Michael S. Schimmel

Ductal Closure With Paracetamol: A Surprising New Approach to Patent Ductus Arteriosus Treatment

Standard pharmacologic closure of the patent ductus arteriosus currently involves the administration of 1 of 2 cyclooxygenase inhibitors: either indomethacin or ibuprofen. However, both of these drugs can be associated with potentially significant adverse effects. We present here the cases of 5 preterm infants (gestational age: 26–32 weeks; postnatal age: 3–35 days) with large, hemodynamically significant patent ductus arteriosus who had either failed or had contraindications to ibuprofen therapy. Each of these infants was treated with off-label oral paracetamol (15 mg/kg per dose every 6 hours). Ductal closure was achieved within 48 hours in all the treated infants. No toxicity was observed.

Procalcitonin in preterm infants during the first few days of life: introducing an age related nomogram

Objective: To determine normal concentrations of procalcitonin in preterm infants shortly after birth and to assess its accuracy in detecting bacterial infection. Methods: Blood samples of 100 preterm infants were prospectively drawn during the first 4 days of life for determination of procalcitonin concentration. Infants were classified into four groups according to their sepsis status. Results: Mean (SD) gestational age and birth weight were 32 (2.9) weeks and 1682 (500) g respectively. A total of 283 procalcitonin concentrations from healthy infants were plotted to construct nomograms of physiologically raised procalcitonin concentration after birth, stratified by two groups to 24–30 and 31–36 weeks gestation. The peak 95th centile procalcitonin concentration was plotted at 28 hours of age; values return to normal after 4 days of life. Only 12 infants were infected, and 13 of their 16 procalcitonin concentrations after birth were higher than the 95th centile, whereas samples taken at birth were lower. In a multivariable analysis, gestational age, premature rupture of membrane, and sepsis status influenced procalcitonin concentration independently, but maternal infection status did not. Conclusions: The suggested neonatal nomograms of preterm infants are different from those of term infants. Procalcitonin concentrations exceeding the 95th centile may be helpful in detecting congenital infection, but not at birth.

Indomethacin Tocolysis Increases Postnatal Patent Ductus Arteriosus Severity

Postnatally, therapeutic indomethacin administration is usually effective in mediating patent ductus arteriosus (PDA) constriction in premature infants. There are infants, however, who remain resistant to indomethacin and require more aggressive surgical intervention to facilitate ductal closure. Indomethacin tocolysis has been reported to increase the incidence of persistent PDA in premature infants. It was our impression that infants exposed to antenatal indomethacin not only suffered from an increased incidence of PDA, but that they were more symptomatic from PDA and that for them, PDA was more resistant to medical closure. It is this observation that we sought to examine in this study. Methods. Medical records of all mothers and premature neonates with birth weight ≤1500 g, admitted to the neonatal intensive care unit of the Shaare Zedek Medical Center during 1996 and 1997, who survived for at least 1 week, were reviewed retrospectively. Data on maternal indomethacin and steroid exposure, birth weight and gestational age, and ductus status and treatment were analyzed. In our obstetrics department, indomethacin is the medication of choice to inhibit premature labor. Mothers who arrive in premature labor are started on indomethacin therapy, if delivery is not imminent. All infants ≤1500 g were studied by a pediatric cardiologist between 24 and 72 hours of life using two-dimensional echocardiography with color flow mapping to assess ductal patency. Decisions to treat were based on echocardiographic evidence of PDA, along with any of the following clinical signs: bounding pulses, diastolic pressure of ≤25 mm Hg, pulmonary plethora and/or cardiomegaly on chest x-ray, or increasing oxygen requirement with no other explanation. Initial treatment is with indomethacin, if there are no contraindications. Our general approach is to begin therapy with a continuous indomethacin infusion, followed by a course of bolus indomethacin if the infant does not respond. However, each attending neonatologist may treat according to his/her preference (ie, bolus vs continuous). All infants with PDA are followed with serial echocardiographic examinations until the ductus is closed. Results. A total of 105 premature infants met the above criteria. Thirty-six of these 105 infants had echocardiographic signs of a PDA (34.3%). Those with PDA were less mature (gestational age, 28.9 ± 2.6 vs 30.3 ± 2.6 weeks, respectively) and tended to be smaller (1060 ± 270 vs 1166 ± 261 g). Of the 36 infants with PDA, 15 (42%) resolved spontaneously and 21 (58%) were symptomatic and required treatment with indomethacin. There were no differences in gestational age or birth weight between infants whose PDA resolved spontaneously and those requiring indomethacin therapy. Four of the 21 (19%) treated infants remained unresponsive to indomethacin and required ductal ligation. Of 17 infants with PDA who responded to indomethacin therapy, 1 (6%) was treated with a single course of bolus indomethacin, to which he responded, and 16 (94%) were treated with continuous indomethacin and responded promptly. The differences in therapeutic responsiveness to initial treatment with continuous vs bolus indomethacin were not significant. Of the 105 infants, 29 were exposed to indomethacin tocolysis. Those who were exposed to antenatal indomethacin and those who were not were well-matched with respect to birth weight and gestational age. Fifteen (52%) of the 29 exposed infants versus 18 (24%) of the 76 infants not exposed to antenatal indomethacin developed a PDA postnatally (relative risk = 2.1; 95% confidence interval: 1.22–3.74), and 45% of the antenatally exposed infants versus 12% of the nonexposed infants were symptomatic and required indomethacin (relative risk = 1.9; 95% confidence interval: 1.17–3.20). Four of the exposed infants versus none of the unexposed infants required surgical ligation. Among the indomethacin-exposed infants, the nonresponsive and responsive infants were well-matched with regard to birth weight, gestational age, antenatal steroid exposure, and day of life on which indomethacin therapy was initiated. Multiple regression analyses found prenatal indomethacin exposure to be the most significant antecedent variable associated with both the incidence and the severity of PDA, as indicated by the need for indomethacin treatment. Conclusions. We have demonstrated that prenatal indomethacin exposure increases both the incidence and the clinical severity of postnatal PDA, as manifested by increased need for therapeutic indomethacin and surgical ligation. Furthermore, we have shown it to be a more significant risk factor than gestational age, birth weight, or antenatal steroid exposure in both the development and the severity of postnatal PDA. These data should be considered in considerations as to choice of tocolytic therapy.

Post-phototherapy neonatal bilirubin rebound: a potential cause of significant hyperbilirubinaemia

Aim: To determine the incidence of post-phototherapy neonatal plasma total bilirubin (PTB) rebound. Methods: A prospective clinical survey was performed on 226 term and near-term neonates treated with phototherapy in the well baby nursery of the Shaare Zedek Medical Center from January 2001 to September 2002. Neonates were tested for PTB 24 hours (between 12 and 36 hours) after discontinuation of phototherapy, with additional testing as clinically indicated. The main outcome measure, significant bilirubin rebound, was defined as a post-phototherapy PTB ⩾256 μmol/l. Phototherapy was not reinstituted in all cases of rebound, but rather according to clinical indications. Results: A total of 30 (13.3%) neonates developed significant rebound (mean (SD) PTB 287 (27) μmol/l, upper range 351 μmol/l). Twenty two of these (73%) were retreated with phototherapy at mean PTB 296 (29) μmol/l. Multiple logistic regression analysis showed significant risk for aetiological risk factors including positive direct Coombs test (odds ratio 2.44, 95% CI 1.25 to 4.74) and gestational age <37 weeks (odds ratio 3.21, 95% CI 1.29 to 7.96). A greater number of neonates rebounded among those in whom phototherapy was commenced ⩽72 hours (26/152, 17%) compared with >72 hours (4/74, 5.4%) (odds ratio 3.61, 95% CI 1.21 to 10.77). Conclusion: Post-phototherapy neonatal bilirubin rebound to clinically significant levels may occur, especially in cases of prematurity, direct Coombs test positivity, and those treated ⩽72 hours. These risk factors should be taken into account when planning post-phototherapy follow up.

Amelioration of ischemia-reperfusion injury in rat intestine by pentoxifylline-mediated inhibition of xanthine oxidase.

BACKGROUND Intestinal ischemia-reperfusion (IR) injury results in cell destruction, which may be mediated by the generation of reactive oxygen species, potentially toxic metabolites of xanthine oxidase. Pentoxifylline (PTX) possesses a variety of biochemical and antioxidant properties that can improve capillary flow and tissue oxygenation. Because of these combined effects, it has been hypothesized that pentoxifylline would protect against intestinal IR. METHODS Young adult rats were randomly assigned to one of four experimental groups: IR/Placebo (n = 12) in which superior and inferior mesenteric arteries were clamped for 45 minutes and then reopened; IR/PTX (n = 11) in which IR was induced as in the Placebo group, but with 25 mg/kg PTX at 0, 30, and 60 minutes; No IR/Placebo (n = 12); and No IR/PTX (n = 6) in which placebo and PTX were applied with no IR. Blood and intestinal samples were taken for serial thiobarbituric acid-reducing substances (TBARS; index of lipid peroxidation), for xanthine oxidase-xanthine dehydrogenase ratios, glutathione, myeloperoxidase, and histopathology. RESULTS Animals in the IR/PTX group had lower TBARS and the least severe histopathologic injury. Xanthine oxidasexanthine dehydrogenase ratios were elevated only in IR/ Placebo (0.67+/-0.22 vs. 0.45+/-0.14 in IR/PTX; 0.42+/-0.22 in No IR/Placebo; and 0.40+/-0.11 in No IR/PTX; p = 0.0009). Reduced glutathione was diminished in IR/PTX animals (38.9 +/-1.35 vs. 46.1+/-7.0 in IR/Placebo; 41.1+/-2.5 in No IR/ Placebo; 43.6+/-1.0 in No IR/PTX; p = 0.048). No differences were recorded in myeloperoxidase levels among groups. CONCLUSIONS Pentoxifylline ameliorates histopathologic signs of injury and decreases lipid peroxidation (TBARS). Normal xanthine oxidase-xanthine dehydrogenase ratios in the treated compared with IR-only animals imply that the protective effect of PTX is at least partially mediated through inhibition of xanthine oxidase.

The role of procalcitonin as a predictor of nosocomial sepsis in preterm infants

Aim: To assess the role of procalcitonin in detecting nosocomial sepsis in preterm infants, after the onset of clinical symptoms. Subjects: 100 preterm infants, 24–36 wk of gestation, were followed from the age of 3 d until discharge. Procalcitonin and C‐reactive protein (CRP) levels were measured within 3 d of sepsis workup events. Results: 141 blood samples were drawn from 36 infants during 85 episodes of sepsis workup performed between 4 and 66 d of life. Of these episodes, 51 (60%) were not a result of documented sepsis and thereby served as the negative comparison group. Median procalcitonin levels were higher in the septic group compared with the non‐septic group at the time of the sepsis workup (2.7 vs 0.5 ng/ml, p=0.003), at 1–24 h after the sepsis workup (4.6 vs 0.6 ng/ml, p=0.003), and at 25–48 h (6.9 vs 2.0 ng/ml, p=0.016). Using high cutoff levels, both procalcitonin (2.3 ng/ml) and CRP (30 mg/l) had high specificity and positive predictive value (97%, 91% and 96%, 87%, respectively) but low sensitivity (48% and 41%, respectively) to detect sepsis. Areas under the ROC curve for procalcitonin and CRP were 0.74 and 0.73, respectively.

Ibuprofen Versus Continuous Indomethacin in Premature Neonates With Patent Ductus Arteriosus: Is the Difference in the Mode of Administration?

Ibuprofen has been proposed as a preferential alternative to indomethacin in treating patent ductus arteriosus (PDA), because it is purported to have less renal, mesenteric, and cerebral vasoconstrictive effects. However, short and long-term safety concerns regarding ibuprofen remain. Continuous slow infusion of indomethacin also eliminates peripheral vasoconstriction and may thus offer similar benefits to ibuprofen without safety concerns. In this study, our objective was to show that treating a PDA with continuous indomethacin is similar to ibuprofen in its effect on urine output, renal function, and blood flow velocities in the renal, superior mesenteric, and anterior cerebral arteries. Sixty four prematures with PDA were randomly, prospectively assigned to either treatment. PDA closure rates were similar (74 versus 59%; p = 0.123). Nine indomethacin-treated babies (29%) versus twelve ibuprofen babies (38%) underwent repeated therapy (p = 0.656). Two indomethacin and four ibuprofen infants required surgical ligation (p = 0.672). Serum creatinine, oliguria, estimated glomerular filtration rate, and fractional excretion of sodium were similar in both groups, as were blood flow velocity parameters in the vessels studied. There were no differences in necrotizing enterocolitis, BPD, intraventricular hemorrhage, and/or retinopathy of prematurity. In conclusion, PDA treatment with either continuous indomethacin infusion or ibuprofen was equally devoid of adverse renal effects and/or peripheral vasoconstrictive effects.

The effect of meconium staining of amniotic fluid on the growth of Escherichia coli and group B streptococcus.

OBJECTIVE: To compare the effect of meconium staining on the growth rate of Escherichia coli and group B streptococci (GBS) in amniotic fluid.STUDY DESIGN: Sterile meconium was added in different concentrations to pooled sterile amniotic fluid obtained from term mothers. Meconium concentration was equal to: 1, 1.5, 3, 6, and 12 mg meconium/ml amniotic fluid. Amniotic fluid was quantitatively inoculated with E. coli and GBS type II and type III organisms (103 organisms/ml). Clear amniotic fluid and Todd-Hewitt broth served as controls. Growth rates of organisms were measured at 2, 4, 6, 8, and 24 hours after inoculation.RESULTS: Clear amniotic fluid was completely inhibitory for growth of E. coli even after 24 hours of incubation. In contrast, after 6 hours of incubation, significantly increased growth of GBS occurred (105 organisms/ml) (p<0.0001). The inhibitory effect on E. coli was observed even with meconium concentration of up to 1.5 mg/ml. In contrast, even the smallest concentration of meconium (1 mg/ml) resulted in a 2-log fold increase of GBS within 4 hours. The more rapid growth rate of GBS compared to E. coli persisted even at moderate staining of amniotic fluid (6 mg/ml) in the first 8 hours of incubation (p<0.005). In the presence of thick meconium (12 mg/ml), during the first 6 hours of incubation, the growth rates of GBS and E. coli were nearly similar.CONCLUSIONS: GBS (type II and III) growth, in contrast to E. coli, was less inhibited by amniotic fluid, occurred at a more rapid rate, and was enhanced at lower concentrations of meconium. As such, the presence of even light meconium staining in cases of rupture of membranes of even less than 6 hours in a mother who is a GBS carrier should be considered as a risk factor for the development of perinatal GBS infection.

Neonatal Cardiopulmonary Arrest in the Delivery Room

To the Editor .— Cardiopulmonary arrest of a healthy term infant in the delivery room after an uneventful vaginal delivery is an extremely rare event.1,2 We recently encountered 2 such cases in term infants born after uneventful pregnancies and nonmedicated vaginal deliveries. In the first, infant breastfeeding was initiated in the delivery room, unobserved, immediately after birth. A short time later, the infant was found pale and motionless while still on the breast. After resuscitation and NICU care, the infant was discharged without obvious neurologic deficit. Similarly, the second infant initiated breastfeeding unobserved in the delivery room shortly after birth. A few minutes later, …

Pulmonary hypoplasia–diaphragmatic hernia–anophthalmia–cardiac defect (PDAC) syndrome due to STRA6 mutations—What are the minimal criteria?†

Microphthalmic syndrome 9 (OMIM601186) is a genetically and phenotypically variable condition, comprising anophthalmia, pulmonary hypoplasia, diaphragmatic hernia, and cardiac malformations (PDAC syndrome). Reported cases have all been associated with fetal/neonatal death or developmental delay. Recessive stimulated by retinoic acid gene 6 homolog (STRA6) mutations have recently been identified as the cause of cases of PDAC in which distinct, “bushy” eyebrows have been observed. We describe a patient with clinical anophthalmia, bushy eyebrows, patent ductus arteriosus, and normal development at age 30 months, who is a compound heterozygote for two novel STRA6 missense mutations. This patients phenotype is consistent with the multisystemic malformations of PDAC syndrome, but is somewhat milder. This is the first living patient with compound heterozygous STRA6 mutations, which may explain her milder phenotype. We conclude that STRA6 analysis should be considered in all patients with clinical anophthalmia. Genetic counseling should be cautious with respect to long‐term developmental outcomes.