Impact of Early Hemodynamic Screening on Extremely Preterm Outcomes in a High-Performance Center.

Rationale: Increasing survival of extremely preterm infants with a stable rate of severe intraventricular hemorrhage represents a growing health risk for neonates. Objectives: To evaluate the role of early hemodynamic screening (HS) on the risk of death or severe intraventricular hemorrhage. Methods: All eligible patients 22-26+6 weeks' gestation born and/or admitted <24 hours postnatal age were included. As compared with standard neonatal care for control subjects (January 2010-December 2017), patients admitted in the second epoch (October 2018-April 2022) were exposed to HS using targeted neonatal echocardiography at 12-18 hours. Measurements and Main Results: A primary composite outcome of death or severe intraventricular hemorrhage was decided a priori using a 10% reduction in baseline rate to calculate sample size. A total of 423 control subjects and 191 screening patients were recruited with a mean gestation and birth weight of 24.7 ± 1.5 weeks and 699 ± 191 g, respectively. Infants born at 22-23 weeks represented 41% (n = 78) of the HS epoch versus 32% (n = 137) of the control subjects (P = 0.004). An increase in perinatal optimization (e.g., antepartum steroids) but with a decline in maternal health (e.g., increased obesity) was seen in the HS versus control epoch. A reduction in the primary outcome and each of severe intraventricular hemorrhage, death, death in the first postnatal week, necrotizing enterocolitis, and severe bronchopulmonary dysplasia was seen in the screening era. After adjustment for perinatal confounders and time, screening was independently associated with survival free of severe intraventricular hemorrhage (OR 2.09, 95% CI [1.19, 3.66]). Conclusions: Early HS and physiology-guided care may be an avenue to further improve neonatal outcomes; further evaluation is warranted.

Left ventricular function before and after percutaneous patent ductus arteriosus closure in preterm infants.

BACKGROUND: Definitive closure of the patent ductus arteriosus (PDA) is associated with significant changes in the loading conditions of the left ventricle (LV), which may lead to cardiovascular and respiratory instability. The objective of the study was to evaluate targeted neonatal echocardiography (TnECHO) characteristics and the clinical course of preterm infants ≤2 kg undergoing percutaneous PDA closure. METHODS: Retrospective cohort study of prospectively acquired pre- and post-closure TnECHOs to assess hemodynamic changes. Cardiorespiratory parameters in the first 24 h following PDA closure were also evaluated. RESULTS: Fifty patients were included with a mean age of 30.6 ± 9.6 days and weight of 1188 ± 280 g. LV global longitudinal strain decreased from -20.6 ± 2.6 to -14.9 ± 2.9% (p < 0.001) after 1 h. There was a decrease in LV volume loading, left ventricular output, LV systolic and diastolic parameters. Cardiorespiratory instability occurred in 24 (48%) [oxygenation failure in 44%] but systolic hypotension and/or need for cardiovascular medications was only seen in 6 (12%). Patients with instability had worse baseline respiratory severity score and lower post-closure early diastolic strain rates. CONCLUSIONS: Percutaneous PDA closure leads to a reduction in echocardiography markers of LV systolic/diastolic function. Post-closure cardiorespiratory instability is characterized primarily by oxygenation failure and may relate to impaired diastolic performance. IMPACT: Percutaneous patent ductus arteriosus closure leads to a reduction in echocardiography markers of left ventricular volume loading, cardiac output, and left ventricular systolic/diastolic function. Post-procedural cardiorespiratory instability is characterized primarily by oxygenation failure. Post-procedural cardiorespiratory instability may relate to impaired diastolic performance.

Novel Method of Calculating Pulse Pressure Variation to Predict Fluid Responsiveness to Transfusion in Very Low Birth Weight Infants.

A novel technique was used to calculate pulse pressure variation. The algorithm reliably predicted fluid responsiveness to transfusion, with a receiver operating characteristic area under the curve of 0.89. This technique may assist clinicians in the management of fluids and vasoactive medications for premature infants.

Creatinine filtration kinetics in critically Ill neonates.

BACKGROUND: Creatinine values are unreliable within the first weeks of life; however, creatinine is used most commonly to assess kidney function. Controversy remains surrounding the time required for neonates to clear maternal creatinine. METHODS: Eligible infants had multiple creatinine lab values and were admitted to the neonatal intensive care unit (NICU). A mathematical model was fit to the lab data to estimate the filtration onset delay, creatinine filtration half-life, and steady-state creatinine concentration for each subject. Infants were grouped by gestational age (GA) [(1) 22-27, (2) >27-32, (3) >32-37, and (4) >37-42 weeks]. RESULTS: A total of 4808 neonates with a mean GA of 34.4 ± 5 weeks and birth weight of 2.34 ± 1.1 kg were enrolled. Median (95% confidence interval) filtration onset delay for Group 1 was 4.3 (3.71, 4.89) days and was significantly different than all other groups (p < 0.001). Creatinine filtration half-life of Groups 1, 2, and 3 were significantly different from each other (p < 0.001). There was no difference in steady-state creatinine concentration among the groups. CONCLUSIONS: We quantified the observed kidney behavior in a large NICU population as a function of day of life and GA using creatinine lab results. These results can be used to interpret individual creatinine labs for infants to detect those most at risk for acute kidney injury. IMPACT: One of the largest cohorts of premature infants to describe the evolution of kidney development and function over their entire hospitalization. New concept introduced of the kidney filtration onset delay, the time needed for the kidney to begin clearance of creatinine, and that it can be used as an early indicator of kidney function. The smallest premature infants from 22 to 27 weeks gestation took the longest time to begin and complete maternal creatinine clearance. Clinicians can easily compare the creatinine level of their patient to the normative curves to improve understanding of kidney function at the bedside.

Critical Closing Pressure by Diffuse Correlation Spectroscopy in a Neonatal Piglet Model.

The critical closing pressure (CrCP) of the cerebral vasculature is the arterial blood pressure (ABP) at which cerebral blood flow (CBF) ceases. Because the ABP of preterm infants is low and close to the CrCP, there is often no CBF during diastole. Thus, estimation of CrCP may become clinically relevant in preterm neonates. Transcranial Doppler (TCD) ultrasound has been used to estimate CrCP in preterm infants. Diffuse correlation spectroscopy (DCS) is a continuous, noninvasive optical technique that measures microvascular CBF. Our objective was to compare and validate CrCP measured by DCS versus TCD ultrasound. Hemorrhagic shock was induced in 13 neonatal piglets, and CBF was measured continuously by both modalities. CrCP was calculated using a model of cerebrovascular impedance, and CrCP determined by the two modalities showed good correlation by linear regression, median r 2 = 0.8 (interquartile range (IQR) 0.71-0.87), and Bland-Altman analysis showed a median bias of -3.5 (IQR -4.6 to -0.28). This is the first comparison of CrCP determined by DCS versus TCD ultrasound in a neonatal piglet model of hemorrhagic shock. The difference in CrCP between the two modalities may be due to differences in vasomotor tone within the microvasculature of the cerebral arterioles versus the macrovasculature of a major cerebral artery.

Observed and calculated cerebral critical closing pressure are highly correlated in preterm infants.

BACKGROUND: Cerebrovascular critical closing pressure (CrCP) is the arterial blood pressure (ABP) at which cerebral blood flow ceases. Preterm ABP is low and close to CrCP. The diastolic closing margin (diastolic ABP minus CrCP) has been associated with intraventricular hemorrhage in preterm infants. CrCP is estimated from middle cerebral artery cerebral blood flow velocity (CBFV) and ABP waveforms. However, these estimations have not been validated due to a lack of gold standard. Direct observation of the CrCP in preterm infants with hypotension is an opportunity to validate synchronously estimated CrCP. METHODS: ABP and CBFV tracings were obtained from 24 extremely low birth weight infants. Recordings where diastolic CBFV was zero were identified. The gold standard CrCP was delineated using piecewise regression of ABP and CBFV values paired by rank ordering and then estimated using a published formula. The measured and estimated values were compared using linear regression and Bland-Altman analysis. RESULTS: Linear regression showed a high degree of correlation between measured and calculated CrCP (r2 = 0.93). CONCLUSIONS: This is the first study to validate a calculated CrCP by comparing it to direct measurements of CrCP from preterm infants when ABP is lower than CrCP.

Accuracy and reliability of qualitative echocardiography assessment of right ventricular size and function in neonates.

BACKGROUND: Subjective assessment of right ventricular (RV) function by neonatal echocardiography lacks validation. Incorrect diagnostic assignment in patients with suspected pulmonary hypertension (PH) may lead to unnecessary treatment or missed treatment opportunities. METHODS: Six evaluators (experts [n = 3], novice [n = 3]) were asked to independently rate RV characteristics (global function, dilation, and septal flattening) based on standardized echocardiography images. We randomly selected 60 infants, ≥35 weeks gestation at birth, of whom 30 were clinically unwell with acute pulmonary hypertension (aPH) and 30 were healthy controls. aPH was defined by echocardiography presence of right-left shunting across transitional shunts or elevated right ventricular systolic pressure as estimated by the magnitude of the regurgitant jet across the tricuspid valve with impaired oxygenation. Inter-rater comparative evaluation within groups and between groups was performed using Kappa statistics. RESULTS: Global agreement between evaluators for subjective assessment of RV function (0.3 [0.03], P < 0.001), size (0.14 [0.02], P < 0.001), and septal flattening (0.2 [0.02], P < 0.001) was uniformly poor. Agreement in RV function assessment was marginally better for both expert (0.32 [0.08], P < 0.001 vs 0.13 [0.081], and P < 0.001) and novice (0.4 [0.08], P < 0.001 vs 0.06 [0.07], and P < 0.001) evaluators. Overall, the diagnosis of aPH vs control was misclassified in 18% of cases. CONCLUSION: This study demonstrated significant variability in qualitative assessment of RV size and function by trained evaluators, regardless of level of expertise attained. The reliability of objective measures of RV hemodynamics requires prospective evaluation.

Elevated Diastolic Closing Margin Is Associated with Intraventricular Hemorrhage in Premature Infants.

OBJECTIVE: To determine whether the diastolic closing margin (DCM), defined as diastolic blood pressure minus critical closing pressure, is associated with the development of early severe intraventricular hemorrhage (IVH). STUDY DESIGN: A reanalysis of prospectively collected data was conducted. Premature infants (gestational age 23-31 weeks) receiving mechanical ventilation (n = 185) had ∼1-hour continuous recordings of umbilical arterial blood pressure, middle cerebral artery cerebral blood flow velocity, and PaCO2 during the first week of life. Models using multivariate generalized linear regression and purposeful selection were used to determine associations with severe IVH. RESULTS: Severe IVH (grades 3-4) was observed in 14.6% of the infants. Irrespective of the model used, Apgar score at 5 minutes and DCM were significantly associated with severe IVH. A clinically relevant 5-mm Hg increase in DCM was associated with a 1.83- to 1.89-fold increased odds of developing severe IVH. CONCLUSION: Elevated DCM was associated with severe IVH, consistent with previous animal data showing that IVH is associated with hyperperfusion. Measurement of DCM may be more useful than blood pressure in defining cerebral perfusion in premature infants.

Vasopressin versus dopamine for treatment of hypotension in extremely low birth weight infants: a randomized, blinded pilot study.

OBJECTIVE: To evaluate vasopressin vs dopamine as initial therapy in extremely low birth weight (ELBW) infants with hypotension during the first 24 hours of life. STUDY DESIGN: ELBW infants with hypertension ≤ 30 weeks' gestation and ≤ 24 hours old randomly received treatment with vasopressin or dopamine in a blinded fashion. Normotensive infants not receiving vasopressor support served as a comparison group. RESULTS: Twenty ELBW infants with hypertension received vasopressin (n = 10) or dopamine (n = 10), and 50 were enrolled for comparison. Mean gestational age was 25.6 ± 1.4 weeks and birth weight 705 ± 154 g. Response to vasopressin paralleled that of dopamine in time to adequate mean blood pressure (Kaplan-Meier curve, P = .986); 90% of infants in each treatment group responded with adequate blood pressure. The vasopressin group received fewer doses of surfactant (P < .05), had lower PaCO2 values (P < .05), and were not tachycardic (P < .001) during vasopressin administration, compared with the dopamine group. CONCLUSIONS: Vasopressin in ELBW infants as the initial agent for early hypotension appeared safe. This pilot study supports a larger randomized controlled trial of vasopressin vs dopamine therapy in ELBW infants with hypotension.

Trends in pharmacotherapy for neonatal hypotension.

OBJECTIVE: To determine trends in pharmacotherapy for neonatal hypotension in all infants and in extremely low birth weight (ELBW, birth weight 300-1000 g) infants. STUDY DESIGN: We queried the Pediatric Health Information System database for all infants ≤28 days with a diagnosis code for hypotension that were discharged between January 2001 and December 2012. Patients were excluded if they had complex congenital heart disease or cardiac surgery, sepsis or meningitis, or had extracorporeal membrane oxygenation. We determined trends in pharmacotherapy for hypotension in all infants and ELBW infants, an especially vulnerable group. RESULTS: A total of 8019 hypotensive infants met study criteria. The 2 most prescribed medications were dopamine (65.3%) and dobutamine (19.9%). For 1487 hypotensive ELBW infants, the 2 most prescribed medications were dopamine (83.4%) and hydrocortisone (33%). During the study period, the use of dobutamine decreased, and hydrocortisone and vasopressin use increased for all infants and for ELBW infants. CONCLUSIONS: Treatment of neonatal hypotension varies widely between institutions and individual practitioners, and pharmacotherapy for neonatal hypotension has changed over the past decade. Although dopamine and dobutamine were the most frequently used agents, their use has declined and the uses of hydrocortisone and vasopressin have increased.

Asphyxia, Therapeutic Hypothermia, and Pulmonary Hypertension.

Neonates with a perinatal hypoxic insult and subsequent neonatal encephalopathy are at risk of acute pulmonary hypertension (aPH) in the transitional period. The phenotypic contributors to aPH following perinatal asphyxia include a combination of hypoxic vasoconstriction of the pulmonary vascular bed, right heart dysfunction, and left heart dysfunction. Therapeutic hypothermia is the standard of care for neonates with moderate-to-severe hypoxic ischemic encephalopathy. This review summarizes the underlying risk factors, causes of aPH in neonates with perinatal asphyxia, discusses the unique phenotypical contributors to disease, and explores the impact of the initial insult and subsequent therapeutic hypothermia on aPH.

Echocardiography Assessment of Left Ventricular Function in Extremely Preterm Infants, Born at Less Than 28 Weeks' Gestation, With Bronchopulmonary Dysplasia and Systemic Hypertension.

BACKGROUND: The survival of smaller and more immature premature infants has been associated with lifelong cardiorespiratory comorbidities. Infants with bronchopulmonary dysplasia (BPD) undergo routine screening echocardiography to evaluate for development of chronic pulmonary hypertension, a late manifestation of pulmonary vascular disease. METHODS: Our aim was to evaluate left ventricular (LV) performance in infants with BPD and pulmonary vascular disease who developed systemic hypertension. We hypothesized that infants with hypertension were more likely to have impaired LV performance. We present a single-center cross-sectional study of premature infants born at less than 28 0/7 weeks' gestational age with a clinical diagnosis of BPD. Infants were categorized by the systolic arterial pressure (SAP) at time of echocardiography as hypertensive (SAP ≥90 mm Hg) or normotensive (SAP <90 mm Hg). Sixty-four patients were included. RESULTS: Infants with hypertension showed altered LV diastolic function with prolonged tissue Doppler imaging-derived isovolumic relaxation time (54.2 ± 5.1 vs 42.9 ± 8.2, P < .001), lower E:A, and higher E:e'. Indices of left heart volume/pressure loading (left atrium:aorta and LV end-diastolic volume [6.1 ± 2 vs 4.2 ± 1.2, P < .001]) were also higher in the hypertensive group. Finally, infants in the hypertensive group had higher pulmonary vascular resistance index (4.42 ± 1.1 vs 3.69 ± 0.8, P = .004). CONCLUSIONS: We conclude that extremely preterm infants with BPD who develop systemic hypertension are at risk of abnormal LV diastolic dysfunction. Increased pulmonary vascular resistance index in the hypertensive group may relate to pulmonary venous hypertension secondary to LV dysfunction. This is an important consideration in this cohort when selecting the physiologically most appropriate treatment.

Exposure to persistent hemodynamically significant patent ductus arteriosus is associated with retinopathy of prematurity.

BACKGROUND: Hemodynamically significant patent ductus arteriosus (hsPDA) shunt may predispose infants to retinopathy of prematurity (ROP) because of its higher preductal cardiac output and blood oxygen content, which may augment ocular oxygen delivery. METHODS: A retrospective cohort study of preterm infants, born at <27 weeks' gestation and admitted at <24h postnatal age to a large quaternary referral was conducted. The primary composite outcome was death at <32 weeks or moderate-to-severe ROP (≥stage 2 or requiring treatment) in either eye. Secondary outcomes included ROP requiring treatment, and any ROP. Univariate analysis of patient characteristics and outcomes was performed as well as logistic regression. A receiver operating characteristics curve was generated for the outcome of ROP ≥stage 2 or requiring treatment. RESULTS: A total of 91 patients were screened, of whom 86 (54 hsPDA, 32 controls) were eligible for inclusion. hsPDA patients were younger and lighter at birth and had a higher burden of hyperglycemia and respiratory illness. The rates of the composite outcome (death <32 weeks or moderate-to-severe ROP) and of any ROP were more frequent in the hsPDA group. hsPDA shunt exposure was independently associated with development of any ROP among survivors to assessment (P = 0.006). PDA cumulative exposure score of 78 (clinical equivalent = 7 days high-volume shunt exposure) predicts moderate-to-severe ROP with 80% sensitivity and 78% specificity. CONCLUSIONS: Among infants <27 weeks, hsPDA shunt is associated with increased risks of a composite outcome of death or moderate-to-severe ROP, as well as ROP of any stage. Shunt modulation as a strategy to reduce ROP represents a biologically plausible avenue for investigation.

Response categorization and outcomes in extremely premature infants born at 22-26 weeks gestation that received inhaled nitric oxide for hypoxic respiratory failure.

OBJECTIVE: To evaluate the outcomes of extremely premature infants who received inhaled nitric oxide(iNO) for hypoxic respiratory failure(HRF). STUDY DESIGN: Retrospective analysis of 107 infants born 22-26 weeks gestation who received iNO for HRF at a single institution. Infants were categorized as positive, negative, or no responders based on change in FiO2 or OI. Underlying physiology was determined using Echocardiography/Radiography/Biochemistry. RESULTS: 63% of infants had a positive response; they received iNO earlier and were more likely to have acute pulmonary hypertension(PH). Positive response correlated with decreased incidence of death or grade 3 BPD at 36 weeks postmenstrual age, as compared to a negative response. CONCLUSIONS: Extremely premature infants have a positive response rate to iNO comparable to term infants when used for PH in the transitional period. Infants with a negative response to iNO had worse outcomes, necessitating the determination of the underlying physiology of HRF prior to iNO initiation.

Patent ductus arteriosus (PDA) and response to late surfactant treatment in premature infants.

OBJECTIVE: To determine the clinical/echocardiography (ECHO) phenotype of patients with hypoxic respiratory failure (HRF) and response to late surfactant, according to patent ductus arteriosus (PDA) status. STUDY DESIGN: This retrospective study included infants ≤26+6 weeks gestation who received ≥1 surfactant dose after 6 postnatal days and where PDA status was available by ECHO. Response to surfactant was appraised based on change in respiratory severity score over 48 h. The relationship between PDA status and response to surfactant was evaluated via univariate analysis. RESULT: We studied late surfactant (n = 71 doses) administration in 35 preterm infants born at a mean weight and GA at birth were 595 g (508, 696) and 23.3 (22.7, 25) weeks, respectively of whom 16 (46%) had a diagnosis of PDA. Positive response to late surfactant treatment was independently associated with absence of PDA [OR 26 (2, 334), p = 0.01] whereas presence of PDA was independently associated with negative response [OR 12 (1.1, 126), p = 0.04]. CONCLUSIONS: In neonates ≤26+6 weeks gestation, with HRF, response to surfactant after postnatal day 6 is influenced by PDA status. Future trials should consider PDA status which may enhance diagnostic precision and refine patient selection for late surfactant treatment.

Training pathways and careers for neonatologists interested in cardiovascular care.

Neonatologists and neonatal-perinatal trainees continue to be invested in the cardiovascular care of the newborn, many focusing their careers in this area of expertise. Multiple formalized structured and non-structured training pathways have evolved for neonatologists caring for infants with congenital heart disease and other cardiovascular pathologies. Furthermore, the evolution of neonatal hemodynamic science over the past decade has also spawned a formal training pathway in hemodynamics consultation to enhance standard of care and guide the management of infants at risk for cardiovascular compromise. Neonatologists have also chosen to expand upon on their neonatology training with clinical and research exposure to enhance their roles in neonatal cardiovascular care, including fetal care consultation, delivery room management, and perioperative cardiac intensive care consultation. To provide insight and career guidance to interested neonatal trainees and early career physicians, this perspective article highlights several different pathways in the care of neonates with cardiovascular disease.

Efficacy of Low-Dose Epinephrine Continuous Infusion in Neonatal Intensive Care Unit Patients.

OBJECTIVES: Although epinephrine is used in the neonatal intensive care unit, few data exist on efficacy of doses <0.05 mcg/kg/min. This study evaluates the efficacy and safety of low-dose epinephrine continuous infusion at doses <0.05 mcg/kg/min in infants. METHODS: Single-center, retrospective review of hypotensive infants from 2011-2018. Charts were reviewed for initial and maximum epinephrine doses, additional vasoactive agents, short-term efficacy, and adverse effects. The primary outcome was percentage of patients initiated on low-dose epinephrine whose dose did not require titration to ≥0.05 mcg/kg/min. RESULTS: A total of 115 patients met study criteria with 131 distinct occurrences of low-dose epinephrine initiation. Most patients were unresponsive to other vasopressors at the time of epinephrine initiation. The median (IQR) starting dose of low-dose epinephrine was 0.01 (0.01-0.04) mcg/kg/min and median (IQR) maximum dose was 0.04 (0.02-0.08) mcg/kg/min. Fifty-five percent were responders. Patients in this cohort demonstrated significant improvement of blood pressure and urine output (p < 0.001) without adverse effects. CONCLUSIONS: Low-dose epinephrine infusion may be considered as an alternative treatment to standard starting doses in hypotensive neonatal intensive care unit patients.

Anatomic Concordance of Neonatologist-Performed Echocardiography as Part of Hemodynamics Consultation and Pediatric Cardiology.

BACKGROUND: Targeted neonatal echocardiography (TnECHO) performed by neonatologists as part of a hemodynamics consultation is increasingly being used in neonatal intensive care units. To minimize delays in obtaining physiologic data, first echocardiograms may be obtained by the neonatal hemodynamics team and reviewed afterward by a pediatric cardiologist. This practice has not been systematically evaluated. The aim of this study was to compare concordance between anatomic findings on TnECHO and pediatric cardiology reports. METHODS: This was a retrospective evaluation of 339 infants at low risk for congenital heart disease (CHD) admitted to two large referral centers with established neonatal hemodynamics programs who underwent comprehensive TnECHO as their first postnatal echocardiographic examinations. The protocol included comprehensive imaging of intracardiac anatomy, outflow tract concordance and integrity, aortic arch anatomy, pulmonary vein location and flow, and transitional shunts. The hemodynamics consultation note was compared with the cardiology report to determine anatomic concordance or major or minor discrepancies in all first studies. RESULTS: Anatomic concordance occurred in 97.9% (κ = 0.862; 95% CI, 0.762-0.962; P < .001). There were seven minor discrepancies (small muscular ventricular septal defects and coronary fistulas). The index population included 23 infants (6.7%) with CHD, of whom only one (0.3%) had a ductal-dependent lesion (coarctation of the aorta) which was correctly identified by both teams. CONCLUSIONS: The rate of major CHD in patients considered eligible for hemodynamics consultation was low, and there was high diagnostic concordance between trained neonatal hemodynamics specialists and pediatric cardiology. First echocardiograms obtained by subspecialty neonatologists may provide imaging of sufficient quality to evaluate a critically unwell neonate with low suspicion for critical CHD lesions. These results should not be extrapolated to infants in whom CHD is suspected. This study highlights the importance of formalized, rigorous, and standardized training for neonatologists with hemodynamics expertise who perform timely assessments using TnECHO.