Lisa M. Herkert

Timing of repair of congenital diaphragmatic hernia in patients supported by extracorporeal membrane oxygenation (ECMO)

PURPOSE The optimal timing of repair for congenital diaphragmatic hernia (CDH) in patients requiring extracorporeal membrane oxygenation (ECMO) is controversial. Repair during ECMO may improve respiratory function by restoring normal anatomy. However, there is increased risk of complications including surgical bleeding. The purpose of this study was to examine the impact of timing of CDH repair on outcomes in a large cohort of patients treated at a single institution. METHODS We retrospectively reviewed charts of all CDH patients in our Pulmonary Hypoplasia Program from 2004 to 2013. Categorical variables were analyzed by Fishers exact test and continuous variables by Mann-Whitney t-test (p<0.05). RESULTS A total of 77 CDH patients required ECMO support during the study dates. Of these, 16 patients did not survive to repair, 3 patients were repaired prior to cannulation, 41 patients were repaired during ECMO, and 17 patients were repaired after decannulation. Survival was 67%, 43.9%, and 100% for those repaired prior to, during, or post ECMO, respectively, with statistical significance associated with repair after decannulation (P<0.0001). Operative bleeding requiring transfusion occurred in 12 patients repaired on ECMO, while no significant bleeding occurred in patients repaired after decannulation (P=0.003). CONCLUSION Outcomes were improved in CDH patients undergoing surgical repair following ECMO with significantly increased survival, lower rates of surgical bleeding, and decreased total duration of ECMO therapy compared to patients repaired on ECMO. In patients who can be successfully weaned from ECMO, our study supports a role for delayed repair off ECMO with reduced operative morbidity and increased survival.

Neurodevelopmental outcome at one year of age in congenital diaphragmatic hernia infants not treated with extracorporeal membrane oxygenation

BACKGROUND We evaluated the neurodevelopmental (ND) outcome at one year of age for congenital diaphragmatic hernia (CDH) children who have not undergone extracorporeal membrane oxygenation (ECMO) treatment during the neonatal period. MATERIAL AND METHODS Between 01/2005 and 06/2012, 63 consecutive CDH patients underwent ND assessment using the BSID-III at a median age of 12 months. ND delay was defined by a score of ≤ 85 in any of the composite scales. Severe impairment was defined as a score of ≤ 69 in at least one domain. RESULTS Mean ± SD cognitive, language, and motor functions were 94 ± 14, 86 ± 14, 90 ± 15, respectively (normal 100 ± 15, P<0.01 for each). Forty-three-percent scored within the average range for all scales. Forty-four-percent had mild, and 13% had severe delays in at least one domain. Prolonged NICU stay, intubation and O2 requirement, fundoplication, abnormal BAERs, and tracheostomy were associated with lower scores in all domains. Right-sided CDH, male gender, lower 5 min APGAR, pulmonary hypertension, and delayed start of enteral feeding were predictive of lower cognitive and/or language scores. CONCLUSION At one year of age, a high percentage of CDH children whose illness did not necessitate ECMO have below normal ND scores. Modifiable and non-modifiable factors are significant determinants of adverse outcomes.

Incidence and factors associated with sensorineural and conductive hearing loss among survivors of congenital diaphragmatic hernia

PURPOSE The reported incidence of sensorineural hearing loss (SNHL) in long-term survivors of congenital diaphragmatic hernia varies widely in the literature. Conductive hearing loss (CHL) is also known to occur in CDH patients, but has been less widely studied. We sought to characterize the incidence and risk factors associated with SNHL and CHL in a large cohort of CDH patients who underwent standardized treatment and follow-up at a single institution. METHODS We retrospectively reviewed charts of all CDH patients in our pulmonary hypoplasia program from January 2004 through December 2012. Categorical variables were analyzed by Fishers exact test and continuous variables by Mann-Whitney t-test (p≤0.05). RESULTS A total of 112 patients met study inclusion criteria, with 3 (2.7%) patients diagnosed with SNHL and 38 (34.0%) diagnosed with CHL. SNHL was significantly associated with requirement for ECMO (p=0.0130), prolonged course of hospitalization (p=0.0011), duration of mechanical ventilation (p=0.0046), requirement for tracheostomy (p=0.0013), and duration of loop diuretic (p=0.0005) and aminoglycoside therapy (p=0.0003). CONCLUSIONS We have identified hearing anomalies in over 30% of long-term CDH survivors. These findings illustrate the need for routine serial audiologic evaluations throughout childhood for all survivors of CDH and stress the importance of targeted interventions to optimize long-term developmental outcomes pertaining to speech and language.

Neurodevelopmental outcomes at 5 years of age in congenital diaphragmatic hernia

OBJECTIVE To evaluate neurodevelopmental sequelae in congenital diaphragmatic hernia (CDH) children at 5years of age. MATERIALS AND METHODS The study cohort of 35 CDH patients was enrolled in our follow-up program between 06/2004 and 09/2014. The neurodevelopmental outcomes assessed at a median of 5years (range, 4-6) included cognition (Wechsler Preschool and Primary Scale of Intelligence [WPPSI], n=35), Visual-Motor-Integration (n=35), academic achievement (Woodcock-Johnson Tests of Achievement, n=25), and behavior problems (Child Behavior Check List [CBCL], n=26). Scores were grouped as average, borderline, or extremely low by SD intervals. RESULTS Although mean Full (93.9±19.4), Verbal (93.4±18.4), and Performance (95.2±20.9) IQ were within the expected range, significantly more CDH children had borderline (17%) and extremely low (17%) scores in at least one domain compared to normative cohorts (P<0.02). The Visual-Motor-Integration score was below population average (P<0.001). Academic achievement scores were similar to expected means for those children who were able to complete testing. CBCL scores for the emotionally reactive (23%) and pervasive developmental problems scales (27%) were more likely to be abnormal compared to normal population scores (P=0.02 and P=0.0003, respectively). Autism was diagnosed in 11%, which is significantly higher than the general population (P<0.01). Univariate analysis suggests that prolonged NICU stay, prolonged intubation, tracheostomy placement, pulmonary hypertension, autism, hearing impairment, and developmental delays identified during infancy are associated with worse cognitive outcomes (P<0.05). CONCLUSION The majority of CDH children have neurodevelopmental outcomes within the average range at 5years of age. However, rates of borderline and extremely low IQ scores are significantly higher than in the general population. CDH survivors are also at increased risk for developing symptoms of emotionally reactive and pervasive developmental problems. Risk of autism is significantly elevated. Disease severity and early neurological dysfunction appear to be predictive of longer-term impairments.

Patient characteristics are important determinants of neurodevelopmental outcome during infancy in giant omphalocele.

OBJECTIVE To examine patient-specific factors as potential predictors of neurodevelopmental (ND) outcome in children with giant omphalocele (GO). MATERIALS Between 06/2005 and 07/2012, 31 consecutive GO survivors underwent ND assessment using the BSID-III at a median of 24months (range 6-35). ND delay was defined by a score of ≤84 in any composite score. Severe impairments were defined as a score of ≤69 in at least one domain. Correlations between ND outcome and patient-specific factors were analyzed by one-way ANOVA, chi-square, or logistic regression as appropriate. RESULTS The mean cognitive score (86.8±16.8) was in the low average range. Mean language (83.2±21.1) and motor (81.5±16.2) scores were below average. Forty-six-percent scored within the average range for all scales. Mild deficits were found in 19%, and 35% had severe delays in at least one domain. Hypotonicity was present in 55%. Autism was suspected/confirmed in 13%. Predictors of lower ND scores were prolonged ventilator support (P<0.01), high-frequency oscillatory ventilation (P<0.01), tracheostomy placement (P<0.001), O2 supplementation at day of life 30 (P<0.02), pulmonary hypertension (P<0.02), delayed enteral feeding (P=0.01), need for feeding tube (P<0.001), GERD (P=0.05), abnormal BAER hearing screen (P<0.006), prolonged hospitalization (P=0.01), and failure to thrive (P=0.001). Autism was associated with delays in cognitive and language outcomes (P<0.03). Delayed staged closure (P=0.007), older age at final repair (P=0.03), and hypotonicity (P=0.02) were associated with motor dysfunction. CONCLUSIONS Neurological impairments were present in more than half of GO survivors. Disease severity was associated with ND dysfunction. Autism and hypotonicity were often co-morbidities with ND delays and poor motor function.

Right- versus left-sided congenital diaphragmatic hernia: a comparative outcomes analysis

PURPOSE Right-sided congenital diaphragmatic hernia (R-CDH) occurs in up to 25% of all CDH cases, but has been less widely studied compared to left-sided defects. We sought to compare characteristics and outcomes of left- versus right-sided defects in a large cohort of CDH patients who underwent standardized treatment and follow-up at a single institution. METHODS We retrospectively reviewed charts of all CDH patients in our pulmonary hypoplasia program from January 2002 through December 2014. Categorical variables were analyzed by Fishers exact test and continuous variables by Mann-Whitney t-test (p≤0.05). RESULTS A total of 330 CDH patients were treated more than the 12-year study period, with 274 (83%) left-sided and 56 (17%) right-sided cases identified. Specific pulmonary morbidities were associated with R-CDH, with increased duration of nitric oxide therapy, increased requirement for tracheostomy, increased requirement for supplemental oxygen at the time of NICU discharge, and increased chronic pulmonary hypertension with requirement for long-term Sildenafil therapy. CONCLUSIONS In this series, R-CDH was not associated with increased mortality, but was associated with increased requirement for pulmonary vasodilatory therapy and requirement for tracheostomy. The high incidence of pulmonary complications indicates increased severity of pulmonary hypoplasia in R-CDH, supporting a role for delivery in tertiary centers with expertise in CDH management.

Brain-type natriuretic peptide levels correlate with pulmonary hypertension and requirement for extracorporeal membrane oxygenation in congenital diaphragmatic hernia

PURPOSE B-type natriuretic peptide (BNP), an established biomarker of ventricular pressure overload, is used in the assessment of children with pulmonary hypertension (PH). PH is commonly observed in congenital diaphragmatic hernia (CDH). However, the use of BNP levels to guide treatment in this patient population has not been well defined. In this study, we investigate BNP levels in a large cohort of CDH patients treated at a single institution. METHODS We retrospectively reviewed charts of all CDH patients enrolled in our pulmonary hypoplasia program from 2004-2013. PH was assessed by echocardiography using defined criteria, and patients were further stratified into the following cohorts: no PH, short-term PH (requiring nitric oxide but no additional vasodilatory therapy), long-term PH (requiring continued vasodilatory therapy post-discharge), and ECMO (requiring ECMO therapy). RESULTS A total of 132 patients were studied. BNP levels were significantly increased in patients with PH compared to patients with normal pulmonary pressures (P<0.01). BNP levels were not significantly different between the ST-PH, LT-PH, and ECMO cohorts, but all levels in all three cohorts were significantly increased compared to patients who did not develop PH. CONCLUSION Our findings indicate that plasma BNP levels correlate with pulmonary hypertension as well as the requirement for ECMO in CDH patients. Monitoring of serial BNP levels may provide a useful prognostic tool in the management of CDH.

Systemic hypertension in giant omphalocele: An underappreciated association

PURPOSE To evaluate the incidence, severity and duration of systemic hypertension in infants born with giant omphalocele (GO). METHODS A retrospective review of patients born from 2003 through 2013 with a GO or intestinal atresia (control population) and managed at a single institution was performed. The hospital course was reviewed including all blood pressures, method of omphalocele repair, requirement for antihypertensive medications and renal function. RESULTS Forty-five GO and 20 control patients met criteria for the study. Thirty-three GO patients underwent Schuster repair and 12 GO patients underwent delayed repair after epithelialization. Overall, 78% of GO patients had episodes of hypertension (82% Schuster and 67% delayed repair) compared to 15% of control patients (P<0.001). The majority of episodes were transient and occurred in the postoperative period (97%). Hypertension was persistent in 4 GO patients. These patients required antihypertensive medication at discharge, which was discontinued as an outpatient. No patient demonstrated significant evidence of renal abnormalities as indicated by renal ultrasound, urinalysis and/or serum creatinine level at the time of hypertension. CONCLUSION Episodes of systemic hypertension are frequent in patients with GO. Episodes are often post-operative, transient and can be present in patients undergoing either a delayed or Schuster repair. A small subset of patients will have persistent hypertension requiring antihypertensive medication that can be weaned off in an outpatient setting.

Rate of increase of lung-to-head ratio over the course of gestation is predictive of survival in left-sided congenital diaphragmatic hernia.

PURPOSE Congenital diaphragmatic hernia (CDH) is associated with high postnatal mortality because of pulmonary hypoplasia. The prognostic utility of serial lung-to-head circumference measurements as a marker of lung growth has not been described. Our objective was to examine the relationship between the rate of interval increase of LHR and postnatal survival in left-sided CDH. METHODS We retrospectively reviewed charts of all left-sided CDH patients from January 2004 to July 2014. All ultrasound studies performed at our institution (n=473) were reviewed. Categorical and continuous data were analyzed by chi-square and Mann-Whitney t-test, respectively, and slope analysis was performed by linear regression analysis (p<0.05). RESULTS A total of 226 patients were studied, with 154 long-term survivors and 72 non-survivors. Established markers of CDH severity, including intrathoracic liver position and requirement for patch repair, were significantly increased in non-survivors (p<0.0001). The rate of LHR increase as measured by linear regression and slope analysis was significantly increased in long-term survivors (p=0.0175). CONCLUSIONS Our findings indicate that the interval increase in LHR levels over the course of gestation correlate with survival in left-sided CDH patients. Regular ultrasonographic re-evaluation of LHR throughout gestation following diagnosis of CDH may provide prognostic insight and help guide patient management.

Treprostinil Improves Persistent Pulmonary Hypertension Associated with Congenital Diaphragmatic Hernia

Objective To evaluate the effect of continuous treprostinil in infants with severe pulmonary hypertension associated with congenital diaphragmatic hernia (CDH) on specific markers of pulmonary hypertension severity and to report the safety and tolerability of treprostinil. Study design We conducted a retrospective cohort study of infants with CDH‐associated pulmonary hypertension treated with treprostinil from January 2011 to September 2016. Severity of pulmonary hypertension was assessed by echocardiogram and serum B‐type natriuretic peptide (BNP) by using time points before initiation and 24 hours, 1 week, and 1 month after treprostinil initiation. Fisher exact tests, Wilcoxon‐rank sum tests, and mixed‐effects models were used for analysis. Results Seventeen patients were treated with treprostinil for a median of 54.5 days (IQR 44.3‐110 days). Compared with the concurrent CDH population (n = 147), infants treated with treprostinil were more likely to require extracorporeal support (76.5% vs 25.2%, P < .0001), to have a longer hospital stay (144 vs 60 days, P < .0001), and to need longer mechanical ventilator support (76.5 vs 30.9 days, P < .0001). Following treprostinil initiation, there was a significant reduction in BNP at 1 week (1439 vs 393 pg/mL, P < .01) and 1 month (1439 vs 242 pg/mL, P = .01). Severity of pulmonary hypertension by echocardiogram improved at 1 month (OR 0.14, CI 95% 0.04‐0.48, P = .002). Despite these improvements, overall mortality remained high (35%). There were no adverse events related to treprostinil, including no hypotension, hypoxia, or thrombocytopenia. Conclusions In this cohort, treprostinil use was associated with improved severity of pulmonary hypertension assessed by echocardiogram and decreased BNP, with no significant side effects.