Amish Jain

Diagnosis, Evaluation, and Management of Patent Ductus Arteriosus in Preterm Neonates

Patent ductus arteriosus (PDA) poses a diagnostic and therapeutic dilemma for clinicians. Diagnosis of persistent PDA and determination of its clinical and hemodynamic significance are challenging. Although the condition has been associated with substantial neonatal morbidities such as intraventricular hemorrhage, bronchopulmonary dysplasia, and necrotizing enterocolitis, most therapeutic approaches have failed to show improvement in these outcomes. As such, clinicians have tended toward conservative management strategies; however, the benefits and risks of such an approach are unclear. In this review, we explore various clinical diagnostic modalities, echocardiographic parameters for assessment of shunt presence, shunt volume and its effect on cardiovascular and hemodynamic status, and challenges in determining if a PDA is hemodynamically significant and clinically relevant. From the therapeutic aspect, we review current evidence on conservative, pharmacological, and mechanical (surgical or nonsurgical ligation) approaches to PDA closure. Dose, route, duration, and comparison of pharmacological strategies are reviewed, with implications for future research.

Non-invasive cardiac output monitoring in neonates using bioreactance: a comparison with echocardiography.

Objectives: Non-invasive cardiac output monitoring is a potentially useful clinical tool in the neonatal setting. Our aim was to evaluate a new method of non-invasive continuous cardiac output (CO) measurement (NICOM™) based on the principle of bioreactance in neonates. Methods: In this prospective observational study, 10 neonates underwent 97 paired NICOM and echocardiography (echo) assessments of left ventricular output (LVO). For each neonate, NICOM measurements of left ventricular stroke volume (SV) and LVO over a 2- to 4-hour period were correlated with blinded, simultaneous, discrete echo measurements of SV and LVO. The precision and accuracy of the NICOM monitor relative to echo during periods of steady state were assessed. Results: The infants’ median birth weight was 2.72 kg (IQR 1.56–3.23 kg, range 1.44–4.00) and their median gestation was 37 weeks (IQR 31–40 weeks, range 31–41). Median NICOM SV and LVO readings were consistently lower than echo (2.6 ml [IQR 1.4–3.2, range 0.6–5.3] vs. 3.5 ml [IQR 2.1–4.4, range 1.1–6.8], and 400 ml/min [IQR 233–476] vs. 559 ml/min [IQR 386–652], p < 0.001). The NICOM LVO readings were lower than the echo readings by a mean of 153 ± 56 ml/kg. NICOM consistently under-read LVO by 31 ± 8%, and this systematic difference was constant across the range of LVOs obtained. There was a strong correlation between NICOM and echo measurements of LVO (r = 0.95, p < 0.001). Conclusion: Non-invasive cardiac output monitoring is feasible in neonates. Further validation studies in neonatal animal experimental models and human neonates need to be conducted before routine clinical use.

Ligation of the Patent Ductus Arteriosus in Preterm Infants: Understanding the Physiology

T he diagnosis and management of preterm neonates with a patent ductus arteriosus (PDA) that fails to close after medical management poses a major challenge. The association of prolonged ductal patency withmorbidities including feeding intolerance, necrotizing enterocolitis (NEC), severe intraventricular hemorrhage (IVH), metabolic acidosis, renal failure, increased ventilator dependence, bronchopulmonary dysplasia (BPD), and pulmonary hemorrhage are well recognized. In addition, a PDA failing medical treatment is associated with a 4to 7-fold increase in mortality. This association remains significant after adjustment for gestation, birth weight, disease severity, and other comorbidities, including IVH, NEC, and sepsis. The decision to perform surgical PDA ligation has been challenged recently, owing to its possible association with adverse neurologic outcomes. Themagnitude of postoperative instability in some patients often dissuades neonatologists from choosing surgery. Neonatologists face uncertainty regarding the optimal approach to this patient population. In this article, we outline the concerns surrounding PDA ligation, review the selection process for intervention, and discuss the perioperative physiological changes that may explain the link between ligation and adverse neurodevelopmental outcomes. In addition, we propose a postoperative management strategy aimed at minimizing hemodynamic compromise after PDA ligation.

Assessment of myocardial performance in preterm infants less than 29 weeks gestation during the transitional period.

BACKGROUND The transitional circulation and its effect on myocardial performance are poorly understood in preterm infants. AIMS We assessed myocardial performance in infants less than 29 weeks gestation in the first 48 h of life using a comprehensive echocardiographic assessment. DESIGN Infants <29 weeks gestation were prospectively enrolled. Small for gestation, infants on inotropes and/or inhaled nitric oxide and septic infants were excluded. Conventional echocardiography, left ventricular (LV), septal and right ventricular (RV) tissue Doppler imaging (TDI) and tissue Doppler-derived strain and strain rate (SR), tricuspid annular plane systolic excursion (TAPSE) and global RV fractional area change (FAC) were assessed at a median of 10 and 45 h post-delivery. RESULTS Fifty-four infants with a median [IQR] gestation and birth weight of 26.5 weeks [25.8-28.0 weeks] and 915 g [758-1142 g] were included. There was no change in shortening or ejection fraction across the two time points. Systolic and diastolic TDI of the LV, septum and RV increased across the two time points (all p values ≤ 0.01). There was an increase in septal peak systolic and early diastolic SR (p=0.002). Septal systolic strain and late diastolic SR did not change. With the exception of RV strain and early diastolic SR, all RV functional parameters including SR, late diastolic SR, TAPSE, and FAC increased across the two time points (all p values<0.01). CONCLUSION Describing the normal hemodynamic adaptations in stable preterm infants during the transitional period provides the necessary information for the assessment of those parameters in various disease states.

Efficacy of paracetamol on patent ductus arteriosus closure may be dose dependent: evidence from human and murine studies

Background:We evaluated the clinical effectiveness of variable courses of paracetamol on patent ductus arteriosus (PDA) closure and examined its effect on the in vitro term and preterm murine ductus arteriosus (DA).Methods:Neonates received one of the following three paracetamol regimens: short course of oral paracetamol (SCOP), long course of oral paracetamol (LCOP), and intravenous paracetamol (IVP) for 2–6 d. Pressure myography was used to examine changes in vasomotor tone of the preterm and term mouse DA in response to paracetamol or indomethacin. Their effect on prostaglandin synthesis by DA explants was measured by mass spectroscopy.Results:Twenty-one preterm infants were included. No changes in PDA hemodynamics were seen in SCOP infants (n = 5). The PDA became less significant and eventually closed in six LCOP infants (n = 7). PDA closure was achieved in eight IVP infants (n = 9). On pressure myograph, paracetamol induced a concentration-dependent constriction of the term mouse DA, up to 30% of baseline (P < 0.01), but required >1 µmol/l. Indomethacin induced greater DA constriction and suppression of prostaglandin synthesis (P < 0.05).Conclusion:The clinical efficacy of paracetamol on PDA closure may depend on the duration of treatment and the mode of administration. Paracetamol is less potent than indomethacin for constriction of the mouse DA in vitro.Pediatric Research (2014); 76 3, 238–244. doi:10.1038/pr.2014.82

Peripherally inserted central catheter tip position and risk of associated complications in neonates

Objective:To characterize the relationship between peripherally inserted central catheters (PICC) tip positions and associated complications in neonates.Study Design:Catheter tip position for 319 infants was classified into superior vena cava (SVC, n=131), inferior vena cava (IVC, n=72), brachiocephalic (BC, n=59), midclavicular (MC, n=49) or iliac. Duration of catheter stay and complication profile was compared between central (SVC/IVC) vs non-central PICC, and between SVC vs IVC, SVC vs BC and SVC vs MC. Kaplan–Meier survival analysis and regression models were used.Result:Overall length of catheter stay was similar between central and non-central group. Non-central catheters (n=116) had higher complication rates (47 vs 29%; P=0.001), non-elective removals (45 vs 27%; P=0.002) and shorter time to complication (6.2 vs 11.4 days; P=0.043). This difference was primarily due to the complications encountered in MC group, which had the highest rate of infiltration (P<0.001) and mechanical complications while outcomes were similar among other subgroups. Interestingly, catheter survival probability was similar in all groups for first 4 days. Rate and types of blood stream infections were not related to catheter tip position.Conclusion:Non-central PICCs are associated with higher rates of infiltration and mechanical complications when the tip is in MC region. BC catheters may have comparable outcomes to SVC in neonates. A careful risk-benefit analysis is warranted when MC catheters are used in neonates.

Therapeutic hypercapnia prevents bleomycin-induced pulmonary hypertension in neonatal rats by limiting macrophage-derived tumor necrosis factor-α

Bleomycin-induced lung injury is characterized in the neonatal rat by inflammation, arrested lung growth, and pulmonary hypertension (PHT), as observed in human infants with severe bronchopulmonary dysplasia. Inhalation of CO(2) (therapeutic hypercapnia) has been described to limit cytokine production and to have anti-inflammatory effects on the injured lung; we therefore hypothesized that therapeutic hypercapnia would prevent bleomycin-induced lung injury. Spontaneously breathing rat pups were treated with bleomycin (1 mg/kg/d ip) or saline vehicle from postnatal days 1-14 while being continuously exposed to 5% CO(2) (Pa(CO(2)) elevated by 15-20 mmHg), 7% CO(2) (Pa(CO(2)) elevated by 35 mmHg), or normocapnia. Bleomycin-treated animals exposed to 7%, but not 5%, CO(2), had significantly attenuated lung tissue macrophage influx and PHT, as evidenced by normalized pulmonary vascular resistance and right ventricular systolic function, decreased right ventricular hypertrophy, and attenuated remodeling of pulmonary resistance arteries. The level of CO(2) neither prevented increased tissue neutrophil influx nor led to improvements in decreased lung weight, septal thinning, impaired alveolarization, or decreased numbers of peripheral arteries. Bleomycin led to increased expression and content of lung tumor necrosis factor (TNF)-α, which was found to colocalize with tissue macrophages and to be attenuated by exposure to 7% CO(2). Inhibition of TNF-α signaling with the soluble TNF-2 receptor etanercept (0.4 mg/kg ip from days 1-14 on alternate days) prevented bleomycin-induced PHT without decreasing tissue macrophages and, similar to CO(2), had no effect on arrested alveolar development. Our findings are consistent with a preventive effect of therapeutic hypercapnia with 7% CO(2) on bleomycin-induced PHT via attenuation of macrophage-derived TNF-α. Neither tissue macrophages nor TNF-α appeared to contribute to arrested lung development induced by bleomycin. That 7% CO(2) normalized pulmonary vascular resistance and right ventricular function without improving inhibited airway and vascular development suggests that vascular hypoplasia does not contribute significantly to functional changes of PHT in this model.

Association of Patent Ductus Arteriosus Ligation With Death or Neurodevelopmental Impairment Among Extremely Preterm Infants

Importance Observational studies have associated patent ductus arteriosus (PDA) ligation among preterm infants with adverse neonatal outcomes and neurodevelopmental impairment in early childhood, with a resultant secular trend away from surgical treatment. However, to our knowledge, studies have inadequately addressed sources of residual bias, including survival bias and major neonatal morbidities arising before exposure to ligation. Objective Evaluate the association between PDA ligation vs medical management and neonatal and neurodevelopmental outcomes. Design, Setting, and Participants This retrospective cohort study of preterm infants younger than 28 weeks gestational age born between January 1, 2006, and December 31, 2012, with clinical and echocardiography diagnoses of hemodynamically significant PDA was conducted at 3 tertiary neonatal intensive care units and affiliated follow-up programs. Exposure Surgical ligation vs medical management. Main Outcomes and Measures The primary outcome was a composite of death or neurodevelopmental impairment (NDI) at 18 to 24 months corrected age. Secondary outcomes included death before discharge, NDI, moderate-severe chronic lung disease, and severe retinopathy of prematurity. Multivariable logistic regression analysis was used to adjust for perinatal and postnatal confounders. Results Of 754 infants with hemodynamically significant PDA (mean [standard deviation] gestational age 25.7 [1.2] weeks and birth weight 813 [183] grams), 184 (24%) underwent ligation. Infants who underwent ligation had a higher frequency of morbidities before PDA closure, including sepsis, necrotizing enterocolitis, and a dependence on mechanical ventilation. After adjusting for perinatal characteristics and preligation morbidities, there was no difference in the odds of death or NDI (adjusted odds ratio (aOR), 0.83; 95% CI, 0.52-1.32), NDI (aOR, 1.27; 95% CI, 0.78-2.06), chronic lung disease (aOR, 1.36; 95% CI, 0.78-2.39) or severe retinopathy of prematurity (aOR, 1.61; 95% CI, 0.85-3.06). Ligation was associated with lower odds of mortality (aOR, 0.09; 95% CI, 0.04-0.21). Conclusions and Relevance Patent ductus arteriosus ligation among preterm neonates younger than 28 weeks gestational age was not associated with the composite outcome of death or NDI, and there were no differences in chronic lung disease, retinopathy of prematurity, or NDI among survivors. Mortality was lower among infants who underwent ligation, though residual survival bias could not be excluded. Previously reported associations of ligation with increased morbidity may be because of bias from confounding by indication.

Sustained therapeutic hypercapnia attenuates pulmonary arterial Rho-kinase activity and ameliorates chronic hypoxic pulmonary hypertension in juvenile rats.

Sustained therapeutic hypercapnia prevents pulmonary hypertension in experimental animals, but its rescue effects on established disease have not been studied. Therapies that inhibit Rho-kinase (ROCK) and/or augment nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) signaling can reverse or prevent progression of chronic pulmonary hypertension. Our objective in the present study was to determine whether sustained rescue treatment with inhaled CO(2) (therapeutic hypercapnia) would improve structural and functional changes of chronic hypoxic pulmonary hypertension. Spontaneously breathing pups were exposed to normoxia (21% O(2)) or hypoxia (13% O(2)) from postnatal days 1-21 with or without 7% CO(2) (Pa(CO(2)) elevated by ∼25 mmHg) or 10% CO(2) (Pa(CO(2)) elevated by ∼40 mmHg) from days 14 to 21. Compared with hypoxia alone, animals exposed to hypoxia and 10% CO(2) had significantly (P < 0.05) decreased pulmonary vascular resistance, right-ventricular systolic pressure, right-ventricular hypertrophy, and medial wall thickness of pulmonary resistance arteries as well as decreased lung phosphodiesterase (PDE) V, RhoA, and ROCK activity. Rescue treatment with 10% CO(2), or treatment with a ROCK inhibitor (15 mg/kg ip Y-27632 twice daily from days 14 to 21), also increased pulmonary arterial endothelial nitric oxide synthase and lung NO content. In contrast, cGMP content and cGMP-dependent protein kinase (PKG) activity were increased by exposure to 10% CO(2), but not by ROCK inhibition with Y-27632. In vitro exposure of pulmonary artery smooth muscle cells to hypercapnia suppressed serum-induced ROCK activity, which was prevented by inhibition of PKG with Rp-8-Br-PET-cGMPS. We conclude that sustained hypercapnia dose-dependently inhibited ROCK activity, augmented NO-cGMP-PKG signaling, and led to partial improvements in the hemodynamic and structural abnormalities of chronic hypoxic PHT in juvenile rats. Increased PKG content and activity appears to play a major upstream role in CO(2)-induced suppression of ROCK activity in pulmonary arterial smooth muscle.

Non-Invasive Cardiac Output Monitoring in Preterm Infants Undergoing Patent Ductus Arteriosus Ligation: A Comparison with Echocardiography

Background: Non-invasive cardiac output monitoring (NICOM; NICOM™) may be useful in the management of extremely premature preterm infants. Objectives: To evaluate a new bioreactance-based method of continuous NICOM in preterm infants following patent ductus arteriosus (PDA) ligation. Methods: Infants underwent three paired NICOM and echocardiography assessments of stroke volume (SV) and left ventricular output (LVO) in the postoperative period: at 1, 6-8, and 16-18 h postoperatively. NICOM- and echocardiography-measured SV and LVO during those periods were compared using Bland-Altman analysis and the intraclass correlation coefficient (ICC). Results: Twenty-five infants with a median (interquartile range) gestational age and birth weight of 25.0 weeks (24.5-25.9) and 700 g (615-775), respectively, were included. The overall systematic bias (limits of agreement) across all time points between the NICOM and echocardiography SV readings was 39% (8-69) with NICOM consistently underestimating echocardiography values. There was moderate consistency between NICOM and echocardiography SV values (ICC 0.78, p < 0.001). Compared with the 1-hour scans, the 6- to 8- and 16- to 18-hour scans had increased biases of 7.9% (95% CI 2.5-13.2) and 9.7% (95% CI 3.6-15.8), respectively. Conclusion: Continuous LVO measurement using NICOM was feasible and demonstrated a consistent systematic bias compared with echocardiography in unstable extremely preterm infants without a PDA ligation. NICOM may be used as a trending tool for continuous monitoring in this population, but wide limits of agreement and increasing bias over time suggest it is not interchangeable with echocardiography.