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Ventricular Performance is Associated with Need for Extracorporeal Membrane Oxygenation in Newborns with Congenital Diaphragmatic Hernia
ARTICLE IN PRESS THE JOURNAL OF PEDIATRICS • www.jpeds.com
ORIGINAL ARTICLES
Ventricular Performance is Associated with Need for Extracorporeal Membrane Oxygenation in Newborns with Congenital Diaphragmatic Hernia Gabriel Altit, MDCM, FRCPC, FAAP1,2,3, Shazia Bhombal, MD, FAAP2,3, Krisa Van Meurs, MD, FAAP2,3, and Theresa A. Tacy, MD, FAAP1,3 Objective To compare echocardiography (ECHO) findings of patients with congenital diaphragmatic hernia (CDH) who required extracorporeal membrane oxygenation (ECMO) to non-ECMO treated patients.
Study design We reviewed clinical and ECHO data of newborns with CDH born between 2009 and 2016. Exclusions included major anomalies, genetic syndromes, or no ECHO prior to ECMO. Pulmonary hypertension was assessed by ductal shunting and tricuspid regurgitant jet. Speckle tracking echocardiography (STE) assessed function by quantifying deformation. Results Patients with CDH (15 ECMO and 29 with no ECMO) were analyzed. Most patients had a left CDH (88.6%). Age at ECHO was similar between groups. Outborn status (P = .009) and liver position (P = .009) were associated with need for ECMO. Compared with non-ECMO patients, patients who required ECMO had significantly decreased left and right ventricular function by both conventional and STE measures, as well as decreased right and left ventricular output. The right ventricular eccentricity index was higher in ECMO vs non-ECMO patients (2.2 vs 1.8, P = .02). There was no difference in pulmonary hypertension between CDH groups. Conclusions Need for ECMO was associated with decreased left and right ventricular function, as assessed by standard and STE measures. There was no difference in pulmonary hypertension between non ECMO and ECMO patients. Abnormal cardiac function may explain nonresponse to pulmonary vasodilators in patients with CDH. Management strategies to improve cardiac function may reduce the need for ECMO in newborns with CDH. (J Pediatr 2017;■■:■■-■■).
N
ewborns with congenital diaphragmatic hernia (CDH) have pulmonary hypoplasia and pulmonary hypertension. CDH occurs in about 1 in 3000 live births1 and is associated with decreased cross-sectional area of the pulmonary vascular bed, abnormal increase in vascular smooth muscle cells, altered vasoreactivity, and abnormal vascular response, all of which contribute to delayed transition and increased need for extracorporeal membrane oxygenation (ECMO).2,3 Inhaled nitric oxide (iNO) reduces the need for ECMO or death in term and near-term newborns with hypoxic respiratory failure associated with echocardiographic or clinical evidence of persistent pulmonary hypertension of the newborn.4 However, multiple studies have failed to document a benefit of iNO in the population with CDH.4 For many years, the evaluation and management of patients with CDH has focused on the high pulmonary vascular resistance and pulmonary hypertension.3 In addition to iNO, other pharmacologic management options include milrinone, sildenafil, prostacyclin analogs, vasopressin, and norepinephrine, although data regarding efficacy remain based on small case series.3,5 Echocardiography is often used in infants with CDH to assess cardiac anatomy and performance and estimate pulmonary
AT/RVET CDH ECMO EDSR EF FAC iNO LVOT pGLS pGLSR PW RVOT sBP sPAP STE TAPSE VTI
Acceleration time to right ventricular ejection time Congenital diaphragmatic hernia Extracorporeal membrane oxygenation Early diastolic strain rate Ejection fraction Fractional area change Inhaled nitric oxide Left ventricular outflow tract Peak global longitudinal systolic Peak global longitudinal strain rate Pulsed wave Right ventricular outflow tract Systemic systolic blood pressure Systolic pulmonary arterial pressure Speckle tracking echocardiography Tricuspid annular plane systolic excursion Velocity time integral
From the 1Division of Pediatric Cardiology; 2Division of Neonatal and Developmental Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford; and 3Lucile Packard Children’s Hospital Stanford, Palo Alto, CA The authors declare no conflicts of interest. 0022-3476/$ - see front matter. © 2017 Elsevier Inc. All rights reserved. https://doi.org10.1016/j.jpeds.2017.08.060
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THE JOURNAL OF PEDIATRICS • www.jpeds.com pressures. Conventionally employed assessments of systolic cardiac function of the left ventricle include shortening fraction (percent change of the inner diameter of the left ventricle during contraction) and ejection fraction (EF, percent change in the volume of the left ventricle during contraction). Speckle tracking echocardiography (STE) assesses ventricular function by looking at the myocardial deformation and measures the percent change in myocardial length (strain) and the speed at which it occurs (strain rate) during contraction.6 STE tracks the grayscale speckles present on the echo image from frame to frame to derive information about the regional wall function of the myocardium.7 There are limited data on echocardiography measurements and their predictive value in the population with CDH in the first few days of life. Our objective was to compare echocardiography measures of right ventricular and left ventricular function including STE and pulmonary pressures in patients with CDH who required ECMO vs non-ECMO treated patients with CDH.
Methods Clinical and echocardiographic data of newborns with CDH hospitalized at Lucile Packard Children’s Hospital were collected retrospectively between 2009 and 2016. All patients with CDH were identified from the CDH Study Group and the Stanford Center for Clinic Informatics databases. Study data were collected and managed using REDCap electronic data capture tools hosted at the Stanford Center for Clinical Informatics (hosted at Stanford University, Palo Alto, CA; developed at Vanderbilt University, Nashville, TN). REDCap is a secure, webbased application designed to support data capture for research.8 Only patients with a diagnosis of CDH made during neonatal period were included. Patients were excluded if they had major anomalies, genetic syndromes, or no echocardiography was performed at our institution. Pulmonary pressure was assessed by ductus flow velocity-derived gradient during systole or, if no ductus was present, tricuspid regurgitation jet velocity plus estimated right atrial pressure (5 mm Hg), when a full Doppler envelop was available. Pulmonary hypertension has traditionally been defined as a mean pulmonary arterial pressure above 25 mm Hg or a systolic pulmonary arterial pressure above 40 mm Hg.9 However, this definition does not take into account the transitional physiology of the newborn. Hence, in our population of newborns with CDH, pulmonary hypertension was assessed by comparing the estimated systolic main pulmonary artery pressure to the systolic systemic blood pressure at the time of the echocardiography. Our institutional ECMO criteria include 1 or more of the following: inability to maintain preductal O2 saturations greater than 85% despite optimization of ventilation (with limitation of peak inspiratory pressure of 24 cm H2O on conventional ventilation or, mean airway pressure of 15 cm H2O on high frequency oscillatory ventilation) and initiation of iNO, oxygenation index (mean airway pressure × FiO2/PaO2) of more than 40 for at least 3 hours, metabolic acidosis, and/or hypotension resistant to fluid boluses and appropriate inotropic
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support. Duration of ventilation was measured from the date of the first intubation to the date of the final extubation during the first hospitalization. Duration of hospitalization was calculated for patients who survived. The first echocardiogram was analyzed for each patient. Stored images on the LPCH image server were reviewed. Images had been acquired using Philips iE33, Philips EPIQ 7 (Philips Medical Systems, Bothell, Washington), Siemens Sequoia C512, or Siemens SC2000 (Siemens Medical Solutions USA, Mountain View, California). The echocardiogram measures were performed by 1 investigator, blinded to the ECMO status of the patient at the time of image analysis. EF was calculated using 2 methods for each patient. The 5/6 area length method calculates left ventricular EF using the left ventricular chamber area from the parasternal short axis and the longitudinal dimension of the left ventricle in the 4-chamber view.10-12 The modified Simpson’s method calculates left ventricular EF using the summation of disks to estimate the enddiastolic and end-systolic volume from the apical 4-chamber endocardial area tracing. Fractional area change (FAC) of the right ventricle was calculated from the endocardial area tracing of the right ventricle in the apical 4-chamber view.13 Tricuspid annular plane systolic excursion (TAPSE) was measured from the lateral tricuspid valve annulus.14 Measurements of the right ventricle size (tricuspid valve, basal diameter, midcavity diameter, and longitudinal dimension) were performed at end diastole.15 Eccentricity index is the ratio of largest left ventricle dimension (parallel to the septum at the midpapillary muscle view in the parasternal short axis), to the dimension perpendicular to the septum at end systole.14 It is a quantification of septal configuration and the transmural pressure gradient. Right ventricular outflow tract (RVOT) acceleration time to right ventricular ejection time (AT/RVET) ratio was measured from the pulsed wave (PW) Doppler envelope of the RVOT. This ratio, a surrogate of pulmonary vascular resistance, compares the time to reach peak stroke distance in the pulmonary artery with the overall right ventricular ejection time but is influenced by cardiac output.14,16,17 Velocity time integral (VTI) of the RVOT was measured by tracing the PW Doppler envelope of the RVOT in the parasternal short axis view. VTI of the left ventricular outflow tract (LVOT) was measured in the apical 3-chamber view. VTI is a surrogate measure for output in the corresponding vessel.18 Images of the apical 4-chamber view were stored as Digital Imaging and Communications in Medicine format and were transferred on the VVI platform for strain analysis (VVI 3.01.45; Siemens Medical Solutions USA). Myocardial deformation assessment by speckle-tracking echocardiography (STE) measures myocardial function by regional and global myocardial strain and strain rate quantification.19,20 The measure of strain refers to the change in distance separating 2 areas of the myocardium during 1 cardiac cycle compared with its initial distance, whereas strain rate is the strain divided by the systolic time interval.20 Peak global longitudinal strain (pGLS) and peak global longitudinal strain rate (pGLSR) of the left ventricle are thought to be more sensitive to changes in left ventricular
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function, compared with the conventional echocardiographic measures of shortening and EF.21 EF tends to fall with significant and late cardiac dysfunction and does not allow detection of early myocardial disease. pGLS is also a useful measure of right ventricular function in the pulmonary hypertension population. Images were stored between 30 and 60 frames per second. Tracing of the right and left ventricular endocardium were done manually (Figure 1; available at www.jpeds.com). Tracing was optimized to ensure appropriate endocardial tracking, as previously described.22 Two to 3 consecutive cardiac cycles were used for analysis. The PW Doppler envelope of LVOT or RVOT flow signal was measured to determine the systolic duration time for strain assessment. Peak global longitudinal systolic strain and strain rate were calculated. From the average strain rate curve, the peak of the early strain rate curve was measured to provide the peak diastolic e’ strain rate value (EDSR).22,23 When peak e’ and peak a’ strain rate curves were fused, peak diastolic strain rate was collected as EDSR. The Fisher exact test and c2 test were used to compare categorical characteristics and Student t test was used to compare continuous variables between infants with CDH receiving ECMO vs no ECMO. Statistical analysis was done with GraphPad Software QuickCalcs (La Jolla, California) webbased platform. The level of significance was set at 5% for all comparisons. Results are described as mean with SDs or median with ranges. This study was approved by the Stanford University Institutional Review Board.
Table I. Demographics and clinical characteristics ECMO (n = 15) Gestation age (wk) Preterm (%) Male (%) Small for gestational age (%) Birth weight (g) Cesarean delivery (%) Maternal hypertension (%) Chorioamnionitis (%) Prenatal diagnosis (%) Median age at first echo (d, range) Left CDH (%) Spleen in chest (%) Liver in chest (%) Stomach in chest (%) Inpatient birth (%) Intubation in first 30 min (%) Surfactant trial (%) Days of ventilation Age at discharge (d) Use of HFOV in first wk (%) iNO use in first wk (%) Dopamine in first wk (%) Hydrocortisone in first wk (%) Epinephrine in first wk (%) Prostacyclin in first wk (%) Bicarbonate in first wk (%) Age at surgery (d) Patch repair (%) Laparotomy (%) Thoracoscopy (%) Alive at last follow-up n (%)
39.1 0/15 12 3 3141 3 2 2 7 0 12 11 11 7 5 14 5 49 86 15 14 15 10 6 3 9 18.9 14 14 5 12
(1.0) (0) (80) (20) (614) (20) (13) (13) (47) (1-7) (80) (73) (73) (47) (33) (93) (33) (60) (70) (100) (93) (100) (67) (40) (20) (60) (6) (93) (93) (33) (80)
Non-ECMO (n = 29)
P value
38.4 (1.5) 4/29 (14) 13 (45) 2 (7) 3176 (741) 10 (36) 3 (10) 3 (10) 21 (72) 1 (0-8) 27 (93) 19 (66) 8 (28) 15 (52) 22 (76) 24 (83) 2 (7) 14.4 (12) 41.1 (35) 12 (41) 10 (53) 20 (69) 9 (31) 4 (14) 0 (0) 1 (3) 6.7 (3) 12 (41) 9 (31) 24(83) 28 (96.6)
.15 .28 .052 .32 .88 .49 1.00 1.00 .47 .68 .32 .74 .009 1.00 .009 .65 .04 .006 .009 .0001 .0003 .02 .03 .07 .03 .0001 .0001 .001 .0001 .002 .107
All results are expressed as mean (SD).
Results From 2009 to 2016, 59 patients with CDH were born at or transferred to our institution within the neonatal period. Fifteen patients met at least 1 exclusion criteria (Figure 2; available at www.jpeds.com). Forty-four patients with CDH were included in this analysis. The clinical and demographic characteristics are summarized in Table I. Fifteen patients required ECMO and 29 did not. Mean gestational age, sex, mode of delivery, birth weight, prenatal diagnosis, and age at first echocardiography were similar between ECMO and nonECMO treated patients. One patient in the non-ECMO group underwent fetal tracheal occlusion, and 1 patient in each group had prolonged rupture of membranes of more than 24 hours. ECMO characteristics are summarized in Table II (available at www.jpeds.com). The majority were managed on venoarterial ECMO (93%) with a median duration of 12 days (723 days). Median age in postnatal days at ECMO cannulation was 2 days (0-13) and oxygenation index was 53 ± 32 immediately prior to ECMO initiation. The majority of infants had a left CDH (88.6%). Outborn status and liver position were associated with the need for ECMO, but not spleen or stomach position. Rates of intubation within the first 30 minutes after birth and first arterial blood gas were similar between groups. Patients requiring ECMO had longer duration of ventilation, higher use of high frequency oscillatory ventilation, and longer hospital stays. Use of iNO and dopamine at time of ECHO was higher in the
ECMO group. Surgery was performed at an older chronologic age in the ECMO group, with 3 patients repaired on ECMO and 12 after ECMO. ECMO patients were repaired more often with a patch and by laparotomy, and non-ECMO patients were more often corrected by a thoracoscopic approach. Some patients had a thoracoscopy but were converted to laparotomy (4 in each group) and were counted as having both interventions. Echocardiography data for ECMO and non-ECMO patients are summarized in Table III. Median age at first echocardiography was similar between ECMO and nonECMO patients. The ECMO group had higher heart rate but similar systemic systolic blood pressure (sBP) on the first echocardiogram. Left to right and bidirectional atrial shunts were found in similar proportions in the ECMO vs nonECMO groups. Sizes of main pulmonary artery, right pulmonary artery, and left pulmonary artery were similar. Tricuspid valve annular size, right ventricular basal diameter, right ventricular midcavity diameter, and longitudinal size were similar between groups, indicating similar degree of size, filling, and/ or dilatation. Left ventricular EF was lower in the ECMO group by both 5/6 area length and modified Simpson assessments. Right ventricular systolic function by both TAPSE and FAC was decreased in the ECMO group. End diastolic area of the right ventricle was similar between groups, indicating similar right
Ventricular Performance is Associated with Need for Extracorporeal Membrane Oxygenation in Newborns with Congenital Diaphragmatic Hernia FLA 5.5.0 DTD ■ YMPD9418_proof ■ October 13, 2017
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THE JOURNAL OF PEDIATRICS • www.jpeds.com Table III. Conventional echocardiography parameters ECMO (n = 15) Heart rate (bpm) Systolic blood pressure (mm Hg) Left to right PFO (%) Bidirectional PFO (%) EF by A4C (%) EF by 5/6 (%) TAPSE (mm) FAC of RV (%) E/A ratio of TV E/A ratio of MV AT on RVET of RVOT VTI of RVOT (cm) VTI of LVOT (cm) Eccentricity index LV estimated end-diastolic volume by Simpson rule (mL) RV end-diastolic area (cm2) TV annular size (mm) RV basal diameter (mm) RV midcavity diameter (mm) RV longitudinal size (mm) Size of MPA (cm) Size of RPA (cm) Size of LPA (cm)
Non-ECMO (n = 29)
158 60 7/13 6/13 52.2 54.9 4.7 21.0 0.82 0.90 0.25 6.9 7.5 2.17 3.13
(24) (12) (54) (46) (14.0) (14.8) (1.3) (9.3) (0.20) (0.24) (0.08) (1.7) (2.9) (0.44) (1.54)
136 59 11/24 13/24 67.3 66.7 6.0 32.5 0.82 0.98 0.35 9.2 10.8 1.82 3.47
(18) (9) (46) (54) (8.9) (7.6) (1.6) (10.1) (0.17) (0.31) (0.10) (2.8) (3.1) (0.45) (1.00)
.002 .67 .74 .74 .0002 .003 .01 .0009 .94 .51 .005 .01 .003 .02 .56
3.04 1.25 1.60 1.43 2.31 1.08 0.5 0.4
(0.75) (0.32) (0.30) (0.27) (0.37) (0.17) (0.1) (0.1)
3.52 1.18 1.53 1.39 2.71 1.00 0.46 0.4
(1.02) (0.27) (0.26) (0.28) (0.37) (0.16) (0.08) (0.1)
.051 .437 .399 .577 .0003 .15 .94 .77
ventricle sizes. The E wave on A wave ratio of the mitral and tricuspid valves inflow (marker of diastolic function) was similar between groups. Strain analyses in the 2 ECMO groups are displayed in Table IV. pGLS strain of the right and left ventricle were decreased in the ECMO population (right ventricle: −5.2 ± 3.9 vs −10.7 ± 5.0 %, P = .001; left ventricle: −9.1 ± 4.9 vs −14.9 ± 5.3 %, P = .002), as well as the pGLS strain rate of the right ventricle (right ventricle: −0.68 ± 0.41 vs −1.12 ± 0.33 1/second, P = .0007). EDSR of the right ventricle but not the left ventricle, was decreased in the ECMO compared with nonECMO group. Assessment of systolic pulmonary arterial pressure (sPAP) in mm Hg by ductal or tricuspid regurgitant jet velocity were possible in 80% of studies for both groups (Table V). Ratio of sPAP to sBP was similar between the ECMO and nonECMO group. Eccentricity index was increased in the ECMO population, although the AT/RVET ratio was decreased. VTI
Table IV. Deformation measurements
RV pGLS (%) RV pGLSR (1/s) RV EDSR (1/s) LV pGLS (%) LV pGLSR (1/s) LV EDSR (1/s)
−5.2 −0.68 0.78 −9.1 −1.10 1.2
(3.9) (0.41) (0.43) (4.9) (0.50) (0.5)
All results are expressed as mean (SD).
Non-ECMO (n = 29) −10.7 −1.12 1.28 −14.9 −1.46 1.4
(5.0) (0.33) (0.57) (5.3) (0.56) (0.7)
Table V. Pulmonary echocardiography
P value
A4C, apical 4 chamber view; E/A ratio, early to late ventricular filling velocities ratio; LPA, left pulmonary artery; LV, left ventricular; MPA, main pulmonary artery; MV, mitral valve; PFO, patent foramen ovale; RPA, right pulmonary artery; RV, right ventricular; TV, tricuspid valve. All results are expressed as mean (SD).
ECMO (n = 15)
Volume ■■
P value .001 .0007 .007 .002 .053 .43
pressure ECMO (n = 15)
Pulmonary/systemic ratio by PDA/TR (%) TR or PDA available (%) TR jet available (%) PDA available (%) Right to left PDA (%) Bidirectional PDA (%) Flat or bowing SC in systole (%)
103 (4) 12 8 10 2/10 8/10 15
(80) (53.3) (66.7) (20) (80) (100)
assessment Non-ECMO (n = 29) 103 (16) 23 20 18 2/18 13/18 24
(79) (69) (62) (11) (72) (83)
by
P value 1.00 1.00 .34 1.00 .58 .67 .15
PDA, patent ductus arteriosus; SC, septal curve; TR, tricuspid regurgitation. All results are expressed as mean (SD).
of the LVOT, RVOT, right pulmonary artery, and left pulmonary artery were significantly decreased in the ECMO population. Although the ECMO cohort had markers of decreased right and left ventricular function, the subgroup of patients who were placed on ECMO >24 hours after their initial ECHO had decreased left ventricular function by EF 5/6 method and left ventricular pGLSR, as well as decreased right ventricular function by right ventricular pGLS (Table VI; available at www.jpeds.com). Both groups had similar degrees of sPAP/ sBP ratio and eccentricity index. Also, 6 patients were cannulated within the first 24 hours of life, and no differences were found in parameters of right and left ventricular function, eccentricity index, and sPAP/sBP ratio vs those cannulated later.
Discussion In our population, decreased left and right ventricular performance as measured by left ventricular EF, right ventricular FAC, TAPSE, LVOT and RVOT VTI and left ventricular and right ventricular strain were significantly associated with need for ECMO. In contrast, the peak pulmonary to systemic pressure ratio was similar between the ECMO and the nonECMO population. Conventional measures of cardiac function by echocardiography such as left ventricular EF and right ventricular FAC may not identify subclinical myocardial disease. Shortening fraction calculated in the context of abnormal septal movements, as seen in patients with pulmonary hypertension, does not allow for reliable quantification of left ventricular function. Also, segmental dysfunction might only be uncovered by analyzing the deformation of individual myocardial segments. Some patients may have noncontractile regions tethered to functioning segments that might be moving in time without effectively participating in cardiac performance, giving a false impression of global appropriate function. In this context, left ventricular EF or right ventricular FAC may fail to detect areas of tissue dysfunction. In the population with CDH with multiple risk factors for cardiac dysfunction including abnormal postnatal transition, pulmonary vascular disease, and cardiac shift within the thoracic cavity,
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deformation analysis can be useful to document segmental cardiac anomalies. There has been great interest in trying to predict the course of infants affected by CDH. Prenatal ultrasound and fetal magnetic resonance imaging measures such as lung to head ratio, observed to expected lung to head ratio, magnetic resonance imaging lung volumetry, status of liver herniation, and quantity of amniotic fluid are used for prediction of severity and for counselling.24-26 A previous postnatal study reported an association between hilar pulmonary artery size and mortality.27 In addition, left pulmonary artery diameter, ratio of left to right pulmonary artery diameters, left pulmonary arterial flow and the McGoon index (left + right pulmonary artery diameters divided by descending aorta diameter) have been assessed as predictors of mortality.3 In our population, pulmonary artery diameters were similar within groups. In 1 study, early diastolic dysfunction predicted length of stay and duration of respiratory support in a cohort of 20 infants with CDH.28 Another recent report found that the degree pulmonary hypertension severity at 2 weeks strongly predicts mortality and respiratory morbidity.29 None of those studies evaluated the role cardiac function plays in outcome of patients with CDH. In our cohort, severe pulmonary hypertension was present in all patients, indicating that pulmonary hypertension is not the sole determinant of need for ECMO. The majority of newborns had a ductus arteriosus or a complete tricuspid regurgitation envelope, allowing for estimation of pulmonary pressures. The presence of left ventricular systolic dysfunction may explain the failure of pulmonary arterial vasodilators in the population with CDH. Indeed, decreased left ventricular performance can lead to left atrial hypertension and pulmonary venous congestion.30 In our population, all infants with CDH had abnormal markers of left ventricular systolic function, suggesting that infants with CDH might have varying degrees of impaired left ventricular filling and pulmonary venous hypertension. Initiation of a pulmonary arterial vasodilator such as iNO in this setting may promote pulmonary vascular congestion and pulmonary edema, impact left ventricular preload, and lead to decreased cardiac output. Regional or global pulmonary edema can further worsen pulmonary mechanics, perfusion to ventilation mismatch, oxygen and carbon dioxide exchange, as well as lead to reflex pulmonary vasoconstriction and surfactant inactivation. Previous reports have described structural smaller left ventricles in the population with CDH; however, we did not find a difference in estimated end diastolic volume of the left ventricle between our ECMO and non-ECMO populations.31,32 Current literature does not support the use of a specific agent in the management of cardiac dysfunction in the neonatal population with CDH. Future research should focus on therapeutic agents that target cardiac function in the population of CDH with right and/or left ventricular dysfunction, such as agents like milrinone that promote afterload reduction and contractility. By using lung protective ventilation strategies33 and a protocolized approach,34-36 survival of patients with CDH has modestly improved with decreased use of ECMO.37 ECMO is
an invasive and costly method associated with short- and longterm morbidities including bleeding, thrombosis, stroke, infection, hearing loss, and acute kidney injury. Using a mortality risk calculation based on birth weight and 5-minute Apgar score, ECMO was found to improve survival of patients with CDH with a predictive mortality risk of 80% or higher.37 ECMO is often initiated in infants with CDH and severe pulmonary hypertension with progressive increase in oxygenation index, thought to represent a failure of pulmonary oxygenation capacity.38,39 By addressing poor cardiac performance in the population with CDH early in their course, we postulate that ECMO use may decrease. Inotropic support or agents such as milrinone (a phosphodiesterase-3 inhibitor with inotropic and lusitropic properties) may improve contractility and cardiac relaxation, thereby improving pulmonary and systemic cardiac output, allowing for better pulmonary and systemic blood flow.5,40 In addition, some patients with CDH may benefit from the right to left ductal shunt to ensure appropriate systemic blood flow, in light of the poor left ventricular performance. In our population, ECMO patients had lower VTI in the right and left ventricular outflow tracts compared with nonECMO patients, indicating decreased ventricular output. In light of decreased ventricular performance, one may consider the use of prostaglandins to prevent ductal closure or restriction in order to unload the right ventricle and promote systemic cardiac output.41 Despite similar pulmonary pressures, the left ventricular eccentricity index was higher in ECMO vs non-ECMO patients. Septal deformation is dependent on ventricular conduction activation, biventricular contraction and relaxation, synchrony between ventricular performance, ventricular afterload, and presence of atrio-ventricular or semilunar valvar regurgitation. As such, eccentricity index is a marker of ventricular interaction but has often been used as a pulmonary pressure indicator in the context of isolated pulmonary hypertension.14,42 In the context of right and left ventricular dysfunction, it is not surprising to find abnormal septal deformation in in infants with CDH, despite similar pulmonary to systemic pressure ratio. Similarly, patients requiring ECMO had a smaller initial AT/RVET ratio than those not requiring ECMO. A decreased AT on RVET ratio has been associated with increased pulmonary vascular resistance.13,14 However, a decrease in overall right ventricular output also affects the ratio, with maximal ejection at the beginning of systole.43 Decreased stroke distance found in the patient population requiring ECMO might explain this significant decrease in AT/RVET ratio. Finally, when looking at the ECMO subgroup cannulated >24 hours after initial ECHO compared with those cannulated on the day of the ECHO, pulmonary pressures were similar but the group placed on ECMO later had worse markers of right and left ventricular dysfunction. We speculate that these patients had progressive worsening of cardiac performance over time. This study analyzed cardiac performance as a predictor of need for ECMO in the population with CDH. We also describe the use of deformational analysis and ventricular output in the
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THE JOURNAL OF PEDIATRICS • www.jpeds.com early neonatal period of patients with CDH. There are some limitations to our analysis. Although our center’s survival rates are comparable with cohorts described in large volume centers,5,38 this was a single center study and its generalizability should be tested in a multi-institutional study with a larger sample size. Multiple echocardiographic platforms were used to image the patients, possibly introducing systemic differences between vendors,44 although we used 1 software program for deformation analysis to decrease this variability.45,46 STE analysis was done by a single reader and inter-reader reliability was not explored. Reports have described a high reproducibility of strain measurements by the same reader or a different reader using different strain vendors47 and using different echocardiography machines.45 Analyzed echocardiography images were originally acquired at a low frame rate of 3060 Hz, when 2-dimensional STE recommendations advocate for 80-100 Hz. However, a recent report observed no difference between strain measurements at lower (below 60 Hz) and higher (≥60 Hz) frame rates.46 Also, some views or Doppler sampling were not available for analysis in certain patients because of either the retrospective nature of the study or the technical difficulty of performing an echocardiography in patients on high frequency ventilation and with abnormal cardiac position. Decreased cardiac function as assessed by standard and STE measures was associated with need for ECMO in this cohort of newborns with CDH. There was no difference in pulmonary hypertension between non-ECMO and ECMO patients. STE may provide additional data on cardiac function in neonates with CDH, and abnormal cardiac function may explain the nonresponse to pulmonary arterial vasodilators such as iNO in patients with CDH. Early assessment and ongoing monitoring by echocardiography may be useful to determine the use of targeted therapies to support the underlying hemodynamic state of infants with CDH, and these management strategies may reduce the need for ECMO in newborns with CDH. ■ Submitted for publication Mar 27, 2017; last revision received Jul 13, 2017; accepted Aug 22, 2017 Reprint requests: Gabriel Altit, MDCM, FRCPC, FAAP, Division of Neonatal and Developmental Medicine, 750 Welch Road, Suite 315, Palo Alto, CA 94304. E-mail: [email protected]
References 1. McGivern MR, Best KE, Rankin J, Wellesley D, Greenlees R, Addor M-C, et al. Epidemiology of congenital diaphragmatic hernia in Europe: a register-based study. Arch Dis Child Fetal Neonatal Ed 2014;100:F13744. fetalneonatal-2014-306174. 2. George DK, Cooney TP, Chiu BK, Thurlbeck W. Hypoplasia and immaturity of the terminal lung unit (acinus) in congenital diaphragmatic hernia. Am Rev Respir Dis 1987;136:947-50. 3. Pierro M, Thebaud B. Understanding and treating pulmonary hypertension in congenital diaphragmatic hernia. Semin Fetal Neonatal Med 2014;19:357-63. 4. Barrington KJ, Finer N, Pennaforte T, Altit G. Nitric oxide for respiratory failure in infants born at or near term. Cochrane Database Syst Rev 2017;1:CD000399.
Volume ■■ 5. Puligandla PS, Grabowski J, Austin M, Hedrick H, Renaud E, Arnold M, et al. Management of congenital diaphragmatic hernia: a systematic review from the APSA outcomes and evidence based practice committee. J Pediatr Surg 2015;50:1958-70. 6. Kutty S, Deatsman SL, Nugent ML, Russell D, Frommelt PC. Assessment of regional right ventricular velocities, strain, and displacement in normal children using velocity vector imaging. Echocardiography 2008;25:294-307. 7. Fukuda Y, Tanaka H, Sugiyama D, Ryo K, Onishi T, Fukuya H, et al. Utility of right ventricular free wall speckle-tracking strain for evaluation of right ventricular performance in patients with pulmonary hypertension. J Am Soc Echocardiogr 2011;24:1101-8. 8. Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)—a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform 2009;42:377-81. 9. Abman SH, Hansmann G, Archer SL, Ivy DD, Adatia I, Chung WK, et al. Pediatric pulmonary hypertension. Circulation 2015;132:203799. 10. Lu JC, Ensing GJ, Yu S, Thorsson T, Donohue JE, Dorfman AL. 5/6 Area length method for left-ventricular ejection-fraction measurement in adults with repaired tetralogy of Fallot: comparison with cardiovascular magnetic resonance. Pediatr Cardiol 2013;34:231-9. 11. Margossian R, Chen S, Sleeper LA, Tani LY, Shirali G, Golding F, et al. The reproducibility and absolute values of echocardiographic measurements of left ventricular size and function in children are algorithm dependent. J Am Soc Echocardiogr 2015;28:549-58, e1. 12. Wyatt H, Heng MK, Meerbaum S, Gueret P, Hestenes J, Dula E, et al. Crosssectional echocardiography. II. Analysis of mathematic models for quantifying volume of the formalin- fixed left ventricle. Circulation 1980;61:1119-25. 13. Jone PN, Ivy DD. Echocardiography in pediatric pulmonary hypertension. Front Pediatr 2014;2:124. 14. Altit G, Dancea A, Renaud C, Perreault T, Lands LC, Sant’Anna G. Pathophysiology, screening and diagnosis of pulmonary hypertension in infants with bronchopulmonary dysplasia — a review of the literature. Paediatr Respir Rev 2016;23:16-26. 15. Lopez L, Colan SD, Frommelt PC, Ensing GJ, Kendall K, Younoszai AK, et al. Recommendations for quantification methods during the performance of a pediatric echocardiogram: a report from the Pediatric Measurements Writing Group of the American Society of Echocardiography Pediatric and Congenital Heart Disease Council. J Am Soc Echocardiogr 2010;23:465-95. 16. Subhedar N, Shaw N. Changes in pulmonary arterial pressure in preterm infants with chronic lung disease. Arch Dis Child Fetal Neonatal Ed 2000;82:F243-7. 17. Subhedar N, Shaw N. Intraobserver variation in Doppler ultrasound assessment of pulmonary artery pressure. Arch Dis Child Fetal Neonatal Ed 1996;75:F59-61. 18. Punn R, Axelrod DM, Sherman-Levine S, Roth SJ, Tacy TA. Predictors of mortality in pediatric patients on venoarterial extracorporeal membrane oxygenation. Pediatr Crit Care Med 2014;15:870. 19. Arunamata A, Selamet Tierney ES, Tacy TA, Punn R. Echocardiographic measures associated with early postsurgical myocardial dysfunction in pediatric patients with mitral valve regurgitation. J Am Soc Echocardiogr 2015;28:284-93. 20. Lorch SM, Ludomirsky A, Singh GK. Maturational and growth-related changes in left ventricular longitudinal strain and strain rate measured by two-dimensional speckle tracking echocardiography in healthy pediatric population. J Am Soc Echocardiogr 2008;21:1207-15. 21. Even a high schooler can measure strain. J Am Soc Echocardiogr 2016;29:A19-21. 22. Fine NM, Shah AA, Han IY, Yu Y, Hsiao JF, Koshino Y, et al. Left and right ventricular strain and strain rate measurement in normal adults using velocity vector imaging: an assessment of reference values and intersystem agreement. Int J Cardiovasc Imaging 2013;29:571-80. 23. Carasso S, Biaggi P, Rakowski H, Mutlak D, Lessick J, Aronson D, et al. Velocity Vector Imaging: standard tissue-tracking results acquired in
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normals–the VVI-STRAIN study. J Am Soc Echocardiogr 2012;25:54352. Jani J, Nicolaides K, Keller R, Benachi A, Peralta C, Favre R, et al. Observed to expected lung area to head circumference ratio in the prediction of survival in fetuses with isolated diaphragmatic hernia. Ultrasound Obstet Gynecol 2007;30:67-71. Bebbington M, Victoria T, Danzer E, Moldenhauer J, Khalek N, Johnson M, et al. Comparison of ultrasound and magnetic resonance imaging parameters in predicting survival in isolated left-sided congenital diaphragmatic hernia. Ultrasound Obstet Gynecol 2014;43:670-4. Gorincour G, Bouvenot J, Mourot M, Sonigo P, Chaumoitre K, Garel C, et al. Prenatal prognosis of congenital diaphragmatic hernia using magnetic resonance imaging measurement of fetal lung volume. Ultrasound Obstet Gynecol 2005;26:738-44. Suda K, Bigras J-L, Bohn D, Hornberger LK, McCrindle BW. Echocardiographic predictors of outcome in newborns with congenital diaphragmatic hernia. Pediatrics 2000;105:1106-9. Moenkemeyer F, Patel N. Right ventricular diastolic function measured by tissue Doppler imaging predicts early outcome in congenital diaphragmatic hernia. Pediatr Crit Care Med 2014;15:49-55. Lusk LA, Wai KC, Moon-Grady AJ, Steurer MA, Keller RL. Persistence of pulmonary hypertension by echocardiography predicts short-term outcomes in congenital diaphragmatic hernia. J Pediatr 2015;166:251-6, e1. Gien J, Kinsella J. Management of pulmonary hypertension in infants with congenital diaphragmatic hernia. J Perinatol 2016;36:S28-31. Byrne F, Keller R, Meadows J, Miniati D, Brook M, Silverman N, et al. Severe left diaphragmatic hernia limits size of fetal left heart more than does right diaphragmatic hernia. Ultrasound Obstet Gynecol 2015;46:68894. Stressig R, Fimmers R, Eising K, Gembruch U, Kohl T. Preferential streaming of the ductus venosus and inferior caval vein towards the right heart is associated with left heart underdevelopment in human fetuses with leftsided diaphragmatic hernia. Heart 2010;96:1564-8. Kays DW, Langham MR Jr, Ledbetter DJ, Talbert JL. Detrimental effects of standard medical therapy in congenital diaphragmatic hernia. Ann Surg 1999;230:340. Zalla JM, Stoddard GJ, Yoder BA. Improved mortality rate for congenital diaphragmatic hernia in the modern era of management: 15year experience in a single institution. J Pediatr Surg 2015;50:524-7. van den Hout L, Schaible T, Cohen-Overbeek T, Hop W, Siemer J, van de Ven K, et al. Actual outcome in infants with congenital diaphragmatic
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hernia: the role of a standardized postnatal treatment protocol. Fetal Diagn Ther 2011;29:55-63. Reiss I, Schaible T, van den Hout L, Capolupo I, Allegaert K, van Heijst A, et al. Standardized postnatal management of infants with congenital diaphragmatic hernia in Europe: the CDH EURO Consortium consensus. Neonatology 2010;98:354-64. Harting MT, Lally KP. The congenital diaphragmatic hernia study group registry update. Seminars in fetal and neonatal medicine. Elsevier; 2014. p. 370-5. Losty PD. Congenital diaphragmatic hernia: where and what is the evidence? Semin Pediatr Surg 2014;23:278-82. Group UCET. UK collaborative randomised trial of neonatal extracorporeal membrane oxygenation. Lancet 1996;348:75-82. Patel N. Use of milrinone to treat cardiac dysfunction in infants with pulmonary hypertension secondary to congenital diaphragmatic hernia: a review of six patients. Neonatology 2012;102:130-6. Inamura N, Kubota A, Nakajima T, Kayatani F, Okuyama H, Oue T, et al. A proposal of new therapeutic strategy for antenatally diagnosed congenital diaphragmatic hernia. J Pediatr Surg 2005;40:13159. Puwanant S, Park M, Popovic´ ZB, Tang WW, Farha S, George D, et al. Ventricular geometry, strain, and rotational mechanics in pulmonary hypertension. Circulation 2010;121:259-66. Marra AM, Benjamin N, Ferrara F, Vriz O, D’Alto M, D’Andrea A, et al. Reference ranges and determinants of right ventricle outflow tract acceleration time in healthy adults by two- dimensional echocardiography. Int J Cardiovasc Imaging 2016;1-8. Brooks PA, Khoo NS, Hornberger LK. Systolic and diastolic function of the fetal single left ventricle. J Am Soc Echocardiogr 2014;27:9727. Risum N, Ali S, Olsen NT, Jons C, Khouri MG, Lauridsen TK, et al. Variability of global left ventricular deformation analysis using vendor dependent and independent two-dimensional speckle-tracking software in adults. J Am Soc Echocardiogr 2012;25:1195-203. Liu MY, Tacy T, Chin C, Obayashi DY, Punn R. Assessment of speckletracking echocardiography-derived global deformation parameters during supine exercise in children. Pediatr Cardiol 2016;37:519-27. Costa SP, Beaver TA, Rollor JL, Vanichakarn P, Magnus PC, Palac RT. Quantification of the variability associated with repeat measurements of left ventricular two-dimensional global longitudinal strain in a realworld setting. J Am Soc Echocardiogr 2014;27:50-4.
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Figure 1. Echocardiographic image from the apical 4-chamber view showing STE using VVI. The length of the vector is proportional to the traced speckle’s velocity, which is used in myocardial deformation analysis. The top panel shows tracking of the right ventricular endocardium, and the bottom panel shows tracking of the left ventricular endocardium.
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Figure 2. Flow diagram for patient inclusion.
Table II. ECMO characteristics (n = 15) ECMO modes ECMO run (d) ECMO run median (d, range) Last PaO2 prior to ECMO OI before cannulation MAP before cannulation Age at ECMO median (d, range) Patients with ECHO on d of ECMO (%) Median time between ECHO and ECMO for subgroup undergoing ECMO the d of echocardiography (range) Repaired on ECMO n (%) Repaired post-ECMO n (%)
13 VA, 1 VV 1 VV to VA 12.8 12 34.2 52.6 15.34 2 7 6 h 54 min
(4.5) (7-23) (10.0) (31.9) (4.41) (0-13) (46) (1h 04-23 h15)
3 (20) 12 (80)
MAP, mean airway pressure; OI, Oxygenation Index; PaO2, partial pressure of oxygen in arterial blood; VA, veno-arterial; VV, veno-venous. Unless otherwise specified, results are expressed as mean (SD).
Table VI. ECMO population based on timing of ECHO to cannulation Cannulated on day of ECHO (n = 7) EF by A4C EF by 5/6 TAPSE of RV FAC of RV RV pGLS (%) RV pGLSR (1/s) LV pGLS (%) LV pGLSR (1/s) Eccentricity index sPAP/sBP
57.9 63.2 4.7 24.9 −7.56 −0.87 −10.9 −1.39 2.19 103.5
(12.6) (6.4) (1.4) (9.6) (3.66) (0.24) (5.9) (0.52) (0.31) (4.3)
Cannulated at > 24 h of ECHO (n = 8) 45.5 44.8 4.6 18.0 −3.20 −0.52 −7.3 −0.79 2.15 102.5
(13.2) (16.3) (1.3) (8.5) (3.04) (0.50) (3.1) (0.27) (0.55) (3.4)
P value .11 .03 .90 .18 .04 .12 .23 .03 .88 .67
All results are expressed as mean (SD).
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Ventricular Performance is Associated with Need for Extracorporeal Membrane Oxygenation in Newborns with Congenital Diaphragmatic Hernia Gabriel Altit, MDCM, FRCPC, FAAP1,2,3, Shazia Bhombal, MD, FAAP2,3, Krisa Van Meurs, MD, FAAP2,3, and Theresa A. Tacy, MD, FAAP1,3 Objective To compare echocardiography (ECHO) findings of patients with congenital diaphragmatic hernia (CDH) who required extracorporeal membrane oxygenation (ECMO) to non-ECMO treated patients.
Study design We reviewed clinical and ECHO data of newborns with CDH born between 2009 and 2016. Exclusions included major anomalies, genetic syndromes, or no ECHO prior to ECMO. Pulmonary hypertension was assessed by ductal shunting and tricuspid regurgitant jet. Speckle tracking echocardiography (STE) assessed function by quantifying deformation. Results Patients with CDH (15 ECMO and 29 with no ECMO) were analyzed. Most patients had a left CDH (88.6%). Age at ECHO was similar between groups. Outborn status (P = .009) and liver position (P = .009) were associated with need for ECMO. Compared with non-ECMO patients, patients who required ECMO had significantly decreased left and right ventricular function by both conventional and STE measures, as well as decreased right and left ventricular output. The right ventricular eccentricity index was higher in ECMO vs non-ECMO patients (2.2 vs 1.8, P = .02). There was no difference in pulmonary hypertension between CDH groups. Conclusions Need for ECMO was associated with decreased left and right ventricular function, as assessed by standard and STE measures. There was no difference in pulmonary hypertension between non ECMO and ECMO patients. Abnormal cardiac function may explain nonresponse to pulmonary vasodilators in patients with CDH. Management strategies to improve cardiac function may reduce the need for ECMO in newborns with CDH. (J Pediatr 2017;■■:■■-■■).
N
ewborns with congenital diaphragmatic hernia (CDH) have pulmonary hypoplasia and pulmonary hypertension. CDH occurs in about 1 in 3000 live births1 and is associated with decreased cross-sectional area of the pulmonary vascular bed, abnormal increase in vascular smooth muscle cells, altered vasoreactivity, and abnormal vascular response, all of which contribute to delayed transition and increased need for extracorporeal membrane oxygenation (ECMO).2,3 Inhaled nitric oxide (iNO) reduces the need for ECMO or death in term and near-term newborns with hypoxic respiratory failure associated with echocardiographic or clinical evidence of persistent pulmonary hypertension of the newborn.4 However, multiple studies have failed to document a benefit of iNO in the population with CDH.4 For many years, the evaluation and management of patients with CDH has focused on the high pulmonary vascular resistance and pulmonary hypertension.3 In addition to iNO, other pharmacologic management options include milrinone, sildenafil, prostacyclin analogs, vasopressin, and norepinephrine, although data regarding efficacy remain based on small case series.3,5 Echocardiography is often used in infants with CDH to assess cardiac anatomy and performance and estimate pulmonary
AT/RVET CDH ECMO EDSR EF FAC iNO LVOT pGLS pGLSR PW RVOT sBP sPAP STE TAPSE VTI
Acceleration time to right ventricular ejection time Congenital diaphragmatic hernia Extracorporeal membrane oxygenation Early diastolic strain rate Ejection fraction Fractional area change Inhaled nitric oxide Left ventricular outflow tract Peak global longitudinal systolic Peak global longitudinal strain rate Pulsed wave Right ventricular outflow tract Systemic systolic blood pressure Systolic pulmonary arterial pressure Speckle tracking echocardiography Tricuspid annular plane systolic excursion Velocity time integral
From the 1Division of Pediatric Cardiology; 2Division of Neonatal and Developmental Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford; and 3Lucile Packard Children’s Hospital Stanford, Palo Alto, CA The authors declare no conflicts of interest. 0022-3476/$ - see front matter. © 2017 Elsevier Inc. All rights reserved. https://doi.org10.1016/j.jpeds.2017.08.060
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THE JOURNAL OF PEDIATRICS • www.jpeds.com pressures. Conventionally employed assessments of systolic cardiac function of the left ventricle include shortening fraction (percent change of the inner diameter of the left ventricle during contraction) and ejection fraction (EF, percent change in the volume of the left ventricle during contraction). Speckle tracking echocardiography (STE) assesses ventricular function by looking at the myocardial deformation and measures the percent change in myocardial length (strain) and the speed at which it occurs (strain rate) during contraction.6 STE tracks the grayscale speckles present on the echo image from frame to frame to derive information about the regional wall function of the myocardium.7 There are limited data on echocardiography measurements and their predictive value in the population with CDH in the first few days of life. Our objective was to compare echocardiography measures of right ventricular and left ventricular function including STE and pulmonary pressures in patients with CDH who required ECMO vs non-ECMO treated patients with CDH.
Methods Clinical and echocardiographic data of newborns with CDH hospitalized at Lucile Packard Children’s Hospital were collected retrospectively between 2009 and 2016. All patients with CDH were identified from the CDH Study Group and the Stanford Center for Clinic Informatics databases. Study data were collected and managed using REDCap electronic data capture tools hosted at the Stanford Center for Clinical Informatics (hosted at Stanford University, Palo Alto, CA; developed at Vanderbilt University, Nashville, TN). REDCap is a secure, webbased application designed to support data capture for research.8 Only patients with a diagnosis of CDH made during neonatal period were included. Patients were excluded if they had major anomalies, genetic syndromes, or no echocardiography was performed at our institution. Pulmonary pressure was assessed by ductus flow velocity-derived gradient during systole or, if no ductus was present, tricuspid regurgitation jet velocity plus estimated right atrial pressure (5 mm Hg), when a full Doppler envelop was available. Pulmonary hypertension has traditionally been defined as a mean pulmonary arterial pressure above 25 mm Hg or a systolic pulmonary arterial pressure above 40 mm Hg.9 However, this definition does not take into account the transitional physiology of the newborn. Hence, in our population of newborns with CDH, pulmonary hypertension was assessed by comparing the estimated systolic main pulmonary artery pressure to the systolic systemic blood pressure at the time of the echocardiography. Our institutional ECMO criteria include 1 or more of the following: inability to maintain preductal O2 saturations greater than 85% despite optimization of ventilation (with limitation of peak inspiratory pressure of 24 cm H2O on conventional ventilation or, mean airway pressure of 15 cm H2O on high frequency oscillatory ventilation) and initiation of iNO, oxygenation index (mean airway pressure × FiO2/PaO2) of more than 40 for at least 3 hours, metabolic acidosis, and/or hypotension resistant to fluid boluses and appropriate inotropic
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support. Duration of ventilation was measured from the date of the first intubation to the date of the final extubation during the first hospitalization. Duration of hospitalization was calculated for patients who survived. The first echocardiogram was analyzed for each patient. Stored images on the LPCH image server were reviewed. Images had been acquired using Philips iE33, Philips EPIQ 7 (Philips Medical Systems, Bothell, Washington), Siemens Sequoia C512, or Siemens SC2000 (Siemens Medical Solutions USA, Mountain View, California). The echocardiogram measures were performed by 1 investigator, blinded to the ECMO status of the patient at the time of image analysis. EF was calculated using 2 methods for each patient. The 5/6 area length method calculates left ventricular EF using the left ventricular chamber area from the parasternal short axis and the longitudinal dimension of the left ventricle in the 4-chamber view.10-12 The modified Simpson’s method calculates left ventricular EF using the summation of disks to estimate the enddiastolic and end-systolic volume from the apical 4-chamber endocardial area tracing. Fractional area change (FAC) of the right ventricle was calculated from the endocardial area tracing of the right ventricle in the apical 4-chamber view.13 Tricuspid annular plane systolic excursion (TAPSE) was measured from the lateral tricuspid valve annulus.14 Measurements of the right ventricle size (tricuspid valve, basal diameter, midcavity diameter, and longitudinal dimension) were performed at end diastole.15 Eccentricity index is the ratio of largest left ventricle dimension (parallel to the septum at the midpapillary muscle view in the parasternal short axis), to the dimension perpendicular to the septum at end systole.14 It is a quantification of septal configuration and the transmural pressure gradient. Right ventricular outflow tract (RVOT) acceleration time to right ventricular ejection time (AT/RVET) ratio was measured from the pulsed wave (PW) Doppler envelope of the RVOT. This ratio, a surrogate of pulmonary vascular resistance, compares the time to reach peak stroke distance in the pulmonary artery with the overall right ventricular ejection time but is influenced by cardiac output.14,16,17 Velocity time integral (VTI) of the RVOT was measured by tracing the PW Doppler envelope of the RVOT in the parasternal short axis view. VTI of the left ventricular outflow tract (LVOT) was measured in the apical 3-chamber view. VTI is a surrogate measure for output in the corresponding vessel.18 Images of the apical 4-chamber view were stored as Digital Imaging and Communications in Medicine format and were transferred on the VVI platform for strain analysis (VVI 3.01.45; Siemens Medical Solutions USA). Myocardial deformation assessment by speckle-tracking echocardiography (STE) measures myocardial function by regional and global myocardial strain and strain rate quantification.19,20 The measure of strain refers to the change in distance separating 2 areas of the myocardium during 1 cardiac cycle compared with its initial distance, whereas strain rate is the strain divided by the systolic time interval.20 Peak global longitudinal strain (pGLS) and peak global longitudinal strain rate (pGLSR) of the left ventricle are thought to be more sensitive to changes in left ventricular
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function, compared with the conventional echocardiographic measures of shortening and EF.21 EF tends to fall with significant and late cardiac dysfunction and does not allow detection of early myocardial disease. pGLS is also a useful measure of right ventricular function in the pulmonary hypertension population. Images were stored between 30 and 60 frames per second. Tracing of the right and left ventricular endocardium were done manually (Figure 1; available at www.jpeds.com). Tracing was optimized to ensure appropriate endocardial tracking, as previously described.22 Two to 3 consecutive cardiac cycles were used for analysis. The PW Doppler envelope of LVOT or RVOT flow signal was measured to determine the systolic duration time for strain assessment. Peak global longitudinal systolic strain and strain rate were calculated. From the average strain rate curve, the peak of the early strain rate curve was measured to provide the peak diastolic e’ strain rate value (EDSR).22,23 When peak e’ and peak a’ strain rate curves were fused, peak diastolic strain rate was collected as EDSR. The Fisher exact test and c2 test were used to compare categorical characteristics and Student t test was used to compare continuous variables between infants with CDH receiving ECMO vs no ECMO. Statistical analysis was done with GraphPad Software QuickCalcs (La Jolla, California) webbased platform. The level of significance was set at 5% for all comparisons. Results are described as mean with SDs or median with ranges. This study was approved by the Stanford University Institutional Review Board.
Table I. Demographics and clinical characteristics ECMO (n = 15) Gestation age (wk) Preterm (%) Male (%) Small for gestational age (%) Birth weight (g) Cesarean delivery (%) Maternal hypertension (%) Chorioamnionitis (%) Prenatal diagnosis (%) Median age at first echo (d, range) Left CDH (%) Spleen in chest (%) Liver in chest (%) Stomach in chest (%) Inpatient birth (%) Intubation in first 30 min (%) Surfactant trial (%) Days of ventilation Age at discharge (d) Use of HFOV in first wk (%) iNO use in first wk (%) Dopamine in first wk (%) Hydrocortisone in first wk (%) Epinephrine in first wk (%) Prostacyclin in first wk (%) Bicarbonate in first wk (%) Age at surgery (d) Patch repair (%) Laparotomy (%) Thoracoscopy (%) Alive at last follow-up n (%)
39.1 0/15 12 3 3141 3 2 2 7 0 12 11 11 7 5 14 5 49 86 15 14 15 10 6 3 9 18.9 14 14 5 12
(1.0) (0) (80) (20) (614) (20) (13) (13) (47) (1-7) (80) (73) (73) (47) (33) (93) (33) (60) (70) (100) (93) (100) (67) (40) (20) (60) (6) (93) (93) (33) (80)
Non-ECMO (n = 29)
P value
38.4 (1.5) 4/29 (14) 13 (45) 2 (7) 3176 (741) 10 (36) 3 (10) 3 (10) 21 (72) 1 (0-8) 27 (93) 19 (66) 8 (28) 15 (52) 22 (76) 24 (83) 2 (7) 14.4 (12) 41.1 (35) 12 (41) 10 (53) 20 (69) 9 (31) 4 (14) 0 (0) 1 (3) 6.7 (3) 12 (41) 9 (31) 24(83) 28 (96.6)
.15 .28 .052 .32 .88 .49 1.00 1.00 .47 .68 .32 .74 .009 1.00 .009 .65 .04 .006 .009 .0001 .0003 .02 .03 .07 .03 .0001 .0001 .001 .0001 .002 .107
All results are expressed as mean (SD).
Results From 2009 to 2016, 59 patients with CDH were born at or transferred to our institution within the neonatal period. Fifteen patients met at least 1 exclusion criteria (Figure 2; available at www.jpeds.com). Forty-four patients with CDH were included in this analysis. The clinical and demographic characteristics are summarized in Table I. Fifteen patients required ECMO and 29 did not. Mean gestational age, sex, mode of delivery, birth weight, prenatal diagnosis, and age at first echocardiography were similar between ECMO and nonECMO treated patients. One patient in the non-ECMO group underwent fetal tracheal occlusion, and 1 patient in each group had prolonged rupture of membranes of more than 24 hours. ECMO characteristics are summarized in Table II (available at www.jpeds.com). The majority were managed on venoarterial ECMO (93%) with a median duration of 12 days (723 days). Median age in postnatal days at ECMO cannulation was 2 days (0-13) and oxygenation index was 53 ± 32 immediately prior to ECMO initiation. The majority of infants had a left CDH (88.6%). Outborn status and liver position were associated with the need for ECMO, but not spleen or stomach position. Rates of intubation within the first 30 minutes after birth and first arterial blood gas were similar between groups. Patients requiring ECMO had longer duration of ventilation, higher use of high frequency oscillatory ventilation, and longer hospital stays. Use of iNO and dopamine at time of ECHO was higher in the
ECMO group. Surgery was performed at an older chronologic age in the ECMO group, with 3 patients repaired on ECMO and 12 after ECMO. ECMO patients were repaired more often with a patch and by laparotomy, and non-ECMO patients were more often corrected by a thoracoscopic approach. Some patients had a thoracoscopy but were converted to laparotomy (4 in each group) and were counted as having both interventions. Echocardiography data for ECMO and non-ECMO patients are summarized in Table III. Median age at first echocardiography was similar between ECMO and nonECMO patients. The ECMO group had higher heart rate but similar systemic systolic blood pressure (sBP) on the first echocardiogram. Left to right and bidirectional atrial shunts were found in similar proportions in the ECMO vs nonECMO groups. Sizes of main pulmonary artery, right pulmonary artery, and left pulmonary artery were similar. Tricuspid valve annular size, right ventricular basal diameter, right ventricular midcavity diameter, and longitudinal size were similar between groups, indicating similar degree of size, filling, and/ or dilatation. Left ventricular EF was lower in the ECMO group by both 5/6 area length and modified Simpson assessments. Right ventricular systolic function by both TAPSE and FAC was decreased in the ECMO group. End diastolic area of the right ventricle was similar between groups, indicating similar right
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THE JOURNAL OF PEDIATRICS • www.jpeds.com Table III. Conventional echocardiography parameters ECMO (n = 15) Heart rate (bpm) Systolic blood pressure (mm Hg) Left to right PFO (%) Bidirectional PFO (%) EF by A4C (%) EF by 5/6 (%) TAPSE (mm) FAC of RV (%) E/A ratio of TV E/A ratio of MV AT on RVET of RVOT VTI of RVOT (cm) VTI of LVOT (cm) Eccentricity index LV estimated end-diastolic volume by Simpson rule (mL) RV end-diastolic area (cm2) TV annular size (mm) RV basal diameter (mm) RV midcavity diameter (mm) RV longitudinal size (mm) Size of MPA (cm) Size of RPA (cm) Size of LPA (cm)
Non-ECMO (n = 29)
158 60 7/13 6/13 52.2 54.9 4.7 21.0 0.82 0.90 0.25 6.9 7.5 2.17 3.13
(24) (12) (54) (46) (14.0) (14.8) (1.3) (9.3) (0.20) (0.24) (0.08) (1.7) (2.9) (0.44) (1.54)
136 59 11/24 13/24 67.3 66.7 6.0 32.5 0.82 0.98 0.35 9.2 10.8 1.82 3.47
(18) (9) (46) (54) (8.9) (7.6) (1.6) (10.1) (0.17) (0.31) (0.10) (2.8) (3.1) (0.45) (1.00)
.002 .67 .74 .74 .0002 .003 .01 .0009 .94 .51 .005 .01 .003 .02 .56
3.04 1.25 1.60 1.43 2.31 1.08 0.5 0.4
(0.75) (0.32) (0.30) (0.27) (0.37) (0.17) (0.1) (0.1)
3.52 1.18 1.53 1.39 2.71 1.00 0.46 0.4
(1.02) (0.27) (0.26) (0.28) (0.37) (0.16) (0.08) (0.1)
.051 .437 .399 .577 .0003 .15 .94 .77
ventricle sizes. The E wave on A wave ratio of the mitral and tricuspid valves inflow (marker of diastolic function) was similar between groups. Strain analyses in the 2 ECMO groups are displayed in Table IV. pGLS strain of the right and left ventricle were decreased in the ECMO population (right ventricle: −5.2 ± 3.9 vs −10.7 ± 5.0 %, P = .001; left ventricle: −9.1 ± 4.9 vs −14.9 ± 5.3 %, P = .002), as well as the pGLS strain rate of the right ventricle (right ventricle: −0.68 ± 0.41 vs −1.12 ± 0.33 1/second, P = .0007). EDSR of the right ventricle but not the left ventricle, was decreased in the ECMO compared with nonECMO group. Assessment of systolic pulmonary arterial pressure (sPAP) in mm Hg by ductal or tricuspid regurgitant jet velocity were possible in 80% of studies for both groups (Table V). Ratio of sPAP to sBP was similar between the ECMO and nonECMO group. Eccentricity index was increased in the ECMO population, although the AT/RVET ratio was decreased. VTI
Table IV. Deformation measurements
RV pGLS (%) RV pGLSR (1/s) RV EDSR (1/s) LV pGLS (%) LV pGLSR (1/s) LV EDSR (1/s)
−5.2 −0.68 0.78 −9.1 −1.10 1.2
(3.9) (0.41) (0.43) (4.9) (0.50) (0.5)
All results are expressed as mean (SD).
Non-ECMO (n = 29) −10.7 −1.12 1.28 −14.9 −1.46 1.4
(5.0) (0.33) (0.57) (5.3) (0.56) (0.7)
Table V. Pulmonary echocardiography
P value
A4C, apical 4 chamber view; E/A ratio, early to late ventricular filling velocities ratio; LPA, left pulmonary artery; LV, left ventricular; MPA, main pulmonary artery; MV, mitral valve; PFO, patent foramen ovale; RPA, right pulmonary artery; RV, right ventricular; TV, tricuspid valve. All results are expressed as mean (SD).
ECMO (n = 15)
Volume ■■
P value .001 .0007 .007 .002 .053 .43
pressure ECMO (n = 15)
Pulmonary/systemic ratio by PDA/TR (%) TR or PDA available (%) TR jet available (%) PDA available (%) Right to left PDA (%) Bidirectional PDA (%) Flat or bowing SC in systole (%)
103 (4) 12 8 10 2/10 8/10 15
(80) (53.3) (66.7) (20) (80) (100)
assessment Non-ECMO (n = 29) 103 (16) 23 20 18 2/18 13/18 24
(79) (69) (62) (11) (72) (83)
by
P value 1.00 1.00 .34 1.00 .58 .67 .15
PDA, patent ductus arteriosus; SC, septal curve; TR, tricuspid regurgitation. All results are expressed as mean (SD).
of the LVOT, RVOT, right pulmonary artery, and left pulmonary artery were significantly decreased in the ECMO population. Although the ECMO cohort had markers of decreased right and left ventricular function, the subgroup of patients who were placed on ECMO >24 hours after their initial ECHO had decreased left ventricular function by EF 5/6 method and left ventricular pGLSR, as well as decreased right ventricular function by right ventricular pGLS (Table VI; available at www.jpeds.com). Both groups had similar degrees of sPAP/ sBP ratio and eccentricity index. Also, 6 patients were cannulated within the first 24 hours of life, and no differences were found in parameters of right and left ventricular function, eccentricity index, and sPAP/sBP ratio vs those cannulated later.
Discussion In our population, decreased left and right ventricular performance as measured by left ventricular EF, right ventricular FAC, TAPSE, LVOT and RVOT VTI and left ventricular and right ventricular strain were significantly associated with need for ECMO. In contrast, the peak pulmonary to systemic pressure ratio was similar between the ECMO and the nonECMO population. Conventional measures of cardiac function by echocardiography such as left ventricular EF and right ventricular FAC may not identify subclinical myocardial disease. Shortening fraction calculated in the context of abnormal septal movements, as seen in patients with pulmonary hypertension, does not allow for reliable quantification of left ventricular function. Also, segmental dysfunction might only be uncovered by analyzing the deformation of individual myocardial segments. Some patients may have noncontractile regions tethered to functioning segments that might be moving in time without effectively participating in cardiac performance, giving a false impression of global appropriate function. In this context, left ventricular EF or right ventricular FAC may fail to detect areas of tissue dysfunction. In the population with CDH with multiple risk factors for cardiac dysfunction including abnormal postnatal transition, pulmonary vascular disease, and cardiac shift within the thoracic cavity,
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ORIGINAL ARTICLES
deformation analysis can be useful to document segmental cardiac anomalies. There has been great interest in trying to predict the course of infants affected by CDH. Prenatal ultrasound and fetal magnetic resonance imaging measures such as lung to head ratio, observed to expected lung to head ratio, magnetic resonance imaging lung volumetry, status of liver herniation, and quantity of amniotic fluid are used for prediction of severity and for counselling.24-26 A previous postnatal study reported an association between hilar pulmonary artery size and mortality.27 In addition, left pulmonary artery diameter, ratio of left to right pulmonary artery diameters, left pulmonary arterial flow and the McGoon index (left + right pulmonary artery diameters divided by descending aorta diameter) have been assessed as predictors of mortality.3 In our population, pulmonary artery diameters were similar within groups. In 1 study, early diastolic dysfunction predicted length of stay and duration of respiratory support in a cohort of 20 infants with CDH.28 Another recent report found that the degree pulmonary hypertension severity at 2 weeks strongly predicts mortality and respiratory morbidity.29 None of those studies evaluated the role cardiac function plays in outcome of patients with CDH. In our cohort, severe pulmonary hypertension was present in all patients, indicating that pulmonary hypertension is not the sole determinant of need for ECMO. The majority of newborns had a ductus arteriosus or a complete tricuspid regurgitation envelope, allowing for estimation of pulmonary pressures. The presence of left ventricular systolic dysfunction may explain the failure of pulmonary arterial vasodilators in the population with CDH. Indeed, decreased left ventricular performance can lead to left atrial hypertension and pulmonary venous congestion.30 In our population, all infants with CDH had abnormal markers of left ventricular systolic function, suggesting that infants with CDH might have varying degrees of impaired left ventricular filling and pulmonary venous hypertension. Initiation of a pulmonary arterial vasodilator such as iNO in this setting may promote pulmonary vascular congestion and pulmonary edema, impact left ventricular preload, and lead to decreased cardiac output. Regional or global pulmonary edema can further worsen pulmonary mechanics, perfusion to ventilation mismatch, oxygen and carbon dioxide exchange, as well as lead to reflex pulmonary vasoconstriction and surfactant inactivation. Previous reports have described structural smaller left ventricles in the population with CDH; however, we did not find a difference in estimated end diastolic volume of the left ventricle between our ECMO and non-ECMO populations.31,32 Current literature does not support the use of a specific agent in the management of cardiac dysfunction in the neonatal population with CDH. Future research should focus on therapeutic agents that target cardiac function in the population of CDH with right and/or left ventricular dysfunction, such as agents like milrinone that promote afterload reduction and contractility. By using lung protective ventilation strategies33 and a protocolized approach,34-36 survival of patients with CDH has modestly improved with decreased use of ECMO.37 ECMO is
an invasive and costly method associated with short- and longterm morbidities including bleeding, thrombosis, stroke, infection, hearing loss, and acute kidney injury. Using a mortality risk calculation based on birth weight and 5-minute Apgar score, ECMO was found to improve survival of patients with CDH with a predictive mortality risk of 80% or higher.37 ECMO is often initiated in infants with CDH and severe pulmonary hypertension with progressive increase in oxygenation index, thought to represent a failure of pulmonary oxygenation capacity.38,39 By addressing poor cardiac performance in the population with CDH early in their course, we postulate that ECMO use may decrease. Inotropic support or agents such as milrinone (a phosphodiesterase-3 inhibitor with inotropic and lusitropic properties) may improve contractility and cardiac relaxation, thereby improving pulmonary and systemic cardiac output, allowing for better pulmonary and systemic blood flow.5,40 In addition, some patients with CDH may benefit from the right to left ductal shunt to ensure appropriate systemic blood flow, in light of the poor left ventricular performance. In our population, ECMO patients had lower VTI in the right and left ventricular outflow tracts compared with nonECMO patients, indicating decreased ventricular output. In light of decreased ventricular performance, one may consider the use of prostaglandins to prevent ductal closure or restriction in order to unload the right ventricle and promote systemic cardiac output.41 Despite similar pulmonary pressures, the left ventricular eccentricity index was higher in ECMO vs non-ECMO patients. Septal deformation is dependent on ventricular conduction activation, biventricular contraction and relaxation, synchrony between ventricular performance, ventricular afterload, and presence of atrio-ventricular or semilunar valvar regurgitation. As such, eccentricity index is a marker of ventricular interaction but has often been used as a pulmonary pressure indicator in the context of isolated pulmonary hypertension.14,42 In the context of right and left ventricular dysfunction, it is not surprising to find abnormal septal deformation in in infants with CDH, despite similar pulmonary to systemic pressure ratio. Similarly, patients requiring ECMO had a smaller initial AT/RVET ratio than those not requiring ECMO. A decreased AT on RVET ratio has been associated with increased pulmonary vascular resistance.13,14 However, a decrease in overall right ventricular output also affects the ratio, with maximal ejection at the beginning of systole.43 Decreased stroke distance found in the patient population requiring ECMO might explain this significant decrease in AT/RVET ratio. Finally, when looking at the ECMO subgroup cannulated >24 hours after initial ECHO compared with those cannulated on the day of the ECHO, pulmonary pressures were similar but the group placed on ECMO later had worse markers of right and left ventricular dysfunction. We speculate that these patients had progressive worsening of cardiac performance over time. This study analyzed cardiac performance as a predictor of need for ECMO in the population with CDH. We also describe the use of deformational analysis and ventricular output in the
Ventricular Performance is Associated with Need for Extracorporeal Membrane Oxygenation in Newborns with Congenital Diaphragmatic Hernia FLA 5.5.0 DTD ■ YMPD9418_proof ■ October 13, 2017
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THE JOURNAL OF PEDIATRICS • www.jpeds.com early neonatal period of patients with CDH. There are some limitations to our analysis. Although our center’s survival rates are comparable with cohorts described in large volume centers,5,38 this was a single center study and its generalizability should be tested in a multi-institutional study with a larger sample size. Multiple echocardiographic platforms were used to image the patients, possibly introducing systemic differences between vendors,44 although we used 1 software program for deformation analysis to decrease this variability.45,46 STE analysis was done by a single reader and inter-reader reliability was not explored. Reports have described a high reproducibility of strain measurements by the same reader or a different reader using different strain vendors47 and using different echocardiography machines.45 Analyzed echocardiography images were originally acquired at a low frame rate of 3060 Hz, when 2-dimensional STE recommendations advocate for 80-100 Hz. However, a recent report observed no difference between strain measurements at lower (below 60 Hz) and higher (≥60 Hz) frame rates.46 Also, some views or Doppler sampling were not available for analysis in certain patients because of either the retrospective nature of the study or the technical difficulty of performing an echocardiography in patients on high frequency ventilation and with abnormal cardiac position. Decreased cardiac function as assessed by standard and STE measures was associated with need for ECMO in this cohort of newborns with CDH. There was no difference in pulmonary hypertension between non-ECMO and ECMO patients. STE may provide additional data on cardiac function in neonates with CDH, and abnormal cardiac function may explain the nonresponse to pulmonary arterial vasodilators such as iNO in patients with CDH. Early assessment and ongoing monitoring by echocardiography may be useful to determine the use of targeted therapies to support the underlying hemodynamic state of infants with CDH, and these management strategies may reduce the need for ECMO in newborns with CDH. ■ Submitted for publication Mar 27, 2017; last revision received Jul 13, 2017; accepted Aug 22, 2017 Reprint requests: Gabriel Altit, MDCM, FRCPC, FAAP, Division of Neonatal and Developmental Medicine, 750 Welch Road, Suite 315, Palo Alto, CA 94304. E-mail: [email protected]
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Ventricular Performance is Associated with Need for Extracorporeal Membrane Oxygenation in Newborns with Congenital Diaphragmatic Hernia FLA 5.5.0 DTD ■ YMPD9418_proof ■ October 13, 2017
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Figure 1. Echocardiographic image from the apical 4-chamber view showing STE using VVI. The length of the vector is proportional to the traced speckle’s velocity, which is used in myocardial deformation analysis. The top panel shows tracking of the right ventricular endocardium, and the bottom panel shows tracking of the left ventricular endocardium.
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Figure 2. Flow diagram for patient inclusion.
Table II. ECMO characteristics (n = 15) ECMO modes ECMO run (d) ECMO run median (d, range) Last PaO2 prior to ECMO OI before cannulation MAP before cannulation Age at ECMO median (d, range) Patients with ECHO on d of ECMO (%) Median time between ECHO and ECMO for subgroup undergoing ECMO the d of echocardiography (range) Repaired on ECMO n (%) Repaired post-ECMO n (%)
13 VA, 1 VV 1 VV to VA 12.8 12 34.2 52.6 15.34 2 7 6 h 54 min
(4.5) (7-23) (10.0) (31.9) (4.41) (0-13) (46) (1h 04-23 h15)
3 (20) 12 (80)
MAP, mean airway pressure; OI, Oxygenation Index; PaO2, partial pressure of oxygen in arterial blood; VA, veno-arterial; VV, veno-venous. Unless otherwise specified, results are expressed as mean (SD).
Table VI. ECMO population based on timing of ECHO to cannulation Cannulated on day of ECHO (n = 7) EF by A4C EF by 5/6 TAPSE of RV FAC of RV RV pGLS (%) RV pGLSR (1/s) LV pGLS (%) LV pGLSR (1/s) Eccentricity index sPAP/sBP
57.9 63.2 4.7 24.9 −7.56 −0.87 −10.9 −1.39 2.19 103.5
(12.6) (6.4) (1.4) (9.6) (3.66) (0.24) (5.9) (0.52) (0.31) (4.3)
Cannulated at > 24 h of ECHO (n = 8) 45.5 44.8 4.6 18.0 −3.20 −0.52 −7.3 −0.79 2.15 102.5
(13.2) (16.3) (1.3) (8.5) (3.04) (0.50) (3.1) (0.27) (0.55) (3.4)
P value .11 .03 .90 .18 .04 .12 .23 .03 .88 .67
All results are expressed as mean (SD).
7.e1
Altit et al FLA 5.5.0 DTD ■ YMPD9418_proof ■ October 13, 2017