Congenital Diaphragmatic Hernia: Predictors of Severity in the ECMO Era By Jay M. Wilson, Dennis P. Lund, Craig W. Lillehei, and Joseph P. Vacanti Boston, Massachusetts 0 Infants with congenital diaphragmatic hernia (CDH) demonstrate a wide range of anatomic and physiologic abnormalities, making it difficult
risk and included in this study if they presented with respiratory distress within the first 6 hours of life (n = 94). In order to focus on predictors of pulmonary insufficiency, patients who died of nonpulmonary causes or had other significant congenital anomalies were excluded from this review, leaving 59 patients for analysis. All the infants during this period had intensive pharmacological and ventilatory support. When needed, ECMO was offered postoperatively from 1984 to 1987, and preoperatively from 1987 to the present. Forty-five of 59 had a best postductal PO, (BPDPO,) > 100 mm Hg, and 41 of these responders survived (91%). Fourteen patients had a BPDPO, < 100 mm Hg and only one survived (7%) (P = .OOOl). Mean BPDPO, between survivors with or without ECMO, and nonsurvivors were also significantly different (P = 891). To incorporate ventilatory information, an oxygenation/ventilation index was devised: [OVI = PO,/(mean airway pressure x respiratory rate) x 1001. Differences in OVI between these three groups were also significant. When analyzing the data by the method proposed by Bohn (PCO, v VI), no correlation between ventilatory parameters and outcome was found. However when the best (lowest) PCO, x VI for each patient was used, a plot of PCO, versus VI was predictive. We conclude that: (1) BPDPO, is an accurate predictor of mortality and severity in high-risk CDH infants, but is highly dependant on degree of ventilation and alkalosis; (2) OVI is predictive of mortality and severity and by correlating PO, with ventilation parameters may allow comparisons among institutions; (3) Bohn’s criteria, when applied at prespecified intervals, did not correlate well with severity or outcome in our population, but a plot based on the best PCO, x VI achieved by each patient was predictive; and (4) nonresponders to maximum conventional mechanical ventilation (BPDPO, < 199; BPDPCO, > 40 with VI > 1,000) have not benefited from the introduction of ECMO and continue to be nonsalvagable.
Copyright o 1991 by WA Saunders Company INDEX WORDS: Congenital diaphragmatic poreal membrane oxygenation (ECMO).
P
hernia; extracor-
RIOR TO THE ADVENT of extracorporeal membrance oxygenation (ECMO), little impact had been made on the mortality of high-risk congenital diaphragmatic hernia (CDH) in patients symptomatic within the first 6 hours of life. Most published series reported survivals of approximately 50%.le4 Many predictors of mortality have been proposed, 1028
based on pH, PCO,, (A-a)DO,, or best preductal or postductal P0,.2,3,5,6All were useful in their respective institutions, but none have been found to be universally applicable. This was due in part to varying methods of management of the neonate with CDH. In addition, measurements were taken at different anatomic sites and at different times relative to repair of the defect. Bohn used ventilatory parameters to prognosticate by plotting PCO, versus ventilation index (VI = ventilator-y rate x mean airway pressure),7 and was accurately able to predict outcome in a series of 58 consecutive infants with CDH. This prediction was based on a single measurement taken 2 hours postoperatively. He subsequently used preoperative measurements with similar results.’ Prior to the widespread use of ECMO, Bohn’s method worked well because patients who deteriorated after a stable interval or who never stabilized, usually did not survive. Therefore, predictions of survival based on arterial blood gas (ABG) and ventilatory data, measured at predetermined intervals, were accurate. The introduction of ECMO made the predictibility of mortality more difficult. In some instances, ECMO is capable of reversing the deterioration heralded by the development of transient pulmonary hypertension and the resulting right-to-left shunting. This has clearly resulted in salvage of individual infants who would have otherwise died.” Accordingly, CDH infants who were predicted to die by pre-ECMO criteria have been saved with ECMO and an increase in overall survival of CDH infants has been noted in some institutions.11-13However, other institutions have not seen overall survival improved with ECM0.14 This study was undertaken to examine severity of illness parameters in infants with CDH in a single large institution in order to determine whether any predictors of severity could be identified in the
From the Department of Surgery, The Children’s Hospital, and Harvard Medical School, Boston, MA. presented at the 42nd Annual Meeting of the Surgical Section of the American Academy of Pediatrics, Boston, Massachusetts, October 6-7, 1990. Address reprint requests to Jay M. Wilson, MD, Depanment of Sutgety, The Children ‘s Hospital Fegan 4,300 Longwood Ave, Boston, MA 02115. Copyright o 1991 by W.B. Saunders Company 0022-3468191 f2609-0004$03.00/0 JournatofPediatric Surgety, Vol26, No 9 (September), 1991: pp 1028-1034
CDH: PREDICTORS OF SEVERITY
1029
ECMO era. To improve communication and facilitate comparisons of results, we also attempted to identify new methods of analysis that might transcend institutional differences in population severity and management. MATERIALS
AND METHODS
We reviewed the charts of all patients with CDH treated at this institution since 1984, when ECMO became available (n = 110). Ninety-four infants presented with respiratory distress within the first 6 hours of life and were categorized as high risk. In order to focus on illness attributable to pulmonary insufficiency alone, patients with other anomalies incompatible with survival (eg, cardiac or CNS lesions), or who died of complications unrelated to pulmonary status (eg, intracranial hemorrhage), were excluded from this review (n = 35) leaving 59 for analysis. All infants were intubated and were given intravenous pancuronium bromide (0.1 to 0.2 mg/kg) and fentanyl(l0 to 50 kg/kg/h). They were mechanically ventilated at rates ranging from 35 to 150 breaths/mitt, and peak inspiratory pressures up to 45 cm H,O to maintain PaO, > 100 mm Hg, PaCO, < 30 mm Hg, and pH > 7.5. Intravenous sodium bicarbonate and/or THAM (tromethamine; Abbott Pharmaceuticals, Chicago, IL) were used as necessary to enhance alkalosis. All infants had post-ductal arterial lines placed during initial resuscitation. Between 1984 and 1987, all patients underwent CDH repair immediately upon arrival at our institution. During this era, ECMO was offered postoperatively. Between 1987 and 1989 surgical repair was delayed up to 36 hours to allow preoperative stabilization, including ECMO if necessary. Prior to 1987, ECMO criteria were: preductal and postductal PO, 100, VI < 1,000; (C) PO, < 100, VI > 1,000; (D) PO, > 100, VI > 1,000.
distribution of all blood gases in survivors. Because of this variation with individual patients over time, Bohn’s plots made at predetermined intervals were not predictive of outcome in our experience. However, because BPDPO, and BPDPCO, were predictive where random values were not, an analysis was made of best PaCO, x VI. The best gas was judged by the lowest product of PaCO, x VI, namely, the lowest PaCO, relative to the ventilation required to achieve it. The results are shown in Fig 6, and, once again, severity groups tended to stratify. In box B (PaCO, < 40 mm Hg, VI < 1,000) survival was lOO%, with 3 of 19 (15%) requiring ECMO. In box D (PaCO, < 40 mm Hg, VI > l,OOO),8 of 14 patients (55%) survived but all patients required ECMO. In box C (PaCO, > 40 mm Hg, VI > 1,000) survival was only one of seven (14%), despite ECMO in all patients (P < .OOl). Only one patient landed in box A (PaCO, > 40 mm Hg, VI < 1,000) and that patient survived with ECMO. Significant differences were achieved between boxes B and C, B and D, and C and D (P < .OOl). Box A with one patient could not be evaluated. These results are similar to Bohn’s original distribution and, again, allow predictions based on ventilatory parameters.
Table 2. OVI in 40 Patients
Table 3. BPDCO, and VI in 40 Patients
Outcome
pao,*
Survived without ECMO
322 + 27
430 + 45
Survived with ECMO
246 + 31
1263 2 115
75 k 18
1932 k 219
Died despite ECMO
I
0-l
Vlt
OVIS 84k
10
27 k 7 4kl
NOTE. All values expressed as mean +SEM. P < .OOOl.Post-hoc
Outcome
BPDC02t
VIS
Survived without ECMO
23.1 + 1.4
456 2 41
Survived with ECMO*
31.3 * 3.4’
1264 + 168*
Died despite ECMO
42.8 2 3.8
1945 + 239
NOTE. All values expressed as mean + SEM. Post-hoc testing of all
testing of all pairwise comparison were significant by the Scheffe F test
pairwise comparisons were significant by the Scheffe F test of P < ,001,
atP < ,001.
except the pair indicated by *.
*F = 19.6.
*These were significant by the Fisher PLSD at P < ,001.
tF = 35.6.
tF = 11.5.
SF = 43.5.
SF = 24.6.
CDH: PREDICTORS OF SEVERITY
1031
0
80
A
60
+
0
n
0 0
++
.D +m
. n
0
t +
+ +
IO_ 0
Fig 4. PaCO, values correlated with VI in a single patient who survived. Multiple time points are charted.
DISCUSSION
this study, ABG data and ventilatory information were used to predict the severity of pulmonary insufficiency in infants with CDH. Only a subset (60%) of our population, selected for the absence of associated lethal anomalies and/or nonpulmonary complications, was evaluated, so that outcome would be linked only to severity of pulmonary disease. Fifty-nine cases were analyzed as to BPDPO,, whereas the most recent 40 patients were analyzed by all other criteria. Our results indicate that pulmonary insufficiency in CDH ranges from mild to profound, which is in agreement with other reports.2*3,5-7.9,15 Our results also indicate that this spectrum can be divided into physiological groups in which outcome can be predicted. The prognostic usefulness of BPDPO, in CDH has been previously reported from this institution.q*‘5 Furthermore, Geggel et alI6 have shown by morphometric analysis that nonresponders had smaller lungs with a decreased vascular cross-sectional area as compared with responders. In a separate study, O’Rourke et all5 reported statistically significant differences between the pulmonary arteriograms of
1
1000
2000
3000
4000
VI Fig 6. PaCO, values correlated values were the best (lowest) ratio patient (P < ,001). (A) PaC02 >40, < 1,000; (C) PaCO, > 40, VI > 1,000;
with VI in 40 patients. Plotted of PaCO, x VI achieved by each VI < 1,000; (6) PaCO, ~40, VI (D) PaCO, < 40. VI > 1.000.
In
Fig 5. PaCO, values correlated wlth VI in 25 survivors. There is no statistical significance to the distribution.
responders and nonresponders. Nonresponders had smaller main pulmonary arteries bilaterally, smaller lungs ipsilaterally, and increased peripheral pulmonary vascular obstruction. Current data showing 91% survival in responders and 7% survival in nonresponders (P = .OOOl)further support the usefulness of BPDPO, in predicting outcome. The fact that mean BPDPO, differed significantly between survivors without ECMO, survivors with ECMO, and nonsurvivors suggests that it may be used to predict severity as well as outcome. It also appears that the main impact of ECMO on survival has been in the responder group. Nonresponders continue to be unsalvagable despite ECMO. Furthermore, delayed surgery with preoperative ECMO has not improved their survival.‘7 Based on these findings, the argument can certainly be made that nonresponders represent a subgroup whose predominant lesion is pulmonary hypoplasia too severe to permit survival. Although BPDPO, alone has been predictive within our own institution, other groups have not found it useful.” Since BPDPO, is dependent on pH and ventilation,” it may be that differences in ventilatory management and alkalinization account for this disparity. Therefore, to incorporate ventilatory information, PO, was plotted against VI. An attempt was made to keep pH constant at 7.5 to 7.6. The resulting OVI stratified our CDH population in a statistically significant fashion (P < .OOl). With this addition of ventilatory information, BPDPO, may be useful to normalize physiologic parameters between different institutions and allow results to be compared. Survivors with or without ECMO and nonsurvivors could be differentiated by the best (lowest) mean PaCO, (P < .OOl). Ventilatory indexes (VIs) of these populations were l&wise statistically significant (P < .OOl).
WILSON ET AL
1032
However, when PaCO, versus VI was plotted at prespecified time points (Bohn’s boxes), no consistent correlation could be found with outcome. In fact, most patients traveled through several boxes during their course of therapy. If the patients ultimately required ECMO, their final ABG invariably placed them in box C (PaCO, > 40 mm Hg, VI > 1,000) or D (PaCO, l,OOO), but this was not predictive of outcome. In contrast, when the best Bohn’s box (lowest PaCO, x VI) achieved by each patient was plotted, the population distribution was both significant and predictive. Survivors without ECMO, survivors with ECMO, and nonsurvivors could be distinguished. This concept of “best” being more predictive than “first, middle or last” probably reflects the impact of ECMO. It also may explain why some institutions have reported that ECMO has salvaged Bohn’s C patients (PaCO, > 40 mm Hg, VI > 1,000)13when, by “best Bohn’s,” we have found them unsalvageable. ECMO is capable of supporting the patients whose respiratory insufficiency is based upon persistant pulmonary hypertension (PPHN) but is incapable of affecting the underlying biology (pulmonary hypoplasia). Therefore, the individual CDH patient whose primary problem is PPHN, regardless of how ill he/she has become, can probably be salvaged with
ECMO, but the patient whose predominant problem is hypoplasia cannot be saved. It is likely that the severity of the CDH population varies from institution to institution, being influenced by such factors as inborn/outborn ratios, antenatal referrals, and availability of ECMO. This, taken with the fact that no measure of population severity has met with widespread acceptance, has made it difficult to evaluate the efficacy of new therapies such as ECMO and has resulted in conflicting reports of impact.13.‘4 We have shown BPDPO,, BPDCO,, VI, OVI (BPDPO, v VI), and best Bohn’s (BPDCO, v VI) to have predictive value in our institution’s large population. Because they provide ventilatory information, the latter two methods may also allow physiological comparisons of severity between institutions, but this remains to be determined. If predictive criteria can be developed to transcend differing management strategies, then results from novel therapy can be more accurately assessed. Our data also indicate that the most severely affected infants, nonresponders, have been unaided by any current postnatal intervention. New approaches such as antenatal intervention,” lung transplantationzl and biologic manipulation of pulmonary growth or maturation will be necessary for salvage of this group.
REFERENCES 1. Fitzgerald RJ: Congenital diaphragmatic hernia: A study of mortality factors. Ir J Med Sci 146:280-284, 1977 2. Mishalany HG, Nakada K, Wooley MM: Congenital diaphragmatic hernias: Eleven years’ experience. Arch Surg 114:118-23, 1979 3. Ruff SJ, Campbell JR, Harrison MW, et al: Pediatric diaphragmatic hernias. Am J Surg 139:641-645, 1980 4. Harrison MR, deLorimier AA: Congenital diaphragmatic hernia. Surg Clin North Am 61:1023,1981 5. Boix-Ochoa J, Peguro G, Seijo G, et al: Acid base balance and blood gas in prognosis and therapy of congenital diaphragmatic hernia. J Pediatr Surg 19:49-57,1974 6. Dibbins AW, Wiener ES: Mortality from diaphragmatic hernia. J Pediatr Surg 9:653-662,1974 7. Bohn DJ, Tamura M, Perein D, et al: Ventilatoty predictors of pulmonary hypoplasia in congenital diaphragmatic hernia confirmed by morphometry. J Pediatr 111:423-431,1987 8. Bohn D: Ventilatory and blood gas parameters in predicting survival in congenital diaphragmatic hernia. Pediatr Surg Int 2:336-340, 1987 9. Vacanti JP, O’Rourke PP, Lillehei CW, et al: The cardiopulmonary consequences of high risk congenital diaphragmatic hernia. Pediatr Surg Int 3:1-5,1988 10. Bartlett RH, Cassaniga AB, Tomasian J, et al: Extra corporeal membrane oxygenation (ECMO) in neonatal respiratory failure, 100 cases. Ann Surg 204:236, 1986 11. Sawter SF, Falterman KE, Goldsmith JP, et al: Improving
survival in the treatment of congenital diaphragmatic hernia. Ann Thorac Surg 41:75-78,1986 12. Weber TR, Connors RH, Pennington G, et al: Neonatal diaphragmatic hernia: An improving outlook with extra corporeal membrane oxygenation. Arch Surg 1221615618,1987 13. Redmond C, Heaton J, Calix J, et al: A correlation of pulmonary hypoplasia, mean airway pressure and survival in congenital diaphragmatic hernia treated with extra corporeal membrane oxygenation. J Pediatr Surg 22:1143-1149,1987 14. O’Rourke PP, Lillehei CW, Crone RK, JP: The effect of extracorporeal membrane oxygenation (ECMO) on the survival of neonates with high risk congenital diaphragmatic hernia: 45 cases from a single institution. J Pediatr Surg 26:147-152,199l 1.5. Geggel RL, Murphy JD, Langleben MD, et al: Congenital diaphragmatic hernia: Arterial structural changes and persistent pulmonary hypertension after surgical repair. J Pediatr 107:457464,1985 16. CYRourke PP, Vacanti JP, Crone RK, et al: Use of postductal PaCO, as a predictor of pulmonary vascular hypoplasia in infants with congenital diaphragmatic hernia. J Pediatr Surg 23:904-907,1988 17. Wilson JM, Lund DP, Lillehei CW, et al: Delayed surgery and preoperative ECMO does not improve survival in high risk congenital diaphragmatic hernia. Presented at the annual meeting of the American Pediatric Surgical Association, Lake Buena Vista, FL, May 15,199l 18. Newman KD, Anderson KD, Vanmeurs L, et al: Extra corporeal membrane oxygenation and congenital diaphragmatic
CDH:
PREDICTORS
OF SEVERITY
1033
hernia: Which infants should be excluded. J Pediatr Surg 25: 1048-1053,199O 19. Drummond WH, Gregory GA, Heymann MA, et al: The independent effects of hypertension, tolazoline, and dopamine on infants with persistent pulmonary hypertension. J Pediatr 98:603611,198l 20. Harrison MR, Adzick NS, Longaker MP, et al: Successful
repair in utero of a fetal diaphragmatic hernia after removal of herniated viscera from the left thorax. N Engl J Med 322:15221524,199O 21. Crombleholme TM, Adzick NS, Hardy K, et al: Pulmonary lobar transplantation in neonatal swine: A model for treatment of congenital diaphragmatic hernia. J Pediatr Surg 25:11-16, 1990
Discussion C. Stolar (New York, NY): You and your coauthors join many of us in trying to devine when and what to do with congenital diaphragmatic hernia patients in the ECMO era. Despite our protestations to the contrary, for the moment we, too, have concluded that the complex interface between pulmonary hypoplasia, pulmonary hypertension, a variety of conventional therapies, and a variety of ECMO interfaces make a single institutional experience virtually uninterpretable. This also makes it extraordinarily difficult to expound a parochial view for broader application. You attempted to assess severity measures in your own institution and concluded that a postductal PaO, in the context of ventilatory support needed to achieve it was of predictive value in the ECMO era. Other permutations of statistics were not. Before using your approach elsewhere, could you consider the following: (1) How complete were your blood gas data sheets? How many data points do you have to determine a best PaO, and a best PaCO,? How did you obtain clinical data from referring hospitals? How did you find out what really happened to them before they came to you? (2) Your survival rate of ECMO-treated diaphragmatic hernia infants was actually 13 of 24-not out of line with the ELSO registry results. Most of your deaths were in box C, with a PaO, of less than 100 and a VI over 1,000. Other institutions, such as Washington, New Orleans, and New York, have regularly reported box C infants surviving with ECMO support despite your apparent bad outcome. Do you have any thoughts as to why this discrepancy exists? (3) As reported in a previous issue of the Journal of Pediatric Surgery from your institution, a considerable number of congenital diaphragmatic hernia infants supported successfully with ECMO died subsequently of bronchopulmonary dysplasia. Dr Price just told us in a multicenter review, which, unfortunately, didn’t incIude your institutional dysplasia acexperience, that bronchopulmonary counted for only 6% of deaths. Could this discrepancy be related to the aggressive ventilator strategy you described, and, if so, how can one apply your observa-
tions to centers employing very different respiratory strategies? Finally, 50% of the infants with congenital diaphragmatic hernia survive without ECMO and, of the remaining 50%, half survived with ECMO. Thus, the overall survival for infants with congenital diaphragmatic hernia in the ECMO era should be 75%. The remaining 25% mortality continues to be a challenge, and studies such as yours are important to keep us focused on that resistant fraction. J.M. Wilson (response): All of the patients in this report were personally managed by one of the coauthors. The BPDPO, was obtained from our data base. Since this value is recorded in real time in all of our patients, I believe it is completely accurate. For the other information, a retrospective chart review was necessary. In the 40 infants reported, every blood gas obtained at this institution was reviewed. Of the 59 patients, 19 were excluded from this analysis because we could not recover all blood gas data. About 25% of these patients were transported from other institutions and all came with blood gas data. In this group, it is possible that a “best gas” was missed in an occasional infant, but we believe that the statistical significance of our results are strong enough to absorb such an occurrence. This is not a report of our overall survival of ECMO-treated CDH patients. Rather, it is a subpopulation selected for absence of confounding variables. Our actual survival of ECMO-treated CDH infants is far less than ELSO reports, which may reffect the fact that we do not exclude any infants from ECMO based on presumed hypoplasia and that we have a large inborn population of CDH infants. We differ from other institutions in that we believe that a patient’s best effort is a more reliable indicator of degree of hypoplasia, and more predictive of outcome than his first, middle, or last. We have shown that patients travel through several boxes during their course of therapy, making assignment of severity at prespecified time points. This may explain the discrepancy between our findings and those of other institu-
1034
tions. We also believe that salvage of patients in Box C does reflect the positive impact that ECMO has had, as those patients probably would have died. However, they are not truly the worst patients unless their best effect was in Box C. The article to which you refer reported nine late deaths attributed to bronchopulmonary displasia (BPD). Five of those infants are included in this report and four are excluded because they had confounding variables. Had they been included, the actual numbers would have changed slightly, but the statistical significance of the results would hold. We do see BPD as a problem, however, and modified our ventilation parameters and adopted delayed surgery with preoperative ECMO in an attempt to avoid this iatrogenic injury. This has resulted in a dramatic decrease of BPD in our population, but has not improved the survival of our nonresponders. I believe that Dr Price’s report that only 6% of deaths in CDH were attributable to BPD is low. This may reflect the fact that cause of death in CDH infants is always
WILSON ET AL
multifactorial and that without postmortem examination, BPD might be overlooked. You conclude that overall survival in the ECMO era should be 75%: that is certainly not our experience. We have a 50% overall survival and a 33% survival with ECMO. This discrepancy exists because we are uncovering much of the “hidden mortality” (Harrison) missed at institutions with large outborn populations and exclusionary criteria for ECMO. It is our belief that the overall mortality for infants born alive with CDH is in the vicinity of 50%. Finally, we would agree that carefully controlled, prospective, multiinstitution trials probably provide the most unbiased and, therefore, useful information. However, we think that a multiinstitution retrospective review is no less likely to present the parochial views of its authors than is a single institution review. Therefore, until there is some agreement on severity indexes by which multiinstitutional data can be analyzed, we believe there will still be a role for the large, carefully analyzed, single-institution study.
risk and included in this study if they presented with respiratory distress within the first 6 hours of life (n = 94). In order to focus on predictors of pulmonary insufficiency, patients who died of nonpulmonary causes or had other significant congenital anomalies were excluded from this review, leaving 59 patients for analysis. All the infants during this period had intensive pharmacological and ventilatory support. When needed, ECMO was offered postoperatively from 1984 to 1987, and preoperatively from 1987 to the present. Forty-five of 59 had a best postductal PO, (BPDPO,) > 100 mm Hg, and 41 of these responders survived (91%). Fourteen patients had a BPDPO, < 100 mm Hg and only one survived (7%) (P = .OOOl). Mean BPDPO, between survivors with or without ECMO, and nonsurvivors were also significantly different (P = 891). To incorporate ventilatory information, an oxygenation/ventilation index was devised: [OVI = PO,/(mean airway pressure x respiratory rate) x 1001. Differences in OVI between these three groups were also significant. When analyzing the data by the method proposed by Bohn (PCO, v VI), no correlation between ventilatory parameters and outcome was found. However when the best (lowest) PCO, x VI for each patient was used, a plot of PCO, versus VI was predictive. We conclude that: (1) BPDPO, is an accurate predictor of mortality and severity in high-risk CDH infants, but is highly dependant on degree of ventilation and alkalosis; (2) OVI is predictive of mortality and severity and by correlating PO, with ventilation parameters may allow comparisons among institutions; (3) Bohn’s criteria, when applied at prespecified intervals, did not correlate well with severity or outcome in our population, but a plot based on the best PCO, x VI achieved by each patient was predictive; and (4) nonresponders to maximum conventional mechanical ventilation (BPDPO, < 199; BPDPCO, > 40 with VI > 1,000) have not benefited from the introduction of ECMO and continue to be nonsalvagable.
Copyright o 1991 by WA Saunders Company INDEX WORDS: Congenital diaphragmatic poreal membrane oxygenation (ECMO).
P
hernia; extracor-
RIOR TO THE ADVENT of extracorporeal membrance oxygenation (ECMO), little impact had been made on the mortality of high-risk congenital diaphragmatic hernia (CDH) in patients symptomatic within the first 6 hours of life. Most published series reported survivals of approximately 50%.le4 Many predictors of mortality have been proposed, 1028
based on pH, PCO,, (A-a)DO,, or best preductal or postductal P0,.2,3,5,6All were useful in their respective institutions, but none have been found to be universally applicable. This was due in part to varying methods of management of the neonate with CDH. In addition, measurements were taken at different anatomic sites and at different times relative to repair of the defect. Bohn used ventilatory parameters to prognosticate by plotting PCO, versus ventilation index (VI = ventilator-y rate x mean airway pressure),7 and was accurately able to predict outcome in a series of 58 consecutive infants with CDH. This prediction was based on a single measurement taken 2 hours postoperatively. He subsequently used preoperative measurements with similar results.’ Prior to the widespread use of ECMO, Bohn’s method worked well because patients who deteriorated after a stable interval or who never stabilized, usually did not survive. Therefore, predictions of survival based on arterial blood gas (ABG) and ventilatory data, measured at predetermined intervals, were accurate. The introduction of ECMO made the predictibility of mortality more difficult. In some instances, ECMO is capable of reversing the deterioration heralded by the development of transient pulmonary hypertension and the resulting right-to-left shunting. This has clearly resulted in salvage of individual infants who would have otherwise died.” Accordingly, CDH infants who were predicted to die by pre-ECMO criteria have been saved with ECMO and an increase in overall survival of CDH infants has been noted in some institutions.11-13However, other institutions have not seen overall survival improved with ECM0.14 This study was undertaken to examine severity of illness parameters in infants with CDH in a single large institution in order to determine whether any predictors of severity could be identified in the
From the Department of Surgery, The Children’s Hospital, and Harvard Medical School, Boston, MA. presented at the 42nd Annual Meeting of the Surgical Section of the American Academy of Pediatrics, Boston, Massachusetts, October 6-7, 1990. Address reprint requests to Jay M. Wilson, MD, Depanment of Sutgety, The Children ‘s Hospital Fegan 4,300 Longwood Ave, Boston, MA 02115. Copyright o 1991 by W.B. Saunders Company 0022-3468191 f2609-0004$03.00/0 JournatofPediatric Surgety, Vol26, No 9 (September), 1991: pp 1028-1034
CDH: PREDICTORS OF SEVERITY
1029
ECMO era. To improve communication and facilitate comparisons of results, we also attempted to identify new methods of analysis that might transcend institutional differences in population severity and management. MATERIALS
AND METHODS
We reviewed the charts of all patients with CDH treated at this institution since 1984, when ECMO became available (n = 110). Ninety-four infants presented with respiratory distress within the first 6 hours of life and were categorized as high risk. In order to focus on illness attributable to pulmonary insufficiency alone, patients with other anomalies incompatible with survival (eg, cardiac or CNS lesions), or who died of complications unrelated to pulmonary status (eg, intracranial hemorrhage), were excluded from this review (n = 35) leaving 59 for analysis. All infants were intubated and were given intravenous pancuronium bromide (0.1 to 0.2 mg/kg) and fentanyl(l0 to 50 kg/kg/h). They were mechanically ventilated at rates ranging from 35 to 150 breaths/mitt, and peak inspiratory pressures up to 45 cm H,O to maintain PaO, > 100 mm Hg, PaCO, < 30 mm Hg, and pH > 7.5. Intravenous sodium bicarbonate and/or THAM (tromethamine; Abbott Pharmaceuticals, Chicago, IL) were used as necessary to enhance alkalosis. All infants had post-ductal arterial lines placed during initial resuscitation. Between 1984 and 1987, all patients underwent CDH repair immediately upon arrival at our institution. During this era, ECMO was offered postoperatively. Between 1987 and 1989 surgical repair was delayed up to 36 hours to allow preoperative stabilization, including ECMO if necessary. Prior to 1987, ECMO criteria were: preductal and postductal PO, 100, VI < 1,000; (C) PO, < 100, VI > 1,000; (D) PO, > 100, VI > 1,000.
distribution of all blood gases in survivors. Because of this variation with individual patients over time, Bohn’s plots made at predetermined intervals were not predictive of outcome in our experience. However, because BPDPO, and BPDPCO, were predictive where random values were not, an analysis was made of best PaCO, x VI. The best gas was judged by the lowest product of PaCO, x VI, namely, the lowest PaCO, relative to the ventilation required to achieve it. The results are shown in Fig 6, and, once again, severity groups tended to stratify. In box B (PaCO, < 40 mm Hg, VI < 1,000) survival was lOO%, with 3 of 19 (15%) requiring ECMO. In box D (PaCO, < 40 mm Hg, VI > l,OOO),8 of 14 patients (55%) survived but all patients required ECMO. In box C (PaCO, > 40 mm Hg, VI > 1,000) survival was only one of seven (14%), despite ECMO in all patients (P < .OOl). Only one patient landed in box A (PaCO, > 40 mm Hg, VI < 1,000) and that patient survived with ECMO. Significant differences were achieved between boxes B and C, B and D, and C and D (P < .OOl). Box A with one patient could not be evaluated. These results are similar to Bohn’s original distribution and, again, allow predictions based on ventilatory parameters.
Table 2. OVI in 40 Patients
Table 3. BPDCO, and VI in 40 Patients
Outcome
pao,*
Survived without ECMO
322 + 27
430 + 45
Survived with ECMO
246 + 31
1263 2 115
75 k 18
1932 k 219
Died despite ECMO
I
0-l
Vlt
OVIS 84k
10
27 k 7 4kl
NOTE. All values expressed as mean +SEM. P < .OOOl.Post-hoc
Outcome
BPDC02t
VIS
Survived without ECMO
23.1 + 1.4
456 2 41
Survived with ECMO*
31.3 * 3.4’
1264 + 168*
Died despite ECMO
42.8 2 3.8
1945 + 239
NOTE. All values expressed as mean + SEM. Post-hoc testing of all
testing of all pairwise comparison were significant by the Scheffe F test
pairwise comparisons were significant by the Scheffe F test of P < ,001,
atP < ,001.
except the pair indicated by *.
*F = 19.6.
*These were significant by the Fisher PLSD at P < ,001.
tF = 35.6.
tF = 11.5.
SF = 43.5.
SF = 24.6.
CDH: PREDICTORS OF SEVERITY
1031
0
80
A
60
+
0
n
0 0
++
.D +m
. n
0
t +
+ +
IO_ 0
Fig 4. PaCO, values correlated with VI in a single patient who survived. Multiple time points are charted.
DISCUSSION
this study, ABG data and ventilatory information were used to predict the severity of pulmonary insufficiency in infants with CDH. Only a subset (60%) of our population, selected for the absence of associated lethal anomalies and/or nonpulmonary complications, was evaluated, so that outcome would be linked only to severity of pulmonary disease. Fifty-nine cases were analyzed as to BPDPO,, whereas the most recent 40 patients were analyzed by all other criteria. Our results indicate that pulmonary insufficiency in CDH ranges from mild to profound, which is in agreement with other reports.2*3,5-7.9,15 Our results also indicate that this spectrum can be divided into physiological groups in which outcome can be predicted. The prognostic usefulness of BPDPO, in CDH has been previously reported from this institution.q*‘5 Furthermore, Geggel et alI6 have shown by morphometric analysis that nonresponders had smaller lungs with a decreased vascular cross-sectional area as compared with responders. In a separate study, O’Rourke et all5 reported statistically significant differences between the pulmonary arteriograms of
1
1000
2000
3000
4000
VI Fig 6. PaCO, values correlated values were the best (lowest) ratio patient (P < ,001). (A) PaC02 >40, < 1,000; (C) PaCO, > 40, VI > 1,000;
with VI in 40 patients. Plotted of PaCO, x VI achieved by each VI < 1,000; (6) PaCO, ~40, VI (D) PaCO, < 40. VI > 1.000.
In
Fig 5. PaCO, values correlated wlth VI in 25 survivors. There is no statistical significance to the distribution.
responders and nonresponders. Nonresponders had smaller main pulmonary arteries bilaterally, smaller lungs ipsilaterally, and increased peripheral pulmonary vascular obstruction. Current data showing 91% survival in responders and 7% survival in nonresponders (P = .OOOl)further support the usefulness of BPDPO, in predicting outcome. The fact that mean BPDPO, differed significantly between survivors without ECMO, survivors with ECMO, and nonsurvivors suggests that it may be used to predict severity as well as outcome. It also appears that the main impact of ECMO on survival has been in the responder group. Nonresponders continue to be unsalvagable despite ECMO. Furthermore, delayed surgery with preoperative ECMO has not improved their survival.‘7 Based on these findings, the argument can certainly be made that nonresponders represent a subgroup whose predominant lesion is pulmonary hypoplasia too severe to permit survival. Although BPDPO, alone has been predictive within our own institution, other groups have not found it useful.” Since BPDPO, is dependent on pH and ventilation,” it may be that differences in ventilatory management and alkalinization account for this disparity. Therefore, to incorporate ventilatory information, PO, was plotted against VI. An attempt was made to keep pH constant at 7.5 to 7.6. The resulting OVI stratified our CDH population in a statistically significant fashion (P < .OOl). With this addition of ventilatory information, BPDPO, may be useful to normalize physiologic parameters between different institutions and allow results to be compared. Survivors with or without ECMO and nonsurvivors could be differentiated by the best (lowest) mean PaCO, (P < .OOl). Ventilatory indexes (VIs) of these populations were l&wise statistically significant (P < .OOl).
WILSON ET AL
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However, when PaCO, versus VI was plotted at prespecified time points (Bohn’s boxes), no consistent correlation could be found with outcome. In fact, most patients traveled through several boxes during their course of therapy. If the patients ultimately required ECMO, their final ABG invariably placed them in box C (PaCO, > 40 mm Hg, VI > 1,000) or D (PaCO, l,OOO), but this was not predictive of outcome. In contrast, when the best Bohn’s box (lowest PaCO, x VI) achieved by each patient was plotted, the population distribution was both significant and predictive. Survivors without ECMO, survivors with ECMO, and nonsurvivors could be distinguished. This concept of “best” being more predictive than “first, middle or last” probably reflects the impact of ECMO. It also may explain why some institutions have reported that ECMO has salvaged Bohn’s C patients (PaCO, > 40 mm Hg, VI > 1,000)13when, by “best Bohn’s,” we have found them unsalvageable. ECMO is capable of supporting the patients whose respiratory insufficiency is based upon persistant pulmonary hypertension (PPHN) but is incapable of affecting the underlying biology (pulmonary hypoplasia). Therefore, the individual CDH patient whose primary problem is PPHN, regardless of how ill he/she has become, can probably be salvaged with
ECMO, but the patient whose predominant problem is hypoplasia cannot be saved. It is likely that the severity of the CDH population varies from institution to institution, being influenced by such factors as inborn/outborn ratios, antenatal referrals, and availability of ECMO. This, taken with the fact that no measure of population severity has met with widespread acceptance, has made it difficult to evaluate the efficacy of new therapies such as ECMO and has resulted in conflicting reports of impact.13.‘4 We have shown BPDPO,, BPDCO,, VI, OVI (BPDPO, v VI), and best Bohn’s (BPDCO, v VI) to have predictive value in our institution’s large population. Because they provide ventilatory information, the latter two methods may also allow physiological comparisons of severity between institutions, but this remains to be determined. If predictive criteria can be developed to transcend differing management strategies, then results from novel therapy can be more accurately assessed. Our data also indicate that the most severely affected infants, nonresponders, have been unaided by any current postnatal intervention. New approaches such as antenatal intervention,” lung transplantationzl and biologic manipulation of pulmonary growth or maturation will be necessary for salvage of this group.
REFERENCES 1. Fitzgerald RJ: Congenital diaphragmatic hernia: A study of mortality factors. Ir J Med Sci 146:280-284, 1977 2. Mishalany HG, Nakada K, Wooley MM: Congenital diaphragmatic hernias: Eleven years’ experience. Arch Surg 114:118-23, 1979 3. Ruff SJ, Campbell JR, Harrison MW, et al: Pediatric diaphragmatic hernias. Am J Surg 139:641-645, 1980 4. Harrison MR, deLorimier AA: Congenital diaphragmatic hernia. Surg Clin North Am 61:1023,1981 5. Boix-Ochoa J, Peguro G, Seijo G, et al: Acid base balance and blood gas in prognosis and therapy of congenital diaphragmatic hernia. J Pediatr Surg 19:49-57,1974 6. Dibbins AW, Wiener ES: Mortality from diaphragmatic hernia. J Pediatr Surg 9:653-662,1974 7. Bohn DJ, Tamura M, Perein D, et al: Ventilatoty predictors of pulmonary hypoplasia in congenital diaphragmatic hernia confirmed by morphometry. J Pediatr 111:423-431,1987 8. Bohn D: Ventilatory and blood gas parameters in predicting survival in congenital diaphragmatic hernia. Pediatr Surg Int 2:336-340, 1987 9. Vacanti JP, O’Rourke PP, Lillehei CW, et al: The cardiopulmonary consequences of high risk congenital diaphragmatic hernia. Pediatr Surg Int 3:1-5,1988 10. Bartlett RH, Cassaniga AB, Tomasian J, et al: Extra corporeal membrane oxygenation (ECMO) in neonatal respiratory failure, 100 cases. Ann Surg 204:236, 1986 11. Sawter SF, Falterman KE, Goldsmith JP, et al: Improving
survival in the treatment of congenital diaphragmatic hernia. Ann Thorac Surg 41:75-78,1986 12. Weber TR, Connors RH, Pennington G, et al: Neonatal diaphragmatic hernia: An improving outlook with extra corporeal membrane oxygenation. Arch Surg 1221615618,1987 13. Redmond C, Heaton J, Calix J, et al: A correlation of pulmonary hypoplasia, mean airway pressure and survival in congenital diaphragmatic hernia treated with extra corporeal membrane oxygenation. J Pediatr Surg 22:1143-1149,1987 14. O’Rourke PP, Lillehei CW, Crone RK, JP: The effect of extracorporeal membrane oxygenation (ECMO) on the survival of neonates with high risk congenital diaphragmatic hernia: 45 cases from a single institution. J Pediatr Surg 26:147-152,199l 1.5. Geggel RL, Murphy JD, Langleben MD, et al: Congenital diaphragmatic hernia: Arterial structural changes and persistent pulmonary hypertension after surgical repair. J Pediatr 107:457464,1985 16. CYRourke PP, Vacanti JP, Crone RK, et al: Use of postductal PaCO, as a predictor of pulmonary vascular hypoplasia in infants with congenital diaphragmatic hernia. J Pediatr Surg 23:904-907,1988 17. Wilson JM, Lund DP, Lillehei CW, et al: Delayed surgery and preoperative ECMO does not improve survival in high risk congenital diaphragmatic hernia. Presented at the annual meeting of the American Pediatric Surgical Association, Lake Buena Vista, FL, May 15,199l 18. Newman KD, Anderson KD, Vanmeurs L, et al: Extra corporeal membrane oxygenation and congenital diaphragmatic
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hernia: Which infants should be excluded. J Pediatr Surg 25: 1048-1053,199O 19. Drummond WH, Gregory GA, Heymann MA, et al: The independent effects of hypertension, tolazoline, and dopamine on infants with persistent pulmonary hypertension. J Pediatr 98:603611,198l 20. Harrison MR, Adzick NS, Longaker MP, et al: Successful
repair in utero of a fetal diaphragmatic hernia after removal of herniated viscera from the left thorax. N Engl J Med 322:15221524,199O 21. Crombleholme TM, Adzick NS, Hardy K, et al: Pulmonary lobar transplantation in neonatal swine: A model for treatment of congenital diaphragmatic hernia. J Pediatr Surg 25:11-16, 1990
Discussion C. Stolar (New York, NY): You and your coauthors join many of us in trying to devine when and what to do with congenital diaphragmatic hernia patients in the ECMO era. Despite our protestations to the contrary, for the moment we, too, have concluded that the complex interface between pulmonary hypoplasia, pulmonary hypertension, a variety of conventional therapies, and a variety of ECMO interfaces make a single institutional experience virtually uninterpretable. This also makes it extraordinarily difficult to expound a parochial view for broader application. You attempted to assess severity measures in your own institution and concluded that a postductal PaO, in the context of ventilatory support needed to achieve it was of predictive value in the ECMO era. Other permutations of statistics were not. Before using your approach elsewhere, could you consider the following: (1) How complete were your blood gas data sheets? How many data points do you have to determine a best PaO, and a best PaCO,? How did you obtain clinical data from referring hospitals? How did you find out what really happened to them before they came to you? (2) Your survival rate of ECMO-treated diaphragmatic hernia infants was actually 13 of 24-not out of line with the ELSO registry results. Most of your deaths were in box C, with a PaO, of less than 100 and a VI over 1,000. Other institutions, such as Washington, New Orleans, and New York, have regularly reported box C infants surviving with ECMO support despite your apparent bad outcome. Do you have any thoughts as to why this discrepancy exists? (3) As reported in a previous issue of the Journal of Pediatric Surgery from your institution, a considerable number of congenital diaphragmatic hernia infants supported successfully with ECMO died subsequently of bronchopulmonary dysplasia. Dr Price just told us in a multicenter review, which, unfortunately, didn’t incIude your institutional dysplasia acexperience, that bronchopulmonary counted for only 6% of deaths. Could this discrepancy be related to the aggressive ventilator strategy you described, and, if so, how can one apply your observa-
tions to centers employing very different respiratory strategies? Finally, 50% of the infants with congenital diaphragmatic hernia survive without ECMO and, of the remaining 50%, half survived with ECMO. Thus, the overall survival for infants with congenital diaphragmatic hernia in the ECMO era should be 75%. The remaining 25% mortality continues to be a challenge, and studies such as yours are important to keep us focused on that resistant fraction. J.M. Wilson (response): All of the patients in this report were personally managed by one of the coauthors. The BPDPO, was obtained from our data base. Since this value is recorded in real time in all of our patients, I believe it is completely accurate. For the other information, a retrospective chart review was necessary. In the 40 infants reported, every blood gas obtained at this institution was reviewed. Of the 59 patients, 19 were excluded from this analysis because we could not recover all blood gas data. About 25% of these patients were transported from other institutions and all came with blood gas data. In this group, it is possible that a “best gas” was missed in an occasional infant, but we believe that the statistical significance of our results are strong enough to absorb such an occurrence. This is not a report of our overall survival of ECMO-treated CDH patients. Rather, it is a subpopulation selected for absence of confounding variables. Our actual survival of ECMO-treated CDH infants is far less than ELSO reports, which may reffect the fact that we do not exclude any infants from ECMO based on presumed hypoplasia and that we have a large inborn population of CDH infants. We differ from other institutions in that we believe that a patient’s best effort is a more reliable indicator of degree of hypoplasia, and more predictive of outcome than his first, middle, or last. We have shown that patients travel through several boxes during their course of therapy, making assignment of severity at prespecified time points. This may explain the discrepancy between our findings and those of other institu-
1034
tions. We also believe that salvage of patients in Box C does reflect the positive impact that ECMO has had, as those patients probably would have died. However, they are not truly the worst patients unless their best effect was in Box C. The article to which you refer reported nine late deaths attributed to bronchopulmonary displasia (BPD). Five of those infants are included in this report and four are excluded because they had confounding variables. Had they been included, the actual numbers would have changed slightly, but the statistical significance of the results would hold. We do see BPD as a problem, however, and modified our ventilation parameters and adopted delayed surgery with preoperative ECMO in an attempt to avoid this iatrogenic injury. This has resulted in a dramatic decrease of BPD in our population, but has not improved the survival of our nonresponders. I believe that Dr Price’s report that only 6% of deaths in CDH were attributable to BPD is low. This may reflect the fact that cause of death in CDH infants is always
WILSON ET AL
multifactorial and that without postmortem examination, BPD might be overlooked. You conclude that overall survival in the ECMO era should be 75%: that is certainly not our experience. We have a 50% overall survival and a 33% survival with ECMO. This discrepancy exists because we are uncovering much of the “hidden mortality” (Harrison) missed at institutions with large outborn populations and exclusionary criteria for ECMO. It is our belief that the overall mortality for infants born alive with CDH is in the vicinity of 50%. Finally, we would agree that carefully controlled, prospective, multiinstitution trials probably provide the most unbiased and, therefore, useful information. However, we think that a multiinstitution retrospective review is no less likely to present the parochial views of its authors than is a single institution review. Therefore, until there is some agreement on severity indexes by which multiinstitutional data can be analyzed, we believe there will still be a role for the large, carefully analyzed, single-institution study.
