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Malformations associated with congenital diaphragmatic hernia: Impact on survival
Malformations Associated with Congenital Diaphragmatic Hernia: Impact on Survival Katarina Bojani´c, Ena Pritiˇsanac, Tomislav Lueti´c, Jurica Vukovi´c, Juraj Sprung, Toby N. Weingarten, Darrell R. Schroeder, Ruˇza Grizelj PII: DOI: Reference:
S0022-3468(15)00403-0 doi: 10.1016/j.jpedsurg.2015.07.004 YJPSU 57279
To appear in:
Journal of Pediatric Surgery
Received date: Revised date: Accepted date:
18 March 2015 22 May 2015 1 July 2015
Please cite this article as: Bojani´c Katarina, Pritiˇsanac Ena, Lueti´c Tomislav, Vukovi´c Jurica, Sprung Juraj, Weingarten Toby N., Schroeder Darrell R., Grizelj Ruˇza, Malformations Associated with Congenital Diaphragmatic Hernia: Impact on Survival, Journal of Pediatric Surgery (2015), doi: 10.1016/j.jpedsurg.2015.07.004
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MALFORMATIONS ASSOCIATED WITH CONGENITAL DIAPHRAGMATIC HERNIA: IMPACT ON SURVIVAL 2
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Jurica Vuković, MD, PhD, Juraj Sprung, MD, PhD, Toby N Weingarten, MD, 4
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Darrell R. Schroeder, MS, and Ruža Grizelj MD, PhD
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Katarina Bojanić, MD, Ena Pritišanac, MD, Tomislav Luetić, MD, PhD,
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Consultant, Division of Neonatology, Department of Obstetrics and Gynecology, University Hospital Merkur,
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Zagreb, Croatia 2
Resident, Department of Pediatrics, University of Zagreb, School of Medicine, University Hospital Centre Zagreb,
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Croatia 3
Hospital Centre Zagreb, Croatia 4
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Professor of Surgery, Department of Pediatric Surgery, University of Zagreb, School of Medicine, University
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Croatia
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Associate Professor of Pediatrics, University of Zagreb, School of Medicine, University Hospital Centre Zagreb,
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Professor of Anesthesiology, Mayo Clinic, Rochester, MN
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Associate Professor of Anesthesiology, Mayo Clinic, Rochester, MN
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Assistant Professor of Statistics, Department of Health Sciences Research, Division of Biostatistics, Mayo Clinic,
Rochester MN Address for correspondence: Juraj Sprung, MD, PhD, Department of Anesthesiology, Mayo Clinic, 200 First St SW, Rochester, MN 55905; e-mail: [email protected] Note: Katarina Bojanić, MD, and Ruža Grizelj MD, PhD, equally contributed to this paper.
ACCEPTED MANUSCRIPT Declaration of interest: Authors declare no conflicts of interest. Running title: Survival of outborns with congenital diaphragmatic hernia.
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Sources and support for the work: This project was supported by internal funding from the Department of Anesthesiology, Mayo Clinic Rochester, Minnesota.
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Word count: 2,551
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Abstract
Background/Purpose: Congenital diaphragmatic hernia (CDH) is associated with high mortality. Survival is influenced by the extent of pulmonary hypoplasia and additional congenital defects. The purpose of this study was
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to assess the association of congenital anomalies and admission capillary carbon dioxide levels (P cCO2), as a measure of extent of pulmonary hypoplasia, on survival in neonates with CDH.
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Methods: This is a retrospective review of neonates with CDH admitted to a tertiary neonatal intensive care unit between 1990 and 2014. Logistic regression was used to assess whether hospital survival was associated with admission PcCO2 or associated anomalies (isolated CDH, CDH with cardiovascular anomalies, and CDH with
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noncardiac anomalies). The probabilities of survival (POS) score, based on birth weight and 5-min Apgar as defined
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by the Congenital Diaphragmatic Hernia Study Group was included as a covariate. Results: Of 97 patients, 55 had additional malformations (cardiovascular n=12, non-cardiac anomalies n=43). POS was lower in CDH with other anomalies compared to isolated CDH. Survival rate was 61.9%, 53.5% and 41.7% in
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isolated CDH, CDH with non-cardiac anomalies and CDH with cardiovascular anomalies, respectively. After adjusting for POS score the likelihood of survival in CDH groups with additional anomalies was similar to isolated CDH (OR 0.95, 95%CI 0.22-4.15, and 1.10, 0.39-3.08, for CDH with and without cardiovascular anomalies, respectively). After adjusting for POS score, lower P cCO2 levels (OR=1.25 per 5 mmHg decrease, P=0.003) were associated with better survival. Conclusions: Neonates with CDH have a high prevalence of congenital malformations. However, after adjusting for POS score the presence of additional anomalies was not associated with survival. The POS score and admission PcCO2 were important prognosticating factors for survival. Keywords: Capillary blood gas; capillary blood carbon dioxide level; congenital diaphragmatic hernia; congenital malformations; congenital heart disease; neonate; probability of survival; mortality; risk assessment.
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CDH
congenital diaphragmatic hernia
CDHSG
Congenital Diaphragmatic Hernia Study Group
iNO
inhaled nitric oxide
NICU
neonatal intensive care unit
PaCO2
partial pressure of carbon dioxide in arterial blood
PcCO2
partial pressure of carbon dioxide in capillary blood
POS
probability of survival score
VSD
ventricular septal defect
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atrial septal defect
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ASD
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Abbreviations:
The Role of Authors/Co-authors:
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Katarina Bojanić, MD: Design, data collection, manuscript preparation
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Ena Pritišanac, MD: Data collection, manuscript preparation
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Tomislav Luetić, MD, PhD: Surgeon collected information and manuscript preparation
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Jurica Vuković, MD, PhD: Design, data collection, manuscript preparation Juraj Sprung, MD, PhD: Design, data collection, manuscript preparation Toby N Weingarten, MD: Data analysis, manuscript preparation Darrell R. Schroeder, MS: Statistics, manuscript preparation, manuscript proofing Ruža Grizelj, MD, PhD: Design, data collection, manuscript preparation
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Congenital diaphragmatic hernia (CDH) is a complex malformation associated with high mortality.
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Survival is influenced by the extent of pulmonary hypoplasia and potentially worsened by the presence of additional
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congenital defects, especially cardiovascular and chromosomal abnormalities.1-5 Concomitant anomalies occur frequently in neonates with CDH and according to one report 43% of neonates with CHD had one or more
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malformations, and approximately half of those were cardiac anomalies. 6 The subset of neonates with both CDH and heart anomalies pose particular challenges for management as both conditions can contribute to respiratory distress,
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hypoxemia and hypercarbia. It is not surprising that when CDH is associated with cardiac anomalies survival is lower compared to isolated CHD.3, 6 Early postdelivery presentation of respiratory distress with hypercapnia is a
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marker of pulmonary hypoplasia. Therefore, the level of carbon dioxide in the arterial blood (PaCO2) may indicate the severity of pulmonary involvement,7, 8 or even predict mortality.9 It has been shown that capillary blood gases
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represent a sensitive screening tool for arterial acidosis and hypercarbia.10 The value of admission carbon dioxide end-capillary blood (PcCO2) levels as a predictor of survival needs to be examined.
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The aim of this study is to describe types of congenital anomalies in outborn neonates with CHD
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(“outborn” is defined as born in another institution and transferred to referral center for care). We compare outcomes among neonates with isolated CDH (with no additional anomalies besides CDH) to complex CDH (with one or more
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additional congenital anomalies). We hypothesized that CDH neonates with concomitant anomalies have increased mortality. Furthermore, since the CDH-associated pulmonary hypoplasia leads to a compromised gas exchange we hypothesized that the admission capillary PcCO2 is an independent predictor of survival. 1.
Materials and Methods This study was approved by the Institutional Ethics Committee of the University Hospital Centre (UHC)
Zagreb, Croatia. The medical records of 97 neonates with CDH born between January 1, 1990, and December 31, 2014, who underwent treatment in the UHC neonatal intensive care unit (NICU) were retrospectively reviewed. The UHC is the largest Croatian tertiary referral neonatal institution, and receives neonatal transfers from the entire country. None of the community hospitals with maternity wards in Zagreb have NICU capabilities, while the UHC does not have a maternity ward; therefore, all subjects in this study are outborns (born in another institution with
ACCEPTED MANUSCRIPT maternity wards and transferred to UHC). For purpose of analysis, subjects were divided into three groups: 1) isolated CDH with no additional congenital anomalies, 2) complex CDH with congenital cardiovascular anomalies,
Definitions
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and 3) complex CDH with additional non-cardiac anomalies.
Early presentation is defined as respiratory distress present immediately after delivery (symptomatic within
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the first 6 hours of life). Late presentation is defined as absence of visible breathing difficulties after delivery or respiratory symptoms manifesting >6 hours after delivery. During initial years covered by this study (1990-1999)
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there were limited resources for prenatal screening and protective ventilatory strategies were not available (Croatian war 1990-1995, with lingering economic consequences for several years after). Therefore, the phrase “time period of
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protective strategies” is used to describe the time period 2000-2014 which included improved prenatal screening,
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and the use of both protective ventilation and inhaled nitric oxide (iNO). 1.2 Data collection
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Patient variables that were abstracted included demographic information, disease characteristics including acuity of CDH presentation (early vs. late presentation), preductal capillary blood gases (in particular admission
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PcCO2 level) and vital signs (blood pressure, and body temperature) after delivery. The Congenital Diaphragmatic
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Hernia Study Group (CDHSG) published a logistic regression model designed to predict outcome within the first 5 minutes of life based on Apgar score and birth weight. For our analyses we quantified the severity of CDH using CDHSG-devised probability of survival (POS) equation: POS= 1-1/(1+e-x) where -x = -5.0240 + 0.9165 x (birth weight in kilograms) + 0.4512 x (5 minute Apgar score) in the discrete ordinate range of 0-10.11 The POS score categorizes all neonates with CDH into low (0 to 33%), moderate (34% to 66%), and high (67% to 100%) predicted survival, however the calculated actual POS in our study was used as continuous variable. Variables regarding CHD management abstracted included treatment during, before and after the time of “protective strategies” (after January 1, 2000), which took into account the type of mechanical ventilation used; and the use of iNO, surfactant, and/or potent vasoactive support. Survival to hospital discharge was noted. 1.3.
Statistical analyses
ACCEPTED MANUSCRIPT Data are presented as mean ± SD for continuous variables, and frequency percentages for categorical variables. Characteristics were compared across groups using analysis of variance and Fisher’s exact test. Logistic regression was used to assess whether hospital survival was associated with the presence of associate congenital
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malformation after adjusting for the POS score. Additional logistic regression analysis was performed to examine the association of the POS score and admission level of PcCO2 with survival. These analyses were done separately for the entire cohort and also for neonates with early presentation, as early presenting symptomatology (respiratory
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distress) is a marker of pulmonary involvement. Since the management of CDH changed in year 2000 when
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protective ventilatory strategies were introduced, as well as use of iNO became available, a binary variable indicating admission date after January 1, 2000 was included as a covariate in all logistic regression models. In all
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cases two tailed P values <0.05 were considered statistically significant. Data were analyzed using SAS version 9.3 (SAS Institute Cary, NC). Results
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Between January 1, 1990 and December 30, 2014, 99 neonates with CDH were transferred to UHC NICU
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(Figure 1). Two patients had missing medical records and were excluded. Of the remaining 97 neonates, the most
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common type of CDH was Bochdalek hernia (n=93), while there was a single case of each Morgagni hernia, paraesophageal hernia, central hernia, and severe diaphragmatic eventration. Fifty-five (56.7%) subjects had one or
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multiple malformations associated with CDH (Table 1). Twelve (12.4%) neonates had associated cardiovascular anomalies and are summarized in Table 2. Five neonates with simple isolated cardiovascular anomalies (patent ductus arteriosus [PDA] or atrial septal defect [ASD II]) survived, while 6 with complex cardiovascular anomalies died. These 6 were prenatally diagnosed with CDH and heart defects, and their mothers were transported to high risk maternity wards in Zagreb for delivery. An additional premature neonate (body weight 1.3 kg) with ASD II and a low POS score also died. Table 3 summarizes disease and therapeutic characteristics in those with isolated CDH (n=42), complex CDH with (n=12) and without (n=43) cardiovascular involvement. Compared to isolated CDH and complex CDH without cardiac anomalies, neonates with CDH and cardiovascular malformations had lower birth weight and lower 1-min Apgar scores. Compared to isolated CDH, POS scores were lower, and the frequency of pulmonary hypertension was higher in both complex CDH groups. Compared to isolated CDH, a higher percentage of the
ACCEPTED MANUSCRIPT complex cardiovascular anomalies (92% vs. 57%) were observed after year 2000, when prenatal screening improved. Table 4 presents admission preductal capillary blood gases and vital signs within 12 hours of admission. Compared to isolated CDH neonates with complex cardiovascular anomalies presented with higher disease acuity as
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inferred from the lower PcO2, higher PcCO2, lower pH, and both lower body temperatures and blood pressures. Of patients with isolated CDH 26/42 (61.9%) survived to discharge, compared to 23/43 (53.5%) in
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complex without cardiac anomaly, and 5/12 (41.7%) with cardiovascular anomaly. After adjusting for the POS score (OR for survival with increasing POS=1.61, 95%CI 1.39-1.99, per 10 percentage point increase) the likelihood of
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survival in complex CDH with and without cardiac anomaly was similar to isolated CDH (OR 0.95, 95%CI 0.224.15, and OR 1.10, 95% CI 0.39-3.08, for complex CDH with and without cardiac anomalies, respectively). Overall
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survival was high in neonates with late presentation 21/22 (95.5%), and low in those with early presentation (33/75, 44.0%). From multivariable logistic regression including all patients, a higher POS score (OR=1.59, 95%CI 1.24-
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2.03 per 10 percentage points increase, P<0.001), and a lower PcCO 2 (OR=1.25, 95% CI 1.08-1.44 per 5 mmHg decrease, P=0.003) were associated with better hospital survival. When the analysis was restricted to patient with
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early presentation only, similar results were observed (POS score OR=1.46, 95%CI 1.14-1.88 per 10 percentage points increase, P=0.003; and PcCO2 OR=1.19, 95%CI 1.03-1.38 per 5 mmHg decrease, P=0.017). Mortality of
Discussion
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patients with early presentation according to the admission PcCO2 is shown in Figure 2.
Over half of our study cohort had complex CDH with one or more additional malformations. In general, the POS scores, based on birth weight and 5 minute Apgar score, were more predictive of mortality than the presence of additional congenital malformations. However, within the subgroup of neonates with complex cardiovascular anomalies all died. Finally, we found that the value of admission capillary PcCO2 was an important prognosticating factor for survival. In neonates with CDH there is a large variability in how specific malformation may impact outcome. In particular, a compounding effect of cardiac anomaly with CDH-associated pulmonary hypoplasia can greatly increase presentation of acuity of disease immediately after delivery. In neonates with CDH, even a “simple” cardiac defect such as ASD, may have a negative impact on outcome. For example, in neonate with CDH and pulmonary
ACCEPTED MANUSCRIPT hypertension with concomitant ASD the fraction of intracardiac right-to-left shunting may be increased. In addition, hypercapnia, frequently associated with CDH, will worsen pulmonary hypertension, and may further contribute to increase in intracardiac shunting. Presence of cardiac anomalies (OR 5.2), severe pulmonary hypertension (OR 4.07)
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and chromosomal abnormalities (OR 3.9) all predict mortality in newborns with CDH.12 Indeed, among our 12 CDH patients with cardiovascular anomalies 7 died, of these 5 were with complex cardiac defects, 1 was with ASD, but had low birth weight and POS score, and 1 had major vascular anomaly with right diaphragmatic aplasia and severe
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pulmonary hypoplasia with pulmonary hypertension.
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Early onset of respiratory distress in neonate with CDH may indicate presence of more severe pulmonary and/or cardiac involvement. Early presentation of respiratory distress, a marker of pulmonary hypoplasia, is
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clinically manifested with hypercapnia. PaCO2 levels above 60 mmHg in neonates with CHD may indicate critical pulmonary hypoplasia and is a harbinger of poor prognosis. 7, 8 Salas et al.13 demonstrated that PaCO2>88 mmHg
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before initiating the ECMO was associated with 11% survival, while PaCO2 below 60 mmHg on first blood gas may indicate milder hypoplasia, and was an independent predictor of survival. Schultz et al. 9 suggested that the most
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important factor in predicting survival was the maximum PaCO 2 value, as only 5% of the surviving infants in their study had a maximum PaCO2 greater than 80 mmHg. Others also demonstrated that the admission PaCO 2 and
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preductal oxyhemoglobin saturation were useful in predicting survival in CDH neonates. 14 Even more, among survivors, admission PaCO2≥80 mmHg was associated with higher need for home oxygen therapy, discharge with
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diuretics, requirement for nasogastric or gastrostomy feedings at discharge and longer length of stay. 14 Instead of PaCO2, in our case series, we report arterialized capillary PcCO2 values which closely correlate with PaCO2, and can be used interchangeably with PaCO2 to estimate ventilation in critically ill neonates. We found that the admission PcCO2 is a good prognosticating parameter in children with CDH, and that for every 5 mmHg decrease in PcCO2 the odds of hospital survival increased by 25%. Figure 2 illustrates increasing mortality among patients with early presentation of respiratory distress in our cohort based on 3 levels of capillary PcCO2 obtained on admission. At the same time, in CDH neonates with late presentation the absence of respiratory symptomatology after delivery and lower values of admission capillary PcCO2 were per se excellent prognosticating sign, as this group had 95% survival.
ACCEPTED MANUSCRIPT Graciano 3 reviewed cardiac anomalies and prognosis in 2,636 children with CDH from the CDHSG database. They excluded from review “hemodynamically insignificant” cardiac anomalies such as ASDs and PDAs. Interestingly, their rate of isolated ASD (82/2,636, 3.1%) was identical to ours (3/97, 3.1%), but the rate of
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“significant” heart defects was higher (10.6%)3 than in our cohort (5.2%), which likely represents underreporting related to a referral bias in our series (see study limitations). Three neonates in our series had hemodynamically significant PDA and subsequently required surgical or pharmacological ligation, therefore we included them into
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cardiovascular anomaly group. In our cohort, VSD and ASD, both isolated or in conjunction with other heart malformations, were the most common heart defects (n=8). Survival for isolated CDH in CDHSG report was
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70.2%,3 and in our study was 61.9%, which may reflect the fact that we included patients from the calendar time
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when “non-protective ventilatory strategies” were used. CDHSG reported 41.1% survival for CHD when associated with severe heart anomalies,3 while in our series none of neonates with complex heart defect survived, reflecting the
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lack of resources for treatment of these malformations (see limitations). Of interest, the most frequently recorded anomaly in our series was cryptorchidism (n=29), bilateral in 19
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and unilateral in 10. Some postulated that cryptorchidism can occur in CDH because of ineffective increase in abdominal pressure during the fetal period,15 however this mechanism cannot entirely explain instances of its
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unilateral occurrence. Fauza et al.16 reported 6 CDH patients with cryptorchidism. Another anomaly we encountered
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is 8 (8.2%) neonates was accessory spleen or polysplenia, an anomaly previously reported in CDH patients. 17 One of the limitations of our study is its retrospective design with the possibility for missing data and unforeseen confounders. Extracorporeal membrane oxygenation was not available during the study period. Furthermore, the surgical expertise for the highly complex cardiac anomalies was limited during the study period, therefore our findings cannot be generalized to results from institutions with these resources and expertise. Furthermore, the frequency of skeletal anomalies may be underestimated as radiograms were unavailable for 31 out of 97 patients. In addition, autopsy records were not available for 6 patients. In addition, in Croatia between 2001 and 2011, 34.5% newborns with CDH died before being transferred from the delivery room to a higher level of care (data obtained from The Institute of Public Health, Zagreb, Croatia). This rate was likely higher during the earlier years (Croatian war) of our study cohort. Since these neonates probably had the most severe CDH forms with associated congenital anomalies, our report likely underestimates the true rate of malformations in patients with
ACCEPTED MANUSCRIPT CDH. Thus, the types of malformations and survival rates described in our study reflect only the population of neonates who were viable enough and were transferred to our institution. However, this reporting problem with CDH is universally present as several reports pointed on the effect of "hidden" mortality, i.e., that substantial
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number of infants born with CDH die before they could be treated. 18, 19 Conclusion
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In over a half of our neonates with CDH we identified a wide variety of congenital malformations. POS score determined at delivery was more predictive of mortality than the presence of additional congenital
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malformations. In addition to the POS score, low admission capillary PcCO2 was an important prognosticating
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factor for improved survival. Therefore, routinely obtained capillary blood gas on admission is a useful adjunct for assessment of acuity of CDH and may help in predicting survival. The ease of collection makes a capillary blood gas
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Conflict of Interest statement:
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an attractive alternative to an arterial blood gas in certain patients and settings.
KB declares no conflict of interest related to submitted work.
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EP declares no conflict of interest related to submitted work. TL declares no conflict of interest related to submitted work.
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JV declares no conflict of interest related to submitted work. JS declares no conflict of interest related to submitted work. TNW declares no conflict of interest related to submitted work. DRS declares no conflict of interest related to submitted work. RG declares no conflict of interest related to submitted work.
ACCEPTED MANUSCRIPT References 1. Bohn D. Congenital diaphragmatic hernia. Am J Respir Crit Care Med. 2002; 166(7): 911-5.
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2. Borys D, Taxy JB. Congenital diaphragmatic hernia and chromosomal anomalies: autopsy study. Pediatr Dev
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Pathol. 2004; 7(1): 35-8.
3. Graziano JN. Cardiac anomalies in patients with congenital diaphragmatic hernia and their prognosis: a report
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from the Congenital Diaphragmatic Hernia Study Group. J Pediatr Surg. 2005; 40(6): 1045-9. 4. Langham MR, Jr., Kays DW, Ledbetter DJ, Frentzen B, Sanford LL, Richards DS. Congenital diaphragmatic
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hernia. Epidemiology and outcome. Clin Perinatol. 1996; 23(4): 671-88.
5. Rozmiarek AJ, Qureshi FG, Cassidy L, Ford HR, Hackam DJ. Factors influencing survival in newborns with
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congenital diaphragmatic hernia: the relative role of timing of surgery. J Pediatr Surg. 2004; 39(6): 821-4; discussion -4.
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6. Bedoyan JK, Blackwell SC, Treadwell MC, Johnson A, Klein MD. Congenital diaphragmatic hernia: associated anomalies and antenatal diagnosis. Outcome-related variables at two Detroit hospitals. Pediatr Surg Int. 2004; 20(3):
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170-6.
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7. Dibbins AW, Wiener ES. Mortality from neonatal diaphragmatic hernia. J Pediatr Surg. 1974; 9(5): 653-62. 8. Mishalany HG, Nakada K, Woolley MM. Congenital diaphragmatic hernias: eleven years' experience. Arch Surg.
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1979; 114(10): 1118-23.
9. Schultz CM, DiGeronimo RJ, Yoder BA. Congenital diaphragmatic hernia: a simplified postnatal predictor of outcome. J Pediatr Surg. 2007; 42(3): 510-6. 10. Harrison AM, Lynch JM, Dean JM, Witte MK. Comparison of simultaneously obtained arterial and capillary blood gases in pediatric intensive care unit patients. Crit Care Med. 1997; 25(11): 1904-8. 11. Congenital Diaphragmatic Hernia Study Group. Estimating disease severity of congenital diaphragmatic hernia in the first 5 minutes of life. J Pediatr Surg. 2001; 36(1): 141-5. 12. Brindle ME, Cook EF, Tibboel D, Lally PA, Lally KP. A clinical prediction rule for the severity of congenital diaphragmatic hernias in newborns. Pediatrics. 2014; 134(2): e413-9. 13. Salas AA, Bhat R, Dabrowska K, Leadford A, Anderson S, Harmon CM, et al. The value of Pa(CO2) in relation to outcome in congenital diaphragmatic hernia. Am J Perinatol. 2014; 31(11): 939-46.
ACCEPTED MANUSCRIPT 14. Khmour AY, Konduri GG, Sato TT, Uhing MR, Basir MA. Role of admission gas exchange measurement in predicting congenital diaphragmatic hernia survival in the era of gentle ventilation. J Pediatr Surg. 2014; 49(8): 1197-201.
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15. Hiradfar M, Sadeghipoor S. Intrathoracic testicular ectopia in congenital diaphragmatic hernia. Asian J Surg
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2006; 29(4): 303-5.
16. Fauza DO, Wilson JM. Congenital diaphragmatic hernia and associated anomalies: their incidence,
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identification, and impact on prognosis. J Pediatr Surg. 1994; 29(8): 1113-7.
17. Martinez-Frias ML, Prieto L, Urioste M, Bermejo E. Clinical/epidemiological analysis of congenital anomalies
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associated with diaphragmatic hernia. Am J Med Genet. 1996; 62(1): 71-6.
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18. Harrison MR, Bjordal RI, Langmark F, Knutrud O. Congenital diaphragmatic hernia: the hidden mortality. J Pediatr Surg. 1978; 13(3): 227-30.
19. Brownlee EM, Howatson AG, Davis CF, Sabharwal AJ. The hidden mortality of congenital diaphragmatic
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hernia: a 20-year review. J Pediatr Surg. 2009; 44(2): 317-20.
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Figure/Table Legends Figure 1. Patient with congenital diaphragmatic hernia treated in our institution from 1990 to 2014. Figure 2. Mortality of patients with early presentation according to admission capillary carbon dioxide levels (PcCO2) Table 1. Individual congenital anomalies in 97 patients with congenital diaphragmal hernia Table 2. Clinical details of 12 patients with congenital diaphragmal hernia and associated cardiac or vascular anomalies. Table 3. Demographic and disease characteristics in children with congenital diaphragmatic hernia (CDH). Table 4. Admission capillary blood gases, lowest mean blood pressure and lowest temperature over the first 12 hours after admission.
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Figure 1
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Figure 2
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N*
GASTROINTESTINAL, N=12*
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CARDIOVASCULAR, N=12*
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Table 1. Individual congenital anomalies in 97 patients with congenital diaphragmal hernia.
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Double appendix
1
Atrial septal defect
4
Accessory spleen
Ventricular septal defect
4
Polysplenia
2
d-TGA
1
Mitral atresia
1
6
Esophageal atresia (type IIIB Vogt)
1
Extremely short esophagus
1
1
Anteposition of the anus
1
1
Meckel’s diverticulum
1
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Patent ductus arteriosus
Hypoplastic left ventricle Coarctation of the aorta
2
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Right aortic arch
1
Supernumerary ribs
4
1
Absent ribs
5
Persistent left SVC draining into the coronary sinus
1
Hemivertebrae
1
Dextrocardia
1
Short sternum
1
Leg deformity
6
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Pulmonary artery atresia
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Overriding aorta
SKELETAL, N=14*
GENITOURINARY, N=9* Bicornate uterus
1
Arm deformity
3
Penile hypospadia
1
Head deformity
4
Hydroureter/hydronephrosis
4
Mega-bladder
1
Bilateral renal hypoplasia
1
Bilateral ovarian cysts
1
Edwards syndrome
1
Unilateral multicystic kidney
1
Noonan syndrome
1
MINOR, N=3* Minor facial anomalies
4
SYNDROMES/ASSOCIATION, N=3*
ACCEPTED MANUSCRIPT CRYPTORCHIDISM, N=54 males* 19
Unilateral
10
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Bilateral
1
Frontal lobes atrophy
1
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Bilateral periventricular hypoxicischemic lesion
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1
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CNS, N=2* Bilateral parietal atrophy
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1
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VACTERL association
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Indicates number of patients with one or more malformations in the given organ system. Due to multiple anomalies
in a given patient, the number of individual anomalies within a given organ system may sum to more than the
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number of patients with one or more anomalies in that organ system. Similarly, due to patient having anomalies in
anomalies (n=55).
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multiple organ systems, the sum across organ systems is greater than the total number of patients with one or more
Abbreviations: VACTERL, Vertebral defects, Anal atresia, Cardiac anomaly, TracheoEsophageal fistula, Renal
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anomalies, and Limb abnormalities; SVC, superior vena cava; d-TGA, dextro-transposition of the great arteries; SVC, superior vena cava
ACCEPTED MANUSCRIPT Table 2. Clinical details of 12 patients with congenital diaphragmal hernia and associated cardiac or vascular anomalies
BW, kg
5-min Apgar
PDA
2.95
5
2*
PDA
2.50
9
Hospital Survival
74
YES
79
41
YES
45
151† 70‡
YES
3
PDA
2.30
4
ASD II
2.60
6
51
54
YES
5
ASD II
3.34
10
93
52
YES
6*
PDA + VSD + overriding aorta + pulmonary artery atresia; Noonan syndrome
2.11
6
40
77
No
7*
ASD II
1.32
6
24
62
No
8*
VSD + d-TGA+ mitral atresia+ hypoplastic LV; Edward's syndrome (trisomy 18)
1.96
6
37
61
No
9
VSD + persistent left SVC draining into coronary sinus
1.84
5
24
183
No
10
Right aortic arch§
3.90
4
59
95
No
11
ASD II + Coarctation of the aorta
3.73
4
54
98
No
12*
VSD + dextrocardia + right aortic arch; VACTERL association
2.23
9
50
66
No
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6
Admission PcCO2, mmHg
48
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1
POS score, %
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Cardiac or Vascular Anomaly
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Case
In addition to those listed, these patients had additional non-cardiac anomalies. †Admission blood gas was pH 6.85,
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PcO2 25.9 mmHg, BD -24 mmol/L, PcCO2 151 mmHg, reflecting accidental endotracheal tube dislodging during transfer. ‡Emergent reintubation and ventilation resulted in PcO2 60.8 mmHg, and PcCO2 70 mmHg, therefore “admission” extreme PcCO2 was not a true marker of lung hypoplasia. When this patient was eliminated from
ACCEPTED MANUSCRIPT analysis (see Results) lower PcCO2 showed high association with improved survival (OR=1.39, 95% CI 1.15-1.68 per 5 mmHg decrease, P=0.001, i.e., for every 5 mmHg decrease in PcCO2 the odds of hospital survival increased by 39%). §This patient had right diaphragm aplasia with the liver and gallbladder herniated into the right thorax. This
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patient subsequently developed bilateral pneumothoraces and pulmonary hemorrhage following vigorous resuscitation and ventilation.
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Abbreviations: PcCO2, partial pressure of carbon dioxide in the end-capillary blood; POS, probability of survival score (%); PDA, patent ductus arteriosus; ASD, atrial septal defect; VSD, ventricular septal defect; SVC, superior
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vena cava; LV, left ventricle; d-TGA, dextro-transposition of the great arteries; VACTERL, Vertebral defects, Anal
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atresia, Cardiac anomaly, TracheoEsophageal fistula, Renal anomalies, and Limb abnormalities
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Complex CDH without Cardiac Anomaly (n=43†)
10 (24)
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Isolated CDH (N=42)
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Characteristic
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Table 3. Demographic and disease characteristics in children with congenital diaphragmatic hernia (CDH). Complex CDH with Cardiac Anomaly (N=12)
10 (23)
5 (42)
29 (67)
6 (50)
21 (50)
17 (33)
6 (50)
39.9±1.9*
38.4±2.9†
37.3±2.5
3.1±0.6
3.1±0.6
2.5±0.8a,b
2 (5)
1 (2)
4 (33)a,b
7.0±2.5
6.1±2.9
3.9±2.5a,b
7.1±2.6
5.7±2.9†a
6.2±1.8
29 (69)
34 (79)
11 (92)
Probability of survival score
0.69±0.24
0.57±0.27†a
0.50±0.20a
High (67% to 100%)
25 (60)
20 (48)
2 (17)
Moderate (34% - 66%)
14 (33)
14 (33)
8 (67)
3 (7)
8 (19)
2 (17)
Pulmonary hypertension confirmed‡
8 (30)
17 (59) a
10 (91)a
iNO treatment
11 (26)
14 (33)
8 (67)a
Surfactant treatment
6 (14)
7 (16)
5 (42)
Vasoactive treatment
30 (71)
32 (74)
9 (75)
Period with “protective strategies”
24 (57)
33 (77)
11 (92)a
Prenatal diagnosis of CDH
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Sex
21 (50)
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Male Female
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Gestational age, weeks
Small for gestational age
Apgar 5 minutes
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Early presentation
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Apgar 1 minute
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Birth weight, kg
Low (0% to 33%)
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Data are N (%) or mean ± SD; aP < 005 compared to isolated; bP < 005 compared to complex CDH without cardiac
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anomaly. *Missing for 1 infant. †Missing for 1 infant. ‡Pulmonary hypertension diagnostics was done in 67 infants
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(27 isolated CDH, 29 complex CDH no cardiac, 11 complex CDH cardiac).
ACCEPTED MANUSCRIPT Table 4. Admission capillary blood gases, lowest mean blood pressure and lowest temperature over the first 12 hours after admission.
Mean±SD
PcO2, mmHg
38
59.8±21.1
PcCO2, mmHg
37
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pH
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Lowest temperature, °C
Mean±SD
N*
Mean±SD
34
47.6±17.9 a
11
43.9±21.5 a
34
69.3±26.4
11
88.6±42.2 a,b
7.2±0.2
33
7.1±0.2
11
7.0±0.3 a
36
-4.9±6.1
32
-6.0±8.6
11
-9.6±10.1
32
36.3±0.5
33
36.2±0.6
9
35.8±0.7 a,b
37
40.1±9.6
32
39.6±8.5
10
33.0±12.8 a
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Lowest mean blood pressure, mmHg
Complex CDH with Cardiac Anomaly
37
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Base deficit, mEq/L
N*
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N*
Complex CDH without Cardiac Anomaly
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Isolated CDH
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Admission Blood Gases and Vital Signs
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*Number of neonates with information available. Abbreviation: PcO2 = partial pressure of oxygen in the end-capillary blood; PcCO2 = partial pressure of carbon dioxide in the end-capillary blood.
S0022-3468(15)00403-0 doi: 10.1016/j.jpedsurg.2015.07.004 YJPSU 57279
To appear in:
Journal of Pediatric Surgery
Received date: Revised date: Accepted date:
18 March 2015 22 May 2015 1 July 2015
Please cite this article as: Bojani´c Katarina, Pritiˇsanac Ena, Lueti´c Tomislav, Vukovi´c Jurica, Sprung Juraj, Weingarten Toby N., Schroeder Darrell R., Grizelj Ruˇza, Malformations Associated with Congenital Diaphragmatic Hernia: Impact on Survival, Journal of Pediatric Surgery (2015), doi: 10.1016/j.jpedsurg.2015.07.004
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
MALFORMATIONS ASSOCIATED WITH CONGENITAL DIAPHRAGMATIC HERNIA: IMPACT ON SURVIVAL 2
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Jurica Vuković, MD, PhD, Juraj Sprung, MD, PhD, Toby N Weingarten, MD, 4
6
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Darrell R. Schroeder, MS, and Ruža Grizelj MD, PhD
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Katarina Bojanić, MD, Ena Pritišanac, MD, Tomislav Luetić, MD, PhD,
1
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Consultant, Division of Neonatology, Department of Obstetrics and Gynecology, University Hospital Merkur,
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Zagreb, Croatia 2
Resident, Department of Pediatrics, University of Zagreb, School of Medicine, University Hospital Centre Zagreb,
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Croatia 3
Hospital Centre Zagreb, Croatia 4
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Professor of Surgery, Department of Pediatric Surgery, University of Zagreb, School of Medicine, University
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Croatia
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Associate Professor of Pediatrics, University of Zagreb, School of Medicine, University Hospital Centre Zagreb,
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Professor of Anesthesiology, Mayo Clinic, Rochester, MN
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Associate Professor of Anesthesiology, Mayo Clinic, Rochester, MN
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Assistant Professor of Statistics, Department of Health Sciences Research, Division of Biostatistics, Mayo Clinic,
Rochester MN Address for correspondence: Juraj Sprung, MD, PhD, Department of Anesthesiology, Mayo Clinic, 200 First St SW, Rochester, MN 55905; e-mail: [email protected] Note: Katarina Bojanić, MD, and Ruža Grizelj MD, PhD, equally contributed to this paper.
ACCEPTED MANUSCRIPT Declaration of interest: Authors declare no conflicts of interest. Running title: Survival of outborns with congenital diaphragmatic hernia.
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Sources and support for the work: This project was supported by internal funding from the Department of Anesthesiology, Mayo Clinic Rochester, Minnesota.
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Word count: 2,551
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Abstract
Background/Purpose: Congenital diaphragmatic hernia (CDH) is associated with high mortality. Survival is influenced by the extent of pulmonary hypoplasia and additional congenital defects. The purpose of this study was
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to assess the association of congenital anomalies and admission capillary carbon dioxide levels (P cCO2), as a measure of extent of pulmonary hypoplasia, on survival in neonates with CDH.
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Methods: This is a retrospective review of neonates with CDH admitted to a tertiary neonatal intensive care unit between 1990 and 2014. Logistic regression was used to assess whether hospital survival was associated with admission PcCO2 or associated anomalies (isolated CDH, CDH with cardiovascular anomalies, and CDH with
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noncardiac anomalies). The probabilities of survival (POS) score, based on birth weight and 5-min Apgar as defined
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by the Congenital Diaphragmatic Hernia Study Group was included as a covariate. Results: Of 97 patients, 55 had additional malformations (cardiovascular n=12, non-cardiac anomalies n=43). POS was lower in CDH with other anomalies compared to isolated CDH. Survival rate was 61.9%, 53.5% and 41.7% in
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isolated CDH, CDH with non-cardiac anomalies and CDH with cardiovascular anomalies, respectively. After adjusting for POS score the likelihood of survival in CDH groups with additional anomalies was similar to isolated CDH (OR 0.95, 95%CI 0.22-4.15, and 1.10, 0.39-3.08, for CDH with and without cardiovascular anomalies, respectively). After adjusting for POS score, lower P cCO2 levels (OR=1.25 per 5 mmHg decrease, P=0.003) were associated with better survival. Conclusions: Neonates with CDH have a high prevalence of congenital malformations. However, after adjusting for POS score the presence of additional anomalies was not associated with survival. The POS score and admission PcCO2 were important prognosticating factors for survival. Keywords: Capillary blood gas; capillary blood carbon dioxide level; congenital diaphragmatic hernia; congenital malformations; congenital heart disease; neonate; probability of survival; mortality; risk assessment.
ACCEPTED MANUSCRIPT
CDH
congenital diaphragmatic hernia
CDHSG
Congenital Diaphragmatic Hernia Study Group
iNO
inhaled nitric oxide
NICU
neonatal intensive care unit
PaCO2
partial pressure of carbon dioxide in arterial blood
PcCO2
partial pressure of carbon dioxide in capillary blood
POS
probability of survival score
VSD
ventricular septal defect
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atrial septal defect
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ASD
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Abbreviations:
The Role of Authors/Co-authors:
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Katarina Bojanić, MD: Design, data collection, manuscript preparation
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Ena Pritišanac, MD: Data collection, manuscript preparation
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Tomislav Luetić, MD, PhD: Surgeon collected information and manuscript preparation
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Jurica Vuković, MD, PhD: Design, data collection, manuscript preparation Juraj Sprung, MD, PhD: Design, data collection, manuscript preparation Toby N Weingarten, MD: Data analysis, manuscript preparation Darrell R. Schroeder, MS: Statistics, manuscript preparation, manuscript proofing Ruža Grizelj, MD, PhD: Design, data collection, manuscript preparation
ACCEPTED MANUSCRIPT
Congenital diaphragmatic hernia (CDH) is a complex malformation associated with high mortality.
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Survival is influenced by the extent of pulmonary hypoplasia and potentially worsened by the presence of additional
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congenital defects, especially cardiovascular and chromosomal abnormalities.1-5 Concomitant anomalies occur frequently in neonates with CDH and according to one report 43% of neonates with CHD had one or more
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malformations, and approximately half of those were cardiac anomalies. 6 The subset of neonates with both CDH and heart anomalies pose particular challenges for management as both conditions can contribute to respiratory distress,
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hypoxemia and hypercarbia. It is not surprising that when CDH is associated with cardiac anomalies survival is lower compared to isolated CHD.3, 6 Early postdelivery presentation of respiratory distress with hypercapnia is a
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marker of pulmonary hypoplasia. Therefore, the level of carbon dioxide in the arterial blood (PaCO2) may indicate the severity of pulmonary involvement,7, 8 or even predict mortality.9 It has been shown that capillary blood gases
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represent a sensitive screening tool for arterial acidosis and hypercarbia.10 The value of admission carbon dioxide end-capillary blood (PcCO2) levels as a predictor of survival needs to be examined.
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The aim of this study is to describe types of congenital anomalies in outborn neonates with CHD
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(“outborn” is defined as born in another institution and transferred to referral center for care). We compare outcomes among neonates with isolated CDH (with no additional anomalies besides CDH) to complex CDH (with one or more
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additional congenital anomalies). We hypothesized that CDH neonates with concomitant anomalies have increased mortality. Furthermore, since the CDH-associated pulmonary hypoplasia leads to a compromised gas exchange we hypothesized that the admission capillary PcCO2 is an independent predictor of survival. 1.
Materials and Methods This study was approved by the Institutional Ethics Committee of the University Hospital Centre (UHC)
Zagreb, Croatia. The medical records of 97 neonates with CDH born between January 1, 1990, and December 31, 2014, who underwent treatment in the UHC neonatal intensive care unit (NICU) were retrospectively reviewed. The UHC is the largest Croatian tertiary referral neonatal institution, and receives neonatal transfers from the entire country. None of the community hospitals with maternity wards in Zagreb have NICU capabilities, while the UHC does not have a maternity ward; therefore, all subjects in this study are outborns (born in another institution with
ACCEPTED MANUSCRIPT maternity wards and transferred to UHC). For purpose of analysis, subjects were divided into three groups: 1) isolated CDH with no additional congenital anomalies, 2) complex CDH with congenital cardiovascular anomalies,
Definitions
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1.2.
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and 3) complex CDH with additional non-cardiac anomalies.
Early presentation is defined as respiratory distress present immediately after delivery (symptomatic within
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the first 6 hours of life). Late presentation is defined as absence of visible breathing difficulties after delivery or respiratory symptoms manifesting >6 hours after delivery. During initial years covered by this study (1990-1999)
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there were limited resources for prenatal screening and protective ventilatory strategies were not available (Croatian war 1990-1995, with lingering economic consequences for several years after). Therefore, the phrase “time period of
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protective strategies” is used to describe the time period 2000-2014 which included improved prenatal screening,
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and the use of both protective ventilation and inhaled nitric oxide (iNO). 1.2 Data collection
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Patient variables that were abstracted included demographic information, disease characteristics including acuity of CDH presentation (early vs. late presentation), preductal capillary blood gases (in particular admission
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PcCO2 level) and vital signs (blood pressure, and body temperature) after delivery. The Congenital Diaphragmatic
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Hernia Study Group (CDHSG) published a logistic regression model designed to predict outcome within the first 5 minutes of life based on Apgar score and birth weight. For our analyses we quantified the severity of CDH using CDHSG-devised probability of survival (POS) equation: POS= 1-1/(1+e-x) where -x = -5.0240 + 0.9165 x (birth weight in kilograms) + 0.4512 x (5 minute Apgar score) in the discrete ordinate range of 0-10.11 The POS score categorizes all neonates with CDH into low (0 to 33%), moderate (34% to 66%), and high (67% to 100%) predicted survival, however the calculated actual POS in our study was used as continuous variable. Variables regarding CHD management abstracted included treatment during, before and after the time of “protective strategies” (after January 1, 2000), which took into account the type of mechanical ventilation used; and the use of iNO, surfactant, and/or potent vasoactive support. Survival to hospital discharge was noted. 1.3.
Statistical analyses
ACCEPTED MANUSCRIPT Data are presented as mean ± SD for continuous variables, and frequency percentages for categorical variables. Characteristics were compared across groups using analysis of variance and Fisher’s exact test. Logistic regression was used to assess whether hospital survival was associated with the presence of associate congenital
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malformation after adjusting for the POS score. Additional logistic regression analysis was performed to examine the association of the POS score and admission level of PcCO2 with survival. These analyses were done separately for the entire cohort and also for neonates with early presentation, as early presenting symptomatology (respiratory
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distress) is a marker of pulmonary involvement. Since the management of CDH changed in year 2000 when
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protective ventilatory strategies were introduced, as well as use of iNO became available, a binary variable indicating admission date after January 1, 2000 was included as a covariate in all logistic regression models. In all
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cases two tailed P values <0.05 were considered statistically significant. Data were analyzed using SAS version 9.3 (SAS Institute Cary, NC). Results
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2.
Between January 1, 1990 and December 30, 2014, 99 neonates with CDH were transferred to UHC NICU
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(Figure 1). Two patients had missing medical records and were excluded. Of the remaining 97 neonates, the most
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common type of CDH was Bochdalek hernia (n=93), while there was a single case of each Morgagni hernia, paraesophageal hernia, central hernia, and severe diaphragmatic eventration. Fifty-five (56.7%) subjects had one or
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multiple malformations associated with CDH (Table 1). Twelve (12.4%) neonates had associated cardiovascular anomalies and are summarized in Table 2. Five neonates with simple isolated cardiovascular anomalies (patent ductus arteriosus [PDA] or atrial septal defect [ASD II]) survived, while 6 with complex cardiovascular anomalies died. These 6 were prenatally diagnosed with CDH and heart defects, and their mothers were transported to high risk maternity wards in Zagreb for delivery. An additional premature neonate (body weight 1.3 kg) with ASD II and a low POS score also died. Table 3 summarizes disease and therapeutic characteristics in those with isolated CDH (n=42), complex CDH with (n=12) and without (n=43) cardiovascular involvement. Compared to isolated CDH and complex CDH without cardiac anomalies, neonates with CDH and cardiovascular malformations had lower birth weight and lower 1-min Apgar scores. Compared to isolated CDH, POS scores were lower, and the frequency of pulmonary hypertension was higher in both complex CDH groups. Compared to isolated CDH, a higher percentage of the
ACCEPTED MANUSCRIPT complex cardiovascular anomalies (92% vs. 57%) were observed after year 2000, when prenatal screening improved. Table 4 presents admission preductal capillary blood gases and vital signs within 12 hours of admission. Compared to isolated CDH neonates with complex cardiovascular anomalies presented with higher disease acuity as
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inferred from the lower PcO2, higher PcCO2, lower pH, and both lower body temperatures and blood pressures. Of patients with isolated CDH 26/42 (61.9%) survived to discharge, compared to 23/43 (53.5%) in
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complex without cardiac anomaly, and 5/12 (41.7%) with cardiovascular anomaly. After adjusting for the POS score (OR for survival with increasing POS=1.61, 95%CI 1.39-1.99, per 10 percentage point increase) the likelihood of
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survival in complex CDH with and without cardiac anomaly was similar to isolated CDH (OR 0.95, 95%CI 0.224.15, and OR 1.10, 95% CI 0.39-3.08, for complex CDH with and without cardiac anomalies, respectively). Overall
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survival was high in neonates with late presentation 21/22 (95.5%), and low in those with early presentation (33/75, 44.0%). From multivariable logistic regression including all patients, a higher POS score (OR=1.59, 95%CI 1.24-
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2.03 per 10 percentage points increase, P<0.001), and a lower PcCO 2 (OR=1.25, 95% CI 1.08-1.44 per 5 mmHg decrease, P=0.003) were associated with better hospital survival. When the analysis was restricted to patient with
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early presentation only, similar results were observed (POS score OR=1.46, 95%CI 1.14-1.88 per 10 percentage points increase, P=0.003; and PcCO2 OR=1.19, 95%CI 1.03-1.38 per 5 mmHg decrease, P=0.017). Mortality of
Discussion
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3.
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patients with early presentation according to the admission PcCO2 is shown in Figure 2.
Over half of our study cohort had complex CDH with one or more additional malformations. In general, the POS scores, based on birth weight and 5 minute Apgar score, were more predictive of mortality than the presence of additional congenital malformations. However, within the subgroup of neonates with complex cardiovascular anomalies all died. Finally, we found that the value of admission capillary PcCO2 was an important prognosticating factor for survival. In neonates with CDH there is a large variability in how specific malformation may impact outcome. In particular, a compounding effect of cardiac anomaly with CDH-associated pulmonary hypoplasia can greatly increase presentation of acuity of disease immediately after delivery. In neonates with CDH, even a “simple” cardiac defect such as ASD, may have a negative impact on outcome. For example, in neonate with CDH and pulmonary
ACCEPTED MANUSCRIPT hypertension with concomitant ASD the fraction of intracardiac right-to-left shunting may be increased. In addition, hypercapnia, frequently associated with CDH, will worsen pulmonary hypertension, and may further contribute to increase in intracardiac shunting. Presence of cardiac anomalies (OR 5.2), severe pulmonary hypertension (OR 4.07)
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and chromosomal abnormalities (OR 3.9) all predict mortality in newborns with CDH.12 Indeed, among our 12 CDH patients with cardiovascular anomalies 7 died, of these 5 were with complex cardiac defects, 1 was with ASD, but had low birth weight and POS score, and 1 had major vascular anomaly with right diaphragmatic aplasia and severe
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pulmonary hypoplasia with pulmonary hypertension.
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Early onset of respiratory distress in neonate with CDH may indicate presence of more severe pulmonary and/or cardiac involvement. Early presentation of respiratory distress, a marker of pulmonary hypoplasia, is
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clinically manifested with hypercapnia. PaCO2 levels above 60 mmHg in neonates with CHD may indicate critical pulmonary hypoplasia and is a harbinger of poor prognosis. 7, 8 Salas et al.13 demonstrated that PaCO2>88 mmHg
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before initiating the ECMO was associated with 11% survival, while PaCO2 below 60 mmHg on first blood gas may indicate milder hypoplasia, and was an independent predictor of survival. Schultz et al. 9 suggested that the most
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important factor in predicting survival was the maximum PaCO 2 value, as only 5% of the surviving infants in their study had a maximum PaCO2 greater than 80 mmHg. Others also demonstrated that the admission PaCO 2 and
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preductal oxyhemoglobin saturation were useful in predicting survival in CDH neonates. 14 Even more, among survivors, admission PaCO2≥80 mmHg was associated with higher need for home oxygen therapy, discharge with
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diuretics, requirement for nasogastric or gastrostomy feedings at discharge and longer length of stay. 14 Instead of PaCO2, in our case series, we report arterialized capillary PcCO2 values which closely correlate with PaCO2, and can be used interchangeably with PaCO2 to estimate ventilation in critically ill neonates. We found that the admission PcCO2 is a good prognosticating parameter in children with CDH, and that for every 5 mmHg decrease in PcCO2 the odds of hospital survival increased by 25%. Figure 2 illustrates increasing mortality among patients with early presentation of respiratory distress in our cohort based on 3 levels of capillary PcCO2 obtained on admission. At the same time, in CDH neonates with late presentation the absence of respiratory symptomatology after delivery and lower values of admission capillary PcCO2 were per se excellent prognosticating sign, as this group had 95% survival.
ACCEPTED MANUSCRIPT Graciano 3 reviewed cardiac anomalies and prognosis in 2,636 children with CDH from the CDHSG database. They excluded from review “hemodynamically insignificant” cardiac anomalies such as ASDs and PDAs. Interestingly, their rate of isolated ASD (82/2,636, 3.1%) was identical to ours (3/97, 3.1%), but the rate of
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“significant” heart defects was higher (10.6%)3 than in our cohort (5.2%), which likely represents underreporting related to a referral bias in our series (see study limitations). Three neonates in our series had hemodynamically significant PDA and subsequently required surgical or pharmacological ligation, therefore we included them into
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cardiovascular anomaly group. In our cohort, VSD and ASD, both isolated or in conjunction with other heart malformations, were the most common heart defects (n=8). Survival for isolated CDH in CDHSG report was
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70.2%,3 and in our study was 61.9%, which may reflect the fact that we included patients from the calendar time
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when “non-protective ventilatory strategies” were used. CDHSG reported 41.1% survival for CHD when associated with severe heart anomalies,3 while in our series none of neonates with complex heart defect survived, reflecting the
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lack of resources for treatment of these malformations (see limitations). Of interest, the most frequently recorded anomaly in our series was cryptorchidism (n=29), bilateral in 19
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and unilateral in 10. Some postulated that cryptorchidism can occur in CDH because of ineffective increase in abdominal pressure during the fetal period,15 however this mechanism cannot entirely explain instances of its
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unilateral occurrence. Fauza et al.16 reported 6 CDH patients with cryptorchidism. Another anomaly we encountered
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is 8 (8.2%) neonates was accessory spleen or polysplenia, an anomaly previously reported in CDH patients. 17 One of the limitations of our study is its retrospective design with the possibility for missing data and unforeseen confounders. Extracorporeal membrane oxygenation was not available during the study period. Furthermore, the surgical expertise for the highly complex cardiac anomalies was limited during the study period, therefore our findings cannot be generalized to results from institutions with these resources and expertise. Furthermore, the frequency of skeletal anomalies may be underestimated as radiograms were unavailable for 31 out of 97 patients. In addition, autopsy records were not available for 6 patients. In addition, in Croatia between 2001 and 2011, 34.5% newborns with CDH died before being transferred from the delivery room to a higher level of care (data obtained from The Institute of Public Health, Zagreb, Croatia). This rate was likely higher during the earlier years (Croatian war) of our study cohort. Since these neonates probably had the most severe CDH forms with associated congenital anomalies, our report likely underestimates the true rate of malformations in patients with
ACCEPTED MANUSCRIPT CDH. Thus, the types of malformations and survival rates described in our study reflect only the population of neonates who were viable enough and were transferred to our institution. However, this reporting problem with CDH is universally present as several reports pointed on the effect of "hidden" mortality, i.e., that substantial
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number of infants born with CDH die before they could be treated. 18, 19 Conclusion
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In over a half of our neonates with CDH we identified a wide variety of congenital malformations. POS score determined at delivery was more predictive of mortality than the presence of additional congenital
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malformations. In addition to the POS score, low admission capillary PcCO2 was an important prognosticating
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factor for improved survival. Therefore, routinely obtained capillary blood gas on admission is a useful adjunct for assessment of acuity of CDH and may help in predicting survival. The ease of collection makes a capillary blood gas
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Conflict of Interest statement:
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an attractive alternative to an arterial blood gas in certain patients and settings.
KB declares no conflict of interest related to submitted work.
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EP declares no conflict of interest related to submitted work. TL declares no conflict of interest related to submitted work.
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JV declares no conflict of interest related to submitted work. JS declares no conflict of interest related to submitted work. TNW declares no conflict of interest related to submitted work. DRS declares no conflict of interest related to submitted work. RG declares no conflict of interest related to submitted work.
ACCEPTED MANUSCRIPT References 1. Bohn D. Congenital diaphragmatic hernia. Am J Respir Crit Care Med. 2002; 166(7): 911-5.
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2. Borys D, Taxy JB. Congenital diaphragmatic hernia and chromosomal anomalies: autopsy study. Pediatr Dev
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Pathol. 2004; 7(1): 35-8.
3. Graziano JN. Cardiac anomalies in patients with congenital diaphragmatic hernia and their prognosis: a report
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from the Congenital Diaphragmatic Hernia Study Group. J Pediatr Surg. 2005; 40(6): 1045-9. 4. Langham MR, Jr., Kays DW, Ledbetter DJ, Frentzen B, Sanford LL, Richards DS. Congenital diaphragmatic
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hernia. Epidemiology and outcome. Clin Perinatol. 1996; 23(4): 671-88.
5. Rozmiarek AJ, Qureshi FG, Cassidy L, Ford HR, Hackam DJ. Factors influencing survival in newborns with
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congenital diaphragmatic hernia: the relative role of timing of surgery. J Pediatr Surg. 2004; 39(6): 821-4; discussion -4.
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6. Bedoyan JK, Blackwell SC, Treadwell MC, Johnson A, Klein MD. Congenital diaphragmatic hernia: associated anomalies and antenatal diagnosis. Outcome-related variables at two Detroit hospitals. Pediatr Surg Int. 2004; 20(3):
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170-6.
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7. Dibbins AW, Wiener ES. Mortality from neonatal diaphragmatic hernia. J Pediatr Surg. 1974; 9(5): 653-62. 8. Mishalany HG, Nakada K, Woolley MM. Congenital diaphragmatic hernias: eleven years' experience. Arch Surg.
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1979; 114(10): 1118-23.
9. Schultz CM, DiGeronimo RJ, Yoder BA. Congenital diaphragmatic hernia: a simplified postnatal predictor of outcome. J Pediatr Surg. 2007; 42(3): 510-6. 10. Harrison AM, Lynch JM, Dean JM, Witte MK. Comparison of simultaneously obtained arterial and capillary blood gases in pediatric intensive care unit patients. Crit Care Med. 1997; 25(11): 1904-8. 11. Congenital Diaphragmatic Hernia Study Group. Estimating disease severity of congenital diaphragmatic hernia in the first 5 minutes of life. J Pediatr Surg. 2001; 36(1): 141-5. 12. Brindle ME, Cook EF, Tibboel D, Lally PA, Lally KP. A clinical prediction rule for the severity of congenital diaphragmatic hernias in newborns. Pediatrics. 2014; 134(2): e413-9. 13. Salas AA, Bhat R, Dabrowska K, Leadford A, Anderson S, Harmon CM, et al. The value of Pa(CO2) in relation to outcome in congenital diaphragmatic hernia. Am J Perinatol. 2014; 31(11): 939-46.
ACCEPTED MANUSCRIPT 14. Khmour AY, Konduri GG, Sato TT, Uhing MR, Basir MA. Role of admission gas exchange measurement in predicting congenital diaphragmatic hernia survival in the era of gentle ventilation. J Pediatr Surg. 2014; 49(8): 1197-201.
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15. Hiradfar M, Sadeghipoor S. Intrathoracic testicular ectopia in congenital diaphragmatic hernia. Asian J Surg
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2006; 29(4): 303-5.
16. Fauza DO, Wilson JM. Congenital diaphragmatic hernia and associated anomalies: their incidence,
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identification, and impact on prognosis. J Pediatr Surg. 1994; 29(8): 1113-7.
17. Martinez-Frias ML, Prieto L, Urioste M, Bermejo E. Clinical/epidemiological analysis of congenital anomalies
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associated with diaphragmatic hernia. Am J Med Genet. 1996; 62(1): 71-6.
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18. Harrison MR, Bjordal RI, Langmark F, Knutrud O. Congenital diaphragmatic hernia: the hidden mortality. J Pediatr Surg. 1978; 13(3): 227-30.
19. Brownlee EM, Howatson AG, Davis CF, Sabharwal AJ. The hidden mortality of congenital diaphragmatic
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hernia: a 20-year review. J Pediatr Surg. 2009; 44(2): 317-20.
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Figure/Table Legends Figure 1. Patient with congenital diaphragmatic hernia treated in our institution from 1990 to 2014. Figure 2. Mortality of patients with early presentation according to admission capillary carbon dioxide levels (PcCO2) Table 1. Individual congenital anomalies in 97 patients with congenital diaphragmal hernia Table 2. Clinical details of 12 patients with congenital diaphragmal hernia and associated cardiac or vascular anomalies. Table 3. Demographic and disease characteristics in children with congenital diaphragmatic hernia (CDH). Table 4. Admission capillary blood gases, lowest mean blood pressure and lowest temperature over the first 12 hours after admission.
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Figure 1
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Figure 2
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GASTROINTESTINAL, N=12*
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CARDIOVASCULAR, N=12*
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Table 1. Individual congenital anomalies in 97 patients with congenital diaphragmal hernia.
4
Double appendix
1
Atrial septal defect
4
Accessory spleen
Ventricular septal defect
4
Polysplenia
2
d-TGA
1
Mitral atresia
1
6
Esophageal atresia (type IIIB Vogt)
1
Extremely short esophagus
1
1
Anteposition of the anus
1
1
Meckel’s diverticulum
1
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Patent ductus arteriosus
Hypoplastic left ventricle Coarctation of the aorta
2
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Right aortic arch
1
Supernumerary ribs
4
1
Absent ribs
5
Persistent left SVC draining into the coronary sinus
1
Hemivertebrae
1
Dextrocardia
1
Short sternum
1
Leg deformity
6
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Pulmonary artery atresia
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Overriding aorta
SKELETAL, N=14*
GENITOURINARY, N=9* Bicornate uterus
1
Arm deformity
3
Penile hypospadia
1
Head deformity
4
Hydroureter/hydronephrosis
4
Mega-bladder
1
Bilateral renal hypoplasia
1
Bilateral ovarian cysts
1
Edwards syndrome
1
Unilateral multicystic kidney
1
Noonan syndrome
1
MINOR, N=3* Minor facial anomalies
4
SYNDROMES/ASSOCIATION, N=3*
ACCEPTED MANUSCRIPT CRYPTORCHIDISM, N=54 males* 19
Unilateral
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Bilateral
1
Frontal lobes atrophy
1
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Bilateral periventricular hypoxicischemic lesion
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CNS, N=2* Bilateral parietal atrophy
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VACTERL association
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Indicates number of patients with one or more malformations in the given organ system. Due to multiple anomalies
in a given patient, the number of individual anomalies within a given organ system may sum to more than the
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number of patients with one or more anomalies in that organ system. Similarly, due to patient having anomalies in
anomalies (n=55).
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multiple organ systems, the sum across organ systems is greater than the total number of patients with one or more
Abbreviations: VACTERL, Vertebral defects, Anal atresia, Cardiac anomaly, TracheoEsophageal fistula, Renal
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anomalies, and Limb abnormalities; SVC, superior vena cava; d-TGA, dextro-transposition of the great arteries; SVC, superior vena cava
ACCEPTED MANUSCRIPT Table 2. Clinical details of 12 patients with congenital diaphragmal hernia and associated cardiac or vascular anomalies
BW, kg
5-min Apgar
PDA
2.95
5
2*
PDA
2.50
9
Hospital Survival
74
YES
79
41
YES
45
151† 70‡
YES
3
PDA
2.30
4
ASD II
2.60
6
51
54
YES
5
ASD II
3.34
10
93
52
YES
6*
PDA + VSD + overriding aorta + pulmonary artery atresia; Noonan syndrome
2.11
6
40
77
No
7*
ASD II
1.32
6
24
62
No
8*
VSD + d-TGA+ mitral atresia+ hypoplastic LV; Edward's syndrome (trisomy 18)
1.96
6
37
61
No
9
VSD + persistent left SVC draining into coronary sinus
1.84
5
24
183
No
10
Right aortic arch§
3.90
4
59
95
No
11
ASD II + Coarctation of the aorta
3.73
4
54
98
No
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VSD + dextrocardia + right aortic arch; VACTERL association
2.23
9
50
66
No
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Admission PcCO2, mmHg
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POS score, %
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Cardiac or Vascular Anomaly
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In addition to those listed, these patients had additional non-cardiac anomalies. †Admission blood gas was pH 6.85,
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PcO2 25.9 mmHg, BD -24 mmol/L, PcCO2 151 mmHg, reflecting accidental endotracheal tube dislodging during transfer. ‡Emergent reintubation and ventilation resulted in PcO2 60.8 mmHg, and PcCO2 70 mmHg, therefore “admission” extreme PcCO2 was not a true marker of lung hypoplasia. When this patient was eliminated from
ACCEPTED MANUSCRIPT analysis (see Results) lower PcCO2 showed high association with improved survival (OR=1.39, 95% CI 1.15-1.68 per 5 mmHg decrease, P=0.001, i.e., for every 5 mmHg decrease in PcCO2 the odds of hospital survival increased by 39%). §This patient had right diaphragm aplasia with the liver and gallbladder herniated into the right thorax. This
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patient subsequently developed bilateral pneumothoraces and pulmonary hemorrhage following vigorous resuscitation and ventilation.
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Abbreviations: PcCO2, partial pressure of carbon dioxide in the end-capillary blood; POS, probability of survival score (%); PDA, patent ductus arteriosus; ASD, atrial septal defect; VSD, ventricular septal defect; SVC, superior
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vena cava; LV, left ventricle; d-TGA, dextro-transposition of the great arteries; VACTERL, Vertebral defects, Anal
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atresia, Cardiac anomaly, TracheoEsophageal fistula, Renal anomalies, and Limb abnormalities
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Complex CDH without Cardiac Anomaly (n=43†)
10 (24)
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Isolated CDH (N=42)
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Characteristic
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Table 3. Demographic and disease characteristics in children with congenital diaphragmatic hernia (CDH). Complex CDH with Cardiac Anomaly (N=12)
10 (23)
5 (42)
29 (67)
6 (50)
21 (50)
17 (33)
6 (50)
39.9±1.9*
38.4±2.9†
37.3±2.5
3.1±0.6
3.1±0.6
2.5±0.8a,b
2 (5)
1 (2)
4 (33)a,b
7.0±2.5
6.1±2.9
3.9±2.5a,b
7.1±2.6
5.7±2.9†a
6.2±1.8
29 (69)
34 (79)
11 (92)
Probability of survival score
0.69±0.24
0.57±0.27†a
0.50±0.20a
High (67% to 100%)
25 (60)
20 (48)
2 (17)
Moderate (34% - 66%)
14 (33)
14 (33)
8 (67)
3 (7)
8 (19)
2 (17)
Pulmonary hypertension confirmed‡
8 (30)
17 (59) a
10 (91)a
iNO treatment
11 (26)
14 (33)
8 (67)a
Surfactant treatment
6 (14)
7 (16)
5 (42)
Vasoactive treatment
30 (71)
32 (74)
9 (75)
Period with “protective strategies”
24 (57)
33 (77)
11 (92)a
Prenatal diagnosis of CDH
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Sex
21 (50)
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Male Female
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Gestational age, weeks
Small for gestational age
Apgar 5 minutes
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Early presentation
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Apgar 1 minute
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Birth weight, kg
Low (0% to 33%)
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anomaly. *Missing for 1 infant. †Missing for 1 infant. ‡Pulmonary hypertension diagnostics was done in 67 infants
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(27 isolated CDH, 29 complex CDH no cardiac, 11 complex CDH cardiac).
ACCEPTED MANUSCRIPT Table 4. Admission capillary blood gases, lowest mean blood pressure and lowest temperature over the first 12 hours after admission.
Mean±SD
PcO2, mmHg
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59.8±21.1
PcCO2, mmHg
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pH
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Lowest temperature, °C
Mean±SD
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Mean±SD
34
47.6±17.9 a
11
43.9±21.5 a
34
69.3±26.4
11
88.6±42.2 a,b
7.2±0.2
33
7.1±0.2
11
7.0±0.3 a
36
-4.9±6.1
32
-6.0±8.6
11
-9.6±10.1
32
36.3±0.5
33
36.2±0.6
9
35.8±0.7 a,b
37
40.1±9.6
32
39.6±8.5
10
33.0±12.8 a
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Lowest mean blood pressure, mmHg
Complex CDH with Cardiac Anomaly
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Base deficit, mEq/L
N*
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Complex CDH without Cardiac Anomaly
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Isolated CDH
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Admission Blood Gases and Vital Signs
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*Number of neonates with information available. Abbreviation: PcO2 = partial pressure of oxygen in the end-capillary blood; PcCO2 = partial pressure of carbon dioxide in the end-capillary blood.