nature of bronchial responsiveness after HLT, we performed inhalation studies with bronchodilators and provocation agents in the eight recent HLT recipients and nine long-term survivors. We also documented the evolution of BHR to methacholine over time, the degree of maximum airway narrowing achievable with this agent, and we investigated whether the response was receptor mediated. METHODS

Patient Population We studied eight recent HLT recipients (two male, six female) at 2.3 ± 1.5 months (mean ± SO) (range, 1.0 to 4.5 months) after HLT (Table 1). Prior to surgery, all subjects had suffered from irreversible pulmonary hypertension due to primary pulmonary hypertension (PPH) (n = 2) or to Eisenmenger's syndrome (ES) (n = 6). Age at the time of HLT was 31.4 ± 9.4 years (range, 15 to 40 years). Three of these subjects were restudied subsequently with six other longterm HLT patients (in all five male, four female) at 27.4 ± 16.4 months (range, 12 to 51 months) after HLT (Table 2). Antecedent diagnoses were again PPH (n = 3) and ES (n = 6). Age at date of study was 36.3±7.0 years (range, 21 to 44 years). No patient had had a documented respiratory tract infection in the four weeks before the study, but patients 1,3, and 4 (Table 1) had demonstrated a fourfold rise in complement fixation titers to cytomegalovirus (CMV) while patient 6 had had CMV pneumonia diagnosed on open lung biopsy within the first postoperative month. Bronchial Responsiveness after Heart-Lung Transplantation (Glanville et 81)

Table I-Anthropometric and Lung Function Parameters in Recent Heart-Lung Tranaplam Recipientll (n = 8)· Patient/Age, yr/Sex 1I15IF 2/36IF :lI401M 4139/M 5137/F 61201F 7/36/F 8I28IF Mean:31.4 SD:9.4

Prior Diagnosis ES ES ES PPH ES ES PPH ES

TImet

FEV.

FVC

FEV/ FVC

4.0 2.0 1.5 2.0 1.0 4.5 1.5 2.0 2.3 5.1

2.68(90) 2.44(97) 3.94(96) 3.13(83) 2.37(78) 2.12(61) 2.25(92) 2.17(68) 2.64(83) 0.62(13)

3.02(88) 2.51(78) 4.11(75) 3.65(75) 2.56(66) 2.17(51) 2.54(82) 2.24(56) 2.85(71) 0.70(13)

0.89(102) 0.97(124) 0.96(127) 0.86(112) 0.92(119) 0.97(120) 0.88(112) 0.97(122) 0.93(117) 0.05( 8)

*All lung function parameters are expressed as value (percentage predicted). FEV. = forced expiratory volume in 1 s (L); FVC = forced vital capacity (L); ES = Eisenmenger's syndrome; and PPH = primary pulmonary hypertension. tMonths after heart-lung transplant. The operative procedure and immunosuppressive regimen employed have been described in detail. II At the time of study all patients were taking a maintenance immunosuppressive regimen that comprised cyclosporine (to maintain a trough serum level of 75 to 100 ng/ml by radioimmunoassay), azathioprine (I to 1.5 mWJ
Protocol All patients in Table 1 followed an identical protocol except for the timing of their initial study which depended on the duration of their inhospital stay. Commencing one week after hospital discharge (range, 21 to 90 days after HLT), single-blind studies were performed on a weekly basis for four weeks. The order of agents given was albuterol (salbutamol), ipratropium bromide, methacholine, and propranolol. The majority of patients also performed a standard methacholine inhalation test after pretreatment with ipratropium bromide in the last week of the study Two other stable HLT recipients (Table 2) also performed methacholine tests with and without pretreatment with ipratropium bromide. Spirometric parameters (Table 1) were measured on a waterseal spirometer (Collins DS 520) and results were expressed as percent predicted according to characteristics of the recipient utilizing predictions of Morris et al.' 2

Bronchial responsiveness to the inhaled agents was determined on the Jaeger body test constant volume plethysmograph, the details of which have been described previously,' Normal values for bronchial responsiveness to methacholine using this technique have been described.' Prior to each study, baseline airway resistance was determined during tidal respiration from a minimum of six resistance loops. Intrathoracic gas volume (ITGV) was then measured in standard fashion permitting the calculation of specific airway conductance (sGaw). Forced expiratory volume in 1 s (FEV.) was then measured as the best of three efforts, from standard time volume curves. The sGawand FEV. maneuvers were repeated after inhalation of 1 ml of normal saline solution (NaCI 150 mrnol/L) and if there was no significant change, the study proceeded. On separate days, albuterol, 400 tL~ (0.5 percent solution) and ipratropium bromide, 500 tLg(0.025 percent solution) were inhaled and serial measurements of sCaw and FEV. were performed every three to six minutes for a period of 60 minutes. Results were expressed as the percentage change from baseline sGa\\' and FEV I with respect to duration from drug delivery. Provocation studies to methacholine and propranolol were performed and analyzed as described previously for methacholine.' The initial doses of methacholine and propranolol were 0.05 mg and 0.03 mg, respectively. The provocation dose that caused a 50 percent fall in sGaw (PD50 sGaw) and the provocation dose that

Table 2-Arathropometric and Lung Function Parameters in Long-term Survivors ofHeart-Lung Transplantation (n=9)· Patient!Age, yr/Sex 2Al37/F 3A/41/M 5AfJ8IF 9fJ4/F 10144IM 11142/M 12132/M 1:lI41/F 14121/M Mean:36.3 SD: 7.0

Prior Diagnosis ES ES ES ES ES ES PPH PPH PPH

TImet 12 14 12 12 51 51 24 36 35

27.4 16.4

FEV.

FVC

FEV/ FVC

2.70(107) 3.00( 73) 3.10(103) 2.80( 91) 2.85( 75) 2.51( 72) 3.50( 98) 1.80( 62) 4.00( 83) 2.92( 85) 0.62( 16)

3.00(93) 4.80(88) 3.70(97) 3.10(79) 3.45(68) 2.91(65) 3.90(88) 3.10(82) 4.70(77) 3.63(82) 0.72(11)

0.90(115) 0.63( 83) 0.83(107) 0.90(116) 0.83(110) 0.86(113) 0.92(116) 0.58( 75) 0.85(109) 0.81(105) 0.12( 15)

*A1llung function parameters are expressed as value (percentage predicted). Patients 2A, 3A, and SA are the same as patients 2,3, and 5 in Table 1. FEV) = forced expiratory volume in 1 s (L); FVC = forced vital capacity (L); ES = Eisenmenger's syndrome; and PPH = primary pulmonary hypertension. tMonths after heart-lung transplant. CHEST I 97 I 6 I JUNE, 1990

1381

Table 3-BaseUne Lung Function Prior to Each Inhalation Study in Recent Heart-Lung Tranaplant RecipieratB* sGaw

FEV. Patient

As

IB

MC

P

CV

As

IB

MC

P

CV

1 2 3 4 5 6 7 8 Mean: SD:

2.65 2.65 3.70 2.75 2.30 2.00 2.15 2.15 2.54 0.54

2.60 2.45 3.80 3.00 2.60 2.05 2.20 2.10 2.60 0.58

2.70 2.60 3.90 2.90 2.65 1.90 2.20 2.20 2.63 0.61

2.50 2.50 3.90 3.10 2.55 2.05 2.20 2.25 2.63 0.60

3 3 3 5 6 4 1 3 4 2

0.35 0.28 0.27 0.24 0.16

0.27 0.29 0.15 0.23 0.20

0.35 0.35 0.17 0.25 0.20 0.25 0.42 0.18 0.27 0.09

0.25 0.26 0.09 0.23 0.29 0.36 0.29 0.28 0.26 0.08

16 13 38 4 28 23

0.23

0.36

0.25 0.33 0.26 0.06

0.30 0.15 0.24 0.07

22 33 22

11

·Patient number refers to Table 1. FEV. = forced expiratory volume in 1 s (L); sGaw=speci6c airway conductance (s-·.cm H 2O-·); As = albuterol (salbutamol): IB = ipratropium bromide; MC = methacholine; P = propranalol; and CV = coefficient of variation (percent). caused a 20 percent fall in FEV. (PO 20 FEV.) were determined by linear interpolation from the log dose vs response graph. No extrapolations were made. Methacholine provocation tests were also performed ten minutes after the inhalation of 500 ....g of ipratropium bromide and the P050 sGaw and the PD20 FEV. were calculated in identical fashion. Maximal response to methacholine was determined in a similar fashion commencing with a lower dose (0.0125 mg) because a number of HLT recipients bronchoconstrict with a dose of 0.05 mg. Doses were doubled until a plateau response was determined (defined by no further fall in FEV. with two subsequent doses) or until FEV. fell to less than 1.0 L.

Statistics A two-way repeated measured analysis of variance (ANOVA) was used to assess the group and individual response to each bronchodilator. Comparison of the group mean response to either drug at each time interval was made with a Mann-Whitney U test. Paired Student's t test was used to assess the evolution of individual BHR to methacholine over time and the effect of prior inhalation of ipratropium bromide. RESULTS

Baseline Lung Function

All recent HLT recipients (Table 1) had a restrictive ventilatory defect as previously reported, 10.13 but none of them had evidence of airflow limitation at the time of the stud}: Values of baseline FEV1 and sGaw obtained prior to each inhalation study (Table 3) were essentially stable. The coefficient of variation for FEV 1 was 4 ± 2 percent (range, 1 to 6) and for sGaw it was 22± 11 percent (range, 4 to 38) which are within the reported normal range. 14.15 The majority ot1ong-term survivors (Table 2) also had a mild restrictive pattern. Patients 2A and 5A demonstrated an expected improvement in FEV1 and FVC when compared with values in Table 1. Patients 3A and 13 had mild-moderate airflow limitation, stable over the previous 12 months in patient 13 and progressive over the previous four months in patient 3A, who had a lower FEV 1 than at first study {Table 1). Values of FEVI and sGaw obtained prior to methacholine inhalation and ipratropium bromide/methacholine 1382

inhalation {Table 4) were similar except for patient 4 who showed an increase in FEV1 reflecting improvement of the postoperative restrictive defect in the interval between the studies, in this case three weeks (which was the longest interval between tests). Response to Bronchodilators

Neither albuterol nor ipratropium bromide caused a significant improvement in FEV 1 in recent HLT recipients. However, sGaw did improve significantly (p
Individual dose-response curves to methacholine have been reported previously; 1 hence, the current results are shown in brief (Fig 2). No significant 249 - - - - - - - - - - - - - - - - -

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z ......

299

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129

6

12

18

24

39

36

42

48

54

68

MINUTES AFTER TREATMENT FIGURE 1. The effect of inhaled albuterol (salbutamol) (400 ....g) and ipratropium bromide (500 ....g) on specific airway conductance (sGaw) in recent heart-lung transplant recipients (n = 8). Response to albuterol (upper curve) is greater than to ipratropium bromide (lower curve) (p
Table 4-8tuleUne Lung Function prior to Inhalation of Methacholine and Methacholine Preceded

199

by Ipratropium Bromide·

19

sGaw

FEV.

CD

e

9.19

'1.'11

...

.

RECENT K.T

UN; TERt1

aa

IBIMC

Me

IB/MC

2A 4

2.70 2.90 3.10 1.90 2.20 2.20 2.90 2.50 2.55 0.42

2.90 3.45 3.00 2.10 2.00 2.25 2.85 2.40 2.62 0.51

0.35 0.25 0.20 0.25 0.42 0.18 0.12 0.25 0.25 0.09

0.36 0.32 0.22 0.30 0.32 0.20 0.12 0.26 0.26 0.08

6 7 8 10 11 Mean: SD:

K.T

*Patient number refers to Tables 1 and 2. FEV, = forced expiratory volume in 1 s (L); sGa\v = specific airway conductance (s '.em 1120 -I); Me = methacholine; and IB = ipratropium bromide.

difference was demonstrated between BUR in recent HLT recipients or long-term survivors (PD20 FEV.: 1.73 ± 4.46 mg vs 0.37 ± 0.82 mg: p = ns), Only patient 3 did not respond to the doses employed. Omitting his results, PD20 FEV. for the recent HLT recipients was 0.15 ± 0.17 mg and the PD50 sGaw was 0.07 ± 0.03 mg. We did not find a significant correlation between FEV. (percent predicted) and PD20 FEV. or between sGaw and PD50 sGaw Conversely only patient 6 responded to inhaled propranolol (PD20 FEV. = 1.65 mg and PD50 sGaw= 1.10 mg) with the doses employed.

u ~

Me

5A

FIGURE 2. Bronchial hyperresponsiveness to inhaled methacholine (MC) in eight recent heart-lung transplant (HLT) recipients and nine long-tenn survivors of HLT. PD20 FEV,: provocation dose of methacholine (mg) that causes a 20 percent fall in FEV, from baseline.

12.75

Patient

Effect of Pretreatment with lpratropium Bromide

Pretreatment with inhaled ipratropium bromide (500 JLg) blocked the response to a standard methacholine challenge (Table 4, Fig 3). The PD50 sGaw with and without ipratropium bromide was 6.68 ± 5.14 mg vs 0.07±0.3 mg: p<0.OO5; and the PD20 FEV. was 11.34±3.02 mg vs 0.14±0.16 mg: p<0.OO5. Maximal Response to Methacholine

Five patients established a plateau with a mean fall in FEV. of 29±4 percent (range, 23 to 35 percent)

(A)

(B)

12.75

10.4

6.35

6.35

3.15

3.15 5 11

6

1.55

U

1.55

2

!.-

E ~

<

ca

FIGURE 3 (A and B). The effect of pretreatment with inhaled ipratropium bromide (IB) (500..,g) on response to inhaled methacholine (MC) in heart-lung tranplant recipients (n = 8). PD50 sGaw = the provocation dose of inhaled methacholine (mg) that causes a 50 percent fall in specific airway conductance; PD20 FEV. = the provocation dose of inhaled methacholine (mg) that causes a 20 percent fall in forced expiratory volume in 1 s. Patient number refers to Tables 1 and 2. The horizontal bars show the mean PD50 sGaw and PD20 FEV. with and without IB~ respectively.

0.75

> w

0.75

I.L

Ie0

0.35

0.35

0.15

0.15

0.05

0.05 MC

IB/MC

MC

CL

IB/MC

T

T

p < 0.005

p < 0.0005

CHEST I 97 I 6 I JUNE, 1990

1383

199

.... =>

,....-.,.

69

t.J

4ra

"-'

I.LI

I.&...

....J ....J

a:

e

CD

...-t

::::>

I.&... ~

l.LJ La... cg N

29

C

9.91 9.94 9.99 9.19 9.4 9.8

1.6 3.2 6.4 12.8

CUMULATIUE METHACHOLINE DOSE

(mg)

FIGURE 4. Maximal response study to inhaled methacholine in heart-lung transplant recipients (n = 7). FEV. = forced expiratory volume in 1 s (L).

(Fig 4). Two patients showed marked bronchoconstriction and did not achieve a plateau with a fall in FEV. of 47 percent nad 63 percent, respectively. Maximal response was not related to duration after HLT baseline FEV. (percent predicted), or PD20 FEV.. ' Evolution of BHR to Methacholine Seven HLT recipients underwent repeated methacholine studies 11.3±6.0 months (range, 6 to 24 months) later (Table 5 and Fig 5). Five patients showed no change in PD20 FEV. over time. Patient 3, who had developed mild asymptomatic airflow limitation and who had recommenced smoking in the interval, showed a marked fall in PD20 FEV i - Conversely; patient 9, who was taking high-dose aerosolized beelomethasone diproprionate at the time of the second study, showed a marked improvement in PD20 FEV. although not into the normal range. DISCUSSION

These studies extend our knowledge of the bronchial responsiveness of the denervated transplanted lung. Table 5 - Evolution of Bronchial Hyperresponsivenea to Methacholine after Heart-Lung Transplantation· Second Study

First Study

.

Patient Timet 2 3 5 9 11 13 14 Mean: SD:

2 2 1 4 45 12 27 13.3 16.8

FEV. 2.60 3.90 2.65 2.35 2.40 2.50 4.00 2.91 0.72

.

PD20FEV. Timet 0.12 12.75 0.07 0.05 0.12 0.05 0.31 1.92 1.39

12 14 12 12 51 36 35 24.6 16.0

FEV.

PD20FEV.

2.70 3.00 3.10 2.80 2.50 1.80 4.00 2.84 0.66

0.01 0.04 0.13 2.55 0.09 0.01 0.16 0.43 0.94

*Patient number refers to Tables 1 and 2. FEV. = forced expiratory volume in 1 s (L); PD20 FEV. = provocation dose of methacholine (mg) that causes a 20 percent fall in baseline FEV •. tMonths after heart-lung transplant.

1384

19

~

n,

9.19 9.91

II

METHACHOLINE CHALLENGE FIGURE 5. Evolution of bronchial hyperresponsiveness to methacholine (Me) in heart-lung transplant recipients (n = 7). PD20 FEV. = provocation dose of methacholine that causes a 20 percent fall in baseline forced expiratory volume in 1 s; I = time of first methacholine challenge; and II = time of second methacholine challenge.

They complement previous experiments where the effects of abolishing vagal tone on lung reflexes, airway resistance, and airflow parameters have been studied in humans 13 • 16- 18 and in animals'v" after vagal section. Pulmonary autotransplantation and allotransplantation, however, produce total pulmonary denervation by complete section of all neural pathways. Following pulmonary autotransplantation, neural regeneration occurs by about six months in dogs6.~22 and eight months in baboons." Despite regeneration, neural function remains impaired20-22 as shown by the loss of the Hering-Breuer reflex. Toour knowledge, no human or animal studies to date have evaluated the neuroanatomic sequelae of pulmonary allotransplantation, but there is a fundamental difference between neural regeneration and de novo innervation of an allograft. Our previous work':" suggests that normal pulmonary innervation is not established even several years after human HLT, possibly due to the gross disruption of nerve trunks at the time of surgery Nevertheless, to minimize the possibility of pulmonary reinnervation operating as a confounding variable in our recent HLT group, studies were performed as close to the time of surgery as feasible and within the time frame in which denervation would be expected. 24 In the recent HLT group the magnitude of the bronchodilator response to both inhaled albuterol and ipratropium bromide, as measured by the change in sGa~ was significantly greater than that described in normal subjects. 14 The response to albuterol points to the preservation of bronchial smooth muscle tone despite denervation but obviously cannot distinguish whether tone is due to intrinsic properties of smooth muscle or the autonomous function of airway ganglia. Bronchial Responsiveness after Heart-Lung Transplantation (Glanville et 81)

The response to inhaled ipratropium bromide, however, is more in keeping with the presence of intact airway ganglia and postganglionic parasympathetic efTerents as demonstrated in animal models following The nature section of preganglionic efferents. ~.21.23.25 of the response to the bronchodilators is worthy of comment. There was a marked discordance between improvement seen in sGaw and the lack of improvement in FEV I. We attribute this to the presence of a restrictive defect in the immediate postoperative period related to reductions in chest wall mobility and respiratory muscle strength. 13 As a result, in our group, the maximum possible mean increase of FEV 1 was 7 percent at which time the group mean FEV1IFVC would have been 1.00. None of the patients had airflow limitation, and improvements in FVC were not seen with bronchodilator therapy. As well, sGaw and FEV 1 measure different events, are measured at different lung volumes, and involve tidal and forced maneuvers, respectively, the latter involving the possibility of airway compression. However, How volume loops performed prior to each study did not demonstrate a Howplateau that may occur with variable intrathoracic airflow limitation at the site of the tracheal anastomosis.26 The marked BHR to methacholine has been discussed previously. 1-3 These new studies show that it is, in the main, relatively stable over time despite the fact that HLT recipients are prone to infection, pulmonary rejection, and the development of obliterative bronchiolitis and bronchiectasis. 27-31 The presence of limited airway narrowing to methacholine confirms that the majority of HLT recipients behave more like normal but hypersensitive patients than asthmatics." The finding of major bronchoconstriction in two patients remains unexplained but did not appear to be related to the presence of underlying airflow limitation. We do not know whether the lungs transplanted into these individuals were harvested from asthmatic donors. Whereas maximal airway narrowing in asthmatics is thought to be related to uncoupling of bronchial smooth muscle from surrounding lung tissue due to peribronchial edema, this finding has not been observed in open lung biopsy samples or postmortem tissue of HLT recipients" except in the early postoperative period when it is due to lymphedema. Inflammatory cell infiltrates are seen in the peribronchial and peribronchiolar spaces in pulmonary rejection." but to date, the finding of maximal airway narrowing does not appear to be predictive of the development of obliterative bronchiolitis. While the mechanism of BHR to propranolol is complex and not fully understood, several studies have demonstrated that there is a quantitative difference in response between asthmatics, normal controls, and patients with chronic airflow limitation. In the study

of Woolcock et al,35 all of the asthmatics tested had a PD20 FEV. of less than 12 umol (3.60 mg) of propranolol. Whereas HLT recipients are hyperresponsive to methacholine in the asthmatic range, they do not appear to respond to inhaled propranolol. Of interest, our lone responder had recovered from CMV pneumonia and had the lowest FEV I and FVC of the group tested. Patients who had seroconverted for CMV27 could not be distinguished by their responsiveness. In summary, we have confirmed the presence of BHR to methacholine after HLT, described its evolution with time, and described the finding of limited maximal airway narrowing with this agent. We have described the preservation ofbronchial smooth muscle tone in the denervated lung and found significant reductions in tone with both albuterol and ipratropium bromide. Ipratropium bromide was shown to block the response to methacholine in keeping with a receptor-mediated phenomenon. Heart-lung transplant patients did not respond to inhaled propranolol. We conclude that these results support the concept of denervation hypersensitivity of muscarinic receptors. To what degree the physiologic behavior observed may be attributed to the presence of functioning airway ganglia within the allograft bears further study. ACKNOWLEDGMENTS: The authors thank Mr. James Harvey and Ms. Sue Dollarhide who assisted in the performance of the pulmonary function studies described herein and Dr. Matthew Peters for data processing.

REFERENCES 1 Glanville AR, Burke CM, Theodore J, Baldwin JC, Harvey J, Van Kessel A, et ale Bronchial hyperresponsiveness af\er human cardiopulmonary transplantation. Clin Sci 1987; 73:299-303 2 Banner NR, Heaton R, Hollingshead L, Guz A, Yacoub MH. Bronchial reactivity to methacholine af\er combined heart-lung transplantation. Thorax 1988; 43:955-59 3 Higenbottam T, Jackson M, Rashdi T, Coutts C, Stewart S, Wallwork J. Lung rejection and bronchial hyperresponsiveness to methacholine and ultrasonically nebulized distilled water in heart-lung transplantation patients. Am Rev Respir Dis 1989; 140:52-7 4 Glanville AR, Gabb GM, Theodore J, Robin ED. Bronchial responsiveness to exercise after human cardiopulmonary transplantation. Chest 1989; 96:281-86 5 Maurer J, McLean PA, Cooper J, Chamberlain D~ Grossman RF, Zamel N, et ale Airway hyperreactivity in patients undergoing lung and heartAung transplantation. Am Bev Respir Dis 1989; 139:1038-41 6 Edmunds LH jr, Graf PO, Nadel JA. Reinnervation of the reimplanted canine lung. J Appl Physiol1971; 31:722-27 7 Glanville AR, Yeend RA, Theodore J, Robin ED. The effect of single respiratory maneuvers on specific airway conductance in heart-lung transplant recipients. Clin Sci 1988; 74:311-17 8 Higenbottam T, Jackson M, Woolman ~ Lowry R, Wallwork J. The cough response to ultrasonically nebulized distilled water in heart-lung transplantation patients. Am Rev Respir Dis 1989; 140:58-61 9 Theodore J, Morris AJ, Burke CM, Glanville AR, Van Kessel A, Baldwin JC, et aI. Cardiopulmonary function at maximum CHEST I 97 I 8 I JUNE.1980

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Bronchial Responsivaness after Heart-llqJ Transplentation (Glanville et 81)