Learning to live with patency of the ductus arteriosus in preterm infants.

Treatment of persistent patency of the ductus arteriosus in preterm infants remains heterogeneous and controversial. Routine early treatment to induce ductal closure is not beneficial, but the potential criteria for, timing of, methods for and benefits of later ductal closure have not been determined. Management strategies for infants awaiting spontaneous closure or meeting criteria for treatment may be based on pathophysiological considerations but require evaluation in clinical trials. Better diagnostic tools allowing the identification of infants who might benefit from ductal closure, supplemented by data from clinical trials confirming realization of that potential, are urgently needed.

Treatment of persistent patent ductus arteriosus in preterm infants: time to accept the null hypothesis?

Medical and surgical interventions are widely used to close a persistently patent ductus arteriosus in preterm infants. Objective evidence to support these practices is lacking, causing some to question their usage. Emerging evidence suggests that treatments that close the patent ductus may be detrimental. This review examines the history of and evidence underlying these treatments. Neither individual trials, pooled data from groups of randomized-controlled trials, nor critical examination of the immediate consequences of treatment provide evidence that medical or surgical closure of the ductus is beneficial in preterm infants. These conclusions are supported by sufficient evidence. Neither continued routine use of these treatments nor additional clinical trials using similar designs seems to be justified. A definitive trial, comparing current standard management with novel strategies not primarily intended to achieve ductal closure, may be necessary to resolve doubts regarding the quality or conduct of prior studies.

Combining hand techniques with electric pumping increases milk production in mothers of preterm infants.

OBJECTIVE: Pump-dependent mothers of preterm infants commonly experience insufficient production. We observed additional milk could be expressed following pumping using hand techniques. We explored the effect on production of hand expression of colostrum and hands-on pumping (HOP) of mature milk. STUDY DESIGN: A total of 67 mothers of infants <31 weeks gestation were enrolled and instructed on pumping, hand expression of colostrum and HOP. Expression records for 8 weeks and medical records were used to assess production variables. RESULT: Seventy-eight percent of the mothers completed the study. Mean daily volumes (MDV) rose to 820 ml per day by week 8 and 955 ml per day in mothers who hand expressed >5 per day in the first 3 days. Week 2 and/or week 8 MDV related to hand expression (P<0.005), maternal age, gestational age, pumping frequency, duration, longest interval between pumpings and HOP (P<0.003). Mothers taught HOP increased MDV (48%) despite pumping less. CONCLUSION: Mothers of preterm infants may avoid insufficient production by combining hand techniques with pumping.

Venoarterial versus venovenous extracorporeal membrane oxygenation in congenital diaphragmatic hernia: the Extracorporeal Life Support Organization Registry, 1990-1999.

BACKGROUND/PURPOSE: Venoarterial (VA) extracorporeal membrane oxygenation (ECMO) traditionally has been the mode of support used in congenital diaphragmatic hernia (CDH). A few studies report success using venovenous (VV) ECMO. The purpose of this study is to compare outcomes in CDH patients treated with VA and VV. METHODS: The authors queried the Extracorporeal Life Support Organization Registry for newborns with CDH treated with ECMO from January 1, 1990 through December 31, 1999. They analyzed the pre-ECMO data, ECMO course, and complications. RESULTS: VA was utilized in 2,257 (86%) and VV in 371 (14%) patients. The pre-ECMO status was similar, with greater use of nitric oxide, surfactant, and pressors in VV. Survival rate was similar (58.4% for VV and 52.2% for VA, P =.057). VA was associated with more seizures (12.3% v 6.7%, P =.0024) and cerebral infarction (10.5% v 6.7%, P =.03). Sixty-four treatments were converted from VV to VA (VV-->VA). Survival rate in VV-->VA was not significantly different than VA (43.8% v 52.2%, respectively; P =.23). VV-->VA and VA patients had similar neurologic complications. CONCLUSIONS: CDH patients treated with VV and VA have similar survival rates. VA had more neurologic complications. The authors identified no disadvantage to the use of VV as an initial mode of ECMO for CDH, although some infants may need conversion to VA.

Secondary infection presenting as recurrent pulmonary hypertension.

Primary infection in the neonate, especially group B streptococcal infection, has long been recognized as a cause of persistent pulmonary hypertension of the newborn (PPHN), sometimes requiring treatment with inhaled nitric oxide (iNO) and extracorporeal membrane oxygenation (ECMO). However, secondary nosocomial infections in the neonatal period have not been widely reported as a cause of severe recurrent pulmonary hypertension (PHTN). We now present two cases of secondary infection in the neonate leading to significant PHTN. In both cases, the infants presented with PPHN soon after birth, requiring transfer to a level 3 neonatal intensive care unit and treatment with high-frequency oscillatory ventilation and iNO. After successful resolution of the initial PPHN, including extubation to nasal cannula, both infants developed signs of severe recurrent PHTN, leading to reintubation, high-frequency oscillatory ventilation and iNO therapy, and consideration of ECMO. In both cases, blood cultures taken at the time of recurrence of PHTN returned positive, one for Staphylococcus epidermidis, the other for methicillin-resistant Staphylococcus aureus. These unusual cases present the possibility of severe recurrent PHTN requiring iNO or ECMO in the setting of secondary infection. We speculate that these infants, although extubated after their first episodes of PHTN, were at risk for recurrence of PHTN due to continued pulmonary vascular reactivity.

Mortality and time to death in very low birth weight infants: California, 1987 and 1993.

BACKGROUND: Recent advances in perinatal technology have dramatically increased the survival of very low birth weight (VLBW) infants (<1500 g). The possibility that these advances may also prolong the time to death and increase pain and suffering has been of concern, but there have been no population-based evaluations of this issue. METHODS: Infant, neonatal, and postneonatal mortality rates and time to death for infants 500 to 749 g, 750 to 999 g, 1000 to 1499 g, and all VLBW infants born during 1987 were compared with those outcomes for infants born in 1993 using statewide California linked birth/death cohort files. To assess the effects of improved survival and changes in time until death, we calculated the total days of life preceding an infant death per 1000 live born infants (TDD). RESULTS: VLBW infants comprised.96% of California's live births in 1987 and.92% of those in 1993. Between 1987 and 1993, VLBW infant mortality rate decreased 28.4% (from 290.7 to 208.3 per 1000 live born VLBW infants), VLBW neonatal mortality rate decreased 30. 3% (from 244.5 to 170.4), and VLBW postneonatal mortality rate decreased 25.3% (from 61.2 to 45.7 per 1000 VLBW alive at 28 days; P <.05 for each rate). Infant mortality rates decreased by 18.8% (718. 1 to 583.0 per 1000) for infants 500 to 749 g, 43.3% (375.1 to 202. 6) for infants 750 to 999 g, and 40.1% (127.9 to 76.7) for infants 1000 to 1449 g (P <.05 for each group). Neonatal mortality and postneonatal mortality rates also decreased in all 3 VLBW subgroups. These reductions in mortality rates were not accompanied by a significant difference in the distribution of times to death or a significant increase in the average time to death for all VLBW infants (22.0 vs 23.6 days) or for those with birth weights of 500 to 749 g (12.7 vs 71.5 days). Reduced mortality in larger infants was accompanied by an increase in the average time to death, from 24. 3 to 32.5 days in infants 750 to 999 g and from 32.3 to 47.0 days in infants 1000 to 1449 g. TDD decreased from 6410 to 4908 days for all VLBW infants. TDD was also reduced 26.4% (2401 days), 24.3% (2115 days), and 22.5% (1043 days) for the 3 VLBW birth weight groups. CONCLUSIONS: Both mortality rate and timing of death are important when assessing the impact of advances in perinatal technology. Although the average time to death was significantly increased in VLBW infants weighing >750 g, between 1987 and 1993, advances in perinatal technology dramatically decreased VLBW mortality. In the State of California in 1993, this resulted in 452 fewer VLBW deaths and 8233 fewer days preceding a VLBW death than expected.

Preventing early-onset group B streptococcal sepsis: strategy development using decision analysis.

OBJECTIVE: To evaluate recommended strategies for prevention of early-onset group B streptococcal infections (EOGBS) with reference to strategies optimized using decision analysis. METHODS: The EOGBS attack rate, prevalence and odds ratios for risk factors, and expected effects of prophylaxis were estimated from published data. Population subgroups were defined by gestational age, presence or absence of intrapartum fever or prolonged rupture of membranes, and presence or absence of maternal group B streptococcus (GBS) colonization. The EOGBS prevalence in each subgroup was estimated using decision analysis. The number of EOGBS cases prevented by an intervention was estimated as the product of the expected reduction in attack rate and the number of expected cases in each group selected for treatment. For each strategy, the number of residual EOGBS cases, cost, and numbers of treated patients were calculated based on the composition of the prophylaxis group. Integrated obstetrical-neonatal strategies for EOGBS prevention were developed by targeting the subgroups expected to benefit most from intervention. RESULTS: Reductions in EOGBS rates predicted by this decision analysis were smaller than those previously estimated for the strategies proposed by the American Academy of Pediatrics in 1992 (32.9% vs 90.7%), the American College of Obstetricians and Gynecologists in 1992 (53.8% vs 88.8%), and the Centers for Disease Control and Prevention in 1996 (75.1% vs 86.0%). Strategies based on screening for GBS colonization with rectovaginal cultures at 36 weeks or on use of a rapid test to screen for GBS colonization on presentation for delivery, combining intrapartum prophylaxis for selected mothers and postpartum prophylaxis for some of their infants, would require treatment of fewer patients and prevent more cases (78.4% or 80.1%, respectively) at lower cost. CONCLUSIONS: No strategy can prevent all EOGBS cases, but the attack rate can be reduced at a cost <$12 000 per prevented case. Supplementing intrapartum prophylaxis with postpartum ampicillin in a few infants is more effective and less costly than providing intrapartum prophylaxis for more mothers. Better intrapartum screening tests offer the greatest promise for increasing efficacy. Integrated obstetrical and neonatal regimens appropriate to the population served should be adopted by each obstetrical service. Surveillance of costs, complications, and benefits will be essential to guide continued iterative improvement of these strategies.

Risk factors for early-onset group B streptococcal sepsis: estimation of odds ratios by critical literature review.

OBJECTIVE: To identify and to establish the prevalence of ORs factors associated with increased risk for early-onset group B streptococcal (EOGBS) infection in neonates. streptococcal (EOGBS) infection in neonates. STUDY DESIGN: Literature review and reanalysis of published data. RESULTS: Risk factors for EOGBS infection include group B streptococcal (GBS)-positive vaginal culture at delivery (OR: 204), GBS-positive rectovaginal culture at 28 (OR: 9.64) or 36 weeks gestation (OR: 26. 7), vaginal Strep B OIA test positive at delivery (OR: 15.4), birth weight 18 hours (OR: 7.28), intrapartum fever >37.5 degrees C (OR: 4.05), intrapartum fever, PROM, or prematurity (OR: 9.74), intrapartum fever or PROM at term (OR: 11.5), chorioamnionitis (OR: 6.43). Chorioamnionitis is reported in most (88%) cases in which neonatal infection occurred despite intrapartum maternal antibiotic therapy. ORs could not be estimated for maternal GBS bacteriuria during pregnancy, with preterm premature rupture of membranes, or with a sibling or twin with invasive GBS disease, but these findings seem to be associated with a very high risk. Multiple gestation is not an independent risk factor for GBS infection. CONCLUSIONS: h Mothers with GBS bacteriuria during pregnancy, with another child with GBS disease, or with chorioamnionitis should receive empirical intrapartum antibiotic treatment. Their infants should have complete diagnostic evaluations and receive empirical treatment until infection is excluded by observation and negative cultures because of their particularly high risk for EOGBS infection. Either screening with cultures at 28 weeks gestation or identification of clinical risk factors, ie, PROM, intrapartum fever, or prematurity, may identify parturients whose infants include 65% of those with EOGBS infection. Intrapartum screening using the Strep B OIA rapid test identifies more at-risk infants (75%) than any other method. These risk identifiers may permit judicious selection of patients for prophylactic interventions.

Antimicrobial prevention of early-onset group B streptococcal sepsis: estimates of risk reduction based on a critical literature review.

OBJECTIVE: To identify interventions that reduce the attack rate for early-onset group B streptococcal (GBS) sepsis in neonates. STUDY DESIGN: Literature review and reanalysis of published data. RESULTS: The rate of early-onset GBS sepsis in high-risk neonates can be reduced by administration of antibiotics. Treatment during pregnancy (antepartum prophylaxis) fails to reduce maternal GBS colonization at delivery. With the administration of intravenous ampicillin, the risk of early-onset infection in infants born to women with preterm premature rupture of membranes is reduced by 56% and the risk of GBS infection is reduced by 36%; addition of gentamicin may increase the efficacy of ampicillin. Treatment of women with chorioamnionitis with ampicillin and gentamicin during labor reduces the likelihood of neonatal sepsis by 82% and reduces the likelihood of GBS infection by 86%. Universal administration of penicillin to neonates shortly after birth (postpartum prophylaxis) reduces the early-onset GBS attack rate by 68% but is associated with a 40% increase in overall mortality and therefore is contraindicated. Intrapartum prophylaxis, alone or combined with postnatal prophylaxis for the infants, reduces the early-onset GBS attack rate by 80% or 95%, respectively. CONCLUSIONS: Women with chorioamnionitis or premature rupture of membranes and their infants should be treated with intravenous ampicillin and gentamicin. Intrapartum antimicrobial prophylaxis may be appropriate for other women whose infants are at increased but less extreme risk, and supplemental postpartum prophylaxis may be indicated for some of their infants. Selection of appropriate candidates and prophylaxis strategies requires careful consideration of costs and benefits for each patient. group B streptococcus, neonatal sepsis, early-onset sepsis, prevention, prophylaxis.

Alveolar capillary dysplasia: diagnostic potential for cardiac catheterization.

OBJECTIVE: Alveolar capillary dysplasia is a rare cause of persistent pulmonary hypertension of the newborn. Infants with this condition die despite maximal medical intervention including inhaled nitric oxide therapy and extracorporeal membrane oxygenation. To date, diagnosis of this lethal condition was made by open lung biopsy or during postmortem examination. We examined the possibility that distinct cardiac catheterization findings could be used in the diagnosis of this lethal disorder. STUDY DESIGN: We present three infants with fatal persistent pulmonary hypertension of the newborn refractory to extracorporeal membrane oxygenation and inhaled nitric oxide therapy, two with postmortem autopsy confirmation of alveolar capillary dysplasia. Each infant underwent cardiac catheterization to complete the diagnostic evaluations. RESULTS: Significant right ventricular hypertension and normal pulmonary venous return were demonstrated, but a markedly diminished or absent capillary blush phase was noted in each infant. This finding is distinct from the normal capillary blush seen in infants with persistent pulmonary hypertension of the newborn of other etiologies. CONCLUSION: Cardiac catheterization may provide a useful alternative to tissue examination in the diagnosis of alveolar capillary dysplasia.

Serial serum C-reactive protein levels in the diagnosis of neonatal infection.

OBJECTIVE: To evaluate serial serum C-reactive protein (CRP) levels for diagnosis of neonatal infection. SETTING: A regional intensive care nursery and two community intensive care nurseries. METHODS: All neonates treated for suspected bacterial infection were prospectively evaluated using a standardized clinical pathway. Infants were categorized as having proven sepsis (bacteria isolated from blood, cerebrospinal fluid, or urine culture), probable sepsis (clinical and laboratory findings consistent with bacterial infection without a positive culture), or no sepsis (findings not consistent with sepsis), without consideration of CRP levels. Infants whose blood cultures yielded skin flora but who demonstrated no other signs of bacterial infection were not considered to have sepsis. CRP levels were determined at the initial evaluation and on each of the next two mornings. Sensitivity, specificity, predictive values, and likelihood ratios were calculated for the first (CRP #1), second (CRP #2), higher of the second and third (CRP #2 and #3), or highest of all three CRP levels (CRP x 3). RESULTS: Sepsis was suspected within the first 3 days after birth in 1002 infants (early-onset) and on 184 occasions in 134 older infants (late-onset). There were 20 early-onset and 53 late-onset episodes of proven sepsis, and 74 early-onset and 12 late-onset episodes of probable sepsis. CRP #1 had sensitivities of 39.4% and 64.6% for proven or probable sepsis and 35.0% and 61.5% for proven sepsis in early-onset and late-onset episodes, respectively. CRP levels on the morning after the initial evaluation (CRP #2) had higher sensitivities (92. 9% and 85.0% for proven or probable sepsis and 78.9% and 84.4% for proven sepsis in early-onset and late-onset episodes, respectively), and normal results were associated with lower likelihoods of infection (likelihood ratios for normal results of 0.10 and 0.19 for proven or probable sepsis and 0.27 and 0.21 for proven sepsis, in early-onset and late-onset episodes, respectively). Three serial serum CRP levels had sensitivities of 97.8% and 98.1% for proven or probable sepsis and 88.9% and 97.5% for proven sepsis in early-onset and late-onset episodes, respectively. The negative predictive values for CRP x 3 were 99.7% and 98.7% for both proven or probable sepsis and for proven sepsis in early-onset and late-onset episodes, respectively. A CRP level obtained at the time of the initial evaluation can be omitted without significant loss of sensitivity or negative predictive value: the sensitivities of CRP #2 and #3 were 97.6% and 94.4% for proven or probable sepsis and 88.9% and 96.4% for proven sepsis in early-onset and late-onset episodes, respectively; negative predictive values were 99.7% both for proven and for proven or probable early-onset sepsis, 97.6% for proven or probable late-onset infection, and 98.8% for proven late-onset infection. Serial normal CRP levels were associated with a markedly reduced likelihood of infection as compared with that in the entire population before testing, with likelihood ratios ranging from 0.03 to 0.16 for the various subgroups. Maximum CRP levels >3 mg/dL had positive predictive values >20% for proven or probable early-onset infections and for proven or probable and proven late-onset infections, but only those >6 mg/dL had such a high positive predictive value for proven early-onset sepsis. CONCLUSIONS: Serial CRP levels are useful in the diagnostic evaluation of neonates with suspected infection. Two CRP levels <1 mg/dL obtained 24 hours apart, 8 to 48 hours after presentation, indicate that bacterial infection is unlikely. The sensitivity of a normal CRP at the initial evaluation is not sufficient to justify withholding antibiotic therapy. The positive predictive value of elevated CRP levels is low, especially for culture-proven early-onset infections.

Hemopericardium from coronary artery laceration complicating extracorporeal membrane oxygenation.

OBJECTIVE: We report the clinical course and successful surgical treatment of hemopericardium resulting from coronary artery (CA) laceration in two patients with congenital diaphragmatic hernia (CDH) undergoing extracorporeal membrane oxygenation (ECMO) bypass. STUDY DESIGN: Retrospective case review. RESULTS: Two neonates with CDH had needle aspiration for either pneumothorax or pericardial effusion before initiation of ECMO. While on bypass, progressive hemopericardium led to narrow pulse pressure and decreased venous return that limited bypass flow. Widened cardiac silhouette on chest radiographs suggested hemopericardium; echocardiography was confirmatory in one case. The underlying diagnosis of CA laceration was made during pericardiotomy and treated with surgical patching. CONCLUSIONS: Pre-ECMO history of cardiothoracic needle aspiration is important because complications such as hemothorax or hemopericardium may arise once ECMO bypass is initiated. Inadvertent CA laceration may lead to acute hemopericardium, compromising venous drainage. However, CA laceration can be successfully repaired while the patient is on bypass.

Neonatal severity of illness scoring systems: a comparison.

Several different scoring systems have been developed to predict neonatal morbidity and mortality. In this investigation we compared the utility of four severity of illness scoring systems (SISS) as predictors of days on ventilatory (DOV), length of hospital stay (LOS), and mortality in very-low-birth weight (VLBW) premature infants who required mechanical ventilation. The SISS assessed were the Score for Neonatal Acute Physiology (SNAP); the Score for Neonatal Acute Physiology-Perinatal Extension (SNAP + PE); Clinical Risk Index for Babies (CRIB), and the Sinkin Score at 12 hours (SS12). Results revealed significant correlations among the SS12, SNAP, SNAP + PE, CRIB, birth weight (BW), DOV, and LOS. However, none of the systems we assessed offered striking advantage over BW in a VLBW ventilated group.

Plasma concentrations after rectal administration of acetaminophen in preterm neonates.

Acetaminophen is frequently administered to infants and children for its antipyretic and analgesic properties. Oral administration is the route of choice in daily practice. In some circumstances this is impractical. Rectal administration of acetaminophen is an alternative route. This study measures plasma concentrations following rectal administration of acetaminophen 20 mg.kg-1 (10% Infants' Tylenol Drops, McNeil Consumer Product Co., diluted with an equal volume of sterile water) in five preterm neonates. Serial arterial blood samples were obtained at 0, 15, 30, 60, 120, and 240 min. Pharmacokinetic parameters were (mean +/- SD): Cmax (maximum plasma concentration) of 8.38 +/- 3.92 micrograms.ml-1 and Tmax (time to reach maximum plasma concentration) of 78.0 +/- 40.2 min. Our results show that 20 mg.kg-1 of acetaminophen rectally results in low plasma levels in preterm neonates.

Nitrovasodilator therapy for severe respiratory distress syndrome.

Improved gas exchange in infants with severe respiratory distress syndrome has been reported in association with infusion of nitroprusside and during inhalation of nitric oxide. To evaluate the association between nitrovasodilator therapy and clinical improvement in premature neonates with severe respiratory distress syndrome, we reviewed the courses of 22 infants with severe respiratory distress syndrome who were treated with sodium nitroprusside for at least 24 hours. These infants had birth weights of 2049 +/- 828 gm (range 720 to 3430 gm), gestational ages of 32.5 +/- 3.5 weeks (range 25 to 38 weeks), high ventilator settings before treatment (FIO2 of 100%, peak inspiratory pressures of 37.8 +/- 6.1 cm H2O [range 30 to 50 cm H2O], and mean airway pressures of 18.0 +/- 3.3 cm H2O [range 12.3 to 26 cm H2O]), and low pretreatment PaO2 of 49.3 +/- 9.4 mm Hg (range 27 to 69 mm Hg). Baseline oxygenation indexes were 39.4 +/- 12.1 (range 18.6 to 66.7). Nitroprusside infusion was temporally associated with increased PaO2, decreased PaCO2, and reduced oxygenation index. Potentially beneficial changes were inconsistent in infants with pulmonary interstitial emphysema and were greatest in infants treated with end-expiratory pressures of at least 4 cm H2O. These observations provide a basis for the hypothesis that nitrovasodilator therapy produces improvement in gas exchange in premature infants with severe respiratory distress syndrome.