Effect of multiple INSURE procedures in extremely preterm infants.

OBJECTIVES: Our aim was to evaluate whether single and multiple intubation-surfactant-extubation (INSURE) procedures have similar effects on the need of mechanical ventilation (MV) and occurrence of bronchopulmonary dysplasia (BPD) in extremely preterm infants. METHODS: We studied infants of <30 weeks of gestation with respiratory distress syndrome (RDS) who were treated with single (FiO(2)>0.30 without need of MV) or multiple (FiO(2)>0.40 without need of MV) INSURE procedures. RESULTS: Seventy-five infants were studied: 53 (71%) received single INSURE and 22 (29%) received multiple INSURE procedures. Infants in the single and multiple groups had similar rates of need of MV (15 vs. 23%) and occurrence of BPD (9 vs. 9%), although the latter were more immature and affected by more severe RDS (higher FiO(2), lower a/ApO(2), and pO(2)/FiO(2)) than the former. CONCLUSIONS: Single and multiple INSURE procedures were followed by similar respiratory outcome in a cohort of extremely preterm infants. Further studies are warranted to evaluate whether the multiple INSURE strategy enhances the success rate of INSURE in preventing the need of MV and the occurrence of BPD.

Effects of epidural and systemic maternal analgesia in term infants: the NoPiL study.

The aim of the No Pain in Labour (NoPiL) study was to evaluate the stress and clinical outcome of infants vaginally born without maternal analgesia and after maternal epidural or systemic analgesia. We studied 120 healthy term infants, 41 in the no analgesia group, 38 in the epidural analgesia group, and 41 in the systemic analgesia group. Cortisol, beta-endorphin, oxidative stress markers (ie: total hydroperoxide (TH) and advanced oxidation protein products (AOPP)), interleukin-1beta (IL-1beta), and interleukin-8 (IL-8) cytokines were measured in arterial cord blood samples. Infants in the 3 groups had similar Apgar score, cord blood pH and occurrence of hypoglycaemia, hyperbilirubinemia, and respiratory depression. Cortisol and endorphin plasma levels did not differ in the groups, nor did TH and AOPP values. IL-1beta and IL-8 cytokine were higher in infants born after maternal epidural analgesia than in other groups. Short-term outcome and stress were similar in infants vaginally born without maternal analgesia and after epidural and systemic analgesia. The possible implications of the highest interleukin levels in the epidural analgesia group deserve further study.

Method of delivery and intraventricular haemorrhage in extremely preterm infants.

OBJECTIVES: It has been reported that caesarean delivery (CD) protects against intraventricular haemorrhage (IVH) in the extremely preterm infant, but it is not known whether this effect involve the more severe grades of IVH. Thus, our aim was to confirm the correlation between the occurrence of IVH and the mode of delivery, and to evaluate this correlation for each grade of IVH. METHODS: All infants with gestational age (GA) ≤ 28 weeks admitted to the neonatal intensive care unit of a tertiary hospital were studied for each grade IVH and major complications rate. RESULT: We found that vaginally born infants had a higher rate of each grade of IVH, but the increase was statistically significant only for grade 3 IVH (18% vs. 2%, p < 0.0001) and all grades IVH (45% vs. 20%, p < 0.0001). Multivariate analysis demonstrated that CD (RR: 0.42, 95% CI 0.28-0.63), birth weight ≥ 800 g (RR: 0.48, 95% CI 0.32-0.73), 27-28 weeks of GA (RR: 0.38, 95% CI 0.25-0.60) and antenatal steroids (0.66, 95% CI 0.22-0.46) decrease independently the risk of developing IVH. CONCLUSIONS: Our study demonstrates that CD decreases the risk of developing IVH in extremely preterm infants including the most severe grades of IVH.

The INSURE method in preterm infants of less than 30 weeks' gestation.

OBJECTIVES: Our aim was to identify the clinical characteristics which could distinguish infants who can be managed with INSURE (intubatio-surfactant-extubation) method for preventing mechanical ventilation (MV) and which could predict INSURE success or failure. METHODS: Inborn infants with gestational age <30 weeks were Infants were categorised into three groups: (1) infants who needed MV in the delivery room; (2) infants spontaneously breathing who were treated only with NCPAP; (3) infants who were treated with INSURE method. RESULTS: We studied 125 infants: 30 (24%) required MV, 75 (60%) received INSURE treatment, and 20 (16%) were treated with NCPAP. Sixty-eight (91%) infants were successfully treated with the INSURE method. Infants in the success group had less severe RDS and less occurrence of sepsis and pneumothorax, lower mortality, and shorter duration of stay in the NICU than infants in the failure group. A birth weight <750 g, pO(2)/FiO(2) <218, and a/ApO(2) <0.44 at the first blood gas analysis were independent risk factor for INSURE failure. CONCLUSIONS: The INSURE method can be applied to the majority of extremely preterm infants and is followed by a high percentage of success.

Natural surfactant combined with beclomethasone decreases oxidative lung injury in the preterm lamb.

We performed a randomized study in preterm lambs to assess the hypothesis that the treatment with natural surfactant combined with beclomethasone might decrease pulmonary oxidative stress in an animal model of respiratory distress syndrome (RDS). Animals received 200 mg/kg of porcine natural surfactant or 200 mg/kg of natural surfactant combined with 400 or 800 microg/kg of beclomethasone. Lung tissue oxidation was studied by measuring total hydroperoxide (TH), advanced oxidation protein products (AOPP), and non-protein bound iron (NPBI) in bronchial aspirate samples. In addition, lung mechanics was evaluated. TH was lower in the groups treated with surfactant plus 400 or 800 microg/kg of beclomethasone than in the surfactant group; AOPP was lower in the group treated with surfactant plus 800 microg/kg of beclomethasone than in the other groups; NPBI was similar in all groups. Surfactant treatment was followed by a sustained improvement of tidal volume (TV) and airway resistance, while dynamic compliance did not vary. However, the mean airway pressure needed to obtain similar values of TV was lower in the group treated with surfactant plus 800 microg/kg of beclomethasone than in other groups. We concluded that natural surfactant combined with beclomethasone at 800 microg/kg is effective in reducing the oxidative lung stress and improving the respiratory function in an animal model of RDS.

Superoxide dismutase and catalase activity in naturally derived commercial surfactants.

Despite the role of reactive oxygen species in the development of respiratory distress syndrome (RDS) and bronchopulmonary dysplasia (BPD) in preterm infants, the anti-oxidant properties of commercial surfactants have never been studied. We measured the superoxide dismutase (SOD) and catalase (CAT) activity, the scavenger activity against hydrogen peroxide (H(2)O(2)), and its changes after the addition of SOD and CAT in four natural surfactants, namely Infasurf, Curosurf, Survanta, and Alveofact. We found that they contain measurable amount of SOD and CAT. Curosurf and Survanta seem to have higher antioxidant effect than Infasurf and Alveofact. Moreover, the highest phospholipid concentration and recommended dose of Curosurf imply that its scavenger activity for each treatment dose in preterm infants is likely higher than that of Survanta. Finally, the supplementation with SOD and CAT induced a remarkable increase of antioxidant action in all studied surfactants.

Coagulopathy screening and early plasma treatment for the prevention of intraventricular hemorrhage in preterm infants.

BACKGROUND: Despite the improvement in the assistance and treatment of preterm infants, intraventricular hemorrhage (IVH) remains a frequent complication in these patients. Our aim was to demonstrate the hypothesis that a coagulopathy screening and the early treatment with fresh-frozen plasma (FFP) of proven coagulopathy may contribute to decrease the occurrence of IVH in infants with gestational age of less than 29 weeks. STUDY DESIGN AND METHODS: This study compared two cohorts of infants who received FFP (10 mL/kg) after the evidence of pathologic coagulation tests performed within 2 hours after birth (screening group, n = 127) or after the development of bleedings and evidence of pathologic coagulation tests (no-screening group, n = 91). RESULTS: The screening strategy decreased the relative risk (RR) of developing IVH (RR = 0.65; 95% confidence interval, 0.44-0.98) compared to no-screening strategy, but the effect was limited to infants born at 23 to 26 weeks of gestation in whom screening strategy lowered IVH occurrence (34.5% vs. 61.1%, p = 0.008). CONCLUSIONS: A coagulopathy screening strategy decreases the risk of developing IVH in preterm infants but this effect is limited to infants born at 23 to 26 weeks of gestation.

Effects of red blood cell transfusions during the first week of life on acid-base, glucose, and electrolytes in preterm neonates.

BACKGROUND: More than 90 percent of extremely low-birth-weight infants receive one or more transfusions of red blood cells (RBCs). The objective was to assess if RBC transfusions may induce significant changes of plasma acid-base, electrolyte, and glucose status in extremely preterm infants. STUDY DESIGN AND METHODS: Records of infants with gestational age of less than 31 weeks who were transfused with RBCs during the first week of life were reviewed (n = 61). Blood samples were collected from infants before and after transfusions to evaluate hemoglobin (Hb) level, hematocrit, acid-base, electrolyte, and glucose status. Then infants were stratified into four groups that received a RBC volume of less than 15, 15 to 20, more than 20 to 25, or more than 25 mL per kg. RESULTS: Infants received 20.7 (+/-1.5) mL per kg RBCs. After transfusions, a significant increase of pO(2) (p < 0.0001) and decrease of Ca(2+) (p = 0.047) and glycemia (p < 0.0001) were observed. Infants who were transfused with more than 25 mL per kg were significantly less immature, heavier, and more anemic than infants in other groups. A positive relationship was found between changes of patients' potassium plasma level and K(+) intake through RBC transfusion (r = 0.442, p = 0.008). Three (4.9%) infants developed hyperkalemia, one (1.6%) had an exacerbation of his hypocalcemia, and another (1.6%) of his hypoglycemia. CONCLUSIONS: RBC transfusions were effective in correcting anemia in our patients and induced a slight increase of pH and pO(2) and decrease of Ca(2+) and glycemia, which were not clinically relevant. A linear direct correlation was observed between potassium intake by RBC transfusions and changes of kalemia in our infants, but there was not an increase of K(+) plasma level after transfusions.

The fate of ductus arteriosus in infants at 23-27 weeks of gestation: from spontaneous closure to ibuprofen resistance.

BACKGROUND: Some extremely preterm infants experience spontaneous closure of the ductus arteriosus. On the other side, a high percentage (22-30%) of preterm infants born at the lower gestational age fail to respond to a single course of ibuprofen. AIM: To assess if there are clinical characteristics effective as predictive factors for spontaneous closure of the ductus arteriosus, development of patent ductus arteriosus (PDA) and ibuprofen-resistant PDA. METHODS: A cohort of inborn infants less than 28 weeks of gestation were prospectively studied. We distinguished infants who had spontaneous closure of ductus arteriosus, who developed PDA and who developed ibuprofen-resistant PDA. RESULTS: We studied 34 infants. Eight infants (24%) had spontaneous closure of PDA, 17 infants (50%) had a closure of PDA following the first ibuprofen course, while 9 infants (26%) failed to respond to the first ibuprofen course. Infants born at 23-25 weeks of gestation were found to have lower likelihood of PDA spontaneous closure, and higher risk of developing PDA refractory to ibuprofen therapy. Sepsis was found to increase significantly the risk of ibuprofen failure in closing PDA. CONCLUSION: An important percentage of extremely preterm infants exhibited spontaneous closure of PDA. Among clinical characteristics lowest gestational ages predict PDA and ibuprofen-resistant PDA, while sepsis predicts only ibuprofen-resistant PDA.

Transepidermal water loss and cerebral hemodynamics in preterm infants: conventional versus LED phototherapy.

The aim of our study was to evaluate whether high-intensity gallium nitride light-emitting diode (LED) phototherapy (LPT) influences transepidermal water loss (TEWL) and cerebral hemodynamics in preterm neonates in comparison with conventional phototherapy (CPT). Thirty-one preterm infants were randomized for conventional (n = 14) and for LED (n = 17) phototherapy. All infants were studied using a Tewameter TM 210 and cerebral Doppler ultrasound immediately before phototherapy (time 0), 30 min (time 1), 1-6 h (time 2), and 12-24 h (time 3) after the start of phototherapy, and 6-12 h after discontinuing phototherapy (time 4). The study shows that LPT does not induce significant changes in TEWL (time 0: 2.75 +/- 4.71 ml/m(2)/h; time 3: 14.45 +/- 3.68 ml/m(2)/h), in peak systolic, end diastolic and mean cerebral blood flow velocity (CBFV), and in the resistence index (RI). On the contrary, CPT is associated with a significant increase of TEWL (time 0: 13.22 +/- 5.61 ml/m(2)/h; time 3: 20.94 +/- 3.21 ml/m(2)/h), which disappeared at time 4, when phototherapy had stopped. The peak systolic and mean CBFV increased, respectively, from 0.11 +/- 0.03 m/s at time 0 to 0.16 +/- 0.07 m/s at time 3. We conclude that LPT, emitting light within the 450-470-nm spectrum for optimal bilirubin degradation, can be preferable to CPT for the therapy of hyperbilirubinemia in preterm infants.

Changes of nitric oxide, carbon monoxide and oxidative stress in term infants at birth.

The higher risk of respiratory problem in infants delivered by elective caesarean section in comparison with vaginally born infants may be favoured by lower level of nitric oxide (NO) and carbon monoxide (CO) and higher oxidative stress in infants born by caesarean section. We studied healthy term infants born by vaginal delivery or by elective caesarean section. Nitric oxide, CO, guanosine 3-5 cyclic monophosphate, total hydroperoxide and advanced oxidation protein products (AOPP) were measured at birth and 48-72 h of life. Nitric oxide, CO and cGMP were lower at birth and at 48-72 h of life in infants born by elective caesarean delivery. Total hydroperoxide and AOPP levels were similar in the two groups and increased from birth to 48-72 h of life. In conclusion, nitric oxide and CO concentrations were higher in term infants vaginally born than in infants born by elective caesarean section and decreased from birth to 48-72 h of life. The mode of delivery did not affect the oxidative stress which increases from birth to 48-72 h of life.

Inhaled nitric oxide combined with prostacyclin and adrenomedullin in acute respiratory failure with pulmonary hypertension in piglets.

Our aim was to evaluate if the combined inhalation of both nitric oxide (iNO) and aerosolized prostacyclin or iNO and adrenomedullin (ADM) is more effective in lowering pulmonary arterial pressure (PAP) and improving oxygenation than nitric oxide alone in an animal model with pulmonary hypertension (PH). Moreover, we studied the effect on pulmonary mechanics, surfactant activity, and pulmonary oxidative stress of the different treatments. Twenty-eight piglets with acute lung injury induced by lung lavages with saline were randomized to receive nitric oxide, nitric oxide plus prostacyclin, nitric oxide plus ADM or saline, after. Dynamic compliance, tidal volume, and airway resistance were measured. Lung tissue oxidation was evaluated by measuring total hydroperoxide and advanced oxidation protein products in bronchial aspirate samples. Surface surfactant activity was studied using Capillary Surfactometer. Inhaled nitric oxide combined with prostacyclin or ADM was more effective than nitric oxide alone in lowering PAP and improving oxygenation. Nitric oxide alone or combined increased lung compliance and tidal volume, and decreased airway resistance. No effects on surfactant surface activity and lung tissue oxidation were observed. The treatment with nitric oxide alone or combined with prostacyclin or ADM were effective in decreasing mean PAP and improving oxygenation in a piglet model of PH. However, nitric oxide plus prostacyclin and nitric oxide plus ADM were more effective than nitric oxide alone. The combination of aerosolized prostacyclin and ADM with nitric oxide might have a role in the treatment of infants with PH refractory to nitric oxide alone.

Brain haemodynamic effects of nasal continuous airway pressure in preterm infants of less than 30 weeks' gestation.

AIM: To evaluate the hypothesis that increasing levels of nasal continuous positive airway pressure (NCPAP) may decrease cerebral blood volume (CBV) and cerebral oxygenation in infants with gestational age (GA) less than 30 weeks. METHODS: We prospectively studied a cohort of preterm infants treated with NCPAP using near-infrared spectroscopy (NIRS). The pressure limit of NCPAP was set at 2, 4, 6 and again 2 cm H(2)O for 30 min. RESULTS: Changes of pressure levels were not followed by significant changes of oxygenated haemoglobin (O(2)Hb), deoxygenated haemoglobin (HHb), cerebral intravascular oxygenation (HbD), oxidized-reduced cytochrome aa3 (CtOx), tissue oxygenation index (TOI), tissue haemoglobin index (THI) and cerebral blood volume (DeltaCBV). CONCLUSION: NCPAP at 2-6 cm H(2)O pressure levels did not affect cerebral oxygenation and CBV. These findings are reassuring and confirm the safety of NCPAP in preterm infants with GA less than 30 weeks.

Toxicity of corticosteroids and catecholamines for mice neuronal cell cultures: Role of preservatives.

OBJECTIVE: To confirm previous reports on dexamethasone and sulfite neurotoxicity, and to investigate methylprednisolone, dopamine, and dobutamine neurotoxicity. METHODS: Pure dexamethasone, injectable dexamethasone containing sodium metabisulfite (Soludecadron), pure methylprednisolone, injectable methylprednisolone (Solu-Medrol), pure dopamine, injectable dopamine containing potassium metabisulfite (Revivan), pure dobutamine, injectable dobutamine containing sodium metabisulfite (Dobutrex), and sodium metabisulfite were added to the medium of mixed glial-neuronal cell cultures at concentrations of 0.1, 1, 10, and 100 microM. Cell damage induced by glucocorticoids was assessed by measuring the release of lactate dehydrogenase (LDH) from the injured cells into the extracellular fluid during the 24 hours of exposure to drugs. Cell damage induced by catecholamines was assessed using the fluorescent dye propidium iodide (PI) method 24 hours after exposure to the drugs. RESULTS: Methylprednisolone and Solu-Medrol did not affect neuronal death, which was increased by dexamethasone and Soludecadron at 100 microM and sodium metabisulfite at 10 and 100 microM. Neuronal death was significantly increased by dopamine, Revivan, dobutamine, Dobutrex, and sulfites at 10 and 100 microM concentrations. CONCLUSIONS: In vitro dexamethasone, Soludecadron, and sulfites increase neuronal cell death, while methylprednisolone and Solu-Medrol are not neurotoxic; dopamine and dobutamine were found neurotoxic independently from sulfite toxicity.

Diagnosis of gastro-oesophageal reflux in preterm infants: sonography vs. pH-monitoring.

OBJECTIVES: To compare the ultrasound examination with pH-metry in order to evaluate the diagnostic accuracy of sonography for diagnosis of gastro-oesophageal reflux (GOR) in preterm infants. METHODS: A prospective study was conducted on 31 premature infants <34 weeks with clinically diagnosed GOR. First, they underwent 24-hour pH-monitoring; successively, the sonographic assessment was performed within 12 h after pH-monitoring. The two operators who performed the pH-monitoring and sonography respectively, were unaware of each other's results. RESULTS: Twenty-one patients (67.7%) had significant GOR with a reflux index >5 (GOR group). The median (range) reflux index in this group was 9.19% (6.04-20.1). Ten newborns (32.3%) did not have significant GOR with a reflux index <5. Sonography was positive for GOR in 8 patients (25.8%); all 8 infants with sonographic diagnosis of GOR had a reflux index >5. Therefore, sonographic diagnosis did not produce false positives. Sonography was negative in 23 newborns (74.2%); 13 of these were positive to pH-monitoring and may therefore be considered as false negatives. Respect to continuous 24-hour pH-monitoring, sonography showed a specificity of 100% but a very low sensitivity of 38% with a positive prediction value of 100% and a negative prediction value of 43%. CONCLUSIONS: Sonography should not replace 24-hour pH monitoring for detecting GOR in preterm infants. However, sonography has a very high specificity and a positive predictive value of 100%. When clinicians suspect GOR in preterm infants, it could be useful for selection of cases to refer for pH-metry.

Association between peak serum bilirubin and severity of respiratory distress syndrome in infants of less than 30 weeks' gestation.

INTRODUCTION: Bilirubin can enter the alveolar space where it could inactivate surfactant and act as an anti-oxidant agent. OBJECTIVE: To assess the hypothesis that total serum bilirubin level (TSB) may affect the severity of respiratory distress syndrome (RDS) and the need of respiratory supports in preterm infants. STUDY DESIGN: We performed a retrospective study of 184 preterm infants with RDS, whose peak TSB had a median value of 194.8 micromol/L (=11.3 mg/dL). This value was used to stratify patients into two groups: neonates who developed low and high TSB (< or = or >194.8 micromol/L, respectively). For each patient the highest values of inspired oxygen fraction (FiO(2)), arterial to alveolar oxygen tension ratio (a/APO(2)), oxygenation index (O.I.), ventilatory index (V.I.), and the need and duration of respiratory supports were recorded. RESULTS: Seventy-five infants were included in the low TSB group and 74 were included in the high TSB group. The RDS severity and the need of respiratory supports were similar in both the groups. The first day of life TSB and peak TSB did not correlate with the highest values of FiO(2) and a/APO(2), and the duration of mechanical ventilation. CONCLUSIONS: We did not find any correlation between TSB level and RDS severity. We speculate that this result is because the potential inhibiting effect of bilirubin on surfactant function is neutralized by the exogenous surfactant treatment, while its antioxidant effects do not provide appreciable benefits in the lung tissue.

A trial of preventing early- and late-onset Group B streptococcal sepsis with combined intrapartum chemoprophylaxis and universal neonatal screening.

BACKGROUND: Prevention of early-onset Group B Streptococcal (GBS) infection has been attempted by employing universal maternal screening for GBS, intrapartum chemoprophylaxis, and a single dose of penicillin given to neonates in the first hour of life. This strategy, however, does not seem to prevent the occurrence of late-onset neonatal group B streptococcal disease. STUDY DESIGN: We assessed early and late-onset GBS disease with the use of a before-after study designed to evaluate the implementation of intrapartum antimicrobial prophylaxis. Moreover, universal neonatal screening for colonization of GBS was carried out with swabs of the external ear canal. Newborns with GBS colonization received a preventive treatment with oral amoxicillin for 10 days. RESULTS: Early-onset GBS infection decreased from 0.5 per thousand at baseline period to 0.19 per thousand at the study period. The incidence of late-onset GBS disease decreased from 1:1348 (0.74 per thousand) to 1:20,710 (0.048 per thousand). The overall cost for universal neonatal screening paid for by the Italian Health System in the study period was 31,065 US dollars with an antibiotic prophylaxis cost of 2,399 US dollars. CONCLUSIONS: A combined strategy based on GBS culture screening and assessment of risk factors for perinatal GBS disease can significantly reduce the rate of both early and late-onset GBS infections.

Inhaled nitric oxide in very preterm infants with severe respiratory distress syndrome.

AIM: To test the hypothesis that inhaled nitric oxide therapy can decrease the incidence of bronchopulmonary dysplasia and death in preterm infants with severe respiratory distress syndrome; to evaluate the possible predictive factors for the response to inhaled nitric oxide therapy. METHODS: Preterm infants (less than 30 weeks' gestation) were randomized to receive during the first week of life inhaled nitric oxide, or nothing, if they presented severe respiratory distress syndrome. Then, the treated infants were classified as non responders and responders. RESULTS: Twenty infants were enrolled in the inhaled nitric oxide therapy group and 20 in the control group. Bronchopulmonary dysplasia and death were less frequent in the inhaled nitric oxide group than in the control group (50 vs. 90%, p=0.016). Moreover, nitric oxide treatment was found to decrease as independent factor the combined incidence of death and BPD (OR=0.111; 95% C.I. 0.02-0.610). A birth weight lower than 750 grams had a significant predictive value for the failure of responding to inhaled nitric oxide therapy (OR 12; 95% C.I. 1.3-13.3). CONCLUSION: Inhaled nitric oxide decreases the incidence of bronchopulmonary dysplasia and death in preterm infants with severe respiratory distress syndrome. Birth weight may influence the effectiveness of inhaled nitric oxide therapy in promoting oxygenation improvement in preterm infants.