- Email: [email protected]
Permissive Hypercapnia in the Management of Congenital Diaphragmatic Hernia: Our Institutional Experience
Permissive Hypercapnia in the Management of Congenital Diaphragmatic Hernia: Our Institutional Experience Christopher A Guidry, MD, Tjasa Hranjec, MD, Bradley M Rodgers, MD, FACS, Bartholomew Kane, MD, Eugene D McGahren, MD, FACS Congenital diaphragmatic hernia (CDH) is a potentially lethal anomaly associated with pulmonary hypoplasia and persistent pulmonary hypertension. Permissive hypercapnia is a strategy designed to reduce lung injury from mechanical ventilation in infants. It has been shown to be a potentially superior method of ventilator management for patients with CDH. In 2001, the Divisions of Neonatology and Pediatric Surgery at the University of Virginia Children’s Hospital established permissive hypercapnia as the management strategy for treatment of CDH. We hypothesized that permissive hypercapnia would be associated with improved outcomes in this patient population. STUDY DESIGN: This retrospective review compares outcomes of infants treated for CDH in the extracorporeal membrane oxygenation (ECMO) era before and after initiation of permissive hypercapnia at a single institution. Outcomes were compared using univariate statistical analysis. RESULTS: Ninety-one patients were available for analysis and were divided into 2 groups: 42 (Group 1) treated before and 49 (Group 2) treated after implementation of permissive hypercapnia. Survival was higher in Group 2 (85.8% vs 54.8%; p ⫽ 0.001; relative risk [RR] 3.17). Morbidity was lower in Group 2 and approached statistical significance (65.3% vs 83.3%; p ⫽ 0.052). Patients in Group 2 were repaired later, had a lower rate of ECMO use, and were extubated earlier. There was no difference in hospital stay. CONCLUSIONS: The use of permissive hypercapnia for infants with CDH was associated with decreased mortality, a longer period of ventilation before repair with a shorter period of ventilation after repair, a lower rate of ECMO use, and no lengthening of hospital stay. Permissive hypercapnia remains the standard of care for ventilation of infants with CDH at our institution. (J Am Coll Surg 2012;214:640–647. © 2012 by the American College of Surgeons) BACKGROUND:
Congenital diaphragmatic hernia of the Bochdalek type (CDH) is a potentially lethal birth defect involving herniation of abdominal contents into the thoracic cavity through a defect in the diaphragm. Traditionally, it has been believed that extrinsic compression from abdominal contents on the developing lung results in pulmonary hypoplasia and persistent pulmonary hypertension.1-3 Recent
research, however, suggests that aberrations in pulmonary development itself may be causative in CDH. These studies suggest that the affected lung is intrinsically abnormal and may compromise the development of the diaphragm, resulting in a hernia.4,5 CDH has an estimated incidence of 1:2,200 to 4,000 live births, with a historically expected survival of 50% to 80%.2,3,6-9 Management of an infant with CDH involves early intubation, appropriate ventilator management, treatment of pulmonary hypertension, and surgical correction of the diaphragm defect. Traditional methods of therapy involved an aggressive ventilator management strategy in which high peak inspiratory pressures (PIP), hyperoxygenation, and alkalization via hyperventilation and administration of sodium bicarbonate were used to maintain a postductal arterial oxygen pressure (PaO2) of ⬎90%, pH ⬎7.2, and partial pressure of CO2 (PaCO2) within normal physiologic parameters.1,6,7,10,11 The ventilatory pressures and volumes, and oxygenation required to achieve these goals, were rec-
Disclosure Information: Dr Kane is partial owner of Aegis Biomedical, Inc. and Ancile Biomedical, Inc. Dr Kane receives consulting fees from Sensors for Medicine and Science, Inc. All other authors have nothing to disclose. Presented at the Southern Surgical Association, 123rd Annual Meeting, Hot Springs, VA, December 2011. Received December 16, 2011; Accepted December 20, 2011. From the Department of Surgery (Guidry, Hranjec) and Division of Pediatric Surgery (Rodgers, Kane, McGahren), University of Virginia Health System, Charlottesville, VA. Correspondence address: Eugene McGahren, MD, University of Virginia Health System, Department of Surgery, Box 800709, Charlottesville, VA 22908-0709. email: [email protected]
© 2012 by the American College of Surgeons Published by Elsevier Inc.
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Abbreviations and Acronyms
CDH ECMO FiO2 HFOV IVH PaCO2 PIP UVACH
⫽ ⫽ ⫽ ⫽ ⫽ ⫽ ⫽ ⫽
congenital diaphragmatic hernia extracorporeal membrane oxygenation fraction of inspired oxygen high frequency oscillatory ventilation intraventricular hemorrhage partial pressure of carbon dioxide peak inspiratory pressure University of Virginia Children’s Hospital
ognized as causing lung trauma that was a significant source of morbidity and mortality in this population. Postmortem analysis of patients treated with aggressive ventilator management showed distinct evidence of barotrauma.11 In 1985, Wung and colleagues12 proposed a novel approach, now commonly recognized as “permissive hypercapnia” or “gentle ventilation,” to ventilator management in infants with persistence of fetal circulation (and pulmonary hypertension). It involved limiting the PIP and oxygenation levels in an effort to decrease barotrauma. The PaCO2 was not a controlling parameter and was allowed to rise to a level as high as 60 mmHg. This strategy was later applied to CDH patients and has since demonstrated a potential survival benefit. In particular, as the treatment of CDH has shifted toward delayed rather than emergent repair, the appropriate ventilatory management of underlying pulmonary hypertension and hypoplasia has proven to be vital in maximizing pulmonary outcomes for these patients.7,8 Although permissive hypercapnia has been a promising ventilator strategy for lung protection, its benefit for survival has not been definitively determined.13 In June 2001, the Divisions of Neonatology and Pediatric Surgery at the University of Virginia Children’s Hospital (UVACH) adopted a new guideline establishing permissive hypercapnia as the primary ventilation strategy for infants with CDH (Appendix 1, online only). Ventilatory pressures just high enough to produce chest rise are used with an emphasis to avoid PIP ⬎25 and positive end-expiratory pressure ⬎5 cm H2O. Fraction of inspired oxygen (FiO2) is aggressively weaned to maintain preductal oxygen saturations between 90% and 95%. The pH is maintained within physiologic norms. PaCO2 level is not a primary goal and is allowed to rise to as high as 70 mmHg as long as all other parameters are satisfied. High frequency oscillatory ventilation (HFOV), inhaled nitric oxide, and extracorporeal membrane oxygenation (ECMO) are used where appropriate according to the discretion of the treating physicians. The purpose of this study was to evaluate the effectiveness of permissive hypercapnia in the management of infants with CDH at UVACH. Our primary hypothesis was that survival would be improved in this patient group with the introduction of permissive hypercapnia. A secondary hypothesis was
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that indicators of certain morbidities, particularly posttreatment respiratory insufficiency, would be improved.
METHODS All patients with CDH admitted to the UVACH from May 1994 until October 2010 were enrolled in this retrospective chart review. The study was approved by the Institutional Review Board at the University of Virginia Health System. All patients with CDH were eligible for analysis, with exclusion criteria comprising lethal birth defects precluding definitive repair, delayed presentation outside the neonatal period, death at or immediately after birth or before treatment could be initiated, and lack of sufficient data in the chart to support statistical analyses. In June 2001, a formal guideline establishing the use of permissive hypercapnia to treat patients with CDH was adopted by the Divisions of Neonatology and Pediatric Surgery at UVACH. Our patients were divided into 2 groups based on their chronological association with this guideline. Patients in Group 1 (1994 to 2001) received traditional hyperventilation, oxygenation, and alkalinization therapy before institution of permissive hypercapnia. Patients in Group 2 (2001 to 2010) were managed with permissive hypercapnia. Patients in Group 2 were initially placed on synchronized intermittent mandatory ventilation (SIMV) mode with a PIP only sufficient to produce a chest rise, 100% FiO2, and minimal sedation. FiO2 was then aggressively weaned to maintain preductal oxygen saturations of 90%. Inhaled nitric oxide was used as the initial adjunctive treatment for persistently low oxygen saturations. Arterial pH was maintained between 7.30 and 7.35. PaCO2 was allowed to rise to 70 mmHg as long as the pH remained above 7.25. Sodium bicarbonate or HFOV were considered for persistent acidosis. By 1994, surgical repair of CDH was no longer undertaken on an emergent basis. However, the true elective nature of this operation was still in evolution at that time in our institution and may have resulted in earlier surgical intervention after presentation in the earlier years of our review than in subsequent years. Overall, operations were performed on an elective basis rather than emergently, with the exact timing based on consensus between the pediatric surgical and neonatal ICU treatment teams about the infant’s stability and readiness for repair. ECMO was used in patients with severe or persistent oxygenation and/or ventilation compromise refractory to other treatments including HFOV and inhaled nitric oxide. Early in the time course of this study, if ECMO was required, repair of CDH was accomplished while the infant was on ECMO. More recently, there has been a preference for weaning from ECMO before repair is undertaken. No infant in our review was denied care or operation due to a perceived basis of critical lung hypoplasia.
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Table 1. Patient Demographics Before (Group 1) and After (Group 2) Permissive Hypercapnia Demographic
Group 1 (n ⴝ 42)
Group 2 (n ⴝ 49)
Male, % 61.9 67.3 Female, % 38.1 32.7 Gestational age, wk, 36.4 ⫾ 0.4 37.2 ⫾ 0.4 mean ⫾ SEM Birth weight, g, 2,655.2 ⫾ 122.0 2,969.1 ⫾ 98.9 mean ⫾ SEM Prenatal diagnosis, % 45.2 63.3 Right-sided CDH, % 23.8 16.3 Diaphragmatic patch, % 59.5 49
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Table 2. Mortality Before (Group 1) and After (Group 2) Permissive Hypercapnia
p Value
Mortality
0.59 0.59 0.17
Mortality, % Mortality (anomalies), % ECMO mortality, %
0.05
*Denotes statistical significance, p ⬍ 0.05. ECMO, extracorporeal membrane oxygenation.
0.09 0.37 0.31
CDH, congenital diaphragmatic hernia.
Basic demographics, hospital admission and discharge, use of ECMO, in-hospital death, comorbidities including associated physical anomalies, and in-hospital complication data were entered into a secure, password-protected computer database. Descriptive analyses comparing demographic data between the 2 treatment groups were performed using univariate analysis, with statistical significance set at p ⬍ 0.05. Continuous variables are presented as mean ⫾ SEM and compared using a 2-sample t-test for independent samples. Categorical variables were analyzed using chi-square or Fisher’s exact test. All statistical analyses were performed using SAS software, version 9.1.3 (SAS Institute).
RESULTS A total of 103 patients with CDH were identified at UVACH during the study period. Ultimately, 91 patients met criteria for statistical analysis. Patients were excluded from analysis because of death before surgical intervention (including stillbirth, other lethal anomalies, nonresponse to medical support) (n ⫽ 6), presentation outside the neonatal period (n ⫽ 4), inadequate data in the chart for statistical analysis (n ⫽ 1), and 1 patient with pentalogy of Cantrell was excluded because the diaphragmatic hernia only entered the pericardium and did not result in pulmonary hypoplasia. A total of 42 patients were in Group 1 and 49 in Group 2. Average birth weight was slightly higher in Group 2 and approached statistical significance. The 2 groups were statistically similar in terms of sex, gestational age, rate of prenatal diagnosis, right-sided CDH, and the use of a diaphragmatic patch for repair (Table 1). Overall mortality rates were 42.9% in Group 1 and 14.3% in Group 2. Decreased mortality in Group 2 was also demonstrated for patients who had other congenital anomalies (Table 2). There was no statistical difference in mortality rates for patients with recurrent CDH or ECMO requirements. There were 5 total cases of recurrent CDH during the study: 2 in Group 1 with 1 mortality, and 3 in
Group 1 (n ⴝ 42)
Group 2 (n ⴝ 49)
p Value
42.9 41.2 53.8
14.3 5.9 50
0.002* 0.02* 0.82
Group 2 with no mortalities (p ⫽ 0.4). Mortality rates for infants receiving ECMO were 53.8% in Group 1 and 50.8% in Group 2. Most patients in the study died due to severe pulmonary hypertension (n ⫽ 10). Other causes for mortality were cerebral intraparenchymal hemorrhage (n ⫽ 4), sepsis (n ⫽ 2), multisystem failure (n ⫽ 2), withdrawal of care due to associated anomalies (n ⫽ 2), pulmonary hemorrhage (n ⫽ 1), heart failure (n ⫽ 1), mechanical ECMO failure (n ⫽ 1), withdrawal of support by family members for reasons unclear during chart review (n ⫽ 1), and an acute decompensation of unclear etiology (n ⫽ 1). Overall rates of morbidity (all kinds) were lower in Group 2 and approached statistical significance (Table 3). Morbidity rates were 83.3% and 65.3% in Groups 1 and 2, respectively. There was no difference in recurrent CDH between the 2 groups. Rates of home oxygen requirement after repair as well as manifestations of persistent pulmonary disease, such as bronchopulmonary dysplasia and asthma, were also similar. Likewise, there was no difference between the 2 groups in terms of neurologic, bleeding, infectious, cardiac, gastrointestinal, or renal complication rates. There was a significant (p ⫽ 0.003) difference in the rates of additional or replacement tube thoracostomy between the 2 groups: 35.7% of patients in Group 1 required a replacement or additional chest tube compared with 10.2% in Group 2. Rates of HFOV between the 2 groups were similar but rates of inhaled nitric oxide use were statistically higher in Group 2. ECMO use was statistically lower in Group 2 (28.6%) compared with Group 1 (61.9%). Total days on ECMO were similar, with a mean of 15.2 days in Group 1 vs 13.2 days in Group 2. Overall, patients spent a similar number of days intubated after repair. However, there was a single patient in Group 2 who was intubated for a total of 424 days. With this patient excluded, Group 2 had a statistically shorter intubation period after repair. On average, repair was offered on day of life 5.9 in Group 1 and on day of life 9 in Group 2. There was no statistical difference between preoperative ventilation days between survivors and mortalities in each group (Table 4). There was no difference in overall hospital stay between the 2 groups.
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Table 3. Morbidity Before (Group 1) and After (Group 2) Permissive Hypercapnia Morbidity
Morbidity (overall), % Neurologic, % Cardiac, % Repeat tube thoracostomy, % O2 requirement at discharge, % Persistent pulmonary disease, % Recurrent CDH, % Gastrointestinal (all), % Nissen, % Gastrostomy, % Nissen ⫹ Gastrostomy, % Hematologic, % Infection, % Renal, % ECMO, % Days on ECMO, mean ⫾ SEM iNO†, n (%) HFOV†, n (%) Timing of repair, d, mean ⫾ SEM Days intubated after repair, mean ⫾ SEM Days intubated after repair (modified), mean ⫾ SEM Hospital stay, d, mean ⫾ SEM
Group 1 (n ⴝ 42)
Group 2 (n ⴝ 49)
p Value
83.3 45.2 2.4
65.3 26.5 2.0
0.052 0.06 1.0
35.7
10.2
0.003*
21.4
22.4
0.94
14.3 4.76
10.2 6.1
0.56 1.0
19.1 9.5 16.7
20.4 4.1 12.2
0.87 0.41 0.54
9.5 19.1 14.3 7.1 61.9 15.2 ⫾ 1.6
4.1 6.1 20.4 0 28.6 13.2 ⫾ 2.7
0.41 0.10 0.44 0.09 0.001* 0.49
12/37 (32.4) 26/37 (70.2) 5.9 ⫾ 1.01
27/46 (58.7) 34/45 (75.6) 9 ⫾ 0.93
0.02* 0.59 0.03*
25 ⫾ 3.9
19.9 ⫾ 9.1
0.61
26 ⫾ 3.9
11 ⫾ 1.5
50.9 ⫾ 7.9
42.2 ⫾ 9.2
0.002* 0.48
*Denotes statistical significance, p ⬍ 0.05. † Variation in group size secondary to unobtainable chart data. CDH, congenital diaphragmatic hernia; ECMO, extracorporeal membrane oxygenation; HFOV, high frequency oscillatory ventilation; iNO, inhaled nitric oxide.
DISCUSSION Our study demonstrates a significant decrease in overall mortality after the introduction of permissive hypercapnia as the primary ventilator management strategy for infants with CDH. A recent Cochrane review, although not limited to CDH management, indicated that there is not enough evidence to support the use of permissive hypercapnia over normocapnia as a superior ventilatory management strategy.13 However, our positive results are similar to those at other institutions that have adopted permissive hypercapnia for the management of CDH,6,7,11,14-16A
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Table 4. Comparison of Preoperative Ventilation Days for Survivors vs. Mortalities per Group Group
Survivors
Mortalities
p Value
Group 1, d, mean ⫾ SEM Group 2, d, mean ⫾ SEM
3.1 ⫾ 0.6 7.3 ⫾ 0.9
7.9 ⫾ 2.3 14.6 ⫾ 3.4
0.06 0.09
strong trend toward lower overall morbidity was also identified but was not statistically significant in our study. Overall, our 2 groups were statistically similar, so theoretically there should be no difference in outcomes attributable to demographic differences between the 2 groups. However, the average birth weight in Group 2 was higher, approaching statistical significance. It is unclear what effect, if any, this slight increase in birth weight would have in terms of overall morbidity and mortality. It is reasonable to believe that larger infants may have a survival advantage. Indeed, Sola and colleauges17 demonstrated a survival benefit in CDH patients with a birth weight greater than 3 kg. ECMO is an important treatment modality for severe pulmonary hypertension and CDH. Patients in our permissive hypercapnia group had a lower rate of ECMO use than previously treated patients. A similar trend was noted in a report by Wilson and associates.11 The quoted mortality rates in the literature for patients treated with ECMO range from 32% to 60%.7,8,18,19 We identified similar mortality rates on ECMO for both groups. Although some studies have demonstrated a potential survival benefit, we were unable to demonstrate a survival benefit attributable to ECMO treatment based on ventilator management before or after its initiation.11 Boloker and coworkers7 also noted equal mortality on ECMO in their study of patients treated with permissive hypercapnia vs normocapnia. Interestingly, pre-ECMO PaCO2 less than 60 mmHg has been found to be a predictor of ECMO survival, and elevated PaCO2 may serve as a marker for potentially nonsurvivable pulmonary hypoplasia.20 However, no infant was denied treatment in our series on the basis of any proposed criteria indicating nonsurvivable pulmonary hypoplasia. It is important to recognize the effects of hypercapnia on cerebral perfusion. Hypercapnia causes cerebral vasodilatation and therefore increases cerebral blood flow in preterm infants.21 Studies have suggested that the rate of intraventricular hemorrhage (IVH) is directly proportional to the PaCO2 and that the incidence of IVH is increased with large variations in PaCO2.21,22 Therefore, one might expect to observe an increased rate of IVH or other neurologic complications in patients with permissive hypercapnia. However, this generally has not been demonstrated in the literature.21 A prospective study by Danzer and colleagues23 demonstrated some degree of neurologic impairment in approximately 50% of CDH patients. We found no statistical significance in the rates of IVH or other adverse neu-
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rologic outcomes between our 2 groups. These results are consistent with those noted by Hagen and coauthors.24 It is noteworthy that two of these studies were performed in very low birth weight infants and specifically excluded patients with congenital anomalies. Multiple ventilator modalities exist for the management of patients with CDH, and much attention has been paid to the effect these modalities have on the development of chronic lung disease.25,26 Retrospective studies have demonstrated that 30% to 56% of CDH patients display symptoms of chronic lung disease long-term.27 However, a randomized trial by Mariani and associates28 demonstrated no difference between rates of chronic lung disease between preterm infants who received either permissive hypercapnia or normocapnia. One study by Valfre and colleagues29 found that the degree of pulmonary hypertension in hospitalized neonates has no effect on postdischarge outcomes. Our study suggests that there may be no difference in chronic lung disease between patients treated with permissive hypercapnia and those treated with more traditional aggressive ventilation strategies. Rates of HFOV were similar between the 2 groups. The need for HFOV as the initial ventilatory modality for infants with CDH has been implicated as a risk factor for development of chronic lung disease.27 Rates of inhaled nitric oxide use were statistically lower in our permissive hypercapnia group than in the normocapnia group; however, this may be unreliable due to a lack of consistency in the reporting of inhaled nitric oxide use. CDH repair at our institution typically involves ipsilateral thoracostomy tube placement. Routine thoracostomy tube use has been implicated in increased mortality rates for CDH patients. This phenomenon is thought to result from gross hyperinflation of the ipsilateral lung immediately after repair, resulting in mechanical trauma as well as a decreased ability of the ipsilateral lung to deflate with exhalation.7 Bagolan and coworkers6 noted a decrease in preoperative thoracostomy tube placement for pneumothorax for patients treated with permissive hypercapnia. Our study was not designed to evaluate this association, but we did demonstrate a decrease in the rate of spontaneous pneumothorax requiring either primary placement or replacement (if after surgical repair) of a thoracostomy tube. This may be an effect of decreased peak pressures and associated barotrauma with use of permissive hypercapnia. Perhaps the decrease in damage associated with permissive hypercapnia is greater than any potential damage caused by the thoracostomy tube. Patients with CDH have been shown to have a high rate of associated complications, particularly gastroesophageal reflux disease, and require frequent invasive procedures.30 However, our study was designed primarily to identify mortality and morbidity with respect to ventilator management in this group of infants. Alterations in ventilator management without alterations to fun-
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damental aspects of definitive repair or other critical care parameters might be unlikely to demonstrate statistical differences in morbidity for nonpulmonary organ systems. We found no difference in the rates of cardiac complications, gastroesophageal reflux disease, small bowel obstruction, acute kidney injury, or hematologic or infectious complications between the 2 groups.We found no difference in the rates of Nissen fundoplication or gastrostomy tube placement between the 2 groups. Specifically, other authors have also found no difference in gastroesophageal reflux disease or infection rates for patients treated with permissive hypercapnia vs normocapnia.29 Patients in the permissive hypercapnia group were generally extubated 14 days sooner after definitive repair. This decrease in postoperative intubation time has also been identified in previous studies.7 However, other authors have not identified a decrease in the overall length of time of intubation.28 Our treatment guideline also calls for elective or semielective repair rather than urgent repair. We believe that the combination of these 2 factors resulted in no statistical difference between total hospital days in these 2 groups. In order to determine what role, if any, the length of time of ventilatory and medical management before operation may have in terms of mortality outcomes, we compared preoperative ventilation days for survivors vs mortalities within each group. Ultimately, we found no statistical difference between the numbers of days a patient was ventilated before surgery that related to survival. However, we did note an interesting trend. In both Groups 1 and 2, the patients who ultimately died from their illness were ventilated twice as long before operation than their surviving counterparts. One study noted that patients with more severe pulmonary hypertension, as evidenced by a high pulmonary artery-to-systemic artery ratio, underwent surgery much later than patients with low pulmonary artery-to-systemic artery ratios.31 Perhaps our patients with more severe pulmonary hypertension (who would be more likely to die) took longer to stabilize before intervention than those with less severe pulmonary hypertension. We recognize certain potential shortcomings of this report. First, as a retrospective study, the quality of the information available is of vital importance. During the study period, our institution used no less than 3 separate medical record systems and we must recognize the possibility of data loss, specifically with regard to daily progress notes or laboratory data before implementation of an electronic medical record system. Secondly, inadequate follow-up for some patients may affect outcomes reporting. Finally, this study does not account for changes in outcomes as a result of the overall advances in neonatology care as a whole over the study period.
CONCLUSIONS The goal of permissive hypercapnia in the care of infants with CDH is to reduce lung injury that results from aggressive
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ventilation and oxygenation. Hypercarbia is a secondary effect that is allowed, if necessary, by this strategy of more gentle ventilation, therefore, the term permissive hypercapnia. Perhaps the term gentle ventilation is more appropriate because this reflects the primary goal of the strategy. Our study demonstrates a survival benefit to infants treated for CDH at UVACH since the institution of permissive hypercapnia. Permissive hypercapnia will remain the standard of care for all CDH patients treated at our institution and we endorse it as a strategy to be embraced at other institutions as well. Acknowledgment: The authors would like to acknowledge the Division of Neonatology at the University of Virginia Children’s Hospital as valued partners and colleagues in the treatment of infants with congenital diaphragmatic hernia, and many other infants as well.
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14. Antonoff MA, Hustead VA, Groth SS, Schmeling DJ. protocolized management of infants with congential diaphragmatic hernia: effect on survival. J Pediatr Surg 2011;46:39–46. 15. Tracy ET, Mears SE, Smith PB, et al. Protocolized approach to the management of congenital diaphragmatic hernia: benefits of reducing variability in care. J Pediatr Surg 2010;45: 1343–1348. 16. Kays DW, Langham MR, Ledbetter DJ, Talbert JL. Detrimental effects of standard medical therapy in congenital diaphragmatic hernia. Ann Surg 1999;230:340–351. 17. Sola JE, Bronson SN, Cheung MC, et al. Survival disparities in newborns with congenital diaphragmatic hernia: a national perspective. J Pediatr Surg 2010;45:1336–1342. 18. Aly H, Bianco-Batlles D, Mohamed MA, Hammad TA. Mortality in infants with congential diaphragmatic hernia: a study of the United States National Database. J Perinatol 2010;30:553–557. 19. Odibo AO, Najaf T, Vachharajani A, et al. Predictors of the need for extracorporeal membrane oxygen and survival in congenital diaphragmatic hernia: a center’s 10 year experience. Prenatal Diag 2010;30:518–521. 20. Hoffman SB, Massaro AN, Gingalewski C, Short BL. Predictors of survival in congenital diaphragmatic hernia patients requiring extracorporeal membrane oxygen: CNMC 15-year expernience. J Perinatol 2010;30:546–552. 21. Thome UH, Ambalavanan N. Permissive hypercapnia to decrease lung injury in ventilated preterm neonates. Semin Fetal Neonatal Med 2008;14:21–27. 22. Kaiser JR, Gauss CH, Pont MM, Williams DK. Hypercapnia during the first 3 days of life associated with severe intraventricular hemorrhage in very low birth weight infants. J Perinatol 2006;26:279–285. 23. Danzer E, Gerdes M, Bernbaum J, et al. Neurodevelopmental outcome of infants with congential diaphragmatic hernia prospectively enrolled in an interdisciplinary follow-up program. J Pediatr Surg 2010;45:1759–1766. 24. Hagen EW, Sadek-Badawi M, Carlton DP, Palta M. Permissive hypercapnia and risk for brain injury and developmental impairment. Pediatrics 2008;122:e583–e589. 25. Donn SM, Sinha SK. Can mechanical ventilation strategies reduce chronic lung disease? Semin Neonatol 2003;8:441–448. 26. Ambalavanan N, Carlo WA. Ventilatory strategies for the prevention and management of bronchopulmonary dysplasia. Semin Perinatol 2006;30:192–199. 27. Van den Hout L, Reiss I, Felix J F, et al. Risk factors for chronic lung disease and mortality in newborns with congenital diaphragmatic hernia. Neonatol 2010;98:370–380. 28. Mariani G, Cifuentes J, Carlo WA. Randomized trial of permissive hypercapnia in preterm infants. Pediatrics 1999;104:1082– 1088. 29. Valfre L, Braguglia A, Conforti A, et al. Pulmonary hypertension in neonates with high-risk congenital diaphragmatic hernia does not affect mid-term outcome. European J Pediatr Surg 2011;21: 154–158. 30. Abdullah F, Zhang Y, Sciortino C, et al. Congenital diaphragmatic hernia: outcome review of 2,173 surgical repairs in US infants. Pediatr Surg Int 2009;25:1059–1064. 31. Al-Hathlol K, Elmahdy H, Nawaz S, et al. Perioperative course of pulmonary hypertension in infants with congenital diaphragmatic hernia: impact on outcome following successful repair. J Pediatr Surg 2011;46:625–629.
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Discussion
Discussion DR MAX LANGHAM (Memphis, TN): I want to thank the authors for a terrific talk documenting some outstanding results, which are as good as any published from Boston Children’s, Columbia, Gainesville, Florida, or other leading centers. I believe the authors’ assertion that permissive hypercapnia and general ventilation are important in the treatment of congenital diaphragmatic hernia (CDH). Although I firmly believe this, there are no randomized prospective trials that support this assertion. However, I also believe that permissive hypocapnia alone is not enough. The Congenital Diaphragmatic Hernia Study Group (CDHSG) has developed several ways of assessing risk factors in CDH. The best one is the size of the defect. Small hernias are associated with low risk, and these children with small hernias should be routinely saved; children with the bigger defects are more problematic. We have used or attempted to use permissive hypercapnia in Memphis since I moved there. We have done a poor job on patients who have diaphragmatic agenesis, who should have a 55% survival overall, based on large number from the CDHSG. Without information on risk stratification it is a little hard to interpret the Virginia results, although one suspects with this large a group of patients that they, in fact, have a broad spectrum of diaphragmatic sizes and risk factors. Any information that Dr McGahren and his team could give us about this would be good. There’s also not any information in the manuscript about inborn or outborn status, and how they manage prenatal diagnosis, which is important. I suspect that the general hospital in Charlottesville has a delivery service near the neonatal ICU (NICU), which would be helpful. I found this to be a problem in the freestanding children’s hospital I’m working in now. I think that what Dr McGahren and his team may have documented, I suspect most of all, is the superb teamwork that goes on in Charlottesville between an outstanding group of neonatologists and an outstanding group of pediatric surgeons. In most other institutions that have achieved these types of results, surgical groups have maintained complete dominance in management of the patients. I hope that Dr McGahren can expand a little bit on the magic that they have achieved. I suspect this will spill over in outstanding results in other conditions other than diaphragmatic hernias. DR MARTIN BLAKELY (Nashville, TN): I echo some of Dr Langham’s comments. As the authors realize, comparing two groups of patients from two different time periods runs the risk of comparing patients with important differences and varying risks for poor outcomes. So while the two groups of patients compared in this study are reasonably similar, several features of the earlier patient group may confer a higher risk. For example, there’s an almost 1-week earlier gestational age. In those earlier patients, it was 36 vs 37 weeks estimated gestational age. And that’s a very important difference for babies. There also was a 10% higher need for patch repair in that earlier group, and I think that is a surrogate measure for defect size. These differences may be clinically meaningful, although with relatively small numbers are not statistically significantly different. There was a recent article by Kuojen Tsao published in Surgery in 2010,
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reporting that prematurity was a significant predictor of death. In that paper, survival in the preterm infants was 20% lower than was found in the term infants. Also, disappointingly, when patients did require extracorporeal membrane oxygenation (ECMO), the mortality remained 50%. So in the most recent group of patients, there was a much lower use of ECMO, 29% vs 62%. So this likely had a big impact on the overall survival numbers. Do the authors believe that the permissive hypercapnia ventilation technique directly leads to lower the ECMO use? In my experience, in some infants, ECMO requirement is recognized very early after birth. So when was ECMO initiated in your study patients? Last, the goal in neonatal surgery in general is survival without neurodevelopmental impairment. Your paper reports a neurologic morbidity rate of 27%. So I wondered if you could describe what these neurologic morbidities were more fully. DR J ALEX HALLER (Baltimore, MD): I compliment Dr McGahren on an absolutely beautifully presented paper, and the University of Virginia group for their amazing results using this new technology. Eighty-six percent of your patients survived. That, as far as I know, is the ultimate result in the management of congenital diaphragmatic hernia. No one else can report more than 55%, 65%, or 70%. But I also question your explanation for why you’re getting such good results. I realize that hypercapnia means that the CO2 is allowed to go up fairly high. But that in itself, I think, is only a reflection of the ventilation that’s being carried out. Therefore, it seems to me that what needs to be focused on is the way you’re protecting the pulmonary parenchyma. As we’ve understood more and more over the last decade, the primary problem with congenital diaphragmatic hernia is not the hole, because in good models with big diaphragmatic hernias made, for example, in fetal sheep, they do very well with removing the diaphragm if they are born with normal lungs. We also do not find any problem associated with the various kinds of experimental animals when you do a pneumonectomy, for example, on the affected side. The problem is not lung tissue deficiency. But what we’ve learned clinically is if the patient already has a pneumothorax on the side of the good lung, that patient is likely to die, because the lung tissue has been damaged severely by the rupture of the lung. So the value of ECMO is to allow the lung to recover in patients who present with significant pulmonary insufficiency from lung damage. It seems to me that what you’ve shown us is that you don’t need to damage the remaining lung tissue to try to support these patients, and that hypercapnia, the rise in CO2, is simply a result of that gentle ventilation. So I would ask you, if that seems logical to you — and I certainly agree that you need to have the neonatologists working with you — is this not a standard that we should all be approaching? Because it’s the damage to the lung during too aggressive resuscitation that is probably the explanation for the high mortality associated with congenital diaphragmatic hernia. DR JAMES O’NEILL (Nashville, TN): I would like to congratulate Dr McGahren on what he did, and not necessarily criticize him for what he didn’t do. What I’m referring to is the issue of a randomized study vs a careful clinical observation form of retrospective study, which I believe this represents and is valid.
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His results are excellent. And I think that those of us who have had any involvement in this realize that this takes very careful, continuous bedside surveillance and management. Now, taking that into account, in my view, the main value of this study is that it is thoroughly confirmatory of earlier work on this subject that was originally designed to avoid secondary injury to the lung, particularly in patients who have lung hypoplasia, for which we have many markers such as the need for ECMO, the size of the defect, etc. We don’t expect survivals of 80% in patients with severe hypoplasia and big defects. Yet your results are good. First, realizing that you have indeed confirmed and perhaps improved earlier published reports on this subject, why don’t you say that this is the standard for you in Charlottesville? Are you ready? Do you have sufficient confidence in your results to make a general recommendation that this technique should be used universally? Many of us would agree. Second, could you tell us a little bit about whether you had patients who failed this approach and whether you had then to go on to alternate approaches? And what kinds of patients were they? Finally, in terms of the neurologic results, which, of course, would be concerning with longstanding hypercapnia and perhaps less oxygen saturation at the bedside, you have an early group and a later group. They may not be so comparable in terms of neurologic outcomes, because it really doesn’t matter if you survive but your neurologic outcome is devastating. And so that becomes a question. Do you plan to follow these patients for 10 or 15 years in order to get accurate information about neurologic outcome? DR EUGENE MCGAHREN (Charlottesville, VA): Addressing Dr Langham’s questions first, I would agree that the risk stratification described by Dr Langham regarding the size of the diaphragm hernia would be extremely important to understand. And I believe that Dr Guidry just received the next topic for study, so we will look into that. I do not have data on hand as to how many babies were inborn and outborn. I can say that the vast majority of babies are inborn at the University of Virginia. As Dr Langham suggests, one of the advantages we have in not being a freestanding children’s hospital is that we can see a lot of these mothers prenatally, provide multidisciplinary input from obstetrics, from neonatology, and from our pediatric surgery service. We can then plan for the babies to be born at the University of Virginia and come down one floor from the 8th floor obstetrics unit to the 7th floor NICU. So that has been very valuable.
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In terms of the management in the NICU, unlike some of the programs where there is support provided by pediatric surgery fellows, we do not have a fellowship training program. Management of the ventilation of these infants is done primarily by our neonatologists. Having said that, there was a lot of partnership in developing these guidelines. And there is continuous conversation that occurs on a daily basis between pediatric surgeons and our neonatology colleagues. Dr Blakely brought up the issues of the gestational age and the use of the patch. I acknowledge that there were those differences that he mentioned. The 36- to 37-week range is when significant issues of prematurity kick in, depending on the literature you read. The actual numbers were 36.4 and 37.2 weeks for the first and second groups, respectively, in our series. The patch difference was 60% for the first group, 50% for the second group. So I still have to rely on lack of statistical significance at this time. In terms of the effect of the guidelines on the use of ECMO, the babies now who would get ECMO are probably sicker initially and would tend to get ECMO earlier; in the previous group you would have babies managed a long time, with damaging effects, before receiving ECMO. Regarding Dr Haller’s input, I wholeheartedly agree that the issue here is not allowing CO2 to rise as a primary goal, but rather it is appropriate management of the ventilatory aspects of these babies and limiting the lung damage. A rise in CO2 is a potential secondary effect. This gets into semantics and the words we use in medicine. I refer to this in rounds all the time with students and residents. I think perhaps we could transfer to “gentle ventilation” as the more preferred terminology, but “permissive hypercapnia” has been used in the literature. Finally, with Dr O’Neill’s comments, I agree that we would be confident to recommend this strategy beyond our own center. With regard to neurologic outcomes, the babies who fail ventilatory management are going to be the ones going on ECMO, at least in this group of patients. I would note that the second group had a 26% incidence of neurologic morbidities, compared with 42% in the first group. I will say that our follow-up on neurologic morbidities is relatively soft, and we had to look for any types of neurologic indications in the charts about this. I think we need to do a more robust follow-up in the future to fully understand the neurologic ramifications of these treatments.
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Appendix UVACH Guideline for Permissive Hypercapnia in the Treatment of Infants with Congenital Diaphragmatic Hernia
Ventilation: Patients will initially be ventilated with synchronized intermittent mandatory ventilation and 100% oxygen with pressure not to exceed that required to produce chest rise. A major attempt will be made to avoid PIP ⬎ 25 and PEEP ⬎ 5 cm H2O. Oxygenation: After the first few hours from birth (for example, 6 hours), FiO2 will be adjusted to maintain preductal saturations of 90%. FiO2 will be weaned for saturations ⬎95% and increased only if saturations are persistently ⬍90%. PaO2 of 40 to 60 mmHg will be acceptable. Pre- and postductal saturations will be measured, but adjustments will be made for preductal values only, unless there is evidence of postductal compromise. Acid-base: pH will be maintained in the normal range (7.30 to 7.35). PaCO2 will be permitted to rise to 70 mmHg as long as pH remains ⬎ 7.25. If pH is consistently ⬍ 7.25, HCO3, Tham, or HFOV might be considered. Nitric oxide: It would be reasonable to start NO if high FiO2 requirements persist.
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Sedation: Paralysis will be avoided if possible. Patients will be lightly sedated with a midazolam drip as necessary. Perfusion/hydration: Mean arterial blood pressure will be supported with dopamine or volume expansion as necessary. Fluids will be maintained at approximately 100 mL/kg and adjusted as necessary. Surgery: Operations will be performed electively, rather than emergently, and will sometimes be performed in the neonatal ICU (NICU), with adequate operating room and anesthesia support. If the patient is transported to the operating room for surgery, an attempt will be made to use the NICU ventilator in the operating room. ECMO: ECMO will be used either pre- or postoperatively if the management strategies described above are unable to achieve satisfactory blood gases. Oxygenation index (OI) will not be useful with this new strategy because the OI will be low due to the low mean arterial pressure. A reasonable approach might be to consider ECMO for infants who cannot maintain preductal saturations ⬎ 85% or postductal pO2 ⬎ 30 mmHg or who show evidence of inadequate oxygen delivery using the above described management strategy. Usually, this will have included a trial of HFOV and nitric oxide.
Congenital diaphragmatic hernia of the Bochdalek type (CDH) is a potentially lethal birth defect involving herniation of abdominal contents into the thoracic cavity through a defect in the diaphragm. Traditionally, it has been believed that extrinsic compression from abdominal contents on the developing lung results in pulmonary hypoplasia and persistent pulmonary hypertension.1-3 Recent
research, however, suggests that aberrations in pulmonary development itself may be causative in CDH. These studies suggest that the affected lung is intrinsically abnormal and may compromise the development of the diaphragm, resulting in a hernia.4,5 CDH has an estimated incidence of 1:2,200 to 4,000 live births, with a historically expected survival of 50% to 80%.2,3,6-9 Management of an infant with CDH involves early intubation, appropriate ventilator management, treatment of pulmonary hypertension, and surgical correction of the diaphragm defect. Traditional methods of therapy involved an aggressive ventilator management strategy in which high peak inspiratory pressures (PIP), hyperoxygenation, and alkalization via hyperventilation and administration of sodium bicarbonate were used to maintain a postductal arterial oxygen pressure (PaO2) of ⬎90%, pH ⬎7.2, and partial pressure of CO2 (PaCO2) within normal physiologic parameters.1,6,7,10,11 The ventilatory pressures and volumes, and oxygenation required to achieve these goals, were rec-
Disclosure Information: Dr Kane is partial owner of Aegis Biomedical, Inc. and Ancile Biomedical, Inc. Dr Kane receives consulting fees from Sensors for Medicine and Science, Inc. All other authors have nothing to disclose. Presented at the Southern Surgical Association, 123rd Annual Meeting, Hot Springs, VA, December 2011. Received December 16, 2011; Accepted December 20, 2011. From the Department of Surgery (Guidry, Hranjec) and Division of Pediatric Surgery (Rodgers, Kane, McGahren), University of Virginia Health System, Charlottesville, VA. Correspondence address: Eugene McGahren, MD, University of Virginia Health System, Department of Surgery, Box 800709, Charlottesville, VA 22908-0709. email: [email protected]
© 2012 by the American College of Surgeons Published by Elsevier Inc.
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ISSN 1072-7515/12/$36.00 doi:10.1016/j.jamcollsurg.2011.12.036
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Abbreviations and Acronyms
CDH ECMO FiO2 HFOV IVH PaCO2 PIP UVACH
⫽ ⫽ ⫽ ⫽ ⫽ ⫽ ⫽ ⫽
congenital diaphragmatic hernia extracorporeal membrane oxygenation fraction of inspired oxygen high frequency oscillatory ventilation intraventricular hemorrhage partial pressure of carbon dioxide peak inspiratory pressure University of Virginia Children’s Hospital
ognized as causing lung trauma that was a significant source of morbidity and mortality in this population. Postmortem analysis of patients treated with aggressive ventilator management showed distinct evidence of barotrauma.11 In 1985, Wung and colleagues12 proposed a novel approach, now commonly recognized as “permissive hypercapnia” or “gentle ventilation,” to ventilator management in infants with persistence of fetal circulation (and pulmonary hypertension). It involved limiting the PIP and oxygenation levels in an effort to decrease barotrauma. The PaCO2 was not a controlling parameter and was allowed to rise to a level as high as 60 mmHg. This strategy was later applied to CDH patients and has since demonstrated a potential survival benefit. In particular, as the treatment of CDH has shifted toward delayed rather than emergent repair, the appropriate ventilatory management of underlying pulmonary hypertension and hypoplasia has proven to be vital in maximizing pulmonary outcomes for these patients.7,8 Although permissive hypercapnia has been a promising ventilator strategy for lung protection, its benefit for survival has not been definitively determined.13 In June 2001, the Divisions of Neonatology and Pediatric Surgery at the University of Virginia Children’s Hospital (UVACH) adopted a new guideline establishing permissive hypercapnia as the primary ventilation strategy for infants with CDH (Appendix 1, online only). Ventilatory pressures just high enough to produce chest rise are used with an emphasis to avoid PIP ⬎25 and positive end-expiratory pressure ⬎5 cm H2O. Fraction of inspired oxygen (FiO2) is aggressively weaned to maintain preductal oxygen saturations between 90% and 95%. The pH is maintained within physiologic norms. PaCO2 level is not a primary goal and is allowed to rise to as high as 70 mmHg as long as all other parameters are satisfied. High frequency oscillatory ventilation (HFOV), inhaled nitric oxide, and extracorporeal membrane oxygenation (ECMO) are used where appropriate according to the discretion of the treating physicians. The purpose of this study was to evaluate the effectiveness of permissive hypercapnia in the management of infants with CDH at UVACH. Our primary hypothesis was that survival would be improved in this patient group with the introduction of permissive hypercapnia. A secondary hypothesis was
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that indicators of certain morbidities, particularly posttreatment respiratory insufficiency, would be improved.
METHODS All patients with CDH admitted to the UVACH from May 1994 until October 2010 were enrolled in this retrospective chart review. The study was approved by the Institutional Review Board at the University of Virginia Health System. All patients with CDH were eligible for analysis, with exclusion criteria comprising lethal birth defects precluding definitive repair, delayed presentation outside the neonatal period, death at or immediately after birth or before treatment could be initiated, and lack of sufficient data in the chart to support statistical analyses. In June 2001, a formal guideline establishing the use of permissive hypercapnia to treat patients with CDH was adopted by the Divisions of Neonatology and Pediatric Surgery at UVACH. Our patients were divided into 2 groups based on their chronological association with this guideline. Patients in Group 1 (1994 to 2001) received traditional hyperventilation, oxygenation, and alkalinization therapy before institution of permissive hypercapnia. Patients in Group 2 (2001 to 2010) were managed with permissive hypercapnia. Patients in Group 2 were initially placed on synchronized intermittent mandatory ventilation (SIMV) mode with a PIP only sufficient to produce a chest rise, 100% FiO2, and minimal sedation. FiO2 was then aggressively weaned to maintain preductal oxygen saturations of 90%. Inhaled nitric oxide was used as the initial adjunctive treatment for persistently low oxygen saturations. Arterial pH was maintained between 7.30 and 7.35. PaCO2 was allowed to rise to 70 mmHg as long as the pH remained above 7.25. Sodium bicarbonate or HFOV were considered for persistent acidosis. By 1994, surgical repair of CDH was no longer undertaken on an emergent basis. However, the true elective nature of this operation was still in evolution at that time in our institution and may have resulted in earlier surgical intervention after presentation in the earlier years of our review than in subsequent years. Overall, operations were performed on an elective basis rather than emergently, with the exact timing based on consensus between the pediatric surgical and neonatal ICU treatment teams about the infant’s stability and readiness for repair. ECMO was used in patients with severe or persistent oxygenation and/or ventilation compromise refractory to other treatments including HFOV and inhaled nitric oxide. Early in the time course of this study, if ECMO was required, repair of CDH was accomplished while the infant was on ECMO. More recently, there has been a preference for weaning from ECMO before repair is undertaken. No infant in our review was denied care or operation due to a perceived basis of critical lung hypoplasia.
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Table 1. Patient Demographics Before (Group 1) and After (Group 2) Permissive Hypercapnia Demographic
Group 1 (n ⴝ 42)
Group 2 (n ⴝ 49)
Male, % 61.9 67.3 Female, % 38.1 32.7 Gestational age, wk, 36.4 ⫾ 0.4 37.2 ⫾ 0.4 mean ⫾ SEM Birth weight, g, 2,655.2 ⫾ 122.0 2,969.1 ⫾ 98.9 mean ⫾ SEM Prenatal diagnosis, % 45.2 63.3 Right-sided CDH, % 23.8 16.3 Diaphragmatic patch, % 59.5 49
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Table 2. Mortality Before (Group 1) and After (Group 2) Permissive Hypercapnia
p Value
Mortality
0.59 0.59 0.17
Mortality, % Mortality (anomalies), % ECMO mortality, %
0.05
*Denotes statistical significance, p ⬍ 0.05. ECMO, extracorporeal membrane oxygenation.
0.09 0.37 0.31
CDH, congenital diaphragmatic hernia.
Basic demographics, hospital admission and discharge, use of ECMO, in-hospital death, comorbidities including associated physical anomalies, and in-hospital complication data were entered into a secure, password-protected computer database. Descriptive analyses comparing demographic data between the 2 treatment groups were performed using univariate analysis, with statistical significance set at p ⬍ 0.05. Continuous variables are presented as mean ⫾ SEM and compared using a 2-sample t-test for independent samples. Categorical variables were analyzed using chi-square or Fisher’s exact test. All statistical analyses were performed using SAS software, version 9.1.3 (SAS Institute).
RESULTS A total of 103 patients with CDH were identified at UVACH during the study period. Ultimately, 91 patients met criteria for statistical analysis. Patients were excluded from analysis because of death before surgical intervention (including stillbirth, other lethal anomalies, nonresponse to medical support) (n ⫽ 6), presentation outside the neonatal period (n ⫽ 4), inadequate data in the chart for statistical analysis (n ⫽ 1), and 1 patient with pentalogy of Cantrell was excluded because the diaphragmatic hernia only entered the pericardium and did not result in pulmonary hypoplasia. A total of 42 patients were in Group 1 and 49 in Group 2. Average birth weight was slightly higher in Group 2 and approached statistical significance. The 2 groups were statistically similar in terms of sex, gestational age, rate of prenatal diagnosis, right-sided CDH, and the use of a diaphragmatic patch for repair (Table 1). Overall mortality rates were 42.9% in Group 1 and 14.3% in Group 2. Decreased mortality in Group 2 was also demonstrated for patients who had other congenital anomalies (Table 2). There was no statistical difference in mortality rates for patients with recurrent CDH or ECMO requirements. There were 5 total cases of recurrent CDH during the study: 2 in Group 1 with 1 mortality, and 3 in
Group 1 (n ⴝ 42)
Group 2 (n ⴝ 49)
p Value
42.9 41.2 53.8
14.3 5.9 50
0.002* 0.02* 0.82
Group 2 with no mortalities (p ⫽ 0.4). Mortality rates for infants receiving ECMO were 53.8% in Group 1 and 50.8% in Group 2. Most patients in the study died due to severe pulmonary hypertension (n ⫽ 10). Other causes for mortality were cerebral intraparenchymal hemorrhage (n ⫽ 4), sepsis (n ⫽ 2), multisystem failure (n ⫽ 2), withdrawal of care due to associated anomalies (n ⫽ 2), pulmonary hemorrhage (n ⫽ 1), heart failure (n ⫽ 1), mechanical ECMO failure (n ⫽ 1), withdrawal of support by family members for reasons unclear during chart review (n ⫽ 1), and an acute decompensation of unclear etiology (n ⫽ 1). Overall rates of morbidity (all kinds) were lower in Group 2 and approached statistical significance (Table 3). Morbidity rates were 83.3% and 65.3% in Groups 1 and 2, respectively. There was no difference in recurrent CDH between the 2 groups. Rates of home oxygen requirement after repair as well as manifestations of persistent pulmonary disease, such as bronchopulmonary dysplasia and asthma, were also similar. Likewise, there was no difference between the 2 groups in terms of neurologic, bleeding, infectious, cardiac, gastrointestinal, or renal complication rates. There was a significant (p ⫽ 0.003) difference in the rates of additional or replacement tube thoracostomy between the 2 groups: 35.7% of patients in Group 1 required a replacement or additional chest tube compared with 10.2% in Group 2. Rates of HFOV between the 2 groups were similar but rates of inhaled nitric oxide use were statistically higher in Group 2. ECMO use was statistically lower in Group 2 (28.6%) compared with Group 1 (61.9%). Total days on ECMO were similar, with a mean of 15.2 days in Group 1 vs 13.2 days in Group 2. Overall, patients spent a similar number of days intubated after repair. However, there was a single patient in Group 2 who was intubated for a total of 424 days. With this patient excluded, Group 2 had a statistically shorter intubation period after repair. On average, repair was offered on day of life 5.9 in Group 1 and on day of life 9 in Group 2. There was no statistical difference between preoperative ventilation days between survivors and mortalities in each group (Table 4). There was no difference in overall hospital stay between the 2 groups.
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Table 3. Morbidity Before (Group 1) and After (Group 2) Permissive Hypercapnia Morbidity
Morbidity (overall), % Neurologic, % Cardiac, % Repeat tube thoracostomy, % O2 requirement at discharge, % Persistent pulmonary disease, % Recurrent CDH, % Gastrointestinal (all), % Nissen, % Gastrostomy, % Nissen ⫹ Gastrostomy, % Hematologic, % Infection, % Renal, % ECMO, % Days on ECMO, mean ⫾ SEM iNO†, n (%) HFOV†, n (%) Timing of repair, d, mean ⫾ SEM Days intubated after repair, mean ⫾ SEM Days intubated after repair (modified), mean ⫾ SEM Hospital stay, d, mean ⫾ SEM
Group 1 (n ⴝ 42)
Group 2 (n ⴝ 49)
p Value
83.3 45.2 2.4
65.3 26.5 2.0
0.052 0.06 1.0
35.7
10.2
0.003*
21.4
22.4
0.94
14.3 4.76
10.2 6.1
0.56 1.0
19.1 9.5 16.7
20.4 4.1 12.2
0.87 0.41 0.54
9.5 19.1 14.3 7.1 61.9 15.2 ⫾ 1.6
4.1 6.1 20.4 0 28.6 13.2 ⫾ 2.7
0.41 0.10 0.44 0.09 0.001* 0.49
12/37 (32.4) 26/37 (70.2) 5.9 ⫾ 1.01
27/46 (58.7) 34/45 (75.6) 9 ⫾ 0.93
0.02* 0.59 0.03*
25 ⫾ 3.9
19.9 ⫾ 9.1
0.61
26 ⫾ 3.9
11 ⫾ 1.5
50.9 ⫾ 7.9
42.2 ⫾ 9.2
0.002* 0.48
*Denotes statistical significance, p ⬍ 0.05. † Variation in group size secondary to unobtainable chart data. CDH, congenital diaphragmatic hernia; ECMO, extracorporeal membrane oxygenation; HFOV, high frequency oscillatory ventilation; iNO, inhaled nitric oxide.
DISCUSSION Our study demonstrates a significant decrease in overall mortality after the introduction of permissive hypercapnia as the primary ventilator management strategy for infants with CDH. A recent Cochrane review, although not limited to CDH management, indicated that there is not enough evidence to support the use of permissive hypercapnia over normocapnia as a superior ventilatory management strategy.13 However, our positive results are similar to those at other institutions that have adopted permissive hypercapnia for the management of CDH,6,7,11,14-16A
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Table 4. Comparison of Preoperative Ventilation Days for Survivors vs. Mortalities per Group Group
Survivors
Mortalities
p Value
Group 1, d, mean ⫾ SEM Group 2, d, mean ⫾ SEM
3.1 ⫾ 0.6 7.3 ⫾ 0.9
7.9 ⫾ 2.3 14.6 ⫾ 3.4
0.06 0.09
strong trend toward lower overall morbidity was also identified but was not statistically significant in our study. Overall, our 2 groups were statistically similar, so theoretically there should be no difference in outcomes attributable to demographic differences between the 2 groups. However, the average birth weight in Group 2 was higher, approaching statistical significance. It is unclear what effect, if any, this slight increase in birth weight would have in terms of overall morbidity and mortality. It is reasonable to believe that larger infants may have a survival advantage. Indeed, Sola and colleauges17 demonstrated a survival benefit in CDH patients with a birth weight greater than 3 kg. ECMO is an important treatment modality for severe pulmonary hypertension and CDH. Patients in our permissive hypercapnia group had a lower rate of ECMO use than previously treated patients. A similar trend was noted in a report by Wilson and associates.11 The quoted mortality rates in the literature for patients treated with ECMO range from 32% to 60%.7,8,18,19 We identified similar mortality rates on ECMO for both groups. Although some studies have demonstrated a potential survival benefit, we were unable to demonstrate a survival benefit attributable to ECMO treatment based on ventilator management before or after its initiation.11 Boloker and coworkers7 also noted equal mortality on ECMO in their study of patients treated with permissive hypercapnia vs normocapnia. Interestingly, pre-ECMO PaCO2 less than 60 mmHg has been found to be a predictor of ECMO survival, and elevated PaCO2 may serve as a marker for potentially nonsurvivable pulmonary hypoplasia.20 However, no infant was denied treatment in our series on the basis of any proposed criteria indicating nonsurvivable pulmonary hypoplasia. It is important to recognize the effects of hypercapnia on cerebral perfusion. Hypercapnia causes cerebral vasodilatation and therefore increases cerebral blood flow in preterm infants.21 Studies have suggested that the rate of intraventricular hemorrhage (IVH) is directly proportional to the PaCO2 and that the incidence of IVH is increased with large variations in PaCO2.21,22 Therefore, one might expect to observe an increased rate of IVH or other neurologic complications in patients with permissive hypercapnia. However, this generally has not been demonstrated in the literature.21 A prospective study by Danzer and colleagues23 demonstrated some degree of neurologic impairment in approximately 50% of CDH patients. We found no statistical significance in the rates of IVH or other adverse neu-
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rologic outcomes between our 2 groups. These results are consistent with those noted by Hagen and coauthors.24 It is noteworthy that two of these studies were performed in very low birth weight infants and specifically excluded patients with congenital anomalies. Multiple ventilator modalities exist for the management of patients with CDH, and much attention has been paid to the effect these modalities have on the development of chronic lung disease.25,26 Retrospective studies have demonstrated that 30% to 56% of CDH patients display symptoms of chronic lung disease long-term.27 However, a randomized trial by Mariani and associates28 demonstrated no difference between rates of chronic lung disease between preterm infants who received either permissive hypercapnia or normocapnia. One study by Valfre and colleagues29 found that the degree of pulmonary hypertension in hospitalized neonates has no effect on postdischarge outcomes. Our study suggests that there may be no difference in chronic lung disease between patients treated with permissive hypercapnia and those treated with more traditional aggressive ventilation strategies. Rates of HFOV were similar between the 2 groups. The need for HFOV as the initial ventilatory modality for infants with CDH has been implicated as a risk factor for development of chronic lung disease.27 Rates of inhaled nitric oxide use were statistically lower in our permissive hypercapnia group than in the normocapnia group; however, this may be unreliable due to a lack of consistency in the reporting of inhaled nitric oxide use. CDH repair at our institution typically involves ipsilateral thoracostomy tube placement. Routine thoracostomy tube use has been implicated in increased mortality rates for CDH patients. This phenomenon is thought to result from gross hyperinflation of the ipsilateral lung immediately after repair, resulting in mechanical trauma as well as a decreased ability of the ipsilateral lung to deflate with exhalation.7 Bagolan and coworkers6 noted a decrease in preoperative thoracostomy tube placement for pneumothorax for patients treated with permissive hypercapnia. Our study was not designed to evaluate this association, but we did demonstrate a decrease in the rate of spontaneous pneumothorax requiring either primary placement or replacement (if after surgical repair) of a thoracostomy tube. This may be an effect of decreased peak pressures and associated barotrauma with use of permissive hypercapnia. Perhaps the decrease in damage associated with permissive hypercapnia is greater than any potential damage caused by the thoracostomy tube. Patients with CDH have been shown to have a high rate of associated complications, particularly gastroesophageal reflux disease, and require frequent invasive procedures.30 However, our study was designed primarily to identify mortality and morbidity with respect to ventilator management in this group of infants. Alterations in ventilator management without alterations to fun-
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damental aspects of definitive repair or other critical care parameters might be unlikely to demonstrate statistical differences in morbidity for nonpulmonary organ systems. We found no difference in the rates of cardiac complications, gastroesophageal reflux disease, small bowel obstruction, acute kidney injury, or hematologic or infectious complications between the 2 groups.We found no difference in the rates of Nissen fundoplication or gastrostomy tube placement between the 2 groups. Specifically, other authors have also found no difference in gastroesophageal reflux disease or infection rates for patients treated with permissive hypercapnia vs normocapnia.29 Patients in the permissive hypercapnia group were generally extubated 14 days sooner after definitive repair. This decrease in postoperative intubation time has also been identified in previous studies.7 However, other authors have not identified a decrease in the overall length of time of intubation.28 Our treatment guideline also calls for elective or semielective repair rather than urgent repair. We believe that the combination of these 2 factors resulted in no statistical difference between total hospital days in these 2 groups. In order to determine what role, if any, the length of time of ventilatory and medical management before operation may have in terms of mortality outcomes, we compared preoperative ventilation days for survivors vs mortalities within each group. Ultimately, we found no statistical difference between the numbers of days a patient was ventilated before surgery that related to survival. However, we did note an interesting trend. In both Groups 1 and 2, the patients who ultimately died from their illness were ventilated twice as long before operation than their surviving counterparts. One study noted that patients with more severe pulmonary hypertension, as evidenced by a high pulmonary artery-to-systemic artery ratio, underwent surgery much later than patients with low pulmonary artery-to-systemic artery ratios.31 Perhaps our patients with more severe pulmonary hypertension (who would be more likely to die) took longer to stabilize before intervention than those with less severe pulmonary hypertension. We recognize certain potential shortcomings of this report. First, as a retrospective study, the quality of the information available is of vital importance. During the study period, our institution used no less than 3 separate medical record systems and we must recognize the possibility of data loss, specifically with regard to daily progress notes or laboratory data before implementation of an electronic medical record system. Secondly, inadequate follow-up for some patients may affect outcomes reporting. Finally, this study does not account for changes in outcomes as a result of the overall advances in neonatology care as a whole over the study period.
CONCLUSIONS The goal of permissive hypercapnia in the care of infants with CDH is to reduce lung injury that results from aggressive
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ventilation and oxygenation. Hypercarbia is a secondary effect that is allowed, if necessary, by this strategy of more gentle ventilation, therefore, the term permissive hypercapnia. Perhaps the term gentle ventilation is more appropriate because this reflects the primary goal of the strategy. Our study demonstrates a survival benefit to infants treated for CDH at UVACH since the institution of permissive hypercapnia. Permissive hypercapnia will remain the standard of care for all CDH patients treated at our institution and we endorse it as a strategy to be embraced at other institutions as well. Acknowledgment: The authors would like to acknowledge the Division of Neonatology at the University of Virginia Children’s Hospital as valued partners and colleagues in the treatment of infants with congenital diaphragmatic hernia, and many other infants as well.
REFERENCES 1. Arora M, Bajpai M, Soni TR, Sai Prasad TR. Congenital diaphragmatic hernia. Indian J Pediatr 2000;67:665–670. 2. Smith NP, Jesudason EC, Losty PD. Congential diaphragmatic hernia. Paediatr Respir Rev 2002;3:339–348. 3. Hedrick HL. Management of prenatally diagnosed congenital diaphragmatic hernia. Semin Fetal Neonatal Med 2010;15:21–27. 4. Jesudason EC. Challenging embryological theories on congenital diaphgragmatic hernia: future therapeutic implications for paediatric surgery. Ann Royal Col Surg Eng 2002;84:252–259. 5. Kholdebarin RIBM, Keijzer R. Pulmonary development considerations in the surgical management of congenital diaphragmatic hernia. Early Human Develop 2011;87:755–758. 6. Bagolan P, Casaccia G, Crescenzi F, et al. Impact of a current treatment protocol on outcome of high-risk congenital diaphragmatic hernia. J Pediatr Surg 2004;39:313–318. 7. Boloker J, Bateman DA, Wung J, Stolar CJH. Congenital diaphragmatic hernia in 120 infants treated consecutively with permissive hypercapnea/spontaneous respiration/elective repair. J Pediatr Surg 2002;37:357–366. 8. Finer NN, Tierney A, Etches P C, et al. Congential diaphragmatic hernia: developing a protocolized approach. J Pediatr Surg 1998;33:1331–1337. 9. Chao P, Huang C, Liu C, et al. Congenital diaphragmatic hernia in the neonatal period: review of 21 years’ experience. Pediatr Neonatol 2010;5:97–102. 10. Hirschl RB. Innovative therapies in the management of newborns with congential diaphragmatic hernia. Semin Pediat Surg 1996;5:256–265. 11. Wilson JM, Lund D P, Lillehei C W, Vacanti J P. Congential diaphragmatic hernia - a tale of two cities: The Boston experience. J Pediat Surg 1997;32:401–405. 12. Wung JT, James LS, Kilchevsky E, James E. Management of infants with severe respiratory failure and persistence of fetal circulation, without hyperventilation. Pediatrics 1985;76:488–494. 13. Woodgate PG, Davies WPG. Permissive hypercapnia for the prevention of morbidity and mortality in mechanically ventilated newborn infants. The Cochrane Library 2001:118.
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14. Antonoff MA, Hustead VA, Groth SS, Schmeling DJ. protocolized management of infants with congential diaphragmatic hernia: effect on survival. J Pediatr Surg 2011;46:39–46. 15. Tracy ET, Mears SE, Smith PB, et al. Protocolized approach to the management of congenital diaphragmatic hernia: benefits of reducing variability in care. J Pediatr Surg 2010;45: 1343–1348. 16. Kays DW, Langham MR, Ledbetter DJ, Talbert JL. Detrimental effects of standard medical therapy in congenital diaphragmatic hernia. Ann Surg 1999;230:340–351. 17. Sola JE, Bronson SN, Cheung MC, et al. Survival disparities in newborns with congenital diaphragmatic hernia: a national perspective. J Pediatr Surg 2010;45:1336–1342. 18. Aly H, Bianco-Batlles D, Mohamed MA, Hammad TA. Mortality in infants with congential diaphragmatic hernia: a study of the United States National Database. J Perinatol 2010;30:553–557. 19. Odibo AO, Najaf T, Vachharajani A, et al. Predictors of the need for extracorporeal membrane oxygen and survival in congenital diaphragmatic hernia: a center’s 10 year experience. Prenatal Diag 2010;30:518–521. 20. Hoffman SB, Massaro AN, Gingalewski C, Short BL. Predictors of survival in congenital diaphragmatic hernia patients requiring extracorporeal membrane oxygen: CNMC 15-year expernience. J Perinatol 2010;30:546–552. 21. Thome UH, Ambalavanan N. Permissive hypercapnia to decrease lung injury in ventilated preterm neonates. Semin Fetal Neonatal Med 2008;14:21–27. 22. Kaiser JR, Gauss CH, Pont MM, Williams DK. Hypercapnia during the first 3 days of life associated with severe intraventricular hemorrhage in very low birth weight infants. J Perinatol 2006;26:279–285. 23. Danzer E, Gerdes M, Bernbaum J, et al. Neurodevelopmental outcome of infants with congential diaphragmatic hernia prospectively enrolled in an interdisciplinary follow-up program. J Pediatr Surg 2010;45:1759–1766. 24. Hagen EW, Sadek-Badawi M, Carlton DP, Palta M. Permissive hypercapnia and risk for brain injury and developmental impairment. Pediatrics 2008;122:e583–e589. 25. Donn SM, Sinha SK. Can mechanical ventilation strategies reduce chronic lung disease? Semin Neonatol 2003;8:441–448. 26. Ambalavanan N, Carlo WA. Ventilatory strategies for the prevention and management of bronchopulmonary dysplasia. Semin Perinatol 2006;30:192–199. 27. Van den Hout L, Reiss I, Felix J F, et al. Risk factors for chronic lung disease and mortality in newborns with congenital diaphragmatic hernia. Neonatol 2010;98:370–380. 28. Mariani G, Cifuentes J, Carlo WA. Randomized trial of permissive hypercapnia in preterm infants. Pediatrics 1999;104:1082– 1088. 29. Valfre L, Braguglia A, Conforti A, et al. Pulmonary hypertension in neonates with high-risk congenital diaphragmatic hernia does not affect mid-term outcome. European J Pediatr Surg 2011;21: 154–158. 30. Abdullah F, Zhang Y, Sciortino C, et al. Congenital diaphragmatic hernia: outcome review of 2,173 surgical repairs in US infants. Pediatr Surg Int 2009;25:1059–1064. 31. Al-Hathlol K, Elmahdy H, Nawaz S, et al. Perioperative course of pulmonary hypertension in infants with congenital diaphragmatic hernia: impact on outcome following successful repair. J Pediatr Surg 2011;46:625–629.
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Discussion DR MAX LANGHAM (Memphis, TN): I want to thank the authors for a terrific talk documenting some outstanding results, which are as good as any published from Boston Children’s, Columbia, Gainesville, Florida, or other leading centers. I believe the authors’ assertion that permissive hypercapnia and general ventilation are important in the treatment of congenital diaphragmatic hernia (CDH). Although I firmly believe this, there are no randomized prospective trials that support this assertion. However, I also believe that permissive hypocapnia alone is not enough. The Congenital Diaphragmatic Hernia Study Group (CDHSG) has developed several ways of assessing risk factors in CDH. The best one is the size of the defect. Small hernias are associated with low risk, and these children with small hernias should be routinely saved; children with the bigger defects are more problematic. We have used or attempted to use permissive hypercapnia in Memphis since I moved there. We have done a poor job on patients who have diaphragmatic agenesis, who should have a 55% survival overall, based on large number from the CDHSG. Without information on risk stratification it is a little hard to interpret the Virginia results, although one suspects with this large a group of patients that they, in fact, have a broad spectrum of diaphragmatic sizes and risk factors. Any information that Dr McGahren and his team could give us about this would be good. There’s also not any information in the manuscript about inborn or outborn status, and how they manage prenatal diagnosis, which is important. I suspect that the general hospital in Charlottesville has a delivery service near the neonatal ICU (NICU), which would be helpful. I found this to be a problem in the freestanding children’s hospital I’m working in now. I think that what Dr McGahren and his team may have documented, I suspect most of all, is the superb teamwork that goes on in Charlottesville between an outstanding group of neonatologists and an outstanding group of pediatric surgeons. In most other institutions that have achieved these types of results, surgical groups have maintained complete dominance in management of the patients. I hope that Dr McGahren can expand a little bit on the magic that they have achieved. I suspect this will spill over in outstanding results in other conditions other than diaphragmatic hernias. DR MARTIN BLAKELY (Nashville, TN): I echo some of Dr Langham’s comments. As the authors realize, comparing two groups of patients from two different time periods runs the risk of comparing patients with important differences and varying risks for poor outcomes. So while the two groups of patients compared in this study are reasonably similar, several features of the earlier patient group may confer a higher risk. For example, there’s an almost 1-week earlier gestational age. In those earlier patients, it was 36 vs 37 weeks estimated gestational age. And that’s a very important difference for babies. There also was a 10% higher need for patch repair in that earlier group, and I think that is a surrogate measure for defect size. These differences may be clinically meaningful, although with relatively small numbers are not statistically significantly different. There was a recent article by Kuojen Tsao published in Surgery in 2010,
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reporting that prematurity was a significant predictor of death. In that paper, survival in the preterm infants was 20% lower than was found in the term infants. Also, disappointingly, when patients did require extracorporeal membrane oxygenation (ECMO), the mortality remained 50%. So in the most recent group of patients, there was a much lower use of ECMO, 29% vs 62%. So this likely had a big impact on the overall survival numbers. Do the authors believe that the permissive hypercapnia ventilation technique directly leads to lower the ECMO use? In my experience, in some infants, ECMO requirement is recognized very early after birth. So when was ECMO initiated in your study patients? Last, the goal in neonatal surgery in general is survival without neurodevelopmental impairment. Your paper reports a neurologic morbidity rate of 27%. So I wondered if you could describe what these neurologic morbidities were more fully. DR J ALEX HALLER (Baltimore, MD): I compliment Dr McGahren on an absolutely beautifully presented paper, and the University of Virginia group for their amazing results using this new technology. Eighty-six percent of your patients survived. That, as far as I know, is the ultimate result in the management of congenital diaphragmatic hernia. No one else can report more than 55%, 65%, or 70%. But I also question your explanation for why you’re getting such good results. I realize that hypercapnia means that the CO2 is allowed to go up fairly high. But that in itself, I think, is only a reflection of the ventilation that’s being carried out. Therefore, it seems to me that what needs to be focused on is the way you’re protecting the pulmonary parenchyma. As we’ve understood more and more over the last decade, the primary problem with congenital diaphragmatic hernia is not the hole, because in good models with big diaphragmatic hernias made, for example, in fetal sheep, they do very well with removing the diaphragm if they are born with normal lungs. We also do not find any problem associated with the various kinds of experimental animals when you do a pneumonectomy, for example, on the affected side. The problem is not lung tissue deficiency. But what we’ve learned clinically is if the patient already has a pneumothorax on the side of the good lung, that patient is likely to die, because the lung tissue has been damaged severely by the rupture of the lung. So the value of ECMO is to allow the lung to recover in patients who present with significant pulmonary insufficiency from lung damage. It seems to me that what you’ve shown us is that you don’t need to damage the remaining lung tissue to try to support these patients, and that hypercapnia, the rise in CO2, is simply a result of that gentle ventilation. So I would ask you, if that seems logical to you — and I certainly agree that you need to have the neonatologists working with you — is this not a standard that we should all be approaching? Because it’s the damage to the lung during too aggressive resuscitation that is probably the explanation for the high mortality associated with congenital diaphragmatic hernia. DR JAMES O’NEILL (Nashville, TN): I would like to congratulate Dr McGahren on what he did, and not necessarily criticize him for what he didn’t do. What I’m referring to is the issue of a randomized study vs a careful clinical observation form of retrospective study, which I believe this represents and is valid.
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His results are excellent. And I think that those of us who have had any involvement in this realize that this takes very careful, continuous bedside surveillance and management. Now, taking that into account, in my view, the main value of this study is that it is thoroughly confirmatory of earlier work on this subject that was originally designed to avoid secondary injury to the lung, particularly in patients who have lung hypoplasia, for which we have many markers such as the need for ECMO, the size of the defect, etc. We don’t expect survivals of 80% in patients with severe hypoplasia and big defects. Yet your results are good. First, realizing that you have indeed confirmed and perhaps improved earlier published reports on this subject, why don’t you say that this is the standard for you in Charlottesville? Are you ready? Do you have sufficient confidence in your results to make a general recommendation that this technique should be used universally? Many of us would agree. Second, could you tell us a little bit about whether you had patients who failed this approach and whether you had then to go on to alternate approaches? And what kinds of patients were they? Finally, in terms of the neurologic results, which, of course, would be concerning with longstanding hypercapnia and perhaps less oxygen saturation at the bedside, you have an early group and a later group. They may not be so comparable in terms of neurologic outcomes, because it really doesn’t matter if you survive but your neurologic outcome is devastating. And so that becomes a question. Do you plan to follow these patients for 10 or 15 years in order to get accurate information about neurologic outcome? DR EUGENE MCGAHREN (Charlottesville, VA): Addressing Dr Langham’s questions first, I would agree that the risk stratification described by Dr Langham regarding the size of the diaphragm hernia would be extremely important to understand. And I believe that Dr Guidry just received the next topic for study, so we will look into that. I do not have data on hand as to how many babies were inborn and outborn. I can say that the vast majority of babies are inborn at the University of Virginia. As Dr Langham suggests, one of the advantages we have in not being a freestanding children’s hospital is that we can see a lot of these mothers prenatally, provide multidisciplinary input from obstetrics, from neonatology, and from our pediatric surgery service. We can then plan for the babies to be born at the University of Virginia and come down one floor from the 8th floor obstetrics unit to the 7th floor NICU. So that has been very valuable.
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In terms of the management in the NICU, unlike some of the programs where there is support provided by pediatric surgery fellows, we do not have a fellowship training program. Management of the ventilation of these infants is done primarily by our neonatologists. Having said that, there was a lot of partnership in developing these guidelines. And there is continuous conversation that occurs on a daily basis between pediatric surgeons and our neonatology colleagues. Dr Blakely brought up the issues of the gestational age and the use of the patch. I acknowledge that there were those differences that he mentioned. The 36- to 37-week range is when significant issues of prematurity kick in, depending on the literature you read. The actual numbers were 36.4 and 37.2 weeks for the first and second groups, respectively, in our series. The patch difference was 60% for the first group, 50% for the second group. So I still have to rely on lack of statistical significance at this time. In terms of the effect of the guidelines on the use of ECMO, the babies now who would get ECMO are probably sicker initially and would tend to get ECMO earlier; in the previous group you would have babies managed a long time, with damaging effects, before receiving ECMO. Regarding Dr Haller’s input, I wholeheartedly agree that the issue here is not allowing CO2 to rise as a primary goal, but rather it is appropriate management of the ventilatory aspects of these babies and limiting the lung damage. A rise in CO2 is a potential secondary effect. This gets into semantics and the words we use in medicine. I refer to this in rounds all the time with students and residents. I think perhaps we could transfer to “gentle ventilation” as the more preferred terminology, but “permissive hypercapnia” has been used in the literature. Finally, with Dr O’Neill’s comments, I agree that we would be confident to recommend this strategy beyond our own center. With regard to neurologic outcomes, the babies who fail ventilatory management are going to be the ones going on ECMO, at least in this group of patients. I would note that the second group had a 26% incidence of neurologic morbidities, compared with 42% in the first group. I will say that our follow-up on neurologic morbidities is relatively soft, and we had to look for any types of neurologic indications in the charts about this. I think we need to do a more robust follow-up in the future to fully understand the neurologic ramifications of these treatments.
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Appendix UVACH Guideline for Permissive Hypercapnia in the Treatment of Infants with Congenital Diaphragmatic Hernia
Ventilation: Patients will initially be ventilated with synchronized intermittent mandatory ventilation and 100% oxygen with pressure not to exceed that required to produce chest rise. A major attempt will be made to avoid PIP ⬎ 25 and PEEP ⬎ 5 cm H2O. Oxygenation: After the first few hours from birth (for example, 6 hours), FiO2 will be adjusted to maintain preductal saturations of 90%. FiO2 will be weaned for saturations ⬎95% and increased only if saturations are persistently ⬍90%. PaO2 of 40 to 60 mmHg will be acceptable. Pre- and postductal saturations will be measured, but adjustments will be made for preductal values only, unless there is evidence of postductal compromise. Acid-base: pH will be maintained in the normal range (7.30 to 7.35). PaCO2 will be permitted to rise to 70 mmHg as long as pH remains ⬎ 7.25. If pH is consistently ⬍ 7.25, HCO3, Tham, or HFOV might be considered. Nitric oxide: It would be reasonable to start NO if high FiO2 requirements persist.
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Sedation: Paralysis will be avoided if possible. Patients will be lightly sedated with a midazolam drip as necessary. Perfusion/hydration: Mean arterial blood pressure will be supported with dopamine or volume expansion as necessary. Fluids will be maintained at approximately 100 mL/kg and adjusted as necessary. Surgery: Operations will be performed electively, rather than emergently, and will sometimes be performed in the neonatal ICU (NICU), with adequate operating room and anesthesia support. If the patient is transported to the operating room for surgery, an attempt will be made to use the NICU ventilator in the operating room. ECMO: ECMO will be used either pre- or postoperatively if the management strategies described above are unable to achieve satisfactory blood gases. Oxygenation index (OI) will not be useful with this new strategy because the OI will be low due to the low mean arterial pressure. A reasonable approach might be to consider ECMO for infants who cannot maintain preductal saturations ⬎ 85% or postductal pO2 ⬎ 30 mmHg or who show evidence of inadequate oxygen delivery using the above described management strategy. Usually, this will have included a trial of HFOV and nitric oxide.