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Predictive capabilities of preoperative and postoperative pulmonary function tests in delayed repair of congenital diaphragmatic hernia
Predictive Capabilities of Preoperative and Postoperative Pulmonary Function Tests in Delayed Repair of Congenital Diaphragmatic Hernia By Thomas
F. Tracy, Jr, Patrick V. Bailey, Farouk Sadiq, Akihiko
St @To improve diaphragmatic conventional
the survival
of newborns
hernia (CDH), preoperative ventilatory
brane oxygenation
therapy
with
congenital
stabilization
and extracorporeal
with mem-
(ECMO) have been used. Measurements
that quantify pulmonary function may allow an accurate assessment of lethal pulmonary hypoplasia and predict outcome. Pulmonary function tests (PFTs) were obtained in 20 infants preoperatively and postoperatively; these included measurements of compliance, dynamic compliance, and tidal volume. Overall survival was 75%. Six surviving infants were initially managed with ventilator therapy alone, followed by repair (group 1). The remaining 14 patients, who were moribund at presentation or whose initial ventilator therapy failed, were placed on ECMO and received repair during bypass; nine survived (group 2). and five died (group 3). Compliance, dynamic compliance, and tidal volume obtained at initial presentation
and immediately
preoperatively
were
significantly higher for group 1 as compared with groups 2 and 3. Infants whose initial compliance was greater than 0.25 mL/cm mL/kg
HrO/ kg and initial tidal volume was greater than 3.5 did not require ECMO. Ultimate improvement in
compliance
was noted in 5 of 6 patients
in group 1, 6 of 8
patients in group 2, and 5 of 5 in group 3. This improvement followed an initial decline in compliance in 9 of 14 survivors, from 15% to 76%. All six patients in group 1 had tidal volumes of more than 4 mL/ kg, as did 7 of 9 patients in group 2. Only one patient among the ECMO nonsurvivors (group 3) had a postoperative tidal volume of this magnitude. These data suggest that initial PFTs may predict which infants will require ECMO. A postoperative tidal volume of more than 4 mL/ kg may be critical for survival. Copyright o 1994 by W.B. Saunders Company INDEX WORDS: poreal membrane sia.
Congenital
diaphragmatic
oxygenation
hernia; extracor-
(ECMO); pulmonary
Noguchi,
Mark L. Silen, and Thomas
R. Weber
Louis, Missouri
hypopla-
C when symptomatic ONGENITAL
diaphragmatic hernia (CDH), within the first few hours of life has, until recently, been associated with a mortality rate of approximately 50%.’ Vasoactive drugs and innovative ventilator techniques including high frequency systems, extracorporeal membrane oxygenation (ECMO), and stabilization before repair have contributed to significant increases in survival, of up to 76% of patients.“4 Many infants continue to die of pulmonary hypertension and pulmonary hypoplasia despite the most aggressive treatment. Numerous investigators have sought to define measurable parameters of hemodynamic or pulmonary sequelae of this lesion that accurately predict the need for specific therapeutic modalities or eventual survival.5-i(’ No JournalofPediatric Surgery, Vol 29, No 2 (February), 1994: pp 265-270
study has been able to firmly establish any predictive index of survival that can be consistently reproduced. ECMO provides an excellent treatment option for infants with refractory pulmonary hypertension, and certain indexes have been used to help anticipate which patients will benefit from its use.3-4.7JJ1Unfortunately, comparable indexes have not been as effective for determining lethal pulmonary hypoplasia.2J Pulmonary function tests seem uniquely suited to this purpose. Compliance measurements of Sakai et al and Nakayama et al in infants with CDH demonstrated both the deleterious effects of surgical repair on respiratory mechanics and the benefits of delayed repair.i2J3 The present study was designed to determine whether measurements of pulmonary function performed over the course of management of CDH are adequate predictors of survival, and whether values taken at the time of presentation can be used to predict the need for ECMO as an adjunctive therapy during the period of initial stabilization. MATERIALS
AND METHODS
Patients The study group comprised 20 consecutively treated infants with CDH, who were symptomatic within the first 6 hours of life. All were treated with repair of the diaphragmatic defect after an initial period of preoperative stabilization. ECMO was used in patients who presented with refractory hypoxemia or in those whose clinical course deteriorated despite conventional ventilatoty management.’ Repair of the hernia was undertaken only after the clinical course had improved and pH and PO? were normal. For purposes of comparison, the infants were divided mto three study groups. Six infants (group 1) were successfully managed with ventilator therapy alone and then received repair. The other 14 infants, who were moribund at presentation or whose conventional ventilator therapy failed, were placed on ECMO and had repair during bypass. The nine surviving patients constitute group 2. Group 3 consists of the remaining five patients who did not survive. Data examined for each patient include gestational age, birth weight, and the pulmonary function parameters of compliance,
From the Divisions of Pediattic Suqery and Neonatology Depanmen& of Suqety and Pediatrics, Cardinul Glennon Children’s Hospital, St Louis UniversityMedical Center. St Louis, MO. Presented at the 24th Annual Meeting of the American Pediattic Surgical Association, Hilton Head, South Carolina. May 15-18, 1993. Address reprint requests to Thomas F. Tracy. Jr, MD, Division of Pediattic Surgery. 1465 S Grand Blvd, St Louis. MO 63104. Copyright CCI994 by W.B. Saunders Cornpam 0022-3468/9412902-0025$03.OOlO 265
266
TRACY ET AL
dynamic compliance, and tidal volume. Data were analyzed with the use of a statistical software package (Statview; Brainpower, Inc, Calabasas, CA). All data are expressed as mean plus or minus the standard deviation of the mean (*SD). Data were analyzed for statistical significance using analysis ofvariance and Fisher’s test. A P value of less than .05 was considered significant.
Management All patients were initially managed by endotracheal intubation and mechanical ventilation. Inspired oxygen concentration (FIo~) was adjusted to maintain the arterial oxygen saturation at greater than 90%. Ventilation was adjusted to maintain arterial pH above 7.5 and Pacoz between 35 and 50 mm Hg. Refractory acidemia was treated with either sodium bicarbonate or tromethamine (THAM) to obtain systemic alkalinization. Fluids were restricted to 80 to 100 ml/kg/d. Hypotension was treated with dopamine 5 to 15 kg/kg/ min. The techniques for ECMO cannulation and management have been reported previously.2 The right internal jugular vein and right common carotid artery were cannulated. Flow was maintained to direct approximately 80% of the cardiac output through the extracorporeal circuit. While on bypass, all infants received a continuous infusion of heparin, which maintained activated clotting times of between 180 and 220 seconds. Ventilator support was limited during ECMO to minimize barotrauma and oxygen toxicity, (F10z = 0.4; peak inspiratory pressure = 15 cm HzO; positive end expiratory pressure = 2 cm HzO; intermittent mandatory ventilation = 20 breaths per minute).
and the mean birth weight was 3,006 + 705 g (range, 1,547 to 4,100 g). There were no significant differences in these parameters between groups. The overall survival was 15 of 20 (75%). Serial preoperative pulmonary function measurements were obtained in four patients in group 1, five in group 2, and two in group 3. For patients in whom serial measurements were not obtained, “initial” values were also considered as preoperative values. Compliance data obtained at the initial presentation and preoperatively for all three groups are shown in Fig 1A. Mean compliance was significantly greater A"'1
-I-
0.9
ml/cm
H20
kg 01
Pulmonary Function Measurements Parameters of pulmonary function were measured serially, preoperatively and postoperatively. with a commercially available noninvasive system (PeDS-Pulmonary Evaluation and Diagnostic System, Medical Associated Services, Inc, Hatfield, PA). In this system, concurrent signals of airllow and transpulmonary pressure are used to calculate values of dynamic compliance and pulmonary resistance. Data are analyzed on-line, using a two-factor, leastmean square analysis technique in which the respiratory system is modeled as a single-compartment linear mechanical system based on the Rohrer equation of motion. This technique minimizes the error between measured pressure and calculated pressure, and makes it possible to evaluate the mechanical behavior of the respiratory system over the entire tidal volume range of breathing.i4 Air flow during the respiratory cycle is determined by use of a pneumotachometer connected in series to the patient, The volume change is determined by the digital integration of this airflow signal and then plotted on the x axis. Transpulmonary pressure, plotted on they axis, is calculated as the difference between intrapleural pressure (measured indirectly via an esophageal balloon), and airway pressure. Data are sampled 75 times per second and digitally integrated by a computer that produces a pressure-volume loop for each respiratory cycle. The slope of the hysteresis cutve represents the dynamic compliance in mL/cm HrO. Dynamic compliance is indexed by weight in kilograms to yield compliance (mL/cm HzO/kg) to allow standardization of the pressure-volume relationship for infants of different sizes. Measurements were determined at peak pressures of 15,18,20,22, and 25 cm HzO. RESULTS
Of the 20 infants, 13 were male and seven were female. The mean gestational age was 39 + 3 weeks,
Fig 1. Pulmonary function tests obtained in infants with CDH (as described in Materials and Methods). Solid bars represent initial values; hatched bars represent preoperative values. Data are presented as mean ‘_ SD. Asterisk: P < .05 for both preoperative and initial values of groups 2 and 3 versus those of group 1. (A) Compliance measurements for group 1 (repair without ECMO), group 2 (ECMO survivors), and group 3 (ECMO nonsurvivors). There is no significant difference between initial and preoperative values among any of the groups. (B) Dynamic compliance measurements for the same groups. (C) Tidal volume measurements for the same groups.
PREDICTIVE CAPABILITIES
OF PFTs IN CDH
in group 1 than in either group 2 or group 3. Differences in compliance were significant both at the time of initial presentation as well as just before repair. For infants who had serial preoperative compliance measurements, the difference in the amount of preoperative change between groups was not statistically significant. However, the magnitude of improvement for survivors was virtually the same for ECMO and non-ECMO treated patients (.ll + .14 and .12 t .ll mL/cm H,O/kg, respectively) as compared with ECMO nonsurvivors (.05 + .02 mL/cm H,O/kg). Initial and preoperative data for dynamic compliance are presented in Fig 1B. Values for group 1 were significantly higher than those for groups 2 or 3. Initial and preoperative tidal volume data are shown in Fig 1C. These data are similar to those for compliance and dynamic compliance because there were significantly greater tidal volumes in group 1 patients as compared with groups 2 and 3. This was true of values obtained at initial presentation as well as after stabilization. As was found with compliance, the difference in the amount of improvement in tidal volume during the period of preoperative stabilization was not significant. When serial postoperative pulmonary function was examined, ultimate improvement in compliance was noted in 5 of 6 patients in group 1,8 of 8 patients that had postoperative tests in group 2, and 5 of 5 in group 3. It should be noted that this improvement followed an initial decline in compliance in 9 of 14 survivors from 15% to 76%, which was variable and not significant between groups. When comparing the number of infants who postoperatively achieved a tidal volume of more than 4 mL/kg (50% of the high normal), the following results were obtained. All six patients in group 1 achieved this result, as did 7 of 9 (1 patient not measured, and I < 4 mL/kg) patients in group 2. However, only one patient among the ECMO nonsurvivors (group 3) ever had a postoperative tidal volume this large. DISCUSSION
A combination of pulmonary hypertension and pulmonary hypoplasia is responsible for the ultimate demise of infants with CDH. Use of various forms of therapy, including vasodilators and ECMO for pulmonary hypertension, and high frequency ventilation for pulmonary hypoplasia, has increased the survival for infants with CDH to between 71% and 76%.2,4 A persistently high mortality, despite aggressive therapy, has led to multiple attempts to establish criteria by
267
which survival could be predicted or by which patients might be excluded from consideration for therapy or repair.5-10 Predictors based on pulmonary hypertension include the “honeymoon period,” serial measurements of [A-a]Do2, and the oxygenation index.5-8 Heaton et al reported the survival of four of eight infants who never had a postoperative Pao2 greater than 100 mm Hg when ECMO was used.3 In careful study of 32 infants with CDH, three of seven ECMO-treated infants survived, who never had a “honeymoon”: in addition, serial [A-a]Doz measurements were found to be neither predictive nor practical.’ The study by Newman et al examined the accuracy of the honeymoon period, [A-a]Do,, and oxygenation index in a series of ECMO-treated patients. Seven infants who would have been classified as nonsalvageable survived.i5 In a recent report by Atkinson et al, there was a 69% survival rate for infants treated with ECMO, whose historic counterparts, by the criteria of the oxygenation index, had a survival rate of only 5%.lb Therefore, it appears that these criteria are part of the therapeutic regimen for CDH. Bohn et al proposed the ventilatory index, which appeared to correlate with lethal pulmonary hypoplasia.9J” This index is the product of the mean airway pressure and the respiratory rate. A 100% mortality was predicted for infants who had an index greater than 1,000, along with Pacoz of greater than 40. Unfortunately, this series consisted of a cohort of patients for whom ECMO support was not available. When the index was subsequently applied to patients in ECMO centers, it was not predictive.?J Hazebroek et al stratified infants undergoing preoperative stabilization and delayed repair into three groups. Stratification was based on initial ventilatory requirements, subsequent stabilization, and improvement or deterioration during preoperative delay. Improvement before repair indicated a better chance of survival.” The study by Sakai et al evaluated compliance before and after repair in nine patients with CDH. The four patients whose compliance decreased by more than 50% had increasing hypoxemia and acidemia postoperatively, and did not survive. ECMO was not part of the therapeutic regimen available to these patients.” Nakayama et al obtained compliance measurements in 22 infants who had CDH. These infants were managed with immediate or delayed repair. Compliance improved only slightly in those who underwent immediate repair, but doubled in those whose repair was performed after preoperative stabilization.lj The present study attempted to determine if serial
268
TRACY ET AL
measurements of compliance, dynamic compliance, and tidal volume could be used as predictors of survival, and whether preoperative values could retrospectively define the need for ECMO. All infants underwent a period of stabilization, with either ventilator therapy or extracorporeal support, followed by repair. This delay provided the opportunity to indirectly quantify the degree of pulmonary hypoplasia and to determine the effects of repair on pulmonary mechanics. The results in this group of patients indicate that initial compliance and tidal volume measurements may determine which infants will require ECMO support as part of the preoperative stabilization. The data demonstrate that there are two distinct groups of infants born with CDH. Infants whose initial compliance is greater than 0.2 mL/cm HzO/kg and initial tidal volume is greater than 3.5 mL/kg appear to have adequate pulmonary tissue and do not require ECMO. There were consistent differences in initial and preoperative compliance, dynamic compliance, and tidal volume between the patients for whom ECMO support was not required (group 1) and those for whom survival was possible only with ECMO support (group 2). Serial measurements of pulmonary function parameters during preoperative stabilization facilitate quantification of the amount of improvement in pulmonary function preoperatively. ECMO patients whose amount of improvement in dynamic compliance closely paralleled that of the non-ECMO patients had a distinct survival advantage over ECMO patients who had little or no improvement. Even though these data were not statistically significant, an overall improvement in pulmonary function would be expected to yield a more favorable prognosis. This is consistent
with the findings of Hazebroek et al, discussed previously.i7 The deleterious effects of repair on respiratory mechanics confirm the findings of Sakai et al. Hernia repair results in distortion of the diaphragm, deformation of the infant’s flexible thoracic cage, increased intraabdominal pressure, and hyperinflation of the hypoplastic contralateral lung caused by medial tension from the mediastinum.l* These factors may be responsible for the initial postoperative decline in compliance noted in most of these patients. The significance of the postoperative tidal volume data is the ability to determine which infants might survive. Thirteen of the 15 survivors eventually achieved postoperative tidal volumes of at least 4 mL/kg. In contrast, only one ECMO nonsurvivor ever had a tidal volume this large; this patient was able to be weaned from ECMO. Unfortunately, the patient did not survive an episode of recurrent pulmonary hypertension after decannulation. With further confirmation, these data may prove useful in determining which postoperative infants have no hope of survival. Our findings indicate that pulmonary function tests may be useful in the management of infants who have CDH. Compliance and tidal volume data obtained during initial presentation help to predict which infants will require ECMO during preoperative stabilization. The findings of the present study confirm those of others that repair of the diaphragmatic defect does not improve respiratory mechanics, and it is initially deleterious. Infants who have postoperative tidal volumes of 4 mL/kg have a distinct survival advantage over those who do not. The addition of this useful diagnostic adjunct to the management regimen of CDH is warranted and requires further evaluation.
REFERENCES 1. Anderson KD: Congenital diaphragmatic hernia, KJ, Randolph JG, Ravitch MM, et al (eds): Pediatric Chicago, IL, Year Book Medical, 1986, pp 589-601
in Welch Surgery,
2. Bailey PV, Connors RH. Tracy TF, et al: A critical analysis of extracorporeal membrane oxygenation for congenital diaphragmatic hernia. Surgery 106:611-616, 1989 3. Heaton JFG, Redmond CR, Graves ED, et al: Congenital diaphragmatic hernia, improving survival with extracorporeal membrane oxygenation. Pediatr Surg Int 3:6-10, 1988 4. Heiss K, Manning P, Oldham KT, et al: Reversal of mortality of congenital diaphragmatic hernia with ECMO. Ann Surg 209:225230, 1989 5. Collins DL, Pomerance to congenital posterolateral 12:149-156. 1977
JJ, Travis KW, et al: A new approach diaphragmatic hernia. J Pediatr Surg
6. Langham MR, Krummel TM, Greenfield LJ, et al: Extracorporeal membrane oxygenation following repair of congenital diaphragmatic hernias. Ann Thorac Surg 44:247-252,1987
7. Bartlett RH, Gazzaniga AB, Toomasian J, et al: Extracorporeal membrane oxygenation (ECMO) in neonatal respiratory failure. Ann Surg 204:236-245.1986 8. Krummel TM, Greenfield LJ, Kirkpatrick BV. et al: Alveolararterial oxygen gradients versus the neonatal pulmonary insufficiency index for prediction of mortality in ECMO candidates. J Pediatr Surg 19:380-384, 1984 9. Bohn DJ, James I, Filler RM, et al: The relationship between Pacoz and ventilatory parameters in predicting survival in congenital diaphragmatic hernia. J Pediatr Surg 19:666-671, 1984 10. Bohn D, Tamura M, Perrin D, et al: Ventilatory predictors of pulmonary hypoplasia in congenital diaphragmatic hernia confirmed by morphologic assessment. J Pediatr 111:423-431, 1987 11. Stolar C, Dillon P, Reyes C: Selective use of extracorporeal membrane oxygenation in the management of congenital diaphragmatic hernia. J Pediatr Surg 23:207-211, 1988 12. Sakai H. Tamura
M, Hosokawa
Y, et al: Effects
of surgical
PREDICTIVE CAPABILITIES
OF PFTs IN CDH
269
repair on respiratory mechanics in congenital diaphragmatic hernia. J Pediatr 111:432-438, 1987 13. Nakayama DK. Motoyama EK. Tagge EM: Effects of preoperative stabilization on respiratory system compliance and outcome in newborn infants with congenital diaphragmatic hernia. J Pediatr 118:793-799, 1991 14. Bhutani VK, Sivieri EM, Abbasi S, et al: Evaluation of neonatal pulmonary mechanics and energetics: A two factor least mean square analysis. Pediatr Pulmonol4:150-158, 1988 15. Newman KD, Anderson KD. Van Meurs K, et al: Extracor-
poreal membrane oxygenation and congenital diaphragmatic hernia: Should any infant be excluded? J Pediatr Surg 25:1048-1053, 1990 16. Atkinson JB, Ford EG. Humphries B, et al: The impact of extracorporeal membrane support in the treatment of congenital diaphragmatic hernia. J Pediatr Surg 26:791-793. 1991 17. Hazebroek FWJ, Tibboel D, Bos AP, et al: Congenital diaphragmatic hernia: Impact of preoperative stabilization. A prospective pilot study in 13 patients. J Pediatr Surg 23:1139-l 146, 1988
Discussion M.R. Langham
(Gainesville, FL):
I enjoyed the work very much, and I think the group at Cardinal Glennon in St Louis continues to present good clinical results with diaphragmatic hernia and, importantly, have added physiological information to our knowledge of this disorder. Most of us lack an intimate familiarity with pulmonary function testing; at least I know that I do not use it on a day-to-day basis in my practice, and so in trying to review the manuscript I called Tom Shaeffer, PhD, a physiologist at Temple University who is the man that developed the PEDS system, which is the commercially available system used in this study. I asked Tom what he thought about the application in this population. It was very reassuring to hear Tom say, and I quote, “You would have to go out of your way to screw this up.” As a surgeon, that makes you think there is really something to this. Other people are not quite so kind, though, and implied that there are a lot of ways you could screw this up, including failure to measure airway pressure at occlusion so that there is pressure equilibration. Was this done, and was the phase between the esophageal pressure and the pulmonary pressure in synch? If there is a phase lag in those two pressures, you can get a substantial skewing of the hysteresis curve used to measure compliance. In two previous studies of pulmonary function tests in chiidren with diaphragmatic hernia, a different method was used to determine compliance. This is LaSouef’s method and, I am sorry for the small print, but if you’ll notice, compliance in Sakai’s data and in Nakiyama’s data was substantially higher than what Dr Bailey has just presented. Sakai reported that preoperative compliance was 0.41 (mL/cm HZ0 kg) in those who died and 0.81 (mL/cm Hz0 kg) in those who survived. Postoperative compliance was much higher in Nakiyama’s study than the 0.3 value that we have just been told about. Therefore, there may be several-fold differences in compliance as measured by
different techniques, and the values in this study have to be interpreted in that light. Furthermore, tidal volume is treatment-dependent. If you crank up the pressure on a ventilator, you can increase a child’s tidal volume. You may also destroy his or her lungs. Therefore, the benefits of achieving a tidal volume at 4 mL/kg/min is not something that I think can be extrapolated outside of Cardinal Glennon Hospital and the ventilatory scheme used in that hospital. I have the following questions for the authors. Because compliance seems to be less treatmentdependent than tidal volume and, therefore, a better candidate as a measured variable, what is the interpatient variability of your study? That is, how repeatable was the PEDS system in determining the compliance of each individual patient on a repetitive basis? Do you use the data from an individual patient to alter your day-to-day management of that patient? And, do you think that pulmonary function tests actually may be valuable in identifying a subgroup of smaller, perhaps less mature patients who would benefit from surfactant therapy, as Phil Glick has suggested, or alternatively, might benefit from prenatal therapy with steroids as suggested by the poster from Massachusetts General Hospital presented at this meeting? P.V. Bailey (response): The accuracy of the PEDS System is related to airway occlusion only if spontaneous breaths are being taken. In our study, mechanical breaths were measured initially, preoperatively, and postoperatively. For that reason, the pressure being measured was actually airway pressure. As long as airway pressure guidelines are adhered to as we described for peak inspiratory pressures. then these methodological problems are eliminated. An esophageal balloon is required only for compliance measurements of breaths that are taken spontaneously. Although compliance may be the best candidate for a prognostic variable, our study demonstrated more
270
significant findings with tidal volume. Our system is technology-dependent, as is true of many other studies. With the same respiratory therapist performing these measurements, repetitive measurements made on the same patient, and under the same conditions, we have not found significant variation. As Dr Langham pointed out, we wish to further underscore the need to take repeated tidal volume measurements, as well as compliance measurements, over the range of peak inspiratory pressures, so as not to artificially inflate tidal volume. Our preoperative and postoperative data were obtained on a daily basis, and were determined over three different time points during the same study. In some cases, studies were performed two separate times during a day. The data that we generated with pulmonary function tests were, and continue to be, important to our day-to-day management. In collaboration with our neonatologists, optimal compliance and tidal volume are established on a daily basis, depending on PFT values. This has allowed us to set maximum tidal
TRACY
ET AL
volume measurements without increasing barotrauma. We do think pulmonary function tests may identify a group of patients that could be treated with surfactant. Clearly, because of the overlap between ECMO survivors and nonsurvivors, the issue remains as to whether surfactant would have helped any of the nonsurvivors. We also question whether the time course of improvement in compliance might be shortened by the administration of surfactant to augment pulmonary mechanics, as well as ameliorating pulmonary hypertension, as has been reported. With respect to prenatal administration of steroids, our main consideration is that, because most infants with diaphragmatic hernia are born at full term, administration of steroids may only open the door for perinatal infection. Because of the ready availability of surfactant, and a well-established practice of administration, we would prefer postnatal surfactant at this time, until further data about prenatal steroids have been collected.
F. Tracy, Jr, Patrick V. Bailey, Farouk Sadiq, Akihiko
St @To improve diaphragmatic conventional
the survival
of newborns
hernia (CDH), preoperative ventilatory
brane oxygenation
therapy
with
congenital
stabilization
and extracorporeal
with mem-
(ECMO) have been used. Measurements
that quantify pulmonary function may allow an accurate assessment of lethal pulmonary hypoplasia and predict outcome. Pulmonary function tests (PFTs) were obtained in 20 infants preoperatively and postoperatively; these included measurements of compliance, dynamic compliance, and tidal volume. Overall survival was 75%. Six surviving infants were initially managed with ventilator therapy alone, followed by repair (group 1). The remaining 14 patients, who were moribund at presentation or whose initial ventilator therapy failed, were placed on ECMO and received repair during bypass; nine survived (group 2). and five died (group 3). Compliance, dynamic compliance, and tidal volume obtained at initial presentation
and immediately
preoperatively
were
significantly higher for group 1 as compared with groups 2 and 3. Infants whose initial compliance was greater than 0.25 mL/cm mL/kg
HrO/ kg and initial tidal volume was greater than 3.5 did not require ECMO. Ultimate improvement in
compliance
was noted in 5 of 6 patients
in group 1, 6 of 8
patients in group 2, and 5 of 5 in group 3. This improvement followed an initial decline in compliance in 9 of 14 survivors, from 15% to 76%. All six patients in group 1 had tidal volumes of more than 4 mL/ kg, as did 7 of 9 patients in group 2. Only one patient among the ECMO nonsurvivors (group 3) had a postoperative tidal volume of this magnitude. These data suggest that initial PFTs may predict which infants will require ECMO. A postoperative tidal volume of more than 4 mL/ kg may be critical for survival. Copyright o 1994 by W.B. Saunders Company INDEX WORDS: poreal membrane sia.
Congenital
diaphragmatic
oxygenation
hernia; extracor-
(ECMO); pulmonary
Noguchi,
Mark L. Silen, and Thomas
R. Weber
Louis, Missouri
hypopla-
C when symptomatic ONGENITAL
diaphragmatic hernia (CDH), within the first few hours of life has, until recently, been associated with a mortality rate of approximately 50%.’ Vasoactive drugs and innovative ventilator techniques including high frequency systems, extracorporeal membrane oxygenation (ECMO), and stabilization before repair have contributed to significant increases in survival, of up to 76% of patients.“4 Many infants continue to die of pulmonary hypertension and pulmonary hypoplasia despite the most aggressive treatment. Numerous investigators have sought to define measurable parameters of hemodynamic or pulmonary sequelae of this lesion that accurately predict the need for specific therapeutic modalities or eventual survival.5-i(’ No JournalofPediatric Surgery, Vol 29, No 2 (February), 1994: pp 265-270
study has been able to firmly establish any predictive index of survival that can be consistently reproduced. ECMO provides an excellent treatment option for infants with refractory pulmonary hypertension, and certain indexes have been used to help anticipate which patients will benefit from its use.3-4.7JJ1Unfortunately, comparable indexes have not been as effective for determining lethal pulmonary hypoplasia.2J Pulmonary function tests seem uniquely suited to this purpose. Compliance measurements of Sakai et al and Nakayama et al in infants with CDH demonstrated both the deleterious effects of surgical repair on respiratory mechanics and the benefits of delayed repair.i2J3 The present study was designed to determine whether measurements of pulmonary function performed over the course of management of CDH are adequate predictors of survival, and whether values taken at the time of presentation can be used to predict the need for ECMO as an adjunctive therapy during the period of initial stabilization. MATERIALS
AND METHODS
Patients The study group comprised 20 consecutively treated infants with CDH, who were symptomatic within the first 6 hours of life. All were treated with repair of the diaphragmatic defect after an initial period of preoperative stabilization. ECMO was used in patients who presented with refractory hypoxemia or in those whose clinical course deteriorated despite conventional ventilatoty management.’ Repair of the hernia was undertaken only after the clinical course had improved and pH and PO? were normal. For purposes of comparison, the infants were divided mto three study groups. Six infants (group 1) were successfully managed with ventilator therapy alone and then received repair. The other 14 infants, who were moribund at presentation or whose conventional ventilator therapy failed, were placed on ECMO and had repair during bypass. The nine surviving patients constitute group 2. Group 3 consists of the remaining five patients who did not survive. Data examined for each patient include gestational age, birth weight, and the pulmonary function parameters of compliance,
From the Divisions of Pediattic Suqery and Neonatology Depanmen& of Suqety and Pediatrics, Cardinul Glennon Children’s Hospital, St Louis UniversityMedical Center. St Louis, MO. Presented at the 24th Annual Meeting of the American Pediattic Surgical Association, Hilton Head, South Carolina. May 15-18, 1993. Address reprint requests to Thomas F. Tracy. Jr, MD, Division of Pediattic Surgery. 1465 S Grand Blvd, St Louis. MO 63104. Copyright CCI994 by W.B. Saunders Cornpam 0022-3468/9412902-0025$03.OOlO 265
266
TRACY ET AL
dynamic compliance, and tidal volume. Data were analyzed with the use of a statistical software package (Statview; Brainpower, Inc, Calabasas, CA). All data are expressed as mean plus or minus the standard deviation of the mean (*SD). Data were analyzed for statistical significance using analysis ofvariance and Fisher’s test. A P value of less than .05 was considered significant.
Management All patients were initially managed by endotracheal intubation and mechanical ventilation. Inspired oxygen concentration (FIo~) was adjusted to maintain the arterial oxygen saturation at greater than 90%. Ventilation was adjusted to maintain arterial pH above 7.5 and Pacoz between 35 and 50 mm Hg. Refractory acidemia was treated with either sodium bicarbonate or tromethamine (THAM) to obtain systemic alkalinization. Fluids were restricted to 80 to 100 ml/kg/d. Hypotension was treated with dopamine 5 to 15 kg/kg/ min. The techniques for ECMO cannulation and management have been reported previously.2 The right internal jugular vein and right common carotid artery were cannulated. Flow was maintained to direct approximately 80% of the cardiac output through the extracorporeal circuit. While on bypass, all infants received a continuous infusion of heparin, which maintained activated clotting times of between 180 and 220 seconds. Ventilator support was limited during ECMO to minimize barotrauma and oxygen toxicity, (F10z = 0.4; peak inspiratory pressure = 15 cm HzO; positive end expiratory pressure = 2 cm HzO; intermittent mandatory ventilation = 20 breaths per minute).
and the mean birth weight was 3,006 + 705 g (range, 1,547 to 4,100 g). There were no significant differences in these parameters between groups. The overall survival was 15 of 20 (75%). Serial preoperative pulmonary function measurements were obtained in four patients in group 1, five in group 2, and two in group 3. For patients in whom serial measurements were not obtained, “initial” values were also considered as preoperative values. Compliance data obtained at the initial presentation and preoperatively for all three groups are shown in Fig 1A. Mean compliance was significantly greater A"'1
-I-
0.9
ml/cm
H20
kg 01
Pulmonary Function Measurements Parameters of pulmonary function were measured serially, preoperatively and postoperatively. with a commercially available noninvasive system (PeDS-Pulmonary Evaluation and Diagnostic System, Medical Associated Services, Inc, Hatfield, PA). In this system, concurrent signals of airllow and transpulmonary pressure are used to calculate values of dynamic compliance and pulmonary resistance. Data are analyzed on-line, using a two-factor, leastmean square analysis technique in which the respiratory system is modeled as a single-compartment linear mechanical system based on the Rohrer equation of motion. This technique minimizes the error between measured pressure and calculated pressure, and makes it possible to evaluate the mechanical behavior of the respiratory system over the entire tidal volume range of breathing.i4 Air flow during the respiratory cycle is determined by use of a pneumotachometer connected in series to the patient, The volume change is determined by the digital integration of this airflow signal and then plotted on the x axis. Transpulmonary pressure, plotted on they axis, is calculated as the difference between intrapleural pressure (measured indirectly via an esophageal balloon), and airway pressure. Data are sampled 75 times per second and digitally integrated by a computer that produces a pressure-volume loop for each respiratory cycle. The slope of the hysteresis cutve represents the dynamic compliance in mL/cm HrO. Dynamic compliance is indexed by weight in kilograms to yield compliance (mL/cm HzO/kg) to allow standardization of the pressure-volume relationship for infants of different sizes. Measurements were determined at peak pressures of 15,18,20,22, and 25 cm HzO. RESULTS
Of the 20 infants, 13 were male and seven were female. The mean gestational age was 39 + 3 weeks,
Fig 1. Pulmonary function tests obtained in infants with CDH (as described in Materials and Methods). Solid bars represent initial values; hatched bars represent preoperative values. Data are presented as mean ‘_ SD. Asterisk: P < .05 for both preoperative and initial values of groups 2 and 3 versus those of group 1. (A) Compliance measurements for group 1 (repair without ECMO), group 2 (ECMO survivors), and group 3 (ECMO nonsurvivors). There is no significant difference between initial and preoperative values among any of the groups. (B) Dynamic compliance measurements for the same groups. (C) Tidal volume measurements for the same groups.
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in group 1 than in either group 2 or group 3. Differences in compliance were significant both at the time of initial presentation as well as just before repair. For infants who had serial preoperative compliance measurements, the difference in the amount of preoperative change between groups was not statistically significant. However, the magnitude of improvement for survivors was virtually the same for ECMO and non-ECMO treated patients (.ll + .14 and .12 t .ll mL/cm H,O/kg, respectively) as compared with ECMO nonsurvivors (.05 + .02 mL/cm H,O/kg). Initial and preoperative data for dynamic compliance are presented in Fig 1B. Values for group 1 were significantly higher than those for groups 2 or 3. Initial and preoperative tidal volume data are shown in Fig 1C. These data are similar to those for compliance and dynamic compliance because there were significantly greater tidal volumes in group 1 patients as compared with groups 2 and 3. This was true of values obtained at initial presentation as well as after stabilization. As was found with compliance, the difference in the amount of improvement in tidal volume during the period of preoperative stabilization was not significant. When serial postoperative pulmonary function was examined, ultimate improvement in compliance was noted in 5 of 6 patients in group 1,8 of 8 patients that had postoperative tests in group 2, and 5 of 5 in group 3. It should be noted that this improvement followed an initial decline in compliance in 9 of 14 survivors from 15% to 76%, which was variable and not significant between groups. When comparing the number of infants who postoperatively achieved a tidal volume of more than 4 mL/kg (50% of the high normal), the following results were obtained. All six patients in group 1 achieved this result, as did 7 of 9 (1 patient not measured, and I < 4 mL/kg) patients in group 2. However, only one patient among the ECMO nonsurvivors (group 3) ever had a postoperative tidal volume this large. DISCUSSION
A combination of pulmonary hypertension and pulmonary hypoplasia is responsible for the ultimate demise of infants with CDH. Use of various forms of therapy, including vasodilators and ECMO for pulmonary hypertension, and high frequency ventilation for pulmonary hypoplasia, has increased the survival for infants with CDH to between 71% and 76%.2,4 A persistently high mortality, despite aggressive therapy, has led to multiple attempts to establish criteria by
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which survival could be predicted or by which patients might be excluded from consideration for therapy or repair.5-10 Predictors based on pulmonary hypertension include the “honeymoon period,” serial measurements of [A-a]Do2, and the oxygenation index.5-8 Heaton et al reported the survival of four of eight infants who never had a postoperative Pao2 greater than 100 mm Hg when ECMO was used.3 In careful study of 32 infants with CDH, three of seven ECMO-treated infants survived, who never had a “honeymoon”: in addition, serial [A-a]Doz measurements were found to be neither predictive nor practical.’ The study by Newman et al examined the accuracy of the honeymoon period, [A-a]Do,, and oxygenation index in a series of ECMO-treated patients. Seven infants who would have been classified as nonsalvageable survived.i5 In a recent report by Atkinson et al, there was a 69% survival rate for infants treated with ECMO, whose historic counterparts, by the criteria of the oxygenation index, had a survival rate of only 5%.lb Therefore, it appears that these criteria are part of the therapeutic regimen for CDH. Bohn et al proposed the ventilatory index, which appeared to correlate with lethal pulmonary hypoplasia.9J” This index is the product of the mean airway pressure and the respiratory rate. A 100% mortality was predicted for infants who had an index greater than 1,000, along with Pacoz of greater than 40. Unfortunately, this series consisted of a cohort of patients for whom ECMO support was not available. When the index was subsequently applied to patients in ECMO centers, it was not predictive.?J Hazebroek et al stratified infants undergoing preoperative stabilization and delayed repair into three groups. Stratification was based on initial ventilatory requirements, subsequent stabilization, and improvement or deterioration during preoperative delay. Improvement before repair indicated a better chance of survival.” The study by Sakai et al evaluated compliance before and after repair in nine patients with CDH. The four patients whose compliance decreased by more than 50% had increasing hypoxemia and acidemia postoperatively, and did not survive. ECMO was not part of the therapeutic regimen available to these patients.” Nakayama et al obtained compliance measurements in 22 infants who had CDH. These infants were managed with immediate or delayed repair. Compliance improved only slightly in those who underwent immediate repair, but doubled in those whose repair was performed after preoperative stabilization.lj The present study attempted to determine if serial
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measurements of compliance, dynamic compliance, and tidal volume could be used as predictors of survival, and whether preoperative values could retrospectively define the need for ECMO. All infants underwent a period of stabilization, with either ventilator therapy or extracorporeal support, followed by repair. This delay provided the opportunity to indirectly quantify the degree of pulmonary hypoplasia and to determine the effects of repair on pulmonary mechanics. The results in this group of patients indicate that initial compliance and tidal volume measurements may determine which infants will require ECMO support as part of the preoperative stabilization. The data demonstrate that there are two distinct groups of infants born with CDH. Infants whose initial compliance is greater than 0.2 mL/cm HzO/kg and initial tidal volume is greater than 3.5 mL/kg appear to have adequate pulmonary tissue and do not require ECMO. There were consistent differences in initial and preoperative compliance, dynamic compliance, and tidal volume between the patients for whom ECMO support was not required (group 1) and those for whom survival was possible only with ECMO support (group 2). Serial measurements of pulmonary function parameters during preoperative stabilization facilitate quantification of the amount of improvement in pulmonary function preoperatively. ECMO patients whose amount of improvement in dynamic compliance closely paralleled that of the non-ECMO patients had a distinct survival advantage over ECMO patients who had little or no improvement. Even though these data were not statistically significant, an overall improvement in pulmonary function would be expected to yield a more favorable prognosis. This is consistent
with the findings of Hazebroek et al, discussed previously.i7 The deleterious effects of repair on respiratory mechanics confirm the findings of Sakai et al. Hernia repair results in distortion of the diaphragm, deformation of the infant’s flexible thoracic cage, increased intraabdominal pressure, and hyperinflation of the hypoplastic contralateral lung caused by medial tension from the mediastinum.l* These factors may be responsible for the initial postoperative decline in compliance noted in most of these patients. The significance of the postoperative tidal volume data is the ability to determine which infants might survive. Thirteen of the 15 survivors eventually achieved postoperative tidal volumes of at least 4 mL/kg. In contrast, only one ECMO nonsurvivor ever had a tidal volume this large; this patient was able to be weaned from ECMO. Unfortunately, the patient did not survive an episode of recurrent pulmonary hypertension after decannulation. With further confirmation, these data may prove useful in determining which postoperative infants have no hope of survival. Our findings indicate that pulmonary function tests may be useful in the management of infants who have CDH. Compliance and tidal volume data obtained during initial presentation help to predict which infants will require ECMO during preoperative stabilization. The findings of the present study confirm those of others that repair of the diaphragmatic defect does not improve respiratory mechanics, and it is initially deleterious. Infants who have postoperative tidal volumes of 4 mL/kg have a distinct survival advantage over those who do not. The addition of this useful diagnostic adjunct to the management regimen of CDH is warranted and requires further evaluation.
REFERENCES 1. Anderson KD: Congenital diaphragmatic hernia, KJ, Randolph JG, Ravitch MM, et al (eds): Pediatric Chicago, IL, Year Book Medical, 1986, pp 589-601
in Welch Surgery,
2. Bailey PV, Connors RH. Tracy TF, et al: A critical analysis of extracorporeal membrane oxygenation for congenital diaphragmatic hernia. Surgery 106:611-616, 1989 3. Heaton JFG, Redmond CR, Graves ED, et al: Congenital diaphragmatic hernia, improving survival with extracorporeal membrane oxygenation. Pediatr Surg Int 3:6-10, 1988 4. Heiss K, Manning P, Oldham KT, et al: Reversal of mortality of congenital diaphragmatic hernia with ECMO. Ann Surg 209:225230, 1989 5. Collins DL, Pomerance to congenital posterolateral 12:149-156. 1977
JJ, Travis KW, et al: A new approach diaphragmatic hernia. J Pediatr Surg
6. Langham MR, Krummel TM, Greenfield LJ, et al: Extracorporeal membrane oxygenation following repair of congenital diaphragmatic hernias. Ann Thorac Surg 44:247-252,1987
7. Bartlett RH, Gazzaniga AB, Toomasian J, et al: Extracorporeal membrane oxygenation (ECMO) in neonatal respiratory failure. Ann Surg 204:236-245.1986 8. Krummel TM, Greenfield LJ, Kirkpatrick BV. et al: Alveolararterial oxygen gradients versus the neonatal pulmonary insufficiency index for prediction of mortality in ECMO candidates. J Pediatr Surg 19:380-384, 1984 9. Bohn DJ, James I, Filler RM, et al: The relationship between Pacoz and ventilatory parameters in predicting survival in congenital diaphragmatic hernia. J Pediatr Surg 19:666-671, 1984 10. Bohn D, Tamura M, Perrin D, et al: Ventilatory predictors of pulmonary hypoplasia in congenital diaphragmatic hernia confirmed by morphologic assessment. J Pediatr 111:423-431, 1987 11. Stolar C, Dillon P, Reyes C: Selective use of extracorporeal membrane oxygenation in the management of congenital diaphragmatic hernia. J Pediatr Surg 23:207-211, 1988 12. Sakai H. Tamura
M, Hosokawa
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repair on respiratory mechanics in congenital diaphragmatic hernia. J Pediatr 111:432-438, 1987 13. Nakayama DK. Motoyama EK. Tagge EM: Effects of preoperative stabilization on respiratory system compliance and outcome in newborn infants with congenital diaphragmatic hernia. J Pediatr 118:793-799, 1991 14. Bhutani VK, Sivieri EM, Abbasi S, et al: Evaluation of neonatal pulmonary mechanics and energetics: A two factor least mean square analysis. Pediatr Pulmonol4:150-158, 1988 15. Newman KD, Anderson KD. Van Meurs K, et al: Extracor-
poreal membrane oxygenation and congenital diaphragmatic hernia: Should any infant be excluded? J Pediatr Surg 25:1048-1053, 1990 16. Atkinson JB, Ford EG. Humphries B, et al: The impact of extracorporeal membrane support in the treatment of congenital diaphragmatic hernia. J Pediatr Surg 26:791-793. 1991 17. Hazebroek FWJ, Tibboel D, Bos AP, et al: Congenital diaphragmatic hernia: Impact of preoperative stabilization. A prospective pilot study in 13 patients. J Pediatr Surg 23:1139-l 146, 1988
Discussion M.R. Langham
(Gainesville, FL):
I enjoyed the work very much, and I think the group at Cardinal Glennon in St Louis continues to present good clinical results with diaphragmatic hernia and, importantly, have added physiological information to our knowledge of this disorder. Most of us lack an intimate familiarity with pulmonary function testing; at least I know that I do not use it on a day-to-day basis in my practice, and so in trying to review the manuscript I called Tom Shaeffer, PhD, a physiologist at Temple University who is the man that developed the PEDS system, which is the commercially available system used in this study. I asked Tom what he thought about the application in this population. It was very reassuring to hear Tom say, and I quote, “You would have to go out of your way to screw this up.” As a surgeon, that makes you think there is really something to this. Other people are not quite so kind, though, and implied that there are a lot of ways you could screw this up, including failure to measure airway pressure at occlusion so that there is pressure equilibration. Was this done, and was the phase between the esophageal pressure and the pulmonary pressure in synch? If there is a phase lag in those two pressures, you can get a substantial skewing of the hysteresis curve used to measure compliance. In two previous studies of pulmonary function tests in chiidren with diaphragmatic hernia, a different method was used to determine compliance. This is LaSouef’s method and, I am sorry for the small print, but if you’ll notice, compliance in Sakai’s data and in Nakiyama’s data was substantially higher than what Dr Bailey has just presented. Sakai reported that preoperative compliance was 0.41 (mL/cm HZ0 kg) in those who died and 0.81 (mL/cm Hz0 kg) in those who survived. Postoperative compliance was much higher in Nakiyama’s study than the 0.3 value that we have just been told about. Therefore, there may be several-fold differences in compliance as measured by
different techniques, and the values in this study have to be interpreted in that light. Furthermore, tidal volume is treatment-dependent. If you crank up the pressure on a ventilator, you can increase a child’s tidal volume. You may also destroy his or her lungs. Therefore, the benefits of achieving a tidal volume at 4 mL/kg/min is not something that I think can be extrapolated outside of Cardinal Glennon Hospital and the ventilatory scheme used in that hospital. I have the following questions for the authors. Because compliance seems to be less treatmentdependent than tidal volume and, therefore, a better candidate as a measured variable, what is the interpatient variability of your study? That is, how repeatable was the PEDS system in determining the compliance of each individual patient on a repetitive basis? Do you use the data from an individual patient to alter your day-to-day management of that patient? And, do you think that pulmonary function tests actually may be valuable in identifying a subgroup of smaller, perhaps less mature patients who would benefit from surfactant therapy, as Phil Glick has suggested, or alternatively, might benefit from prenatal therapy with steroids as suggested by the poster from Massachusetts General Hospital presented at this meeting? P.V. Bailey (response): The accuracy of the PEDS System is related to airway occlusion only if spontaneous breaths are being taken. In our study, mechanical breaths were measured initially, preoperatively, and postoperatively. For that reason, the pressure being measured was actually airway pressure. As long as airway pressure guidelines are adhered to as we described for peak inspiratory pressures. then these methodological problems are eliminated. An esophageal balloon is required only for compliance measurements of breaths that are taken spontaneously. Although compliance may be the best candidate for a prognostic variable, our study demonstrated more
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significant findings with tidal volume. Our system is technology-dependent, as is true of many other studies. With the same respiratory therapist performing these measurements, repetitive measurements made on the same patient, and under the same conditions, we have not found significant variation. As Dr Langham pointed out, we wish to further underscore the need to take repeated tidal volume measurements, as well as compliance measurements, over the range of peak inspiratory pressures, so as not to artificially inflate tidal volume. Our preoperative and postoperative data were obtained on a daily basis, and were determined over three different time points during the same study. In some cases, studies were performed two separate times during a day. The data that we generated with pulmonary function tests were, and continue to be, important to our day-to-day management. In collaboration with our neonatologists, optimal compliance and tidal volume are established on a daily basis, depending on PFT values. This has allowed us to set maximum tidal
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volume measurements without increasing barotrauma. We do think pulmonary function tests may identify a group of patients that could be treated with surfactant. Clearly, because of the overlap between ECMO survivors and nonsurvivors, the issue remains as to whether surfactant would have helped any of the nonsurvivors. We also question whether the time course of improvement in compliance might be shortened by the administration of surfactant to augment pulmonary mechanics, as well as ameliorating pulmonary hypertension, as has been reported. With respect to prenatal administration of steroids, our main consideration is that, because most infants with diaphragmatic hernia are born at full term, administration of steroids may only open the door for perinatal infection. Because of the ready availability of surfactant, and a well-established practice of administration, we would prefer postnatal surfactant at this time, until further data about prenatal steroids have been collected.