Umbilical cannulation optimizes circuit flows in premature lambs supported by the EXTra-uterine Environment for Neonatal Development (EXTEND).

KEY POINTS: Bronchopulmonary dysplasia is a disease of extreme prematurity that occurs when the immature lung is exposed to gas ventilation. We designed a novel 'artificial womb' system for supporting extreme premature lambs (called EXTEND) that obviates gas ventilation by providing oxygen via a pumpless arteriovenous circuit with the lamb submerged in sterile artificial amniotic fluid. In the present study, we compare different arteriovenous cannulation strategies on EXTEND, including carotid artery/jugular vein (CA/JV), carotid artery/umbilical vein (CA/UV) and umbilical artery/umbilical vein (UA/UV). Compared to CA/JV and CA/UV cannulation, UA/UV cannulation provided significantly higher, physiological blood flows to the oxygenator, minimized flow interruptions and supported significantly longer circuit runs (up to 4 weeks). Physiological circuit blood flow in UA/UV lambs made possible normal levels of oxygen delivery, which is a critical step toward the clinical application of artificial womb technology. ABSTRACT: EXTEND (EXTra-uterine Environment for Neonatal Development) is a novel system that promotes physiological development by maintaining the premature lamb in a sterile fluid environment and providing gas exchange via a pumpless arteriovenous oxygenator circuit. During the development of EXTEND, different cannulation strategies evolved with the aim of improving circuit flow. The present study examines how different cannulation strategies affect EXTEND circuit haemodynamics in extreme premature lambs. Seventeen premature lambs were cannulated at gestational ages 105-117 days (term 145-150 days) and supported on EXTEND for up to 4 weeks. Experimental groups were distinguished by cannulation strategy: carotid artery outflow and jugular vein inflow (CA/JV; n = 4), carotid artery outflow and umbilical vein inflow (CA/UV; n = 5) and double umbilical artery outflow and umbilical vein inflow (UA/UV; n = 8). Circuit flows and pressures were measured continuously. As we transitioned from CA/JV to CA/UV to UA/UV cannulation, mean duration of circuit run and weight-adjusted circuit flows increased (P < 0.001) and the frequency of flow interruptions declined (P < 0.05). Umbilical vessels generally accommodated larger-bore cannulas, and cannula calibre was directly correlated with circuit pressures and indirectly correlated with flow:pressure ratio (a measure of post-membrane resistance). We conclude that UA/UV cannulation in fetal lambs on EXTEND optimizes circuit flow dynamics and flow stability and also supports circuit flows that closely approximate normal placental flow.

Car Seat Tolerance Screening in the Neonatal Intensive Care Unit: Failure Rates, Risk Factors, and Adverse Outcomes.

OBJECTIVE: To characterize the epidemiology of Car Seat Tolerance Screening (CSTS) failure and the association between test failure and all-cause 30-day postdischarge mortality or hospital readmission in a large, multicenter cohort of preterm infants receiving neonatal intensive care. STUDY DESIGN: This retrospective cohort study used the prospectively collected Optum Neonatal Database. Study infants were born at <37 weeks of gestation between 2010 and 2016. We identified independent predictors of CSTS failure and calculated the risk-adjusted odds of all-cause 30-day mortality or hospital readmission associated with test failure. RESULTS: Of 7899 infants cared for in 788 hospitals, 334 (4.2%) failed initial CSTS. Greater postmenstrual age at testing and African American race were independently associated with decreased failure risk. Any treatment with an antacid medication, concurrent use of caffeine or supplemental oxygen, and a history of failing a trial off respiratory support were associated with increased failure risk. The mean adjusted post-CSTS duration of hospitalization was 3.1 days longer (95% CI, 2.7-3.6) among the infants who failed the initial screening. Rates of 30-day all-cause mortality or readmission were higher among infants who failed the CSTS (2.4% vs 1.0%; P = .03); however, the difference was not significant after confounder adjustment (OR, 0.38; 95% CI, 0.11-1.31). CONCLUSION: CSTS failure was associated with longer post-test hospitalization but no difference in the risk-adjusted odds for 30-day mortality or hospital readmission. Whether CSTS failure unnecessarily prolongs hospitalization or results in appropriate care that prevents adverse postdischarge outcomes is unknown. Further research is needed to address this knowledge gap.

Association between Use of Prophylactic Indomethacin and the Risk for Bronchopulmonary Dysplasia in Extremely Preterm Infants.

OBJECTIVE: To assess the association between prophylactic indomethacin and bronchopulmonary dysplasia (BPD) in a recent, large cohort of extremely preterm infants. STUDY DESIGN: Retrospective cohort study using prospectively collected data for infants with gestational ages < 29 weeks or birth weights of 401-1000 g born between 2008 and 2012 at participating hospitals of the National Institute of Child Health and Human Development Neonatal Research Network. Infants treated with indomethacin in the first 24 hours of life were compared with those who were not. Study outcomes were BPD, defined as use of supplemental oxygen at 36 weeks postmenstrual age among survivors to that time point, death, and the composite of death or BPD. Prespecified subgroup analyses were performed. RESULTS: Prophylactic indomethacin use varied by hospital. Treatment of a patent ductus arteriosus after the first day of life was less common among 2587 infants who received prophylactic indomethacin compared with 5244 who did not (21.0% vs 36.1%, P < .001). After adjustment for potential confounders, use of prophylactic indomethacin was not associated with higher or lower odds of BPD (OR 0.89, 95% CI 0.72-1.10), death (OR 0.80, 95% CI 0.64-1.01), or death or BPD (OR 0.87, 95% CI 0.71-1.05). The only evidence of subgroup effects associated with prophylactic indomethacin were lower odds of death among infants with birth weights above the 10th percentile and those who were not treated for a patent ductus arteriosus after the first day of life. CONCLUSIONS: Prophylactic indomethacin was not associated with either reduced or increased risk for BPD or death. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00063063.

The Association between Positive Tracheal Aspirate Cultures and Adverse Pulmonary Outcomes in Preterm Infants with Severe Bronchopulmonary Dysplasia.

Objective Bacterial colonization of the airway may contribute to the development of bronchopulmonary dysplasia. Whether airway colonization increases risk for later adverse respiratory outcomes is less clear. We described tracheal aspirate culture results obtained from preterm infants receiving mechanical ventilation at 36 weeks postmenstrual age (PMA) and evaluated the association between bacteria type and the risk for prolonged supplemental oxygen use. Study Design We conducted a retrospective, single-center cohort study comparing infants (1) with and without a tracheal aspirate culture that grew a Gram-negative rod (GNR) and (2) with and without a culture that grew a Gram-positive cocci (GPC). Results Among 121 infants, 65 (53.7%) and 51 (42.2%) had a tracheal aspirate culture that grew a potentially pathogenic GNR and GPC prior to 36 weeks PMA, respectively. GNR were associated with increased risk for death or use of supplemental oxygen at discharge (adjusted odds ratio [aOR], 6.2; 95% confidence interval [CI], 1.8-21.1), and use of supplemental oxygen at discharge among survivors (aOR, 5.5; 95% CI, 1.6-19.0). GPC did not affect the risk for any study outcomes. Conclusion GNR but not GPC in the airways of preterm infants receiving mechanical ventilation at 36 weeks PMA is associated with increased risk for prolonged supplemental oxygen use.

High Flow Nasal Cannula Use Is Associated with Increased Morbidity and Length of Hospitalization in Extremely Low Birth Weight Infants.

OBJECTIVE: To determine differences in the incidence of bronchopulmonary dysplasia (BPD) or death in extremely low birth weight infants managed on high flow nasal cannula (HFNC) vs continuous positive airway pressure (CPAP). STUDY DESIGN: This is a retrospective data analysis from the Alere Neonatal Database for infants born between January 2008 and July 2013, weighing ≤1000 g at birth, and received HFNC or CPAP. Baseline demographics, clinical characteristics, and neonatal outcomes were compared between the infants who received CPAP and HFNC, or HFNC ± CPAP. Multivariable regression analysis was performed to control for the variables that differ in bivariate analysis. RESULTS: A total of 2487 infants met the inclusion criteria (941 CPAP group, 333 HFNC group, and 1546 HFNC ± CPAP group). The primary outcome of BPD or death was significantly higher in the HFNC group (56.8%) compared with the CPAP group (50.4%, P < .05). Similarly, adjusted odds of developing BPD or death was greater in the HFNC ± CPAP group compared with the CPAP group (OR 1.085, 95% CI 1.035-1.137, P = .001). The number of ventilator days, postnatal steroid use, days to room air, days to initiate or reach full oral feeds, and length of hospitalization were significantly higher in the HFNC and HFNC ± CPAP groups compared with the CPAP group. CONCLUSIONS: In this retrospective study, use of HFNC in extremely low birth weight infants is associated with a higher risk of death or BPD, increased respiratory morbidities, delayed oral feeding, and prolonged hospitalization. A large clinical trial is needed to evaluate long-term safety and efficacy of HFNC in preterm infants.

Effect of depth and duration of cooling on deaths in the NICU among neonates with hypoxic ischemic encephalopathy: a randomized clinical trial.

IMPORTANCE: Hypothermia at 33.5°C for 72 hours for neonatal hypoxic ischemic encephalopathy reduces death or disability to 44% to 55%; longer cooling and deeper cooling are neuroprotective in animal models. OBJECTIVE: To determine if longer duration cooling (120 hours), deeper cooling (32.0°C), or both are superior to cooling at 33.5°C for 72 hours in neonates who are full-term with moderate or severe hypoxic ischemic encephalopathy. DESIGN, SETTING, AND PARTICIPANTS: A randomized, 2 × 2 factorial design clinical trial performed in 18 US centers in the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network between October 2010 and November 2013. INTERVENTIONS: Neonates were assigned to 4 hypothermia groups; 33.5°C for 72 hours, 32.0°C for 72 hours, 33.5°C for 120 hours, and 32.0°C for 120 hours. MAIN OUTCOMES AND MEASURES: The primary outcome of death or disability at 18 to 22 months is ongoing. The independent data and safety monitoring committee paused the trial to evaluate safety (cardiac arrhythmia, persistent acidosis, major vessel thrombosis and bleeding, and death in the neonatal intensive care unit [NICU]) after the first 50 neonates were enrolled, then after every subsequent 25 neonates. The trial was closed for emerging safety profile and futility analysis after the eighth review with 364 neonates enrolled (of 726 planned). This report focuses on safety and NICU deaths by marginal comparisons of 72 hours' vs 120 hours' duration and 33.5°C depth vs 32.0°C depth (predefined secondary outcomes). RESULTS: The NICU death rates were 7 of 95 neonates (7%) for the 33.5°C for 72 hours group, 13 of 90 neonates (14%) for the 32.0°C for 72 hours group, 15 of 96 neonates (16%) for the 33.5°C for 120 hours group, and 14 of 83 neonates (17%) for the 32.0°C for 120 hours group. The adjusted risk ratio (RR) for NICU deaths for the 120 hours group vs 72 hours group was 1.37 (95% CI, 0.92-2.04) and for the 32.0°C group vs 33.5°C group was 1.24 (95% CI, 0.69-2.25). Safety outcomes were similar between the 120 hours group vs 72 hours group and the 32.0°C group vs 33.5°C group, except major bleeding occurred among 1% in the 120 hours group vs 3% in the 72 hours group (RR, 0.25 [95% CI, 0.07-0.91]). Futility analysis determined that the probability of detecting a statistically significant benefit for longer cooling, deeper cooling, or both for NICU death was less than 2%. CONCLUSIONS AND RELEVANCE: Among neonates who were full-term with moderate or severe hypoxic ischemic encephalopathy, longer cooling, deeper cooling, or both compared with hypothermia at 33.5°C for 72 hours did not reduce NICU death. These results have implications for patient care and design of future trials. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01192776.

Echocardiographic Assessment of Pulmonary Arterial Hypertension Following Inhaled Nitric Oxide in Infants with Severe Bronchopulmonary Dysplasia.

OBJECTIVES: Inhaled nitric oxide (iNO) is an effective pulmonary vasodilator. However, the efficacy of iNO in former premature infants with established bronchopulmonary dysplasia (BPD) has not been studied. This study aimed to determine the efficacy of iNO in reducing pulmonary artery pressure in infants with severe BPD as measured by echocardiography. STUDY DESIGN: Prospective, observational study enrolling infants born at less than 32 weeks gestation and in whom (1) iNO therapy was initiated after admission to our institution, or (2) at the outside institution less than 48 h before transfer and received an echocardiogram prior to iNO initiation, and (3) had severe BPD. Data were collected at three time-points: (1) before iNO; (2) 12-48 h after initiation of iNO; and (3) 48-168 h after initiation of iNO. The primary outcome was the effect of iNO on pulmonary artery pressure measured by echocardiography in patients with severe BPD between 48 and 168 h after initiating iNO therapy. RESULTS: Of 37 enrolled, 81% had echocardiographic evidence of pulmonary arterial hypertension (PAH) before iNO and 56% after 48 h of iNO (p = 0.04). FiO2 requirements were significantly different between time-points (1) and (3) (p = 0.05). There were no significant differences between Tricuspid Annular Plane Systolic Excursion (TAPSE) Z-Scores, time to peak velocity: right ventricular ejection time (TPV:RVET), and ventilator changes. CONCLUSIONS: Although we found a statistically significant reduction of PAH between time-point (1) and (3), future trials are needed to further guide clinical care.

Assessment of Corticosteroid Therapy and Death or Disability According to Pretreatment Risk of Death or Bronchopulmonary Dysplasia in Extremely Preterm Infants.

Importance: Meta-analyses suggest that corticosteroids may be associated with increased survival without cerebral palsy in infants at high risk of bronchopulmonary dysplasia (BPD) but are associated with adverse neurologic outcomes in low-risk infants. Whether this association exists in contemporary practice is uncertain because most randomized clinical trials administered corticosteroids earlier and at higher doses than currently recommended. Objective: To evaluate whether the pretreatment risk of death or grade 2 or 3 BPD at 36 weeks' postmenstrual age modified the association between postnatal corticosteroid therapy and death or disability at 2 years' corrected age in extremely preterm infants. Design, Setting, and Participants: This cohort study analyzed data on 482 matched pairs of infants from 45 participating US hospitals in the National Institute of Child Health and Human Development Neonatal Research Network Generic Database (GDB). Infants were included in the cohort if they were born at less than 27 weeks' gestation between April 1, 2011, and March 31, 2017; survived the first 7 postnatal days; and had 2-year death or developmental follow-up data collected between January 2013 and December 2019. Corticosteroid-treated infants were propensity score matched with untreated controls. Data were analyzed from September 1, 2019, to November 30, 2022. Exposure: Systemic corticosteroid therapy to prevent BPD that was initiated between day 8 and day 42 after birth. Main Outcomes and Measures: The primary outcome was death or moderate to severe neurodevelopmental impairment at 2 years' corrected age. The secondary outcome was death or moderate to severe cerebral palsy at 2 years' corrected age. Results: A total of 482 matched pairs of infants (mean [SD] gestational age, 24.1 [1.1] weeks]; 270 males [56.0%]) were included from 656 corticosteroid-treated infants and 2796 potential controls. Most treated infants (363 [75.3%]) received dexamethasone. The risk of death or disability associated with corticosteroid therapy was inversely associated with the estimated pretreatment probability of death or grade 2 or 3 BPD. The risk difference for death or neurodevelopmental impairment associated with corticosteroids decreased by 2.7% (95% CI, 1.9%-3.5%) for each 10% increase in the pretreatment risk of death or grade 2 or 3 BPD. This risk transitioned from estimated net harm to benefit when the pretreatment risk of death or grade 2 or 3 BPD exceeded 53% (95% CI, 44%-61%). For death or cerebral palsy, the risk difference decreased by 3.6% (95% CI, 2.9%-4.4%) for each 10% increase in the risk of death or grade 2 or 3 BPD and transitioned from estimated net harm to benefit at a pretreatment risk of 40% (95% CI, 33%-46%). Conclusions and Relevance: Results of this study suggested that corticosteroids were associated with a reduced risk of death or disability in infants at moderate to high pretreatment risk of death or grade 2 or 3 BPD but with possible harm in infants at lower risk.

Postpartum Length of Stay and Hospital Readmission Before and During the Coronavirus Disease 2019 (COVID-19) Pandemic.

OBJECTIVE: To compare postpartum hospitalization length of stay (LOS) and hospital readmission among obstetric patients before (March 2017-February 2020; prepandemic) and during the coronavirus disease 2019 (COVID-19) pandemic (March 2020-February 2021). METHODS: We conducted a retrospective cohort study, using Epic Systems' Cosmos research platform, of obstetric patients who delivered between March 1, 2017, and February 28, 2021, at 20-44 weeks of gestation and were discharged within 7 days of delivery. The primary outcome was short postpartum hospitalization LOS (less than two midnights for vaginal births and less than three midnights for cesarean births) and secondary outcome was hospital readmission within 6 weeks of postpartum hospitalization discharge. Analyses compared outcomes before and during the pandemic using standardized differences and Bayesian logistic mixed-effects models, among all births and stratified by mode of delivery. RESULTS: Of the 994,268 obstetric patients in the study cohort, 742,113 (74.6%) delivered prepandemic and 252,155 (25.4%) delivered during the COVID-19 pandemic. During the COVID-19 pandemic, the percentage of short postpartum hospitalizations increased among all births (28.7-44.5%), vaginal births (25.4-39.5%), and cesarean births (35.3-55.1%), which was consistent with the adjusted analysis (all births: adjusted odds ratio [aOR] 2.35, 99% credible interval 2.32-2.39; vaginal births: aOR 2.14, 99% credible interval 2.11-2.18; cesarean births aOR 2.90, 99% credible interval 2.83-2.98). Although short postpartum hospitalizations were more common during the COVID-19 pandemic, there was no change in readmission in the unadjusted (1.4% vs 1.6%, standardized difference=0.009) or adjusted (aOR 1.02, 99% credible interval 0.97-1.08) analyses for all births or when stratified by mode of delivery. CONCLUSION: Short postpartum hospitalization LOS was significantly more common during the COVID-19 pandemic for obstetric patients with no change in hospital readmissions within 6 weeks of postpartum hospitalization discharge. The COVID-19 pandemic created a natural experiment, suggesting shorter postpartum hospitalization may be reasonable for patients who are self-identified or health care professional-identified as appropriate for discharge.

Association Between Increased Seizures During Rewarming After Hypothermia for Neonatal Hypoxic Ischemic Encephalopathy and Abnormal Neurodevelopmental Outcomes at 2-Year Follow-up: A Nested Multisite Cohort Study.

Importance: Compared with normothermia, hypothermia has been shown to reduce death or disability in neonatal hypoxic ischemic encephalopathy but data on seizures during rewarming and associated outcomes are scarce. Objective: To determine whether electrographic seizures are more likely to occur during rewarming compared with the preceding period and whether they are associated with abnormal outcomes in asphyxiated neonates receiving hypothermia therapy. Design, Setting, and Participants: This prespecified nested cohort study of infants enrolled in the Optimizing Cooling (OC) multicenter Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network trial from December 2011 to December 2013 with 2 years' follow-up randomized infants to either 72 hours of cooling (group A) or 120 hours (group B). The main trial included 364 infants. Of these, 194 were screened, 10 declined consent, and 120 met all predefined inclusion criteria. A total of 112 (90%) had complete data for death or disability. Data were analyzed from January 2018 to January 2020. Interventions: Serial amplitude electroencephalography recordings were compared in the 12 hours prior and 12 hours during rewarming for evidence of electrographic seizure activity by 2 central amplitude-integrated electroencephalography readers blinded to treatment arm and rewarming epoch. Odds ratios and 95% CIs were evaluated following adjustment for center, prior seizures, depth of cooling, and encephalopathy severity. Main Outcomes and Measures: The primary outcome was the occurrence of electrographic seizures during rewarming initiated at 72 or 120 hours compared with the preceding 12-hour epoch. Secondary outcomes included death or moderate or severe disability at age 18 to 22 months. The hypothesis was that seizures during rewarming were associated with higher odds of abnormal neurodevelopmental outcomes. Results: A total of 120 newborns (70 male [58%]) were enrolled (66 in group A and 54 in group B). The mean (SD) gestational age was 39 (1) weeks. There was excellent interrater agreement (κ, 0.99) in detection of seizures. More infants had electrographic seizures during the rewarming epoch compared with the preceding epoch (group A, 27% vs 14%; P = .001; group B, 21% vs 10%; P = .03). Adjusted odd ratios (95% CIs) for seizure frequency during rewarming were 2.7 (1.0-7.5) for group A and 3.2 (0.9-11.6) for group B. The composite death or moderate to severe disability outcome at 2 years was significantly higher in infants with electrographic seizures during rewarming (relative risk [95% CI], 1.7 [1.25-2.37]) after adjusting for baseline clinical encephalopathy and seizures as well as center. Conclusions and Relevance: Findings that higher odds of electrographic seizures during rewarming are associated with death or disability at 2 years highlight the necessity of electroencephalography monitoring during rewarming in infants at risk. Trial Registration: ClinicalTrials.gov Identifier: NCT01192776.

Relationship between maternal methadone dose at delivery and neonatal abstinence syndrome.

OBJECTIVE: To estimate the relationship between maternal methadone dose and the incidence of neonatal abstinence syndrome (NAS). STUDY DESIGN: We performed a retrospective cohort study of pregnant women treated with methadone for opiate addiction who delivered live-born neonates between 1996 and 2006. Four dose groups, on the basis of total daily methadone dose, were compared (160 mg/d). The primary outcome was treatment for NAS. Symptoms of NAS were objectively measured with the Finnegan scoring system, and treatment was initiated for a score>24 during the prior 24 hours. RESULTS: A total of 330 women treated with methadone and their 388 offspring were included. Average methadone dose at delivery was 117+/-50 mg/d (range, 20-340 mg/d). Overall, 68% of infants were treated for NAS. Of infants exposed to methadone doses160 mg/d, treatment for NAS was initiated for 68%, 63%, 70%, and 73% of neonates, respectively (P=.48). The rate of maternal illicit opiate abuse at delivery was 26%, 28%, 19%, and 11%, respectively (P=.04). CONCLUSION: No correlation was found between maternal methadone dose and rate of NAS. However, higher doses of methadone were associated with decreased illicit opiate abuse at delivery.

Risk factors for preterm birth among opiate-addicted gravid women in a methadone treatment program.

OBJECTIVE: Prior studies noted elevated preterm birth (PTB) rates among opiate-addicted women treated with methadone. We sought to determine the risk factors for PTB in this population. STUDY DESIGN: We performed a retrospective cohort study of opiate-addicted gravid women treated with methadone who delivered a single neonate between 2000 and 2006. Variables evaluated as potential risk factors for PTB less than 37 weeks included medical and infectious comorbidities and "supplements to methadone" (illicit drugs and/or alcohol). RESULTS: The overall PTB rate was 29.1% (75/258). No medical or infectious comorbidity was predictive of PTB. Among women abusing 0, 1, 2, or 3 or more supplements in addition to methadone, the PTB rate was 24.2% (reference), 25.5% (P = .50), 47.6% (P = .04), and 64.7% (P = .01), respectively. CONCLUSION: The PTB rate among women on methadone (29.1%) is nearly 3 times the national average (11.1%), and those abusing 2 or more supplements to methadone are at further increased risk for PTB.

Heat shock protein 70 secretion by neonatal tracheal tissue during mechanical ventilation: association with indices of tissue function and modeling.

Mechanical ventilation (MV) of the neonatal airway alters mechanical properties and activates tissue-modeling pathways. Heat shock protein (HSP70) is a marker of tissue injury and modulates inflammation, which may influence subsequent pulmonary tissue modeling by matrix metalloproteinases (MMPs). HSP70 secretion is up-regulated in MV airway tissues and associated with changes in airway elasticity and secretion of MMPs. Proximal tracheal segments were isolated in 13 newborn lambs and were either MV for 4 h or SHAM. At baseline and hourly, tracheal segments were flushed and tracheal elasticity was determined. Tracheal wash fluid was assayed for HSP70 by ELISA and for MMPs by substrate zymography. HSP70 secretion increased from baseline to a peak at 1 h in both groups (p < 0.01), greater in the MV group (p < 0.05), and returned to baseline values by 2 h. This response was in contrast to the progressive decrease in tracheal elasticity (p < 0.05). The HSP70 elevation pattern was noted in MMP-2, but beyond 1 h, MMP-2 returned to baseline values in MV group but remained elevated in SHAM (p < 0.05). HSP70 secretion is associated with the degree of biophysical tracheal injury as well as the time course of MMP-2 secretion by tracheal tissues.

Cardiac Output Measurement Using the Ultrasonic Cardiac Output Monitor: A Validation Study in Newborn Infants.

OBJECTIVES: We aimed to determine the accuracy and validity of the Ultrasonic Cardiac Output Monitor (USCOM) measurements of cardiac output (CO) compared to echocardiography in newborn infants, and the inter-rater agreement of USCOM measurements. METHODS: In a single-center study we prospectively evaluated neonates undergoing an echocardiographic evaluation. USCOM measurements of CO were obtained at the pulmonary and aortic valve by 2 physicians blinded to the echocardiographic results. All echocardiographic measurements were performed blinded to USCOM measurements. We first enrolled an ascertainment cohort which was subsequently validated in an independent new cohort. Agreement between echocardiography and USCOM methods was assessed by Bland-Altman analysis. Intra-class correlation coefficients (ICC) assessed the agreement between the 2 operators. The ascertainment cohort correction factors were applied in a second validation cohort and agreement of the calibrated measures evaluated with repeat Bland-Altman comparisons. RESULTS: A total of 50 infants were enrolled in the initial cohort and 15 in the validation cohort. There was a high degree of correlation between the USCOM operators (ICC = 0.975). USCOM measurements of CO were significantly higher compared to echocardiography (left ventricular output bias 95 ± 52 mL/kg/min and right ventricular output bias 64 ± 30 mL/kg/min). There was no difference in the subgroup of infants with and without a ductus arteriosus. After the correction was applied to the validation cohort, there was no longer a significant difference between the measures. CONCLUSIONS: CO measured by USCOM consistently overestimated the results obtained from echocardiography. USCOM is not adequate to provide absolute estimates of CO. However, it may allow longitudinal hemodynamic assessment of sick neonates.

Identifying and treating intrinsic PEEP in infants with severe bronchopulmonary dysplasia.

RATIONALE: Infants with severe bronchopulmonary dysplasia (sBPD) and airway obstruction may develop dynamic hyperinflation and intrinsic positive end-expiratory pressure (PEEPi ), which impairs patient/ventilator synchrony. OBJECTIVES: To determine if PEEPi is present in infants with sBPD during spontaneous breathing and if adjusting ventilator PEEP improves patient/ventilator synchrony and comfort. METHODS: Interventional study in infants with sBPD. PEEPi measured by esophageal pressure (Pes) and pneumotachometer, during pressure-supported breaths. PEEP i defined as the difference between Pes at start of the inspiratory effort minus Pes at onset of inspiratory flow. The set PEEP was adjusted to minimize PEEP i . "Best PEEP" was the setting with minimal wasted efforts (WE), an inspiratory effort seen on the Pes waveform without a corresponding ventilator breath. FiO 2 and SpO 2 measured pre- and post-PEEP adjustment. Sedation requirements evaluated 72 hours preprocedure and postprocedure. RESULTS: Twelve infants were assessed (gestational age, 24.9 ± 1.4 weeks; study age, 48.8 ± 1.5 weeks, postmenstrual age). Mean baseline ventilator PEEP was 16.4 cm H2 O (14-20 cm H 2 O). Eight infants required an increase, one, a reduction, and three, no change in the set PEEP. For the eight infants requiring an increase in set PEEP, there was an 18.9% reduction in WE and a reduction in FiO 2 (0.084 ± 0.058) requirements in the subsequent 24 hours. Conditional sedation was reduced in five infants postprocedure. No adverse events occurred during testing. CONCLUSION: PEEPi is measurable in infants with sBPD with concurrent esophageal manometry and flow-time tracings without the need for pharmacological paralysis. In those with PEEP i , increasing ventilator PEEP to offset PEEP i improves synchrony.

Adverse effects of small for gestational age differ by gestational week among very preterm infants.

OBJECTIVE: To characterise the excess risk for death, grade 3-4 intraventricular haemorrhage (IVH), bronchopulmonary dysplasia (BPD) and stage 3-5 retinopathy of prematurity independently associated with birth small for gestational age (SGA) among very preterm infants, stratified by completed weeks of gestation. METHODS: Retrospective cohort study using the Optum Neonatal Database. Study infants were born <32 weeks gestation without severe congenital anomalies. SGA was defined as a birth weight <10th percentile. The excess outcome risk independently associated with SGA birth among SGA babies was assessed using adjusted risk differences (aRDs). RESULTS: Of 6708 infants sampled from 717 US hospitals, 743 (11.1%) were SGA. SGA compared with non-SGA infants experienced higher unadjusted rates of each study outcome except grade 3-4 IVH among survivors. The excess risk independently associated with SGA birth varied by outcome and gestational age. The highest aRD for death (0.27; 95% CI 0.13 to 0.40) occurred among infants born at 24 weeks gestation and declined as gestational age increased. In contrast, the peak aRDs for BPD among survivors (0.32; 95% CI 0.20 to 0.44) and the composites of death or BPD (0.35; 95% CI 0.24 to 0.46) and death or major morbidity (0.35; 95% CI 0.24 to 0.45) occurred at 27 weeks gestation. The risk-adjusted probability of dying or developing one or more of the evaluated morbidities among SGA infants was similar to that of non-SGA infants born approximately 2-3 weeks less mature. CONCLUSION: The excess risk for neonatal morbidity and mortality associated with being born SGA varies by adverse outcome and gestational age.

Predicting length of treatment for neonatal abstinence syndrome in methadone-exposed neonates.

OBJECTIVE: The objective of the study was to identify maternal variables predicting length of treatment for neonatal abstinence syndrome (NAS). STUDY DESIGN: This was a retrospective cohort study of infants treated for NAS during 2000-2006 whose mothers were on methadone maintenance at delivery. Mixed-effects linear regression was used to examine the interaction of maternal and neonatal variables with length of treatment. RESULTS: Of 204 neonates born to methadone exposed mothers, the average dose at delivery was 127 mg daily (25-340 mg) with median length of treatment 32 days (1-122 days). Trimester of initial exposure (P = .33), methadone dose at delivery (P = .198), body mass index (P = .31), antidepressant use (P = .40), cigarette use (P = .76), race (P = .78), and maternal age (P = .84) did not predict length of treatment. In the multivariate analysis, gestational age at delivery and benzodiazepine use were significant predictors of length of treatment. CONCLUSION: Later gestational age and concomitant benzodiazepine use were associated with longer treatment.

Pumpless arteriovenous extracorporeal membrane oxygenation: A novel mode of respiratory support in a lamb model of congenital diaphragmatic hernia.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) is commonly required in neonates with congenital diaphragmatic hernia (CDH) complicated by pulmonary hypertension (PH). ECMO carries significant risk, and is contraindicated in the setting of extreme prematurity or intracranial hemorrhage. Pumpless arteriovenous ECMO (P-ECMO) may represent an alternative for respiratory support. The present study summarizes our initial experience with P-ECMO in a lamb model of CDH. STUDY DESIGN: Surgical creation of CDH was performed at 65-75days' gestation. At term (135-145days), lambs were delivered into the P-ECMO circuit. Three animals were maintained on a low-heparin infusion protocol (target ACT 160-180) and three animals were maintained with no systemic heparinization. RESULTS: Animals were supported by the circuit for 380.7 +/- 145.6h (range, 102-504h). Circuit flow rates ranged from 97 to 208ml/kg/min, with adequacy of organ perfusion demonstrated by stable serum lactate levels (3.0 +/- 1.7) and pH (7.4 +/- 0.3). Necropsy demonstrated no evidence of thrombogenic complications. CONCLUSION: Pumpless extracorporeal membrane oxygenation achieved support of CDH model lambs for up to three weeks. This therapy has the potential to bridge neonates with decompensated respiratory failure to CDH repair with no requirement for systemic anticoagulation, and may be applicable to patients currently precluded from conventional ECMO support.