Shape of Pulmonary Artery Doppler Flow Profile and Right Ventricular Hemodynamics in Neonates.

OBJECTIVES: To characterize pulmonary artery Doppler flow profile (PAFP) patterns among infants receiving care in neonatal intensive care units and to examine the association of PAFP patterns with pulmonary and right ventricular (RV) hemodynamics. STUDY DESIGN: This is a retrospective study at 2 tertiary intensive care units over 4 years that included neonates who demonstrated a complete tricuspid regurgitation envelope on targeted neonatal echocardiography. Separate personnel reviewed TNEs to characterize PAFP patterns, divide cohort into PAFP groups, and measure quantitative indices of RV hemodynamics (RV systolic pressure, pulmonary artery acceleration time and its ratio with RV ejection time, tricuspid annular plane systolic excursion, and RV output), for intergroup comparisons. RESULTS: We evaluated TNEs from 186 neonates with median gestational age of 28.5 weeks (IQR, 25.9-35.9 weeks). Four distinct PAFP patterns were identified (A) near-isosceles triangle (22%), (B) right-angled triangle (29%), (C) notching (40%), and (D) low peak velocity (<0.4 m/s; 9%). Groups A-C demonstrated a stepwise worsening in all indices of PH, whereas pattern D was associated with lower tricuspid annular plane systolic excursion and RV output. Using common definitions of pulmonary hypertension (PH), pattern A performed best to rule out PH (sensitivity range, 81%-90%) and pattern C for diagnosing PH (specificity range, 63%-78%). CONCLUSIONS: Inspection of PAFP is a simple bedside echocardiography measure that provides clinically meaningful information on underlying RV hemodynamics and may aid in screening and monitoring of patients for PH in intensive care units.

Bloodstream Infections in Preterm Neonates and Mortality-Associated Risk Factors.

OBJECTIVE: To investigate the association of early (±4 hours after onset of bloodstream infection) clinical and laboratory variables with episode-related mortality (<7 days). STUDY DESIGN: This 2-site retrospective study included 142 neonates born at <35 weeks of gestational age with positive blood/cerebrospinal fluid (CSF) culture at >72 hours of age from organisms other than coagulase-negative Staphylococcus. Early variables were compared between those with bloodstream infection-related mortality and survivors. Multivariable analysis was conducted for the primary outcome, and the area under the curve (AUC) was estimated for relevant variables. RESULTS: The neonates who died were of lower gestational age at disease onset. After adjusting for relevant variables, lowest mean blood pressure (MBP) (aOR, 0.10; 95% CI, 1.02-1.19) and highest base deficit (aOR, 1.18; 95% CI, 1.06-1.32) were independently associated with mortality. The AUC was 0.87 (95% CI, 0.78-0.96) for base deficit, increasing to 0.91 (95% CI, 0.83-0.99) with the addition of MBP. CONCLUSION: Low MBP and high base deficit within ±4 hours of bloodstream infection onset identify preterm neonates at risk of mortality.

Physiology of Low Blood Pressure During the First Day After Birth Among Extremely Preterm Neonates.

OBJECTIVE: To investigate the circulatory physiology of hypotension during the first day after birth among stable extremely preterm neonates. STUDY DESIGN: Case-control study of neonates born at ≤276/7 weeks gestational age with hypotension, defined as mean blood pressure in mmHg less than gestational age in weeks for at least 1 hour during the first 24 hours after birth, who underwent comprehensive echocardiography assessment before commencement of cardiovascular drugs. Neonates with hypotension (n = 14) were matched by gestational age and intensity of respiratory support with normotensive neonates (n = 27) who underwent serial echocardiography during the first day after birth, and relatively contemporaneous echocardiography assessments were used for comparison. RESULTS: Neonates with hypotension had a higher frequency of patent ductus arteriosus ≥1.5 mm (71% vs 15%; P < .001) and ductal size (median diameter, 1.6 mm [IQR, 1.4-2.1] vs 1.0 mm [IQR, 0-1.3]; P = .002), higher echocardiography indices of left ventricular systolic function (mean shortening fraction, 34 ± 7% vs 26 ± 4%; P < .001; mean longitudinal strain, -16 ± 5% vs -14 ± 3%; P = .04; and mean velocity of circumferential fiber shortening, 1.24 ± 0.35 circ/s vs 1.01 ± 0.28 circ/s; P = .03), lower estimates of left ventricular afterload (mean end-systolic wall stress, 20 ± 7 g/cm2 vs 30 ± 9 g/cm2; P < .001 and mean arterial elastance, 43 ± 19 mmHg/mL vs 60 ± 22 mmHg/mL; P = .01), without significant difference in stress-velocity index z-score (-0.42 ± 1.60 vs -0.88 ± 1.30; P = .33). Neonates with hypotension had higher rates of any degree of intraventricular hemorrhage (71% vs 22%; P = .006). CONCLUSIONS: Low blood pressure in otherwise well extremely low gestational age neonates was associated with low systemic afterload and larger patent ductus arteriosus, but not left ventricular dysfunction.

Relationship of Patent Ductus Arteriosus Echocardiographic Markers With Descending Aorta Diastolic Flow.

OBJECTIVES: To characterize the relationship of echocardiographic markers of left heart overload and flow in peripheral major end-organ vessels (eg, celiac artery) with the presence of reversed holodiastolic flow in the descending aorta, considered a surrogate marker of an increased transductal shunt volume, in preterm patients with a patent ductus arteriosus (PDA). METHODS: This work was a retrospective study of data from echocardiography performed to investigate the hemodynamic significance of a PDA in preterm patients. We studied differences in echocardiographic markers of the PDA shunt volume according to patterns of flow in the postductal descending aorta (no PDA, PDA with antegrade diastolic flow, and PDA with reversed diastolic flow). The strength of the association between each echocardiographic marker and the presence of aortic holodiastolic flow reversal was investigated. RESULTS: We studied 137 patients with a median (interquartile range) birth weight of 850 (694-1030) g and a median gestational age of 25 (24-27) weeks. Among patients with a PDA (113), those with diastolic flow reversal in the descending aorta (44) presented had increased echocardiographic markers representative of the shunt volume (increased left ventricular output, left atrial-to-aortic ratio, pulmonary vein D wave, and shorter isovolumic relaxation time) compared to those with aortic antegrade diastolic flow. A positive, albeit weak, correlation between diastolic flow reversal and shunt volume echocardiographic markers was found. Abnormal diastolic flow in the celiac artery had the strongest correlation (R2  = 0.24). CONCLUSIONS: In preterm patients with a PDA, echocardiographic markers of the shunt volume were more abnormal in patients with reversed diastolic flow in the descending aorta. These data support the assumption that variance in these markers are related to the shunt volume, which needs consideration when adjudicating hemodynamic significance.

Neonatal Intensive Care Unit-Level Patent Ductus Arteriosus Treatment Rates and Outcomes in Infants Born Extremely Preterm.

OBJECTIVES: To assess associations between neonatal intensive care unit (NICU)-level patent ductus arteriosus (PDA) treatment rates (pharmacologic or surgical) and neonatal outcomes. STUDY DESIGN: This cohort study included infants born at 24-28 weeks of gestation and birth weight <1500 g in 2007-2015 in NICUs caring for ≥100 eligible infants in 6 countries. The ratio of observed/expected (O/E) PDA treatment rates was derived for each NICU by estimating the expected rate using a logistic regression model adjusted for potential confounders and network. The primary composite outcome was death or severe neurologic injury (grades III-IV intraventricular hemorrhage or periventricular leukomalacia). The associations between the NICU-level O/E PDA treatment ratio and neonatal outcomes were assessed using linear regression analyses including a quadratic effect (a square term) of the O/E PDA treatment ratio. RESULTS: From 139 NICUs, 39 096 infants were included. The overall PDA treatment rate was 45% in the cohort (13%-77% by NICU) and the O/E PDA treatment ratio ranged from 0.30 to 2.14. The relationship between the O/E PDA treatment ratio and primary composite outcome was U-shaped, with the nadir at a ratio of 1.13 and a significant quadratic effect (P<.001). U-shaped relationships were also identified with death, severe neurologic injury, and necrotizing enterocolitis. CONCLUSIONS: Both low and high PDA treatment rates were associated with death or severe neurologic injury, whereas a moderate approach was associated with optimal outcomes.

Predictors of Early Extubation after Patent Ductus Arteriosus Ligation among Infants Born Extremely Preterm Dependent on Mechanical Ventilation.

We conducted a retrospective study of 166 ventilator-dependent neonates born extremely preterm in whom patent ductus arteriosus was surgically ligated and evaluated the association of preoperative characteristics and time-to-successful postoperative extubation. Larger patent ductus arteriosus diameter ([>2.5 mm], adjusted hazard ratio 0.51, 95% CI 0.36-0.72) and left-ventricular dilatation (z score ≥2, adjusted hazard ratio 0.61, 95% CI 0.42-0.87) were associated with earlier extubation.

Relationship of Patent Ductus Arteriosus Size to Echocardiographic Markers of Shunt Volume.

OBJECTIVE: To define the technique of estimating ductal diameter (DD) that best correlates with echocardiographic markers of transductal shunt volume in preterm infants >7 days old with persistent patent ductus arteriosus (PDA). STUDY DESIGN: We conducted a retrospective study of 104 neonates born at <30 weeks gestation that had targeted neonatal echocardiography evaluation of PDA performed between 7 and 30 days. We used univariate analysis to determine the association of echocardiographic markers of shunt volume with ductal size definitions: DD, DD indexed to weight, and DD indexed to left pulmonary artery diameter. RESULTS: Two hundred echocardiograms were reviewed from 104 patients with a median gestational age of 25.4 weeks (range, 25-26.3 weeks) and a median birth weight of 810 g (range, 740-920 g). We found a weak correlation of each method of PDA size definition with individual echocardiographic markers of transductal shunt volume, of which nonindexed DD demonstrated the best correlation. The best correlation was found with markers of systemic hypoperfusion, such as diastolic flow reversal in the descending aorta (R2 = 0.24) and celiac artery (R2 = 0.21). Markers of pulmonary overcirculation, such as left ventricular end-diastolic diameter (R2 = 0.19) and left ventricular output (R2 = 0.17), showed fair correlation with nonindexed DD. CONCLUSION: In preterm infants >7 days old with PDA, nonindexed DD demonstrated weak correlations with individual echocardiographic markers of shunt volume. These data highlight the need for comprehensive echocardiographic evaluation in addition to diameter measurements to provide a better understanding of the hemodynamic consequences of PDA.

Cardiopulmonary Adaptation During First Day of Life in Human Neonates.

OBJECTIVE: To characterize the natural history of cardiopulmonary physiology in the first 24 hours after birth. STUDY DESIGN: A prospective observational study of healthy newborns was conducted at a large tertiary perinatal center. Echocardiography was performed at <0.5, 2-3, 7-10, and 22-24 hours of age. Specifically, assessment of pulmonary vascular resistance (PVR) (pulmonary artery acceleration time [PAAT], right ventricular ejection time, right ventricular ejection time:PAAT [PVR index], and PAAT indexed to heart rate [PAATi]), ventricular outputs (right and left), and ventricular function (tricuspid annular planar excursion, right ventricular [RV] fractional area change [FAC], RV/left ventricular [LV] global peak longitudinal strain, and LV ejection fraction) were performed. One-way repeated-measures ANOVA analysis was performed for time-dependent variables. RESULTS: In total, 15 neonates (9 males), born at 40 ± 0.8 weeks and 3.5 ± 0.5 kg, respectively, were studied. We observed increased PAATi (P < .05) by 2-3 hours, followed by a subsequent decline in all indices of PVR (PVR index, PAATi, midsystolic notching, and right-to-left ductal flow [P < .0001]). Although right and left ventricular stroke volume increased over the study interval (P < .001), LV output remained stable. All indices of RV function (tricuspid annular planar excursion, RV fractional area change 4-chamber, and RV global peak longitudinal strain-3 chamber [P < .001]) increased during the study interval. CONCLUSION: The immediate transition after birth is characterized by lower PVR, reversal of the transductal shunt, and increased biventricular stroke volume. The differential adaptive response of the RV and LV is novel and may relate to loading conditions and patent ductus arteriosus closure.

Outcomes of Surgical Ligation after Unsuccessful Pharmacotherapy for Patent Ductus Arteriosus in Neonates Born Extremely Preterm.

A retrospective cohort study of neonates born extremely preterm with persistent patent ductus arteriosus after unsuccessful pharmacologic closure compared outcomes between 166 surgically ligated and 142 nonligated neonates. After adjustment for confounders, ligation was not associated with the composite outcome of death or neurodevelopmental impairment, neurodevelopmental impairment alone, chronic lung disease, or retinopathy of prematurity among survivors.

Left Ventricular Function in Healthy Term Neonates During the Transitional Period.

OBJECTIVES: To evaluate whether incorporating conventional, tissue Doppler imaging and speckle tracking echocardiography are reliable and can characterize changes in left ventricular (LV) function properly in healthy neonates in the early transitional newborn period. STUDY DESIGN: A prospective observational study was conducted in 50 healthy term neonates with a mean ± SD gestational age and birth weight of 39.3 ± 1.2 weeks and 3.5 ± 0.44 kg, respectively. All infants underwent serial echocardiograms at 15 ± 2 (day 1) and 35 ± 2 hours (day 2) of age. The LV dimensions and various functional indices including tissue Doppler imaging velocities and speckle tracking echocardiography-derived peak longitudinal strain, and systolic and diastolic strain rate were acquired and compared between time points. RESULTS: All measurements were feasible from each scan except speckle tracking echocardiography in 10% and 20% of images on days 1 and 2 of age, respectively. LV dimensions, but not functional measures, demonstrated a small to moderate positive correlation with birth weight. On day 2, a small reduction was observed in LV basal diameter, mitral valve inflow velocity time integral, and systolic velocity of the lateral wall and septum. Other indices remained unchanged. Tissue Doppler imaging-derived functional and flow-derived hemodynamic measures demonstrated the least measurement bias, and strain measurements demonstrated better reliability than strain rate, fractional shortening, and ejection fraction. CONCLUSION: The relative reliability of various echocardiographic indices to quantify LV function in neonates establish a normative dataset and provide evidence for their validity during the first 2 days of life.

Assessment and treatment of post patent ductus arteriosus ligation syndrome.

OBJECTIVE: To compare differences in tissue Doppler imaging, global longitudinal strain (GLS), and cardiac troponin T (cTnT) between infants with low (<200 mL/kg/min) and high (>200 mL/kg/min) left ventricular (LV) output 1 hour after duct ligation and assess the impact of milrinone treatment on cardiac output and myocardial performance. STUDY DESIGN: LV function was assessed preoperatively and 1 and 18 hours postoperatively. Infants were categorized into a low-output or a normal-output group based on the echocardiographic assessment of LV output at 1 hour. RESULTS: Thirty infants with a mean gestation of 25.3 weeks were enrolled. LV basal lateral S', basal septal S', and basal right ventricular S' were lower in the low-output group (n = 19) at 1 hour postoperatively, with no significant difference in GLS (low-output -10.3% vs high-output -14.4%, P >.05) or cTnT between the groups. Patients in the low-output group were treated with milrinone, and by 18 hours LV performance recovered to levels comparable with the high output group. cTnT values increased at 18 hours in the whole cohort with no significant difference between the groups. CONCLUSION: Tissue Doppler imaging and GLS provide novel insights and further characterization of myocardial performance immediately after patent ductus arteriosus ligation. A reduction in tissue Doppler-derived LV systolic velocity may further help in monitoring cardiac performance after patent ductus arteriosus ligation and for monitoring the effects of treatment.

Hypotension following patent ductus arteriosus ligation: the role of adrenal hormones.

OBJECTIVE: To test the hypothesis that an impaired adrenal response to stress might play a role in the hypotension that follows patent ductus arteriosus (PDA) ligation. STUDY DESIGN: We performed a multicenter study of infants born at <32 weeks' gestation who were about to undergo PDA ligation. Serum adrenal steroids were measured 3 times: before and after a cosyntropin (1.0 µg/kg) stimulation test (performed before the ligation), and at 10-12 hours after the ligation. A standardized approach for diagnosis and treatment of postoperative hypotension was followed at each site. A modified inotrope score (1 × dopamine [µg/kg/min] + 1 × dobutamine) was used to monitor the catecholamine support an infant received. Infants were considered to have catecholamine-resistant hypotension if their greatest inotrope score was >15. RESULTS: Of 95 infants enrolled, 43 (45%) developed hypotension and 14 (15%) developed catecholamine-resistant hypotension. Low postoperative cortisol levels were not associated with the overall incidence of hypotension after ligation. However, low cortisol levels were associated with the refractoriness of the hypotension to catecholamine treatment. In a multivariate analysis: the OR for developing catecholamine-resistant hypotension was OR 36.6, 95% CI 2.8-476, P = .006. Low cortisol levels (in infants with catecholamine-resistant hypotension) were not attributable to adrenal immaturity or impairment; their cortisol precursor concentrations were either low or unchanged, and their response to cosyntropin was similar to infants without catecholamine-resistant hypotension. CONCLUSION: Infants with low cortisol concentrations after PDA ligation are likely to develop postoperative catecholamine-resistant hypotension. We speculate that decreased adrenal stimulation, rather than an impaired adrenal response to stimulation, may account for the decreased production.

Use of targeted neonatal echocardiography to prevent postoperative cardiorespiratory instability after patent ductus arteriosus ligation.

OBJECTIVES: To investigate the value of targeted neonatal echocardiography (TnECHO) in predicting cardiorespiratory instability after patent ductus arteriosus (PDA) ligation, and to evaluate the impact of TnECHO-directed care. STUDY DESIGN: We reviewed serial echocardiography evaluations of 62 preterm infants after PDA ligation to investigate the relationship between indices of myocardial performance and postoperative cardiorespiratory instability. A predictive model was developed based on TnECHO criteria, with targeted initiation of intravenous milrinone. A comparative evaluation was performed between matched infants in the previous era (epoch 1; n=25) and current era (epoch 2; n=27) of TnECHO-guided treatment. RESULTS: Left ventricular output <200 mL/kg/min at 1 hour after PDA ligation was a sensitive predictor of systemic hypotension and the need for inotropes, and was used for initiation of i.v. milrinone infusion in epoch 2. Infants treated with milrinone had a lower incidence of ventilation failure (15% vs 48%; P=.02) and less need for inotropes (19% vs 56%; P=.01), and showed a trend toward improved oxygenation (P=.08). CONCLUSION: TnECHO facilitates early detection of infants at greatest risk for subsequent cardiorespiratory deterioration. Administration of milrinone to neonates with low cardiac output may lead to improved postoperative stability.