Thomas E. Wiswell

Oropharyngeal and nasopharyngeal suctioning of meconium-stained neonates before delivery of their shoulders: multicentre, randomised controlled trial

BACKGROUNDnMeconium aspiration syndrome (MAS) is a life-threatening respiratory disorder in infants born through meconium-stained amniotic fluid (MSAF). Although anecdotal data concerning the efficacy of intrapartum oropharyngeal and nasopharyngeal suctioning of MSAF are conflicting, the procedure is widely used. We aimed to assess the effectiveness of intrapartum suctioning for the prevention of MAS.nnnMETHODSnWe designed a randomised controlled trial in 11 hospitals in Argentina and one in the USA. 2514 patients with MSAF of any consistency, gestational age at least 37 weeks, and cephalic presentation were randomly assigned to suctioning of the oropharynx and nasopharynx (including the hypopharynx) before delivery of the shoulders (n=1263), or no suctioning before delivery (n=1251). Postnatal delivery-room management followed Neonatal Resuscitation Program guidelines. The primary outcome was incidence of MAS. Clinicians diagnosing the syndrome and designating other study outcomes were masked to group assignment. An informed consent waiver was used. Analysis was by intention to treat.nnnFINDINGSn18 infants in the suction group and 15 in the no suction group did not meet entry criteria after random assignment. 87 in the suction group were not suctioned, and 26 in the no suction group were suctioned. No significant difference between treatment groups was seen in the incidence of MAS (52 [4%] suction vs 47 [4%] no suction; relative risk 0.9, 95% CI 0.6-1.3), need for mechanical ventilation for MAS (24 [2%] vs 18 [1%]; 0.8, 0.4-1.4), mortality (9 [1%] vs 4 [0.3%]; 0.4, 0.1-1.5), or in the duration of ventilation, oxygen treatment, and hospital care.nnnINTERPRETATIONnRoutine intrapartum oropharyngeal and nasopharyngeal suctioning of term-gestation infants born through MSAF does not prevent MAS. Consideration should be given to revision of present recommendations.

A Multicenter, Randomized, Controlled Trial of Lucinactant Versus Poractant Alfa Among Very Premature Infants at High Risk for Respiratory Distress Syndrome

Background. Available therapeutic surfactants are either animal-derived or non–protein-containing synthetic products. Animal-derived surfactants contain variable amounts of surfactant apoproteins, whereas the older-generation synthetic products contain only phospholipids and lack surfactant proteins (SPs). Both decrease morbidity and mortality rates associated with respiratory distress syndrome (RDS) among preterm infants, compared with placebo. However, excess mortality rates have been observed with non–protein-containing synthetic surfactants, compared with the animal-derived products. Evidence suggests that synthetic surfactants consisting solely of phospholipids can be improved with the addition of peptides that are functional analogs of SPs. Lucinactant is a new synthetic peptide-containing surfactant that contains sinapultide, a novel, 21-amino acid peptide (leucine and lysine repeating units, KL4 peptide) designed to mimic human SP-B. It is completely devoid of animal-derived components. Objective. We hypothesized that the outcomes for premature infants treated with lucinactant and poractant alfa would be similar. Therefore, we compared lucinactant (Surfaxin; Discovery Laboratories, Doylestown, PA) with porcine-derived, poractant alfa (Curosurf; Chiesi Farmaceutici, Parma, Italy) in a trial to test for noninferiority. Methods. A total of 252 infants born between 24 and 28 weeks of completed gestation, with birth weights between 600 and 1250 g, were assigned randomly in a multicenter, multinational, noninferiority, randomized, controlled study to receive either lucinactant (n = 124) or poractant alfa (n = 128) within 30 minutes of life. The primary outcome was the incidence of being alive without bronchopulmonary dysplasia (BPD) through 28 days of age. Key secondary outcomes included death at day 28 and 36 weeks postmenstrual age (PMA), air leaks, neuroimaging abnormalities, and other complications related to either prematurity or RDS. An independent, international, data and safety monitoring committee monitored the trial. Results. The treatment difference between lucinactant and poractant alfa for survival without BPD through 28 days was 4.75% (95% confidence interval [CI]: −7.3% to 16.8%) in favor of lucinactant, with the lower boundary of the 95% CI for the difference, ie, −7.3%, being greater than the prespecified noninferiority margin of −14.5%. At 28 days, 45 of 119 infants given lucinactant were alive without BPD (37.8%; 95% CI: 29.1–46.5%), compared with 41 of 124 given poractant alfa (33.1%; 95% CI: 24.8–41.3%); at 36 weeks PMA, the rates were 64.7% and 66.9%, respectively. The corresponding mortality rate through day 28 for the lucinactant group was lower than that for the poractant alfa group (11.8% [95% CI: 6.0–17.6%] vs 16.1% [95% CI: 9.7–22.6%]), as was the rate at 36 weeks PMA (16% and 18.5%, respectively). There were no differences in major dosing complications. In addition, no significant differences were observed in the incidences of common complications of prematurity, including intraventricular hemorrhage (grades 3 and 4) and cystic periventricular leukomalacia (lucinactant: 14.3%; poractant alfa: 16.9%). Conclusions. Lucinactant and poractant alfa were similar in terms of efficacy and safety when used for the prevention and treatment of RDS among preterm infants. The ability to enhance the performance of a synthetic surfactant with the addition of a peptide that mimics the action of SP-B, such as sinapultide, brings potential advantages to exogenous surfactant therapy.

A study of the role of multiple site blood cultures in the evaluation of neonatal sepsis

Background:The optimal number of blood cultures needed to document sepsis in an ill neonate has undergone little critical evaluation. Multiple site cultures may improve pathogen detection if intermittent bacteremia occurs, or if a low density of bacteria is present in the blood. We hypothesized, however, that bacterial clearance is slower and bacteremia more continuous in septic neonates, so that a single site blood culture should be sufficient to accurately document true septicemia.Objective:To determine the need for multiple site blood cultures in the evaluation of neonates for sepsis.Design/Methods:Clinical data were prospectively collected for 216 neonates who had 269 pairs of blood cultures taken from two different peripheral sites for the evaluation of possible sepsis. A minimum of 1u2009ml of blood was obtained from the two peripheral sites within 15–30u2009min of each other. Based on prior retrospective data, we determined that 203 infants would need to have two site blood cultures to demonstrate a significant improvement in pathogen detection at an alpha of 0.05 and a beta of 0.20 (80%) power.Results:A total of 186 culture pairs were taken for evaluation of early-onset sepsis in 186 neonates, while 83 pairs were drawn for evaluation of late-onset sepsis in 43 neonates. In all, 21 neonates from the late-onset group were evaluated more than once, and 12 neonates were evaluated for both early- and late-onset sepsis. In all, 20 (9.2%) of 216 neonates had 22 episodes of culture-proven sepsis at a median age of 18 days. All neonates with positive cultures had the same organism with a similar sensitivity pattern obtained from the two different peripheral sites. The other 196 study neonates had negative blood cultures from both sites. The single episode of early-onset sepsis was caused by Listeria monocytogenes, while all remaining episodes were late-onset with the following organisms: Staphylococcus epidermidis (7), methicillin-resistant Staphylococcus aureus (MRSA) (3), combined MRSA and Candida albicans (2), Candida albicans alone (2), late-onset Group B β-hemolytic Streptococcus (GBS) (2), Klebsiella pneumoniae (2), Enterococcus fecalis (1), Escherichia coli (1), and Serratia marcescens (1). Since no infant grew organisms from only one of the two sites, the data indicate that the diagnosis of sepsis would have been made correctly in all infants with a single site culture.Conclusions:Two site blood cultures for the initial evaluation of neonatal sepsis do not have a better yield in pathogen detection. Sepsis in neonates can be detected with no loss of accuracy with a single site blood culture with blood volume of ⩾1u2009ml.

Multiple site blood cultures in the initial evaluation for neonatal sepsis during the first week of life

We present the first investigation that examines the usefulness of multiple site blood cultures in the initial evaluation for neonatal sepsis during the first week of life. Two sets of blood cultures (1 aerobic and 1 anaerobic bottle/set; BACTEC, NR 6A/7A) from different sites were obtained from 460 inborn infants who were evaluated for possible sepsis. From 0.5 to 1 ml of blood was inoculated into each blood culture bottle. In 18 infants the use of multiple site blood cultures yielded important information. In 8 of these neonates bacteremia was confirmed whereas in 10 cases contamination from skin flora was documented. We could identify no instances in which the delay in antibiotic therapy while the second set of blood cultures was obtained contributed to an adverse outcome. We conclude that multiple site blood cultures are useful in the initial evaluation for suspected sepsis during the first week of life.

Management of asymptomatic, term gestation neonates born to mothers treated with intrapartum antibiotics.

Intrapartum antibiotics are frequently administered to parturient women for suspected chorioamnionitis to treat infection in the mother and to prevent or treat infection in the baby. We sent a questionnaire to the 150 United States fellowship program directors in neonatology and pediatric infectious disease, focusing on recommendations for evaluation and therapy of apparently healthy, pretreated, term gestation infants. Eighty-three (55%) of the completed responses were analyzed. Sixteen (19%) respondents do no initial laboratory evaluation but simply observe the baby, 65 (78%) take a complete blood count as well as a platelet count, 59 (71%) obtain blood cultures, 41 (49%) check urine antigen for Group B Streptococcus (GBS) and 23 (28%) perform a lumbar puncture. Only 39% of respondents would begin antibiotic therapy for all pretreated infants. If the evaluation were unremarkable 65 directors would treat for less than or equal to 3 days. If only the urine GBS antigen were positive 47 would treat for greater than or equal to 7 days, while if an elevated immature neutrophil:total neutrophil ratio were the sole abnormality 19 would treat for greater than or equal to 7 days. Forty-four respondents thought that a combination of an elevated immature neutrophil:total neutrophil ratio and a positive urine GBS antigen should always be considered indicative of bacteremia. Given a different scenario, that of a mother treated with intrapartum antibiotics because of a positive cervical culture for GBS and a risk factor (e.g. temperature greater than or equal to 38 degrees C), 58 respondents would begin antibiotics. There is no consensus regarding management of pretreated, healthy appearing, term gestation neonates.

Histological chorioamnionitis and the risk of early intraventricular hemorrhage in infants born ≤28 weeks gestation

OBJECTIVE:To test the hypothesis that histological chorioamnionitis (CA) is not associated with increased risk of early onset intraventricular hemorrhage (IVH).STUDY DESIGN:Clinical data were prospectively collected for 62 consecutive neonates born before 28 weeks of gestation. Placental histology for CA was performed by a pathologist unaware of the head ultrasound scan (HUS) results. The first HUS was obtained by 30 minutes of life. Follow-up HUS were performed before 24 hours and again at 48 to 72 postnatal hours of life. An IVH (grade I to IV) at less than 72 hours of life was deemed an early hemorrhage.RESULTS:Nine of the 62 (14.5%) infants had early onset IVH. In all, 29 infants were born to women with histological evidence of CA; 33 infants did not have CA. Infants did not differ in birth weight, gestational age, sex, cord blood pH, 5-minute Apgar score of <7, cesarean delivery, prenatal use of steroids, administration of tocolytics, need for resuscitation, presence of pneumothorax, platelet count at birth, or use of surfactant. Early IVH rates (3/29 in CA vs 6/33 in non-CA) were similar (p=0.48). Two infants in each group with early IVH died before 2 weeks of age. Five additional infants from the CA group developed IVH at more than 72 postnatal hours of life (late onset IVH), and two of those infants progressed to develop periventricular leukomalacia (PVL). In contrast, only three non-CA infants had late IVH and none developed PVL. Logistic regression confirmed that no perinatal variables including CA were associated with early onset IVH.CONCLUSION:Chorioamnionitis is not associated with increased risk of early IVH.

Expanded uses of surfactant therapy.

There are few therapies for which the cumulative evidence of benefit is as much as that for surfactant therapy for RDS in premature infants. Exogenous surfactant therapy does seem to be beneficial for a number of non-RDS disorders. Although there are some trials supporting its use in MAS and ALI-ARDS, there are only a few small prospective, randomized, controlled trials supporting surfactant use in non-RDS disorders. Use of surfactant therapy for any disorder other than RDS must be considered off the shelf and experimental. Much work remains to be done to address the role of surfactant therapy in the myriad disorders discussed. Of import for each of the disorders is addressing the optimum type of surfactant to use, and the appropriate dose, method of delivery, and duration of treatment regimens.

When Is Waiver of Consent Appropriate in a Neonatal Clinical Trial

It is difficult to do scientifically rigorous research on treatments that must be administered urgently or emergently. Therefore, such treatments are often provided without a strong evidence base. Research would be facilitated if it were permissible to waive the requirement for parental consent. However, that raises a different set of concerns. Federal regulations allow waiver of the requirement for consent but only if studies meet certain conditions. Institutional review boards must decide whether those conditions are met. Sometimes, reasonable people disagree. We present and analyze a protocol for which investigators request a waiver of consent.

FAILURE OF FUROSEMIDE TO AFFECT THE CLINICAL COURSE OF TRANSIENT OF THE NEWBORN

Transient Tachypnea of the Newborn (TTN) prolongs neonatal hospitalization and occasionally results in serious complications. The most widely accepted theory of the etiology of TTN is a delay in the absorption of fetal lung fluid. Furosemide has been shown to affect fluid dynamics in the lung. We hypothesized that a pharmacologically-induced diuresis of body water may reverse the mechanism of TTN and shorten the course of the illness. We designed a controlled, prospective trial of oral furosemide in infants with TTN. 50 consecutive infants presenting with the clinical and radiographic findings of TTN were randomly assigned to two groups. Infants in the treatment group received 2 mg/kg of oral furosemide at the time of diagnosis followed by a 1 mg/kg dose 12 hours later if the tachypnea (RR> 60) persisted. Infants in the control group received an equal volume of placebo. There were no significant differences in the prenatal and perinatal courses, nor in the demographic characteristics between the two groups. Although mean weight loss at discharge was similar in the two groups, the furosemide-treated group lost significantly more weight in the first 24 hours after birth (p<0.001). Compared to infants in the control group, the furosemide-treated infants demonstrated no statistically significant difference in the duration and severity of symptoms, nor in the duration of hospitalization. We conclude that oral furosemide, at the doses used in this study, does not alter the clinical course of TTN.