Pediatric Pulmonology 11 :49-55 (1991)
Pulmonary Function in Newborns After Repair of Congenital Diaphragmatic Hernia Don K. Nakayama, MD,’ Etsuro K. Motoyama, M D , * , ~ Rebecca L. Mutich, R T , ~and Anastassios C. Koumbourlis, M D ~ Summary. Congenitaldiaphragmatic hernia (CDH) is associated with pulmonary hypoplasiathat limits survival, but the nature and extent of pulmonary dysfunction in neonates with CDH have not been studied. We performed pulmonary function tests (PFTs) in eight intubated infants who survived neonatal repair of CDH (wt, 3.33 ? 0.15 kg; age, 20.1 i 2.7 d; mean S.E.M.). PFTs obtained from six full-term infants (wt, 3.56 5 0.10 kg; age, 25.0 i 3.3 d) with no respiratory illness served as controls. The deflation flow-volume curve technique produced maximum expiratory flow-volume (MEFV) curves, giving reproducible measurements of forced vital Respiratory system capacity (FVC) and maximal expiratory flow at 25% of FVC (MEF,,). compliance (Crs) and resistance (Rrs) were obtained with a modified passive mechanics technique. In seven of eight infants PFTs were repeated after nebulized bronchodilator (0.1Yo isoetharine). In neonates surviving CDH repair, as compared to those with normal lung function, FVC was significantly reduced (20.78 ? 3.32 vs. 39.83 ? 3.30 mL . kg-’, P < 0.05). MEF, was also markedly reduced (8.41 2 1.46vs. 32.32 -t 4.35 mL . kgg’ . s-’, P < 0.05), indicating lower airway obstruction. After administration of nebulized bronchodilator, PFTs showed significant increases from control values in both FVC (15.9%) and MEF, (200%) without changes in Crs and Rrs. These findings indicate that neonates with CDH have restrictive lung defects, reflecting hypoplasia.After surgical repair and mechanical ventilation airway reactivity develops, primarily in smaller airways, and this may complicatethe postoperativecourse. Pediatr Pulmonol. 1991; 11:49-55.
*
Key words: Deflation flow-volume curves; modified passive mechanics technique; respiratory system compliance; resistance; bronchodilator response; lower airway obstruction: restrictive defects.
INTRODUCTION
commonly after a severe form of respiratory distress syndrome (RDS) .* Information on the extent of pulmonary dysfunction in CDH, particularly among survivors during infancy, is difficult to quantify. Recent studies by Bohn and coworkers3 and Sakai and colleaguesy indicate that changes in pulmonary mechanics after surgical repair of CDH influence survival. To characterize the respiratory
Pulmonary hypoplasia is a characteristic of congenital diaphragmatic hernia (CDH). Clinically, inability to maintain adequate ventilation in newborn babies with CDH reflects severe pulmonary hypoplasia. Postmortem studies in such infants document the anatomic features of pulmonary hypoplasia and pulmonary hypertension: decreased numbers of bronchial generations, alveoli ,2,3 and pulmonary vessel^,^*^ and increased muscularity of the pulmonary vascular bed.6 The mortality of CDH From the Departments of Surgery, ’ Anesthesiology,* and Pulremains high, ranging from 50% to 80%, despite ad- m ~ n o l o g yChildren’s ,~ Hospital of Pittsburgh, and the Departments of vances in neonatal intensive care.’ Survivors have mar- Surgery,’ Anesthesiology,’ and Pediatrics,3 University of Pittsburgh ginal respiratory reserve and often require prolonged School of Medicine, Pittsburgh, Pennsylvania. mechanical ventilatory support. Chronic respiratory in- Received January 25, 199 1; (revision) accepted for publication March sufficiency may result as a possible consequence of 11. 1991. pulmonary hypoplasia as well as oxygen toxicity and barotrauma, and is the major cause of late morbidity and Presented at the 1990 World Conference on Lung Health, May 23, m ~ r t a l i t y .Clinically, ~ patients who enter this stage of 1990, Boston, Massachusetts. respiratory care closely resemble premature infants with Address correspondence and reprint requests to Dr. D.K. Nakayama, bronchopulmonary dysplasia (BPD), a progressive dis- Department of Surgery, Children’s Hospital of Pittsburgh, 3705 Fifth ease of the lung parenchyma and airways occurring most Avenue at DeSoto Street, Pittsburgh, PA 15213-3417.
’
0 1991 Wiley-Liss, Inc.
50
Nakayarna et al.
pathophysiology of CDH further, we performed pulmonary function tests (PFTs) in a group of infants less than 1 month of age who survived surgery for CDH as neonates. Our goal was to address the following questions: 1) What aspects of pulmonary dysfunction characterize CDH in the newborn? and 2) Do babies surviving CDH repair develop bronchial reactivity, an early feature of BPD? MATERIALS AND METHODS Patients This study was approved by the institutional review board for research involving human subjects. Informed consent was obtained from the parents of all infants. Fourteen newborn infants were studied, either in the operating room or in the neonatal surgical intensive care unit, all undergoing endotracheal intubation and mechanical ventilation at the time. Twelve infants were admitted to the surgical service for operative repair of CDH from December 1988 through October 1989. Four died within days of birth and were not studied. Eight survived at least 4 weeks and formed the study group; all exhibited respiratory distress during the first 6 hours of life, and all underwent transabdominal repair of the hernia within 12 hours. The patients were given PFTs within 30 days of birth; tests were deferred until the clinical course was sufficiently stable to allow safe manipulation of airway pressure. Six full-term infants less than 30 days of age, free from respiratory illness, served as controls. They were undergoing general endotracheal anesthesia for repair of an inguinal hernia of a size not expected to compromise respiratory function. Clinical Management All patients were treated in a consistent fashion. While being ventilated mechanically during surgery and after operation, all received fentanyl citrate (10 pg kg-' h-', initially, and then 1-2 pg kg-' h-') and pancuronium bromide (100 pg - kg- = h-'). Inspired oxygen fraction (Fio2) and ventilator settings were adjusted to maintain optimal blood gas levels, based upon arterial blood gas determinations on samples drawn from a postductal site, generally through an umbilical artery catheter. We attempted to keep oxygen saturation (So) above 95%, arterial oxygen tension between 100 and 120 mm Hg, and maintain hyperventilation with arterial pH above 7.5 and Pk0, below 35 mm Hg. Infants with acidosis, refractory to ventilatory changes, received sodium bicarbonate (1-2 mEq kg- ') to maintain systemic alkalinization. Tolazoline (1-2 mg kg-' by slow push, followed by 2 mg . kg-' h-') and prostaglandin El (0.1 pg . kg-' min-I) were given by intravenous infusion to selected babies who had postductal arterial
'
1
hypoxemia unresponsive to changes in ventilatory management. Modest fluid restriction (80-100 mL . kg-' d- ') was maintained. Babies who became hypotensive were given inotropic infusions (dopamine, 2-20 pg * k g ' * min- , and/or dobutamine, 2-20 pg * kg- * min- ) as needed. Patients in whom hypoxemia persisted despite all conventional methods of support outlined above received extracorporeal membrane oxygenation (ECMO). We recorded the following measurements and indices during the clinical course, including those obtained immediately after operation and at the time of pulmonary function testing: postductal arterial blood gases (pH, Pao2, and Pa,& alveolar to arterial oxygen tension difference (P,A-a,O,)at Fio2 = 1.O; the ratio of arterial to alveolar oxygen tension (a/A ratio), calculated as postductal Pao,/(713 - PacOz X 0.8) X Fio2; and indices of ventilation, including respiratory rate, peak inspiratory , and mean airway pressures during the ventilatory cycle. Control infants were ventilated by hand with peak inspiratory pressures of 12-20 cm H,O and a positive end-expiratory pressure of 3-6 cm H20. Inspired oxygen fraction was adjusted to maintain optimal Sao2 on pulse oximetry .
'
'
Procedures Pulmonary function was evaluated by deflation flowvolume (DFV) curve analysis, a technique used to obtain maximum expiratory flow-volume (MEFV) curves. This technique is described in detail elsewhere. l o Briefly, it involves inflating the lungs of intubated, paralyzed subjects three times to an airway pressure of +40 cm H 2 0 (defined as total lung capacity, TLC) to set a consistent volume history. The lungs are then deflated from TLC through an endotracheal tube and No. 0 Fleisch pneumotachograph by sudden exposure to a negative pressure reservoir of -40 cm H,O until expiratory flow ceases, or as long as 3 s (FEV,). The volume at cessation of flow, or FEV,, is defined as residual volume (RV). The flow signal and the corresponding volume by integration are displayed on a storage oscillograph as an MEFV curve. The total expired volume displayed by the MEFV curve provides an estimate of forced vital capacity (FVC). The maximal expiratory flow at 25% of FVC from residual volume (MEF,,), which reflects the conductance of airways toward the periphery of the lungs, is obtained from the MEFV tracing. DFV curves may first gradually increase in size due to the initial recruitment of air spaces by manual expansion. Ultimately, superimposable curves are obtained, with negligible within-subject coefficients of variation. The DFV maneuver is repeated until two or three identical curves are obtained, and those values are used. The infants with CDH underwent DFV maneuvers in
Pulmonary Function After CDH Repair
51
TABLE 1-Clinical Characteristics of Patients Patient no.
Agea (d)
Weighta (kg)
CDH group 1 30 3.4 2 19 2.45 3 20 3.0 4 21 3.36 5 18 3.67 6 30 3.59 I 6 3.7 8 17 3.49 20.1 3.33 Mean S.E.M. 2.7 0.15 Control group (n = 6) 25 3.56 Mean S.E.M. 3.3 0.10
Gestational age (wk)
1 min
5 min
PTX
40 35 40 36 40 40 39 36
3 8 1 3 3 5 5 5
5
Yes Yes No No Yes Yes,PIE Yes No
"Ore
8 2 3 5 5
7 I
ECMO (days on)
7 6 3 7 -
9
-
Outcome Died Died Lived Lived Lived Lived Lived Lived
PTX, pneumothorax; PIE, pulmonary interstitial emphysema; ECMO, extracorporeal membrane oxygenation; CDH, congenital diaphragmatic hernia. aAge and weight are those at the time of pulmonary function testing.
three test conditions designed to detect the presence of reversible bronchoconstriction: 1) baseline; 2) after 5 min of ventilation by anesthesia bag with aerosolized normal saline solution (control); and 3) after 8 min of ventilation by bag with nebulized bronchodilator (0.25 mL 1% isoetharine in 3 mL normal saline). When the infants were not paralyzed and their activity interfered with manual ventilation and DFV curve maneuvers, fentanyl (1-2 p,g . kg-I) and atracurium (0.5 mg kg-I) a shortacting, nondepolarizing muscle relaxant, were given to facilitate the study. When FVC changed between saline control and postbronchodilator values, DFV curves were superimposed at TLC, and postbronchodilator MEF,, values were measured at 75% FVC from TLC for saline control. This was based on the assumption that TLC after bronchodilatation in infants, as in children and adults, changes little or even decreases after bronchodilatation. Changes of flows at this volume (MEF2sisc,v)were expressed as the ratio of MEF,,isoVafter bronchodilator to control MEF,, values. Passive expiratory flow-volumes curves were obtained using a modification of the method described in detail by LeSouef et al." After inflating the lungs to TLC, hand ventilation kept the lungs under 10 cm H 2 0 pressure for a few seconds, long enough to allow airway occlusion pressure (Pao) to plateau. A slide valve was then rapidly opened for 1-2 s to allow passive expiration through a pneumotachograph to functional residual capacity (FRC), or relaxation volume, V,. The resultant passive partial flow-volume curves displayed on the oscilloscope allowed calculation of respiratory system compliance (Crs) and resistance (Rrs). Flow versus volume plotting usually produces a straight line after an initial peak. 4
'"
When the straight line portion of the flow-volume curve is extrapolated back to zero volume, the flow-axis intercept gives the estimated flow (Vo) appropriate for the Pao. Rrs = Pao/V0; Crs is obtained by dividing the exhaled volume (V,) by Pao (10 cm H20). Three passive expirations were analyzed in each subject, and mean values were used. Values are expressed as mean ? standard error of the mean (S.E.M.). To compare infants of different body size, we normalized the flow and volume values, dividing them by body weight. MEF,, was also normalized by its ratio to FVC. Statistical comparison between the study group and control patients was performed using Student's unpaired t-test. Statistical comparison of the data before and after bronchodilator administration was performed using Student's paired t-test. Relationships among variables and FVC, MEF,,, and MEF,,/FVC were determined by multiple correlation. A probability value of less than 0.05 was considered significant. RESULTS
Table 1 summarizes the clinical characteristics and early postnatal and postoperative course of all babies with CDH and of control infants. All babies with CDH subsequently required intensive ventilatory care of long duration (range, 6 to 360 d; mean k S.E.M., 69.6 k 41.7 d). The maximum respiratory rate during mechanical ventilation was 79.6 +- 9.2 breaths per minute; the maximum peak inspiratory pressure during ventilatory support was 41.1 k 3.7 cm H20. Fio, exceeded 0.90 for 47.3 5 15.4 h and 0.50, for 227 k 88.9 h. After operation, a/A ratio was 0.29 ? 0.09; P,A.a102,476 k
52
Nakayama et al.
TABLE 2-Pulmonary Function Data in Eight Newborn Infants After CDH-Repair Flow-Volume Technique FVC (mL . kg-l) Pt. no.
MEF25 (mL
. s-I . kg-I)
%
Control
1 2.8 2 12.7 3 32.3 4 19.3 5 20.1 6 24.0 7 21.8 8 26.6 Mean 20.8* S.E.M. 3.3 Control group (n = 6) Mean 39.8 S.E.M. 3.3
Post-BD 3.2 17.1 36.7 23.5 24.2 28.4 21.8 31.5 24.1** 3.6
Change 14.3 34.6 13.6 21.8 11.4 18.3 0 18.4 15.9
Control
Post-BD
0.8 6.1 11.3 8.9 5.7 8.9 13.0 12.6 8.4* 1.4
1.8 27.8 26.7 22.6 34.6 25.6 18.4 44.4 25.2** 4.3
32.3 4.4
Obtained by Deflation
% Change
125 356 I36 154 525 128 42 252 200
MEF25/FVC (s-') %
Isovolume
Control
Post-BD
Change
2.4 4.56 2.36 2.53 6.05 2.88 I .42 3.52 3.22 0.52
0.27 0.48 0.35 0.46 0.28 0.37 0.47 0.47 0.39" 0.03
0.3 I 0.7 1 0.5 5 0.4 I 0.78 0.48 0.66 0.82 0.59** 0.06
14.8 47.9 57.1 - 10.9 I78 29.1 40.4 74.5 51.3
0.84 0.12
CDH, congenital diaphragmatic hernia; FVC, forced vital capacity; MEF25, maximal expiratory flow at 25% of FVC from residual volume; isovolume, ratio of MEF25 after bronchodilator to control values; control, baseline values; post-BD, values taken after administration of neubulized 0.1% isoetharine; % change, percent change from control to post-BD. *P < 0.05, CDH compared with control group. **P < 0.05, CDH, post-bronchodilator compared with control (post-saline) values.
58 mm Hg. At the time of pulmonary function testing both parameters had improved (aiA ratio, 0.37 k 0.05; PLA.alOl,164 rt 31). At the time of our study chest roentgenographs were free from acute changes such as pneumothorax and atelectasis. Volume of the hemithordx, ipsilateral to the hernia, was typically smaller than the contralateral side. Chronic changes in the chest film were not yet present at the time of pulmonary function testing. However, four of eight patients later developed coarse parenchymal densities with radiolucent vacuoles, fibrous strands, and cystic areas consistent with changes seen in moderate to advanced stages of BPD. The results from DFV curve studies, summarized in Table 2, reveal significant decreases in both lung volume and airflow measurements in CDH. FVC in patients with CDH was 52.7% of that in control infants ( P < 0.05), indicating a marked restrictive defect. MEF,, in babies with CDH was 26.0% of that in controls ( P < 0.05). When MEF,, was expressed in terms of MEFz5/FVC, an index of upstream airway conductance, l 2 the mean value for babies with CDH was 46.4% of that in controls (P < 0.05), indicating the presence of lower airway obstruction in peripheral airways. Administration of nebulized bronchodilator caused significant increases in FVC (15.9%), MEF2, (200%), and MEF,,/FVC (51.3%) (all, P < 0.05). Figure 1 gives an example of a DFV study in one patient, illustrating the effects of bronchodilators upon measured parameters. We observed no significant changes in DFV curves under baseline conditions and after administration of normal saline aerosol; a finding we noted in previous studies. l o
Fig. 1. Deflation flow-volume curves in a 20-day-old, 3.0 kg congenital diaphragmatic hernia (CDH) patient (shaded curves), and a 20-day-old, 3.9 kg normal infant (outer curve). Volumes to determine maximal expiratory flow at 25% of forced vital capacity (MEF,,) for each patient are shown as dashed vertical lines. Curves for the CDH patient are obtained after normal saline aerosol (post-saline) and after bronchodilator (post-BD). After bronchodilator there was a small increase in FVC and a 136% increase in MEF,, (dashed line). The shape of the curve also changed, becoming less convex to the volume axis, indicating an improvement in upstream conductance in responseto bronchodilator.
Pulmonary Function After CDH Repair
53
TABLE 3-Respiratory System Compliance (Crs) and Resistance (Rrs) Measured by a Modified Passive Mechanics Techniaue in Six Patients With CDH Crs (mL . cm H2O-I
*
Rrs (cm H20 . mL-l
kg-')
*
s-'
kg-l) % Change
Patient no.
Control
Post-BD
96 Change
Control
Post-BD
1 2 3 5 7 8 Mean S.E.M. Control group Mean S.E.M.
0.12 0.63 1.40 1.64 1.19 0.90 0.98" 0.22 (n = 6) 1.84 0.23
0.12 0.56 1.13 1.44 1.14 0.93 0.87 0.20
0 -I 1 -19 -12 -4 3 -7
0.039 0.038 0.026
0.039 0.038 0.025
0 0 -4
0.024 0.0 18 0.026 0.004
0.020 0.019 0.025 0.004
-17 6 -3
0.020 0.001
CDH, congenital diaphragmatic hernia; post-BD, values taken after administration of nebulized 0.1% isoetharine; % change, from control to post-BD. *P < 0.05, CDH compared with control group.
Table 3 summarizes results of passive expiratory flow-volume curves. Crs normalized to body weight in infants with CDH was 53.3% of that in controls (P < 0.05). The mean Rrs values, which include the flow resistance of the endotracheal tube, were similar in the CDH and control groups. Administration of nebulized bronchodilator had no significant effects upon Crs or Rrs among patients with CDH. Therapy using nebulized isoetharine was initiated after DFV measurements in seven of the eight study patients. Ventilatory parameters 12-24 hours after starting bronchodilators showed small reductions in ventilator rate (22.8 k 3.7 to 20.7 k 3.4 breaths per minute; P = 0.07) and peak inspiratory pressure (33.9 It_ 2.5 to 31.1 L 2.5 cm H,O; P < 0.05). No significant changes occurred in FiO2,Pao,, PacOz, and alA ratio. DISCUSSION
Little is known of the mechanical properties of the lungs of infants severely affected by CDH. Symptomatic patients suffer severe respiratory insufficiency, the combined effect of hypoplasia and surgical repair. Positive pressure ventilation with high Fie, becomes necessary, and its effectiveness is a determinant of prognosis. Bohn and coworkers13 noted that two ventilatory indices predicted a fatal outcome: inability to achieve a postductal Paco, of less than 40 mm Hg, and the requirement for high ventilatory rates and mean airway pressures, such that the product (termed the ventilatory index, VI) exceeded 1,000. The improvement of pulmonary function therefore has significant clinical importance. Pulmonary hypoplasia was characterized by decreases in FVC and Crs to half the values in normal, control '3'
newborn infants. The findings reflect both pulmonary hypoplasia and postoperative changes in pulmonary mechanics caused by surgery and subsequent ventilatory support. Sakai and coworker? found that surgical repair not only decreased Crs from preoperative values, but the degree of change appeared to be related to survival: all those with a decrease of 50% or more died, while all those with less severe changes survived. The authors suggested that surgical repair of CDH leads to a number of changes that adversely affect Crs: a tight surgical closure of the diaphragm, hyperinflation of the contralatera1 lung, and relocated abdominal viscera. Our findings of low postoperative Crs confirm those of Sakai and coworkers. Postoperative changes that contribute to decreased Crs would be expected to also decrease FVC; we found a close correlation between Crs and FVC (r = 0.97). We found that airway reactivity is a prominent feature in patients with CDH who survive the immediate postoperative period. This is reflected by the marked reduction in baseline MEF,, values, and their dramatic increase after administration of nebulized isoetharine, indicating the early development of bronchial reactivity with an involvement of smaller airways. In contrast to MEF,, on DFV curves, administration of nebulized bronchodilator had no significant effects upon Rrs among patients with CDH. These findings suggest that the site of reactive airways in infants with CDH is in the periphery of the lungs, and is quite different from bronchial asthma, which primarily involves central airways. l 4 The failure of Rrs to be affected by bronchodilator administration may reflect the insensitivity of Rrs to changes in air flow in the tidal volume range of an intubated subject. The fixed large airway resistance, represented by the endo-
54
Nakayama et al.
tracheal tube, is a major portion of the total Rrs. Thus, Rrs is insensitive to changes in the upstream segment, which normally constitutes only a fraction of total Rrs. Inhalation of nebulized isoetharine also increased FVC, indicating the recruitment of air spaces that were either isolated with airway closure or collapsed before bronchodilator treatment. An increase in FVC alone would produce a parallel shift of the descending portion of the DFV curve and increase MEF2,,I5 without a significant change in MEF,,/FVC. When administering bronchodilators to CDH patients, we saw proportionately larger increases in MEF,, compared with FVC, leading to increases in the MEF,,/FVC ratio (by 5 1.3% of control values), which is a reflection of upstream conductance. The DFV curve changed shape after bronchodilator administration, becoming less convex to the volume axis (Fig. I ) , in contrast to a parallel shift of the curve. For the purpose of comparing MEF,, between control and postbronchodilatation when FVC increased, we assumed that TLC did not change. Using this assumption to estimate the extent of bronchodilatation is reasonable because infants with CDH have pathologically hyperinflated air spaces. An increase in FVC with bronchodilatation in these patients is caused primarily by a reduction of trapped gas in RV; in adults with reactive airway disease TLC that is abnormally enlarged because of hyperinflation tends to decrease. l 6 , I 7 Thus, our calculation would tend to underestimate the effect of bronchodilatation. This comparison at the isovolume point after bronchodilator has been recommended for clinical as well as for epidemiologic studies. Patients with reactive airways would be expected to benefit from the administration of bronchodilators during postoperative ventilatory management. However, despite the increased air flow after the administration of bronchodilators only small clinical improvements were observed. Respiratory rate and peak inspiratory pressure fell slightly, but Fi, and arterial blood gas values did not improve during tLe first day of bronchodilator administration. Bronchodilators, although increasing MEF,, , often decrease Pa,? due to pulmonary vasodilatation and loss of hypoxic pulmonary vasoconstriction. The clinical benefit of bronchodilator therapy may be modest at best, and overshadowed by the extent of pulmonary failure due to pulmonary hypoplasia and postnatal iatrogenic damage from positive pressure ventilation. A pitfall of the study was that patients varied widely in the degree of respiratory insufficiency. Only one required 6 d of ventilatory support, while two died and one required a tracheostomy for 1 year. Babies with the most severely affected lungs were not included in the study group: those died soon after birth despite aggressive ventilatory and pharmacologic support, including ECMO , Control infants did not receive bronchodilators,
so we cannot assess whether normal infants respond to bronchodilators to the same extent as babies with CDH. In preliminary studies, healthy infants appear to have minimal or no response to bronchodilator; the frequency and extent of such a response is under investigation. Long-term survivors of CDH develop airway reactivity, resembling that of prematurely born infants who developed BPD, l o despite differences in gestational age (premature vs. full term) and underlying pulmonary condition (premature vs. hypoplastic lungs). Chest roentgenographs of four severely affected patients with CDH ultimately resembled moderate to advanced stages of BPD, with densities, radiolucent vacuoles, fibrous strands, and cystic areas.20Infants with CDH in our study experienced physical and chemical insults similar to those associated with BPD after treatment for RDS, including prolonged periods of mechanical ventilation with high concentrations of oxygen,' and high pressures .,* Both are among the factors considered to be responsible for the development of BPD. Tracheobronchial lavage samples from infants with RDS and BPD reveal an influx of inflammatory cells that persist in babies who develop BPD, but decrease in those who recover from RDS without clinically significant sequelae.23Neutrophil-derived chemical mediators may be a mechanism of airway hyperrea~tivity.~~ The same chemically mediated changes may produce complications in the management of CDH. In conclusion, pulmonary hypoplasia, manifested physiologically by unusually low values of FVC and Crs, is a primary pathophysiologic feature of CDH. Bronchial reactivity may be superimposed in severely affected patients, possibly as a nonspecific response to iatrogenic insults from chronic ventilatory support. Bronchodilator therapy may offer some clinical benefit in selected patients.
REFERENCES 1. Hislop A, Reid L. Persistent hypoplasia of the lung after repair of congenital diaphragmatic hernia. Thorax. 1976; 3 1:450-455. 2 . Areechon W, Reid L. Hypoplasia of the lung with congenital
diaphragmatic hernia. Br Med J . 1963; 1:230-233. 3. Bohn D, Tamura M, Perrin D, Barker G, Rabinovitch M. Ventilatory predictors of pulmonary hypoplasia in congenital diaphragmatic hernia, confirmed by morphologic assessment. J Pediatr. 1987; 111:423431. 4. Naeye RL, Shochat SJ, Whiteman V , Maisels MJ. Unsuspected pulmonary vascular abnormalities associated with diaphragmatic hernia. Pediatrics. 1976; 58:902-906. 5 . Levin DL. Morphologic analysis of the pulmonary vascular bed in congenital left-sided diaphragmatic hernia. J Pediatr. 1978; 92:805-809. 6. Geggel RL, Murphy JD, Langleben D, Crone RK, Vacanti JP, Reid LM. Congenital diaphragmatic hernia: Arterial structural changes and persistent pulmonary hypertension after surgical repair. 3 Pediatr. 1985; 107:457464.
Pulmonary Function After CDH Repair 7 . Vacanti JP, O’Rourke PP, Lillehei CW, Crone RK. The cardiopulmonary consequences of high-risk congenital diaphragmatic hernia. Pediatr Surg Int. 1988; 3:l-5. 8. Northway WH Jr, Rosan RC, Porter DY. Pulmonary disease following respirator therapy of hyaline membrane disease: Bronchopulmonary dysplasia. N Engl J Med. 1967; 276:357-368. 9. Sakai H, Tamura M, Hosokawa Y, Bryan AC, Barker GA, Bohn DJ. Effect of surgical repair on respiratory mechanics in congenital diaphragmatic hernia. J Pediatr. 1987; 111:432-438. 10. Motoyama EK, Fort MD, Klesh KW, Mutich RL, Guthrie RD. Early onset of airway reactivity in premature infants with bronchopulmonary dysplasia. Am Rev Respir Dis. 1987; 136:50-57. 1 1. LeSouef PN, England SJ, Bryan AC. Passive respiratory mechanics in newborns and children. Am Rev Respir Dis. 1984; 129:552-556. 12. Mead J, Turner JM, Macklem PT, Little JB. Significance of the relationship between lung recoil and maximum expiratory flow. J Appl Physiol. 1967; 22:95-108. 13. Bohn D, James I, Filler R, Ein SH, Wesson DE, Shandling B, Stephens C, Barker GA. The relationship between Pa,, and ventilation parameters in congenital diaphragmatic h e r i a . J Pediatr Surg. 1984; 19:66&67 I . 14. Loke J, Ganeshananthan M, Palm CR, Motoyama EK. Site of airway obstruction in asymptomatic asthmatic children. Lung. 1981; 159:35-42. 15. Olive JT Jr, Hyatt RE. Maximal expiratory flow and total respiratory resistance during induced bronchoconstriction in asthmatic subjects. Am Rev Respir Dis. 1972; 106:366-376.
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16. Woolcock AJ, Read J. Lung volumes in exacerbation of asthma. Am J Med. 1966; 41:259-273. 17. Peress L, Sybrecht G, Macklem PT. The mechanism of increase in total lung capacity during acute asthma. Am J Med. 1976; 61:165-169. 18. Reis AL. Response to bronchodilator. In: Clausen TL, ed. Pulmonary Function Testing Guidelines and Controversies. New York: Academic Press, 1982:215-221. 19. Lorber DB, Kaltenbom W, Burrows B. Responses to isoprotereno1 in a general population sample. Am Rev Respir Dis. 1978; 118:855-861. 20. Edwards DK. Radiologic aspects of bronchopulmonary dysplasia. J Pediatr. 1979; 95:823-828. 21. Edwards DK, Dyer WM, Northway WH Jr. Twelve years’ experience with bronchopulmonary dysplasia. Pediatrics. 1977; ,59339-846. 22. Taghizadeh A, Reynolds EOR. Pathogenesis of bronchopulmonary dysplasia following hyaline membrane disease. Am J Pathol. 1976; 82:24 1-264. 23. Ogden BE, Murphey SA, Sunders GC, Pathak D, Johnson JD. Neonatal lung neutrophils and elastase-protease inhibitor imbalance. Am Rev Respir Dis. 1984; 130:817-821. 24. Boushey HA, Holzman MJ. Experimental airway inflammation and hyperreactivity: Search for cells and mediators. Am Rev Respir Dis. 1985; 131:312-313.
Pulmonary Function in Newborns After Repair of Congenital Diaphragmatic Hernia Don K. Nakayama, MD,’ Etsuro K. Motoyama, M D , * , ~ Rebecca L. Mutich, R T , ~and Anastassios C. Koumbourlis, M D ~ Summary. Congenitaldiaphragmatic hernia (CDH) is associated with pulmonary hypoplasiathat limits survival, but the nature and extent of pulmonary dysfunction in neonates with CDH have not been studied. We performed pulmonary function tests (PFTs) in eight intubated infants who survived neonatal repair of CDH (wt, 3.33 ? 0.15 kg; age, 20.1 i 2.7 d; mean S.E.M.). PFTs obtained from six full-term infants (wt, 3.56 5 0.10 kg; age, 25.0 i 3.3 d) with no respiratory illness served as controls. The deflation flow-volume curve technique produced maximum expiratory flow-volume (MEFV) curves, giving reproducible measurements of forced vital Respiratory system capacity (FVC) and maximal expiratory flow at 25% of FVC (MEF,,). compliance (Crs) and resistance (Rrs) were obtained with a modified passive mechanics technique. In seven of eight infants PFTs were repeated after nebulized bronchodilator (0.1Yo isoetharine). In neonates surviving CDH repair, as compared to those with normal lung function, FVC was significantly reduced (20.78 ? 3.32 vs. 39.83 ? 3.30 mL . kg-’, P < 0.05). MEF, was also markedly reduced (8.41 2 1.46vs. 32.32 -t 4.35 mL . kgg’ . s-’, P < 0.05), indicating lower airway obstruction. After administration of nebulized bronchodilator, PFTs showed significant increases from control values in both FVC (15.9%) and MEF, (200%) without changes in Crs and Rrs. These findings indicate that neonates with CDH have restrictive lung defects, reflecting hypoplasia.After surgical repair and mechanical ventilation airway reactivity develops, primarily in smaller airways, and this may complicatethe postoperativecourse. Pediatr Pulmonol. 1991; 11:49-55.
*
Key words: Deflation flow-volume curves; modified passive mechanics technique; respiratory system compliance; resistance; bronchodilator response; lower airway obstruction: restrictive defects.
INTRODUCTION
commonly after a severe form of respiratory distress syndrome (RDS) .* Information on the extent of pulmonary dysfunction in CDH, particularly among survivors during infancy, is difficult to quantify. Recent studies by Bohn and coworkers3 and Sakai and colleaguesy indicate that changes in pulmonary mechanics after surgical repair of CDH influence survival. To characterize the respiratory
Pulmonary hypoplasia is a characteristic of congenital diaphragmatic hernia (CDH). Clinically, inability to maintain adequate ventilation in newborn babies with CDH reflects severe pulmonary hypoplasia. Postmortem studies in such infants document the anatomic features of pulmonary hypoplasia and pulmonary hypertension: decreased numbers of bronchial generations, alveoli ,2,3 and pulmonary vessel^,^*^ and increased muscularity of the pulmonary vascular bed.6 The mortality of CDH From the Departments of Surgery, ’ Anesthesiology,* and Pulremains high, ranging from 50% to 80%, despite ad- m ~ n o l o g yChildren’s ,~ Hospital of Pittsburgh, and the Departments of vances in neonatal intensive care.’ Survivors have mar- Surgery,’ Anesthesiology,’ and Pediatrics,3 University of Pittsburgh ginal respiratory reserve and often require prolonged School of Medicine, Pittsburgh, Pennsylvania. mechanical ventilatory support. Chronic respiratory in- Received January 25, 199 1; (revision) accepted for publication March sufficiency may result as a possible consequence of 11. 1991. pulmonary hypoplasia as well as oxygen toxicity and barotrauma, and is the major cause of late morbidity and Presented at the 1990 World Conference on Lung Health, May 23, m ~ r t a l i t y .Clinically, ~ patients who enter this stage of 1990, Boston, Massachusetts. respiratory care closely resemble premature infants with Address correspondence and reprint requests to Dr. D.K. Nakayama, bronchopulmonary dysplasia (BPD), a progressive dis- Department of Surgery, Children’s Hospital of Pittsburgh, 3705 Fifth ease of the lung parenchyma and airways occurring most Avenue at DeSoto Street, Pittsburgh, PA 15213-3417.
’
0 1991 Wiley-Liss, Inc.
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Nakayarna et al.
pathophysiology of CDH further, we performed pulmonary function tests (PFTs) in a group of infants less than 1 month of age who survived surgery for CDH as neonates. Our goal was to address the following questions: 1) What aspects of pulmonary dysfunction characterize CDH in the newborn? and 2) Do babies surviving CDH repair develop bronchial reactivity, an early feature of BPD? MATERIALS AND METHODS Patients This study was approved by the institutional review board for research involving human subjects. Informed consent was obtained from the parents of all infants. Fourteen newborn infants were studied, either in the operating room or in the neonatal surgical intensive care unit, all undergoing endotracheal intubation and mechanical ventilation at the time. Twelve infants were admitted to the surgical service for operative repair of CDH from December 1988 through October 1989. Four died within days of birth and were not studied. Eight survived at least 4 weeks and formed the study group; all exhibited respiratory distress during the first 6 hours of life, and all underwent transabdominal repair of the hernia within 12 hours. The patients were given PFTs within 30 days of birth; tests were deferred until the clinical course was sufficiently stable to allow safe manipulation of airway pressure. Six full-term infants less than 30 days of age, free from respiratory illness, served as controls. They were undergoing general endotracheal anesthesia for repair of an inguinal hernia of a size not expected to compromise respiratory function. Clinical Management All patients were treated in a consistent fashion. While being ventilated mechanically during surgery and after operation, all received fentanyl citrate (10 pg kg-' h-', initially, and then 1-2 pg kg-' h-') and pancuronium bromide (100 pg - kg- = h-'). Inspired oxygen fraction (Fio2) and ventilator settings were adjusted to maintain optimal blood gas levels, based upon arterial blood gas determinations on samples drawn from a postductal site, generally through an umbilical artery catheter. We attempted to keep oxygen saturation (So) above 95%, arterial oxygen tension between 100 and 120 mm Hg, and maintain hyperventilation with arterial pH above 7.5 and Pk0, below 35 mm Hg. Infants with acidosis, refractory to ventilatory changes, received sodium bicarbonate (1-2 mEq kg- ') to maintain systemic alkalinization. Tolazoline (1-2 mg kg-' by slow push, followed by 2 mg . kg-' h-') and prostaglandin El (0.1 pg . kg-' min-I) were given by intravenous infusion to selected babies who had postductal arterial
'
1
hypoxemia unresponsive to changes in ventilatory management. Modest fluid restriction (80-100 mL . kg-' d- ') was maintained. Babies who became hypotensive were given inotropic infusions (dopamine, 2-20 pg * k g ' * min- , and/or dobutamine, 2-20 pg * kg- * min- ) as needed. Patients in whom hypoxemia persisted despite all conventional methods of support outlined above received extracorporeal membrane oxygenation (ECMO). We recorded the following measurements and indices during the clinical course, including those obtained immediately after operation and at the time of pulmonary function testing: postductal arterial blood gases (pH, Pao2, and Pa,& alveolar to arterial oxygen tension difference (P,A-a,O,)at Fio2 = 1.O; the ratio of arterial to alveolar oxygen tension (a/A ratio), calculated as postductal Pao,/(713 - PacOz X 0.8) X Fio2; and indices of ventilation, including respiratory rate, peak inspiratory , and mean airway pressures during the ventilatory cycle. Control infants were ventilated by hand with peak inspiratory pressures of 12-20 cm H,O and a positive end-expiratory pressure of 3-6 cm H20. Inspired oxygen fraction was adjusted to maintain optimal Sao2 on pulse oximetry .
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Procedures Pulmonary function was evaluated by deflation flowvolume (DFV) curve analysis, a technique used to obtain maximum expiratory flow-volume (MEFV) curves. This technique is described in detail elsewhere. l o Briefly, it involves inflating the lungs of intubated, paralyzed subjects three times to an airway pressure of +40 cm H 2 0 (defined as total lung capacity, TLC) to set a consistent volume history. The lungs are then deflated from TLC through an endotracheal tube and No. 0 Fleisch pneumotachograph by sudden exposure to a negative pressure reservoir of -40 cm H,O until expiratory flow ceases, or as long as 3 s (FEV,). The volume at cessation of flow, or FEV,, is defined as residual volume (RV). The flow signal and the corresponding volume by integration are displayed on a storage oscillograph as an MEFV curve. The total expired volume displayed by the MEFV curve provides an estimate of forced vital capacity (FVC). The maximal expiratory flow at 25% of FVC from residual volume (MEF,,), which reflects the conductance of airways toward the periphery of the lungs, is obtained from the MEFV tracing. DFV curves may first gradually increase in size due to the initial recruitment of air spaces by manual expansion. Ultimately, superimposable curves are obtained, with negligible within-subject coefficients of variation. The DFV maneuver is repeated until two or three identical curves are obtained, and those values are used. The infants with CDH underwent DFV maneuvers in
Pulmonary Function After CDH Repair
51
TABLE 1-Clinical Characteristics of Patients Patient no.
Agea (d)
Weighta (kg)
CDH group 1 30 3.4 2 19 2.45 3 20 3.0 4 21 3.36 5 18 3.67 6 30 3.59 I 6 3.7 8 17 3.49 20.1 3.33 Mean S.E.M. 2.7 0.15 Control group (n = 6) 25 3.56 Mean S.E.M. 3.3 0.10
Gestational age (wk)
1 min
5 min
PTX
40 35 40 36 40 40 39 36
3 8 1 3 3 5 5 5
5
Yes Yes No No Yes Yes,PIE Yes No
"Ore
8 2 3 5 5
7 I
ECMO (days on)
7 6 3 7 -
9
-
Outcome Died Died Lived Lived Lived Lived Lived Lived
PTX, pneumothorax; PIE, pulmonary interstitial emphysema; ECMO, extracorporeal membrane oxygenation; CDH, congenital diaphragmatic hernia. aAge and weight are those at the time of pulmonary function testing.
three test conditions designed to detect the presence of reversible bronchoconstriction: 1) baseline; 2) after 5 min of ventilation by anesthesia bag with aerosolized normal saline solution (control); and 3) after 8 min of ventilation by bag with nebulized bronchodilator (0.25 mL 1% isoetharine in 3 mL normal saline). When the infants were not paralyzed and their activity interfered with manual ventilation and DFV curve maneuvers, fentanyl (1-2 p,g . kg-I) and atracurium (0.5 mg kg-I) a shortacting, nondepolarizing muscle relaxant, were given to facilitate the study. When FVC changed between saline control and postbronchodilator values, DFV curves were superimposed at TLC, and postbronchodilator MEF,, values were measured at 75% FVC from TLC for saline control. This was based on the assumption that TLC after bronchodilatation in infants, as in children and adults, changes little or even decreases after bronchodilatation. Changes of flows at this volume (MEF2sisc,v)were expressed as the ratio of MEF,,isoVafter bronchodilator to control MEF,, values. Passive expiratory flow-volumes curves were obtained using a modification of the method described in detail by LeSouef et al." After inflating the lungs to TLC, hand ventilation kept the lungs under 10 cm H 2 0 pressure for a few seconds, long enough to allow airway occlusion pressure (Pao) to plateau. A slide valve was then rapidly opened for 1-2 s to allow passive expiration through a pneumotachograph to functional residual capacity (FRC), or relaxation volume, V,. The resultant passive partial flow-volume curves displayed on the oscilloscope allowed calculation of respiratory system compliance (Crs) and resistance (Rrs). Flow versus volume plotting usually produces a straight line after an initial peak. 4
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When the straight line portion of the flow-volume curve is extrapolated back to zero volume, the flow-axis intercept gives the estimated flow (Vo) appropriate for the Pao. Rrs = Pao/V0; Crs is obtained by dividing the exhaled volume (V,) by Pao (10 cm H20). Three passive expirations were analyzed in each subject, and mean values were used. Values are expressed as mean ? standard error of the mean (S.E.M.). To compare infants of different body size, we normalized the flow and volume values, dividing them by body weight. MEF,, was also normalized by its ratio to FVC. Statistical comparison between the study group and control patients was performed using Student's unpaired t-test. Statistical comparison of the data before and after bronchodilator administration was performed using Student's paired t-test. Relationships among variables and FVC, MEF,,, and MEF,,/FVC were determined by multiple correlation. A probability value of less than 0.05 was considered significant. RESULTS
Table 1 summarizes the clinical characteristics and early postnatal and postoperative course of all babies with CDH and of control infants. All babies with CDH subsequently required intensive ventilatory care of long duration (range, 6 to 360 d; mean k S.E.M., 69.6 k 41.7 d). The maximum respiratory rate during mechanical ventilation was 79.6 +- 9.2 breaths per minute; the maximum peak inspiratory pressure during ventilatory support was 41.1 k 3.7 cm H20. Fio, exceeded 0.90 for 47.3 5 15.4 h and 0.50, for 227 k 88.9 h. After operation, a/A ratio was 0.29 ? 0.09; P,A.a102,476 k
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Nakayama et al.
TABLE 2-Pulmonary Function Data in Eight Newborn Infants After CDH-Repair Flow-Volume Technique FVC (mL . kg-l) Pt. no.
MEF25 (mL
. s-I . kg-I)
%
Control
1 2.8 2 12.7 3 32.3 4 19.3 5 20.1 6 24.0 7 21.8 8 26.6 Mean 20.8* S.E.M. 3.3 Control group (n = 6) Mean 39.8 S.E.M. 3.3
Post-BD 3.2 17.1 36.7 23.5 24.2 28.4 21.8 31.5 24.1** 3.6
Change 14.3 34.6 13.6 21.8 11.4 18.3 0 18.4 15.9
Control
Post-BD
0.8 6.1 11.3 8.9 5.7 8.9 13.0 12.6 8.4* 1.4
1.8 27.8 26.7 22.6 34.6 25.6 18.4 44.4 25.2** 4.3
32.3 4.4
Obtained by Deflation
% Change
125 356 I36 154 525 128 42 252 200
MEF25/FVC (s-') %
Isovolume
Control
Post-BD
Change
2.4 4.56 2.36 2.53 6.05 2.88 I .42 3.52 3.22 0.52
0.27 0.48 0.35 0.46 0.28 0.37 0.47 0.47 0.39" 0.03
0.3 I 0.7 1 0.5 5 0.4 I 0.78 0.48 0.66 0.82 0.59** 0.06
14.8 47.9 57.1 - 10.9 I78 29.1 40.4 74.5 51.3
0.84 0.12
CDH, congenital diaphragmatic hernia; FVC, forced vital capacity; MEF25, maximal expiratory flow at 25% of FVC from residual volume; isovolume, ratio of MEF25 after bronchodilator to control values; control, baseline values; post-BD, values taken after administration of neubulized 0.1% isoetharine; % change, percent change from control to post-BD. *P < 0.05, CDH compared with control group. **P < 0.05, CDH, post-bronchodilator compared with control (post-saline) values.
58 mm Hg. At the time of pulmonary function testing both parameters had improved (aiA ratio, 0.37 k 0.05; PLA.alOl,164 rt 31). At the time of our study chest roentgenographs were free from acute changes such as pneumothorax and atelectasis. Volume of the hemithordx, ipsilateral to the hernia, was typically smaller than the contralateral side. Chronic changes in the chest film were not yet present at the time of pulmonary function testing. However, four of eight patients later developed coarse parenchymal densities with radiolucent vacuoles, fibrous strands, and cystic areas consistent with changes seen in moderate to advanced stages of BPD. The results from DFV curve studies, summarized in Table 2, reveal significant decreases in both lung volume and airflow measurements in CDH. FVC in patients with CDH was 52.7% of that in control infants ( P < 0.05), indicating a marked restrictive defect. MEF,, in babies with CDH was 26.0% of that in controls ( P < 0.05). When MEF,, was expressed in terms of MEFz5/FVC, an index of upstream airway conductance, l 2 the mean value for babies with CDH was 46.4% of that in controls (P < 0.05), indicating the presence of lower airway obstruction in peripheral airways. Administration of nebulized bronchodilator caused significant increases in FVC (15.9%), MEF2, (200%), and MEF,,/FVC (51.3%) (all, P < 0.05). Figure 1 gives an example of a DFV study in one patient, illustrating the effects of bronchodilators upon measured parameters. We observed no significant changes in DFV curves under baseline conditions and after administration of normal saline aerosol; a finding we noted in previous studies. l o
Fig. 1. Deflation flow-volume curves in a 20-day-old, 3.0 kg congenital diaphragmatic hernia (CDH) patient (shaded curves), and a 20-day-old, 3.9 kg normal infant (outer curve). Volumes to determine maximal expiratory flow at 25% of forced vital capacity (MEF,,) for each patient are shown as dashed vertical lines. Curves for the CDH patient are obtained after normal saline aerosol (post-saline) and after bronchodilator (post-BD). After bronchodilator there was a small increase in FVC and a 136% increase in MEF,, (dashed line). The shape of the curve also changed, becoming less convex to the volume axis, indicating an improvement in upstream conductance in responseto bronchodilator.
Pulmonary Function After CDH Repair
53
TABLE 3-Respiratory System Compliance (Crs) and Resistance (Rrs) Measured by a Modified Passive Mechanics Techniaue in Six Patients With CDH Crs (mL . cm H2O-I
*
Rrs (cm H20 . mL-l
kg-')
*
s-'
kg-l) % Change
Patient no.
Control
Post-BD
96 Change
Control
Post-BD
1 2 3 5 7 8 Mean S.E.M. Control group Mean S.E.M.
0.12 0.63 1.40 1.64 1.19 0.90 0.98" 0.22 (n = 6) 1.84 0.23
0.12 0.56 1.13 1.44 1.14 0.93 0.87 0.20
0 -I 1 -19 -12 -4 3 -7
0.039 0.038 0.026
0.039 0.038 0.025
0 0 -4
0.024 0.0 18 0.026 0.004
0.020 0.019 0.025 0.004
-17 6 -3
0.020 0.001
CDH, congenital diaphragmatic hernia; post-BD, values taken after administration of nebulized 0.1% isoetharine; % change, from control to post-BD. *P < 0.05, CDH compared with control group.
Table 3 summarizes results of passive expiratory flow-volume curves. Crs normalized to body weight in infants with CDH was 53.3% of that in controls (P < 0.05). The mean Rrs values, which include the flow resistance of the endotracheal tube, were similar in the CDH and control groups. Administration of nebulized bronchodilator had no significant effects upon Crs or Rrs among patients with CDH. Therapy using nebulized isoetharine was initiated after DFV measurements in seven of the eight study patients. Ventilatory parameters 12-24 hours after starting bronchodilators showed small reductions in ventilator rate (22.8 k 3.7 to 20.7 k 3.4 breaths per minute; P = 0.07) and peak inspiratory pressure (33.9 It_ 2.5 to 31.1 L 2.5 cm H,O; P < 0.05). No significant changes occurred in FiO2,Pao,, PacOz, and alA ratio. DISCUSSION
Little is known of the mechanical properties of the lungs of infants severely affected by CDH. Symptomatic patients suffer severe respiratory insufficiency, the combined effect of hypoplasia and surgical repair. Positive pressure ventilation with high Fie, becomes necessary, and its effectiveness is a determinant of prognosis. Bohn and coworkers13 noted that two ventilatory indices predicted a fatal outcome: inability to achieve a postductal Paco, of less than 40 mm Hg, and the requirement for high ventilatory rates and mean airway pressures, such that the product (termed the ventilatory index, VI) exceeded 1,000. The improvement of pulmonary function therefore has significant clinical importance. Pulmonary hypoplasia was characterized by decreases in FVC and Crs to half the values in normal, control '3'
newborn infants. The findings reflect both pulmonary hypoplasia and postoperative changes in pulmonary mechanics caused by surgery and subsequent ventilatory support. Sakai and coworker? found that surgical repair not only decreased Crs from preoperative values, but the degree of change appeared to be related to survival: all those with a decrease of 50% or more died, while all those with less severe changes survived. The authors suggested that surgical repair of CDH leads to a number of changes that adversely affect Crs: a tight surgical closure of the diaphragm, hyperinflation of the contralatera1 lung, and relocated abdominal viscera. Our findings of low postoperative Crs confirm those of Sakai and coworkers. Postoperative changes that contribute to decreased Crs would be expected to also decrease FVC; we found a close correlation between Crs and FVC (r = 0.97). We found that airway reactivity is a prominent feature in patients with CDH who survive the immediate postoperative period. This is reflected by the marked reduction in baseline MEF,, values, and their dramatic increase after administration of nebulized isoetharine, indicating the early development of bronchial reactivity with an involvement of smaller airways. In contrast to MEF,, on DFV curves, administration of nebulized bronchodilator had no significant effects upon Rrs among patients with CDH. These findings suggest that the site of reactive airways in infants with CDH is in the periphery of the lungs, and is quite different from bronchial asthma, which primarily involves central airways. l 4 The failure of Rrs to be affected by bronchodilator administration may reflect the insensitivity of Rrs to changes in air flow in the tidal volume range of an intubated subject. The fixed large airway resistance, represented by the endo-
54
Nakayama et al.
tracheal tube, is a major portion of the total Rrs. Thus, Rrs is insensitive to changes in the upstream segment, which normally constitutes only a fraction of total Rrs. Inhalation of nebulized isoetharine also increased FVC, indicating the recruitment of air spaces that were either isolated with airway closure or collapsed before bronchodilator treatment. An increase in FVC alone would produce a parallel shift of the descending portion of the DFV curve and increase MEF2,,I5 without a significant change in MEF,,/FVC. When administering bronchodilators to CDH patients, we saw proportionately larger increases in MEF,, compared with FVC, leading to increases in the MEF,,/FVC ratio (by 5 1.3% of control values), which is a reflection of upstream conductance. The DFV curve changed shape after bronchodilator administration, becoming less convex to the volume axis (Fig. I ) , in contrast to a parallel shift of the curve. For the purpose of comparing MEF,, between control and postbronchodilatation when FVC increased, we assumed that TLC did not change. Using this assumption to estimate the extent of bronchodilatation is reasonable because infants with CDH have pathologically hyperinflated air spaces. An increase in FVC with bronchodilatation in these patients is caused primarily by a reduction of trapped gas in RV; in adults with reactive airway disease TLC that is abnormally enlarged because of hyperinflation tends to decrease. l 6 , I 7 Thus, our calculation would tend to underestimate the effect of bronchodilatation. This comparison at the isovolume point after bronchodilator has been recommended for clinical as well as for epidemiologic studies. Patients with reactive airways would be expected to benefit from the administration of bronchodilators during postoperative ventilatory management. However, despite the increased air flow after the administration of bronchodilators only small clinical improvements were observed. Respiratory rate and peak inspiratory pressure fell slightly, but Fi, and arterial blood gas values did not improve during tLe first day of bronchodilator administration. Bronchodilators, although increasing MEF,, , often decrease Pa,? due to pulmonary vasodilatation and loss of hypoxic pulmonary vasoconstriction. The clinical benefit of bronchodilator therapy may be modest at best, and overshadowed by the extent of pulmonary failure due to pulmonary hypoplasia and postnatal iatrogenic damage from positive pressure ventilation. A pitfall of the study was that patients varied widely in the degree of respiratory insufficiency. Only one required 6 d of ventilatory support, while two died and one required a tracheostomy for 1 year. Babies with the most severely affected lungs were not included in the study group: those died soon after birth despite aggressive ventilatory and pharmacologic support, including ECMO , Control infants did not receive bronchodilators,
so we cannot assess whether normal infants respond to bronchodilators to the same extent as babies with CDH. In preliminary studies, healthy infants appear to have minimal or no response to bronchodilator; the frequency and extent of such a response is under investigation. Long-term survivors of CDH develop airway reactivity, resembling that of prematurely born infants who developed BPD, l o despite differences in gestational age (premature vs. full term) and underlying pulmonary condition (premature vs. hypoplastic lungs). Chest roentgenographs of four severely affected patients with CDH ultimately resembled moderate to advanced stages of BPD, with densities, radiolucent vacuoles, fibrous strands, and cystic areas.20Infants with CDH in our study experienced physical and chemical insults similar to those associated with BPD after treatment for RDS, including prolonged periods of mechanical ventilation with high concentrations of oxygen,' and high pressures .,* Both are among the factors considered to be responsible for the development of BPD. Tracheobronchial lavage samples from infants with RDS and BPD reveal an influx of inflammatory cells that persist in babies who develop BPD, but decrease in those who recover from RDS without clinically significant sequelae.23Neutrophil-derived chemical mediators may be a mechanism of airway hyperrea~tivity.~~ The same chemically mediated changes may produce complications in the management of CDH. In conclusion, pulmonary hypoplasia, manifested physiologically by unusually low values of FVC and Crs, is a primary pathophysiologic feature of CDH. Bronchial reactivity may be superimposed in severely affected patients, possibly as a nonspecific response to iatrogenic insults from chronic ventilatory support. Bronchodilator therapy may offer some clinical benefit in selected patients.
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