Maija Pohjavuori

Inositol Supplementation in Premature Infants with Respiratory Distress Syndrome

Abstract Background. Inositol influences cellular function and organ maturation. Feeding premature infants inositol-rich breast milk increases their serum inositol concentrations. Whether inositol supplementation benefits infants receiving fluids for parenteral nutrition, which are inositol-free, is not known. Methods. We carried out a placebo-controlled, randomized, double-blind trial to determine the effects of administering inositol (80 mg per kilogram of body weight per day) during the first five days of life to 221 infants with respiratory distress syndrome who were receiving parenteral nutrition (gestational age, 24 to 32 weeks; birth weight, <2000 g). All the infants were treated with mechanical ventilation and some with surfactant as well. The primary end point was survival at 28 days without bronchopulmonary dysplasia. Results. The 114 patients given inositol had significantly lower mean requirements for inspiratory oxygen (P<0.01) and mean airway pressure (P<0.05) from the 12th through the 144th...

Pharmacokinetics of fluconazole in very low birth weight infants during the first two weeks of life

To find a dose of fluconazole for very low birth weight infants during an outbreak of Candida parapsilosis.

Neonatal Candida parapsilosis outbreak with a high case fatality rate

A Candida parapsilosis outbreak of 58 cases in a neonatal intensive care unit lasted for 55 months. Patients infected by or colonized with C. parapsilosis were mainly very low birth weight infants (birth weight < 1500 g). Their mean birth weight was 817 g and their mean gestational age was 28 weeks. Statistical analysis including logistic regression confirmed that prematurity was the main risk factor. The analysis also suggested that C. parapsilosis infection (or colonization) was associated with a poor prognosis. In infants with gestational age < 29 weeks the risk for death in C. parapsilosis-infected patients was 16-fold greater than in those with no C. parapsilosis infection. The case fatality rate of C. parapsilosis patients was higher than that of the controls (9 of 23 vs. 1 of 40; P < 0.0001). The outbreak was most likely a result of cross-infection because C. parapsilosis could be isolated only from the patients and from the hands of four nurses immediately after they had cared for a colonized patient. Cessation of the outbreak was temporally associated with long term parenteral fluconazole (6 mg/kg/day) prophylaxis.

Effect of surfactant substitution on lung effluent phospholipids in respiratory distress syndrome: evaluation of surfactant phospholipid turnover, pool size, and the relationship to severity of respiratory failure.

ABSTRACT. The turnover and pool size of surfactant has been studied in animals, but there is little similar information in humans. In the present investigation lung effluent phospholipids were studied in 29 small preterm infants with severe RDS. Thirteen were treated with mechanical ventilation, and 16 additionally received natural human surfactant. The first dose (60 mg surfactant/kg body wt) was given between 2 and 10 h of age, and the surfactant was given again if there was an insufficient response. Together 260 aspirates, recovered during routine suctioning of the airways, were analyzed for phospholipids. Phosphatidylglycerol, present only in exogenous surfactant, was used as a specific marker to estimate the apparent pool size and the half-life of surfactant phospholipid. In addition, the saturated phosphatidylcholine/sphingomyelin ratios were correlated with the ventilatory index (mean airway pressure x fractional inspiratory oxygen/arterial oxygen tension). There was a linear correlation between the ventilatory index and the saturated phosphatidylcholine/ sphingomyelin (r ~ -0.70) but no consistent correlation between the ventilatory index and the amount of phospholipids in the aspirate. The saturated phosphatidylcholine/ sphingomyelin ratio increased during the surfactant-induced remission of respiratory failure, decreased during the relapse of respiratory failure (present among 50% of the surfactant-treated infants), and increased again during the recovery. The control infants tended to have lower saturated phosphatidylcholine/sphingomyelin ratios during the first week than the surfactant-treated infants. The recipients of surfactant had slightly more severe lung disease than the controls, when the results were adjusted by covariance to remove the differences in the saturated phosphatidylcholine/ sphingomyelin ratio. Exogenous surfactant increased the apparent endogenous pool size at least fivefold. The apparent half-life of phosphatidylglycerol was 30 h (20–36 h). The half-life was independent of the amount of exogenous surfactant (60 versus 120 mg/kg). Therefore, the apparent turnover rate after 120 was higher than after 60 mg/kg surfactant (p<0.01).

Hemodynamic significance of vasopressin in the newborn infant

In 21 normal deliveries, high concentrations of arginine vasopressin in cord arterial blood were associated with higher blood pressure and lower skin temperatures, indicating peripheral vasoconstriction. Following cesarean section after the onset of labor, cord AVP concentrations and blood pressures were lower than after normal delivery, but higher than after elective cesarean section. Maternal AVP concentrations at delivery were normal, as were plasma AVP concentrations in all infants three days after delivery. We conclude that the massive release of vasopressin is associated with normal delivery, and with peripheral vasoconstriction. These findings reflect favorable hemodynamic adaptation to the hypoxia and stress of delivery, intended to redistribute cardiac output to vital organs.

Mononuclear cell subpopulations in preterm and full-term neonates: independent effects of gestational age, neonatal infection, maternal pre-eclampsia, maternal betamethason therapy, and mode of delivery

Blood samples from 29 preterm (24–32 weeks of gestation) and 21 full‐term (37–42 weeks of gestation) neonates were analysed for surface markers of lymphocyte subtypes and macrophages, and the effects of gestational age, neonatal infection, maternal pre‐eclampsia, maternal betamethason therapy and mode of delivery were assessed with multiple regression analysis. Gestational age alone had few independent effects (increase in CD3+, CD8+CD45RA+, and CD11α+ cells, and decrease in CD14+, HLA‐DR− cells) during the third trimester on the proportions of the immune cell subtypes studied. Neonatal infection and mothers pre‐eclampsia had the broadest and very opposite kinds of effects on the profile of immune cells in the blood. Infection of the neonate increased the proportions of several ‘immature’ cells (CD11α−CD20+, CD40+CD19−, and CD14+HLA‐DR−), whereas mothers pre‐eclampsia decreased the proportions of naive cell types (CD4+CD8+, CD5+CD19+). In addition, neonatal infection increased the proportion of T cells (CD3+, CD3+CD25+, and CD4+/CD8+ ratio, and CD45RA+ cells), while maternal pre‐eclampsia had a decreasing effect on the proportion of CD4+ cells, CD4+/CD8+ ratio, and proportions of CD11α+, CD14+ and CD14+HLA‐DR+ cells. Maternal betamethason therapy increased the proportion of T cells (CD3+) and macrophages (CD14+, CD14+HLA‐DR+), but decreased the proportion of natural killer (NK) cells. Caesarean section was associated with a decrease in the proportion of CD14+ cells. We conclude that the ‘normal range’ of proportions of different mononuclear cells is wide during the last trimester; further, the effect of gestational age on these proportions is more limited than the effects of other neonatal and even maternal factors.

Extracellular Release of Bactericidal/Permeability-Increasing Protein in Newborn Infants

Upon activation, polymorphonuclear leucocytes (PMN) release bactericidal/permability-increasing protein, (BPI) from their azurophil granules. BPI selectively binds to the lipopolysaccharide (LPS) on gram-negative bacteria and induces their death. This study examined plasma BPI concentration levels in healthy newborns and in newborns with clinical sepsis, and the ability of PMN from preterm and term infants to release BPI. We also studied the release of myeloperoxidase (MPO), and the surface expression of adhesion molecule CD11b on PMN. In infants with clinical sepsis, plasma BPI concentration was higher, 27.8 μg/L [8.6–883; median (range)] (n = 11), than in healthy term infants 8.9 μg/L (3.9–179) (n = 17), and in adults 7.3 μg/L (0.7 –18.4) (n = 15);p = 0.014, Kruskal-Wallis. In preterm infants (n = 8), the ability of PMN to release BPI in vitro after stimulation with PMA was 8.8, in term infants it was 15.9 (n = 29;p > 0.05 vs. preterm infants) and in adults 23.4 ng/106 PMN (n = 15;p = 0.024 and p > 0.05 vs. preterm and term infants, respectively). The corresponding values of MPO were 20.0 ng/106 (11.3–46.7) in preterms, 19.0 ng/106 (2.2–223.7) in terms, and 27.8 ng/106 (9.1–80.7) in adults;p = 0.67 between groups. In infants with clinical sepsis, CD11b level was higher, 292 RFU (234–403) than the basal CD11b expression levels in healthy newborn infants, 116 RFU (76–145);P = 0.0001. FMLP-stimulated PMN CD11b expressions in preterm cord blood, 1071 RFU (552–1286) and in term cord blood, 918 (567–1472) were on the same level, but lower than that in adult blood, 1592 (973–1946);p < 0.001, ANOVA. Our findings suggest that in preterm infants the ability to release BPI is lower than in adults and term infants. These findings suggest that premature neonates have an impaired ability to mobilize BPI, possibly contributing to their marked susceptibility to infections with Gram-negative bacteria.

Total parenteral nutrition-associated cholestasis in surgical neonates may be reversed by intravenous cholecystokinin: A preliminary report

Neonatal infants who require total parenteral nutrition (TPN) after major operations are susceptible to total parenteral nutrition-associated cholestasis (TPNAC). A therapeutic dilemma ensues if cholestasis does not resolve after the institution of full enteral nutrition. The authors report the reversal of TPN-associated cholestasis by intravenous cholecystokinin in eight infants who had undergone major surgery during the neonatal period. The indications for surgery were necrotizing enterocolitis in three patients, midgut volvulus in one, gastroschisis in one, diaphragmatic hernia in one, necrosis of the stomach in one, and cardiac anomaly in one. Four of the infants were premature. Median duration of TPN was 25 days (range, 20 to 150 days). Seven patients were weaned from TPN before treatment with cholecystokinin was instituted Mean duration of pretreatment full enteral nutrition in these seven patients was 35 days (range, 20 to 55 days). One girl with short gut syndrome tolerated only 10% of her caloric needs via the enteral route. All patients had alcoholic stools, conjugated hyperbilirubinemia, no excretion of Technetium-labeled HIDA to the biliary tree or duodenum (six patients), and significantly elevated liver enzyme values. In three patients, echography showed biliary sludge or stones in the gall bladder. Porcine cholecystokinin (2 IDU/kg) was administered intravenously for 3 to 5 days. If the stool color did not normalize, cholecystokinin injections were repeated using a larger dose (4 IDU/kg). In seven patients, including the girl with short gut syndrome, the clinical jaundice and conjugated hyperbilirubinemia completely resolved within 1 to six weeks. No biliary sludge or stones were seen in the posttreatment echography in any of the patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Outcome at twelve months of adjusted age in very low birth weight infants with lung immaturity: A randomized, placebo-controlled trial of human surfactant

We compared the neurodevelopmental outcome of extremely premature, surfactant-deficient infants who received either prophylactic surfactant at birth, rescue surfactant after the clinical diagnosis of respiratory distress syndrome was established, or placebo. Infants studied were participants in a randomized, bicenter (San Diego, Calif., and Helsinki, Finland), controlled trial of human surfactant therapy. One hundred fifty infants (prophylaxis group, 63 infants; rescue group, 57; placebo group, 30) were prospectively enrolled at 38 weeks of gestational age. There were no neonatal intergroup differences in the incidence or severity of sonographic central nervous system abnormality or retinopathy. One hundred forty-five infants were alive at 1 year of adjusted age, at which time growth, neurosensory, and neurologic outcome were similar in all three treatment groups at both centers. Cerebral palsy occurred in 20% overall. Five infants (3.5%) were functionally blind. However, infants treated at birth had lower mean mental and motor scores on the Bayley Scales of Infant Development compared with those of infants rescued with surfactant after the onset of respiratory distress syndrome (Mental Development Index: 78 vs 96, p = 0.02; Psychomotor Development Index: 73 vs 87, p = 0.04). Chronic lung disease occurred more frequently in the prophylactically treated group and contributed to the subjects neurologic and developmental morbidity. Because prophylactic surfactant treatment offered no neurodevelopmental advantage and may contribute to poorer outcome, we currently recommend early surfactant replacement only for those infants who have postnatal evidence of respiratory distress syndrome.

Prostacyclin Treatment for Persistent Pulmonary Hypertension of the Newborn

To study the effect of prostacyclin treatment on pulmonary arterial pressure (PAP), systolic pressure (BP), and systemic oxygenation, eight infants with persistent pulmonary hypertension of the newborn (PPHN) born between 34 and 42 weeks’ gestation and having a birth weight of 2540–4130 g were studied using Doppler echocardiography. At a mean age of 19 hours (range 3–32 hours), despite maximal ventilator therapy and an FiO2 of 1.0, the mean PaO2/PAO2 was 0.07 (range 0.04–0.09) and the AaDO2 was 616 mmHg (range 521–654 mmHg). After volume correction and during inotropic medication with dopamine and dobutamine, the mean PAP by echocardiography was 68.6 ± 6.5 mmHg and the mean BP 59.8 ± 4.8 mmHg. Prostacyclin infusion was then started at a dose of 20 ng/kg/min and increased stepwise to a mean dose of 60 ng/kg/min (range 30–120 ng/kg/min) over 4–12 hours, at which time PAP decreased to 49.2 ± 3.5 mmHg (p= 0.0005) and BP to 53.2 ± 9.1 mmHg (p= 0.17); the PAP thereafter remained below the BP. After 72 hours of prostacyclin infusion, PAP was 49.6 ± 18 mmHg, BP 66.1 ± 5.4 mmHg, PaO2/PAO2 0.14 ± 0.12, and AaDO2 428 ± 189 mmHg at FiO2 0.65. The median duration of prostacyclin infusion was 3.6 days and of respirator treatment 7.0 days. All patients survived without extracorporeal membrane oxygenation. At 6–12 months, none of the patients had severe central nervous system complications, but two had bronchopulmonary dysplasia. These findings indicate that prostacyclin is able to reverse the right-to-left shunt in PPHN by decreasing PAP, and that systemic hypotension can be prevented with adequate volume correction and inotropic medication.