Early inhaled nitric oxide therapy in premature newborns with respiratory failure.

BACKGROUND: The safety and efficacy of early, low-dose, prolonged therapy with inhaled nitric oxide in premature newborns with respiratory failure are uncertain. METHODS: We performed a multicenter, randomized trial involving 793 newborns who were 34 weeks of gestational age or less and had respiratory failure requiring mechanical ventilation. Newborns were randomly assigned to receive either inhaled nitric oxide (5 ppm) or placebo gas for 21 days or until extubation, with stratification according to birth weight (500 to 749 g, 750 to 999 g, or 1000 to 1250 g). The primary efficacy outcome was a composite of death or bronchopulmonary dysplasia at 36 weeks of postmenstrual age. Secondary safety outcomes included severe intracranial hemorrhage, periventricular leukomalacia, and ventriculomegaly. RESULTS: Overall, there was no significant difference in the incidence of death or bronchopulmonary dysplasia between patients receiving inhaled nitric oxide and those receiving placebo (71.6 percent vs. 75.3 percent, P=0.24). However, for infants with a birth weight between 1000 and 1250 g, as compared with placebo, inhaled nitric oxide therapy reduced the incidence of bronchopulmonary dysplasia (29.8 percent vs. 59.6 percent); for the cohort overall, such treatment reduced the combined end point of intracranial hemorrhage, periventricular leukomalacia, or ventriculomegaly (17.5 percent vs. 23.9 percent, P=0.03) and of periventricular leukomalacia alone (5.2 percent vs. 9.0 percent, P=0.048). Inhaled nitric oxide therapy did not increase the incidence of pulmonary hemorrhage or other adverse events. CONCLUSIONS: Among premature newborns with respiratory failure, low-dose inhaled nitric oxide did not reduce the overall incidence of bronchopulmonary dysplasia, except among infants with a birth weight of at least 1000 g, but it did reduce the overall risk of brain injury. (ClinicalTrials.gov number, NCT00006401 [ClinicalTrials.gov].).

Factors influencing delivered mean airway pressure during nasal CPAP with the RAM cannula.

OBJECTIVE: To measure mean airway pressure (MAP) delivered through the RAM Cannula® when used with a ventilator in CPAP mode as a function of percent nares occlusion in a simulated nasal interface/test lung model and to compare the results to MAPs using a nasal continuous positive airway pressure (NCPAP) interface with nares fully occluded. STUDY DESIGN: An artificial airway model was connected to a spontaneous breathing lung model in which MAP was measured at set NCPAP levels between 4 and 8 cmH2 O provided by a Dräger Evita XL® ventilator and delivered through three sizes of RAM cannulae. Measurements were performed with varying leakage at the nasal interface by decreasing occlusion from 100% to 29%, half-way prong insertion, and simulated mouth leakage. Comparison measurements were made using the Dräger BabyFlow® NCPAP interface with a full nasal seal. RESULTS: With simulated mouth closed, the Dräger interface delivered MAPs within 0.5 cmH2 O of set CPAP levels. For the RAM cannula, with 60-80% nares occlusion, overall delivered MAPs were 60 ± 17% less than set CPAP levels (P < 0.001). Further, MAP decreased progressively with decreasing percent nares occlusion. The simulated open mouth condition resulted in significantly lower MAPs to <1.7 cmH2 O. The one-half prong insertion depth condition, with closed mouth, yielded MAPs approximately 35 ± 9% less than full insertion pressures (P < 0.001). CONCLUSIONS: In our bench tests, the RAM interface connected to a ventilator in NCPAP mode failed to deliver set CPAP levels when applied using the manufacturer recommended 60-80% nares occlusion, even with closed mouth and full nasal prong insertion conditions.

Effect of dose on response to adrenocorticotropin in extremely low birth weight infants.

CONTEXT: Various cosyntropin doses are used to test adrenal function in premature infants, without consensus on appropriate dose or adequate response. OBJECTIVE: The objective of this study was to test the cortisol response of extremely low birth weight infants to different cosyntropin doses and evaluate whether these doses differentiate between groups of infants with clinical conditions previously associated with differential response to cosyntropin. DESIGN: The design was a prospective, nested study conducted within a randomized clinical trial of low-dose hydrocortisone from November 1, 2001, to April 30, 2003. SETTING: The setting was nine newborn intensive care units. PATIENTS: The patients included infants with 500-999 g birth weight. INTERVENTION: The drug used was cosyntropin, at 1.0 or 0.1 microg/kg, given between 18 and 28 d of birth. MAIN OUTCOME MEASURE: We measured the cortisol response to cosyntropin. RESULTS: Two hundred seventy-six infants were tested. Previous hydrocortisone treatment did not suppress basal or stimulated cortisol values. Cosyntropin, at 1.0 vs. 0.1 microg/kg, yielded higher cortisol values (P < 0.001) and fewer negative responses (2 vs. 21%). The higher dose, but not the lower dose, showed different responses for girls vs. boys (P = 0.02), infants receiving enteral nutrition vs. not (P < 0.001), infants exposed to chorioamnionitis vs. not (P = 0.04), and those receiving mechanical ventilation vs. not (P = 0.02), as well as a positive correlation with fetal growth (P = 0.03). A response curve for the 1.0-microg/kg dose for infants receiving enteral nutrition (proxy for clinically well infants) showed a 10th percentile of 16.96 microg/dl. Infants with responses less than the 10th percentile had more bronchopulmonary dysplasia and longer length of stay. CONCLUSIONS: A cosyntropin dose of 0.1 microg/kg did not differentiate between groups of infants with clinical conditions that affect response. We recommend 1.0 microg/kg cosyntropin to test adrenal function in these infants.

Diagnosis and management of bacterial infections in the neonate.

Perinatally acquired bacterial neonatal sepsis is a low-incidence,high-risk disease. Although incidence of the most common etiology,group B Streptococcus, has been reduced by prophylactic strategies,neonatal sepsis has not been eradicated, and vigilance must remain high. Accurate diagnosis is difficult: signs and symptoms are hard to distinguish from other causes of neonatal distress, and definitive diagnostic tests are not available. The clinician must make a judgment call, considering the perinatal history, the constellation of signs and symptoms, and the results of existing diagnostic tests,before neonatal sepsis can diagnosed or excluded. With diagnosis,knowledge of the specific disease states and clinical algorithms for management aid in formulating a plan of treatment with antimicrobial agents and supportive care.

Regional hemodynamic effects of dopamine in the indomethacin-treated preterm infant.

OBJECTIVE: We have previously demonstrated that dopamine induces selective renal vasodilation without affecting cerebral and mesenteric blood flow in < or = 32 weeks' gestation normotensive preterm infants during the first postnatal day. In the present study, we have examined whether pretreatment with indomethacin affects the regional hemodynamic response to dopamine in >1-day-old normotensive preterm infants with similar gestational age. STUDY DESIGN: The pulsatility index (PI) was used to assess the dopamine-induced changes in renal, mesenteric, and cerebral blood flow using color Doppler ultrasonography in 20 indomethacin-treated normotensive preterm neonates with patent ductus arteriosus (gestational age: 27.2+/-1.5 weeks; postnatal age: 35.7+/-8.2 hours). Dopamine (5 microg/kg per minute) was started 4.9+/-2.1 hours (range: 2 to 8 hours) after the first dose of indomethacin to combat oliguria and/or impaired peripheral perfusion. Blood flow velocity measurements were obtained immediately before and 10 minutes after the start of dopamine with each subject serving as his/her own control. RESULTS: Dopamine increased heart rate and urine output but did not affect blood pressure at the dose applied. Dopamine decreased the PI in the renal and superior mesenteric artery (2.6+/-1.32 vs. 1.61+/-0.7 and 2.36+/-1.12 vs. 1.76+/-0.64, respectively; p<0.05) whereas the PI in the middle cerebral artery remained unchanged. These results are consistent with a dopamine-induced increase in renal and mesenteric blood flow without an effect on cerebral blood flow. CONCLUSIONS: When started at least 2 hours after the first dose of indomethacin, dopamine induces renal and mesenteric vasodilation without affecting cerebral hemodynamics in the >1-day-old indomethacin-treated preterm infant.

Effect of HFNC flow rate, cannula size, and nares diameter on generated airway pressures: an in vitro study.

Increased use of non-invasive forms of respiratory support such as CPAP and HFNC in premature infants has generated a need for further investigation of the pulmonary effects of such therapies. In a series of in vitro tests, we measured delivered proximal airway pressures from a HFNC system while varying both the cannula flow and the ratio of nasal prong to simulated nares diameters. Neonatal and infant sized nasal prongs (3.0 and 3.7 mm O.D.) were inserted into seven sizes of simulated nares (range: 3-7 mm I.D. from anatomical measurements in 1-3 kg infants) for nasal prong-to-nares ratios ranging from 0.43 to 1.06. The nares were connected to an active test lung set at: TV 10 ml, 60 breaths/min, Ti 0.35 sec, compliance 1.6 ml/cm H2O and airway resistance 70 cm H2O/(L/sec), simulating a 1-3 kg infant with moderately affected lungs. A Fisher & Paykel Healthcare HFNC system with integrated pressure relief valve was set to flow rates of 1-6 L/min while cannula and airway pressures and cannula and mouth leak flows were measured during simulated mouth open, partially closed and fully closed conditions. Airway pressure progressively increased with both increasing HFNC flow rate and nasal prong-to-nares ratio. At 6 L/min HFNC flow with mouth open, airway pressures remained <1.7 cm H2O for all ratios; and <10 cm H2O with mouth closed for ratios <0.9. For ratios >0.9 and 50% mouth leak, airway pressures rapidly increased to 18 cm H2O at 2 L/min HFNC flow followed by a pressure relief valve limited increase to 24 cm H2O at 6 L/min. Safe and effective use of HFNC requires careful selection of an appropriate nasal prong-to-nares ratio even with an integrated pressure relief valve.

Early inflammatory markers for prediction of cholestasis in very-low-birth-weight infants.

BACKGROUND: Neonatal cholestasis is associated with increased mortality and other adverse outcomes. There are no tools for prediction of infants at risk for cholestasis. OBJECTIVE: To determine if cholestasis in very-low-birth-weight (VLBW) infants is associated with alterations in cytokines or C-reactive protein (CRP) and, if so, whether inflammatory markers predict which infants will develop cholestasis. METHODS: VLBW infants expected to be on parenteral nutrition for >7 days were enrolled in this prospective cohort study. Infants with direct bilirubin ≥1.0 mg/dl were considered to have a high risk for cholestasis and were compared to infants who never developed direct bilirubin ≥1.0 mg/dl. Standard descriptive statistics were used to compare biomarkers over time. Multivariable models were used to estimate associations between early inflammatory markers and cholestasis. RESULTS: Of 63 infants enrolled, 29 were at risk for cholestasis. CRP was highly correlated with direct bilirubin. Infants in the high-risk group had significantly higher IL-1ß, IL-6, IL-8, and IL-10 at 2, 4, and 6 weeks and CRP at 2 and 6 weeks. In logistic models, CRP (OR = 4.97, p = 0.02) or IL-1ß (OR = 1.11, p = 0.008) at 2 weeks of age was predictive of cholestasis. In linear mixed-effects models, CRP (p < 0.001) or IL-6 (p = 0.02) and IL-8 (p < 0.001) were predictive of cholestasis. CONCLUSION: Elevated CRP and cytokines are associated with cholestasis in VLBW infants. These inflammatory markers are candidates for further research into the pathogenesis, prediction, and prevention of cholestasis.

An open label comparison of calfactant and poractant alfa administration traits and impact on neonatal intensive care unit resources.

OBJECTIVE: To compare calfactant (CA) and poractant alfa (PA) administration traits, short-term clinical responses, and resource use in the neonatal respiratory distress syndrome (RDS) setting. METHODS: An open label series of 277 (213 PA and 64 CA) infants was evaluated for 445 administrations. Registered respiratory therapists collected patient, surfactant administration, and postadministration clinical data. Economic analysis involved labor costs of surfactant administration and usage, wastage, and product average wholesale price. Analysis utilized the Mann-Whitney rank sum test for differences in administration time and either the chi-square or Fisher's exact test for categorical variables. RESULTS: PA had a statistically lower bedside administration time than CA (3.8 minutes vs. 5.3 minutes; P = .006) and a higher percentage of doses administered in less than five minutes (58.9% vs. 4.3%; P < .001). Doses administered per patient were similar (1.67 vs. 1.72). PA and CA were similar in time to recovery (81.4% vs. 74.3%), percent desaturation (24.8% vs. 26.7%), and bradycardia (3.8% vs. 8.5%). Reflux was significantly higher (13.2% vs. 3.5%; P < .001) with CA. Economic analyses found total administration costs per dose were $2.21 for PA and $3.08 for CA. Mean wastage costs were $141.21 for PA and $337.34 for CA (P < .001). CONCLUSIONS: PA appeared to utilize fewer neonatal intensive care unit resources than CA due to reduced administration time and less wastage of drug product. Future studies should more closely evaluate time, resource, wastage, and post-administrative clinical effects to fully assess the impact of surfactant products in this setting.

Neonatal outcome after exposure to indomethacin in utero: a retrospective case cohort study.

OBJECTIVE: This study was undertaken to determine the clinical outcome for neonates who were exposed to indomethacin during gestation. STUDY DESIGN: We identified 124 infants with in utero exposure to indomethacin and matched them to 124 infants whose mothers did not receive indomethacin. The two groups were matched for gestational age at birth, sex, and exposure to antenatal betamethasone. Sixty-two of the indomethacin-exposed infants were born within 48 hours of last exposure. These infants were also compared with their matched controls. RESULTS: There were no significant differences between the indomethacin-exposed infants and control infants in birth weight, Apgar scores, frequency of cesarean section deliveries, and multiple gestation. The incidence of respiratory distress syndrome, need for surfactant treatment, patent ductus arteriosus, necrotizing enterocolitis, and intraventricular hemorrhage was similar between the indomethacin-exposed group and the control group. Indomethacin-exposed infants who were born within 48 hours of last exposure had similar incidence of respiratory distress syndrome but greater need for surfactant treatment (P=.02) compared with controls. All other complication rates were similar. CONCLUSION: Indomethacin exposure in our study was not associated with increased neonatal complications for infants delivered within or beyond 48 hours of last exposure.

The effects of the time interval from antenatal corticosteroid exposure to delivery on neonatal outcome of very low birth weight infants.

OBJECTIVE: The purpose of this study was to determine whether the interval between antenatal steroid exposure and delivery influences neonatal outcome in very low birth weight infants. STUDY DESIGN: A retrospective review was performed of all live-born singleton infants who weighed between 500 and 1500 g and who were exposed to a partial course (1 dose) or a complete course (2 12-mg doses of betamethasone given 24 hours apart) of antenatal corticosteroids. Infants were divided into 4 groups, depending on the interval between the first dose of antenatal corticosteroids and delivery (<24 hours, between 24 and 48 hours, between 48 hours and 7 days, and >7 days). Logistic regression was used to control for differences between the 4 groups. RESULTS: Three hundred twenty-five singleton deliveries were reviewed. Gestational age at delivery and birth weight were similar for all 4 groups. The babies in the last group were treated with antenatal corticosteroids at a slightly earlier gestational age. There was no statistical difference between the groups with respect to respiratory distress syndrome treated with surfactant, intraventricular hemorrhage, necrotizing enterocolitis, and deaths. CONCLUSION: In infants who weighed 500 to 1500 g, the time interval between exposure to antenatal corticosteroids and delivery does not appear to affect neonatal outcome. Further studies should evaluate the effects of antenatal corticosteroids and the effects of the interval from exposure to delivery in very low birth weight infants.

Prophylaxis of early adrenal insufficiency to prevent bronchopulmonary dysplasia: a multicenter trial.

BACKGROUND: Infants developing bronchopulmonary dysplasia (BPD) show decreased cortisol response to adrenocorticotropic hormone. A pilot study of low-dose hydrocortisone therapy for prophylaxis of early adrenal insufficiency showed improved survival without BPD at 36 weeks' postmenstrual age, particularly in infants exposed to histologic chorioamnionitis. METHODS: Mechanically ventilated infants with birth weights of 500 to 999 g were enrolled into this multicenter, randomized, masked trial between 12 and 48 hours of life. Patients received placebo or hydrocortisone, 1 mg/kg per day for 12 days, then 0.5 mg/kg per day for 3 days. BPD at 36 weeks' postmenstrual age was defined clinically (receiving supplemental oxygen) and physiologically (supplemental oxygen required for O2 saturation > or =90%). RESULTS: Patient enrollment was stopped at 360 patients because of an increase in spontaneous gastrointestinal perforation in the hydrocortisone-treated group. Survival without BPD was similar, defined clinically or physiologically, as were mortality, head circumference, and weight at 36 weeks. For patients exposed to histologic chorioamnionitis (n = 149), hydrocortisone treatment significantly decreased mortality and increased survival without BPD, defined clinically or physiologically. After treatment, cortisol values and response to adrenocorticotropic hormone were similar between groups. Hydrocortisone-treated infants receiving indomethacin had more gastrointestinal perforations than placebo-treated infants receiving indomethacin, suggesting an interactive effect. CONCLUSIONS: Prophylaxis of early adrenal insufficiency did not improve survival without BPD in the overall study population; however, treatment of chorioamnionitis-exposed infants significantly decreased mortality and improved survival without BPD. Low-dose hydrocortisone therapy did not suppress adrenal function or compromise short-term growth. The combination of indomethacin and hydrocortisone should be avoided.