Withholding or withdrawing life-sustaining treatment in extremely low gestational age neonates.

OBJECTIVE: To identify sociodemographic and clinical factors associated with withholding or withdrawing life-sustaining treatment (WWLST) for extremely low gestational age neonates. DESIGN: Observational study of prospectively collected registry data from 19 National Institute of Child Health and Human Development Neonatal Research Network centres on neonates born at 22-28 weeks gestation who died >12 hours through 120 days of age during 2011-2016. Sociodemographic and clinical factors were compared between infants who died following WWLST and without WWLST. RESULTS: Of 1168 deaths, 67.1% occurred following WWLST. Withdrawal of assisted ventilation (97.4%) was the primary modality. WWLST rates were inversely proportional to gestational age. Life-sustaining treatment was withheld or withdrawn more often for non-Hispanic white infants than for non-Hispanic black infants (72.7% vs 60.4%; 95% CI 1.00 to 1.92) or Hispanic infants (72.7% vs 67.2%; 95% CI 1.32 to 3.72). WWLST rates varied across centres (38.6-92.6%; p<0.001). The centre with the highest rate had adjusted odds 4.89 times greater than the average (95% CI 1.18 to 20.18). The adjusted odds of WWLST were higher for infants with necrotiing enterocolitis (OR 1.77, 95% CI 1.21 to 2.59) and severe brain injury (OR 1.98, 95% CI 1.44 to 2.74). CONCLUSIONS: Among infants who died, WWLST rates varied widely across centres and were associated with gestational age, race, ethnicity, necrotiing enterocolitis, and severe brain injury. Further exploration is needed into how race, centre, and approaches to care of infants with necrotiing enterocolitis and severe brain injury influence WWLST.

Barriers to enrollment in a randomized controlled trial of hydrocortisone for cardiovascular insufficiency in term and late preterm newborn infants.

OBJECTIVE: To analyze reasons for low enrollment in a randomized controlled trial (RCT) of the effect of hydrocortisone for cardiovascular insufficiency on survival without neurodevelopmental impairment (NDI) in term/late preterm newborns. STUDY DESIGN: The original study was a multicenter RCT. Eligibility: ⩾34 weeks' gestation, <72 h old, mechanically ventilated, receiving inotrope. Primary outcome was NDI at 2 years; infants with diagnoses at high risk for NDI were excluded. This paper presents an analysis of reasons for low patient enrollment. RESULTS: Two hundred and fifty-seven of the 932 otherwise eligible infants received inotropes; however, 207 (81%) had exclusionary diagnoses. Only 12 infants were randomized over 10 months; therefore, the study was terminated. Contributing factors included few eligible infants after exclusions, open-label steroid therapy and a narrow enrollment window. CONCLUSION: Despite an observational study to estimate the population, very few infants were enrolled. Successful RCTs of emergent therapy may require fewer exclusions, a short-term primary outcome, waiver of consent and/or other alternatives.

A case of infant delirium in the neonatal intensive care unit.

Infant delirium is an under-recognized clinical entity in neonatal intensive care, and earlier identification and treatment could minimize morbidities associated with this condition. We describe a case of a 6-month-old former 32 weeks gestation infant undergoing a prolonged mechanical ventilation course diagnosed with delirium related to the combination of his underlying illness and the use of multiple sedative and analgesic medications. Initiation of the atypical antipsychotic risperidone allowed for weaning from continuous infusions of benzodiazepines and opiods, and lower dosages of bolus-dosed sedation and analgesics. The patient experienced no adverse side effects from use of this neuroleptic.

Association of in utero magnesium exposure and spontaneous intestinal perforations in extremely low birth weight infants.

OBJECTIVE: The objective of this study is to determine whether antenatal exposure to magnesium is associated with spontaneous intestinal perforation (SIP) in extremely low birth weight (ELBW) infants (⩽1000 g). STUDY DESIGN: We identified all ELBW infants admitted to 1 of 323 neonatal intensive care units from 2007 to 2013. We used multivariable conditional logistic regression to compare outcomes in the first 21 days after birth between infants exposed and unexposed to magnesium in utero. RESULTS: Of the 28 035 infants, 11 789 (42%) were exposed to antenatal magnesium (AM). There was no difference in the risk of SIP, odds ratio=1.08 (95% confidence interval; 0.91 to 1.29), between infants exposed and unexposed to AM. Mortality in the first 21 days after birth was lower in the magnesium-exposed infants, odds ratio=0.76 (0.70 to 0.83). CONCLUSION: AM exposure in ELBW infants was not associated with increased risk of SIP.

Differences in Eccentricity Index and Systolic-Diastolic Ratio in Extremely Low-Birth-Weight Infants with Bronchopulmonary Dysplasia at Risk of Pulmonary Hypertension.

OBJECTIVE: To compare the left ventricular eccentricity index (EI) and tricuspid valve systolic-diastolic (SD) ratio in infants at risk of bronchopulmonary dysplasia (BPD) and pulmonary hypertension (PH). STUDY DESIGN: Review of echocardiograms performed on infants born at ≤ 28 weeks' postmenstrual age, categorized into the following three cohorts: BPD and PH (n = 13); BPD only (n = 16); and controls (n = 59). EI was measured from a parasternal short axis 2D image. The SD ratio was measured from the continuous wave Doppler tracing. Groups were compared using Kruskal-Wallis and Wilcoxon rank sum tests. RESULT: EI and SD ratios were successfully measured in all infants. There were no differences between controls and BPD cohort. In contrast, the BPD and PH cohort had increased systolic EI (1.46 vs. 1.00-1.01), diastolic EI (1.47 vs. 1.00), and SD ratio (1.12 vs. 0.97-1.00) compared with controls and BPD only cohort (p ≤ 0.01 for all). CONCLUSION: The EI and SD ratio may be useful as a screening tool for PH in this population.

Impact of a palliative care program on end-of-life care in a neonatal intensive care unit.

OBJECTIVE: Evaluate changes in end-of-life care following initiation of a palliative care program in a neonatal intensive care unit. STUDY DESIGN: Retrospective study comparing infant deaths before and after implementation of a Palliative Care Program comprised of medication guidelines, an individualized order set, a nursing care plan and staff education. RESULT: Eighty-two infants died before (Era 1) and 68 infants died after implementation of the program (Era 2). Morphine use was similar (88% vs 81%; P =0.17), whereas benzodiazepines use increased in Era 2 (26% vs 43%; P=0.03). Withdrawal of life support (73% vs 63%; P=0.17) and do-not-resuscitate orders (46% vs 53%; P=0.42) were similar. Do-not-resuscitate orders and family meetings were more frequent among Era 2 infants with activated palliative care orders (n=21) compared with infants without activated orders (n=47). CONCLUSION: End-of-life family meetings and benzodiazepine use increased following implementation of our program, likely reflecting adherence to guidelines and improved communication.

Antenatal magnesium sulfate and spontaneous intestinal perforation in infants less than 25 weeks gestation.

OBJECTIVE: Evaluate spontaneous intestinal perforation (SIP)/death among extremely low birthweight (ELBW) infants before, during and after initiation of an antenatal magnesium for neuroprotection protocol (MgPro). STUDY DESIGN: We tested associations between SIP/death and magnesium exposure, gestational age (GA) and interactions with GA and magnesium exposure in a cohort of inborn ELBW infants before, during and after MgPro. RESULT: One hundred and fifty-five ELBW infants were included, 81 before, 23 during and 51 after MgPro. ELBW infants (78.3%) were exposed to Mg during MgPro compared with 50.6% and 60.8% before and after, respectively. Incidence of SIP on protocol was 30.4% vs 12.9% off protocol (P=0.03). GA was strongly associated with SIP (P<0.01). Antenatal Mg dose was also associated with SIP/death regardless of epoch (odds ratio 9.3 (1.04-104.6)), but increased SIP/death was limited to those <25 weeks gestation. CONCLUSION: Higher Mg dose was associated with higher SIP and death risk among infants with the lowest birthweights. Validation of this observation in larger populations is warranted.

Pulmonary artery thrombus in a premature neonate treated with recombinant tissue plasminogen activator.

Pulmonary artery thrombus is a rarely reported complication in premature neonates. The management of life-threatening thrombotic events in neonates is controversial, especially regarding the use of thrombolytics versus anticoagulation alone for treatment. We report a case of a premature neonate with symptomatic pulmonary artery thrombus treated with recombinant tissue plasminogen activator who survived without bleeding complications.

Effects of low-dose dopamine on urine output in normotensive very low birth weight neonates.

OBJECTIVE: To determine the effects of low-dose dopamine on urine output (UOP) in very low birth weight premature neonates. STUDY DESIGN: Retrospective cohort study of all low-dose (3-5 µg kg(-1) per min) dopamine infusions >24-h duration in neonates 1500 g and 32 weeks gestation from August 2009 through September 2011. Linear regression was used to estimate the impact of covariates on UOP. RESULT: We identified 91 episodes of low-dose dopamine use in 65 neonates. Increased UOP occurred in 64% of episodes. Low-dose dopamine use was associated with a 0.6 ml kg(-1) h(-1) increase in UOP (P<0.001) and a 1.3 ml kg(-1)h(-1) increase when baseline UOP was <1.5 ml kg(-1) h(-1) (P<0.001). The improvement remained statistically significant after controlling for medications (diuretics and hydrocortisone) and fluid intake. CONCLUSION: Low-dose dopamine use was associated with increased UOP in very low birth weight neonates.

Blood stream infection is associated with altered heptavalent pneumococcal conjugate vaccine immune responses in very low birth weight infants.

OBJECTIVE: Sepsis in older children and adults modifies immune system function. We compared serotype-specific antibody responses to heptavalent pneumococcal conjugate vaccine (PCV7) in very low birth weight infants (<1500 g,VLBWs) with and without blood stream infection (BSI) during their birth hospitalization. STUDY DESIGN: Retrospective analysis of prospectively collected data for the Neonatal Research Network study of PCV7 responses among VLBWs. Infants received PCV7 at 2, 4 and 6 months after birth with blood drawn 4 to 6 weeks after third dose. Serotype antibodies were compared between infants with or without a history of BSI. Regression models were constructed with BW groups and other confounding factors identified in the primary study. RESULT: In all, 244 infants completed the vaccine series and had serum antibody available; 82 had BSI. After adjustment, BSI was not associated with reduced odds of serum antibody 0.35 µg ml(-1). CONCLUSION: BSI was not associated with reduced odds of World Health Organization-defined protective PCV7 responses in VLBWs.

Influence of gestational age on death and neurodevelopmental outcome in premature infants with severe intracranial hemorrhage.

OBJECTIVE: To determine whether death and/or neurodevelopmental impairment (NDI) after severe intracranial hemorrhage (ICH; grade 3 or 4) differs by gestational age (GA) at birth in extremely low birth weight (ELBW) infants. STUDY DESIGN: Demographic, perinatal and neonatal factors potentially contributing to NDI for ELBW infants (23 to 28 weeks gestation) were obtained retrospectively; outcome data came from the ELBW Follow-up Study. NDI was defined at 18 to 22 months corrected age as moderate/severe cerebral palsy, Bayley Scales of Infant Development II cognitive or motor score <70, and/or blindness or deafness. Characteristics of younger versus older infants with no versus severe ICH associated with death or NDI were compared. Generalized linear mixed models predicted death or NDI in each GA cohort. RESULT: Of the 6638 infants, 61.8% had no ICH and 13.6% had severe ICH; 39% of survivors had NDI. Risk-adjusted odds of death or NDI and death were higher in the lower GA group. Lower GA increased the odds of death before 30 days for infants with severe ICH. Necrotizing enterocolitis (particularly surgical NEC), late onset infection, cystic periventricular leukomalacia and post-natal steroids contributed to mortality risk. NDI differed by GA in infants without ICH and grade 3, but not grade 4 ICH. Contributors to NDI in infants with severe ICH included male gender, surgical NEC and post-hemorrhagic hydrocephalus requiring a shunt. CONCLUSION: GA contributes to the risk of death in ELBW infants, but not NDI among survivors with severe ICH. Male gender, surgical NEC and need for a shunt add additional risk for NDI.

Repeat lumbar punctures in infants with meningitis in the neonatal intensive care unit.

OBJECTIVE: The purpose of this study is to examine the results of repeat lumbar puncture in infants with initial positive cerebrospinal fluid (CSF) cultures in order to determine the clinical characteristics and outcomes of infants with repeat positive cultures. STUDY DESIGN: Cohort study of infants with an initial positive CSF culture undergoing repeat lumbar puncture between 1997 and 2004 at 150 neonatal intensive care units managed by the Pediatrix Medical group. We compared the clinical outcomes of infants with repeat positive cultures and infants with repeat negative cultures. RESULT: We identified 118 infants with repeat CSF cultures. Of these, 26 infants had repeat positive cultures. A higher proportion with repeat positive cultures died compared with those with repeat negative cultures, 6/23 (26%) vs. 6/81 (7%), respectively (P=0.02). CONCLUSION: Among infants with a positive CSF culture, a repeat positive CSF culture is common. The presence of a second positive culture is associated with increased mortality.

Recombinant activated factor VIIa treatment for refractory hemorrhage in infants.

OBJECTIVE: Report clinical response to recombinant factor VIIa in a cohort of critically ill infants. STUDY DESIGN: We identified all infants who received factor VIIa in the Duke Neonatal Intensive Care Unit between January 2005 and July 2008. Hematological data and volume of blood transfusions before and after factor VIIa treatment were compared. The precipitating diagnosis for each factor VIIa use, and the ensuing clinical outcomes of bleeding, thrombosis and mortality were noted. RESULT: We identified 18 infants with median birth weight of 880 g and median gestational age of 26 weeks. One to six doses of factor VIIa (90 mcg kg(-1) per dose) were administered, with 13 (72%) infants receiving a single dose. Hemostasis was achieved in 13 (72%) of the infants. Prothrombin time and activated partial thromboplastin time significantly decreased following treatment with factor VIIa. Volume of plasma transfusions significantly decreased following treatment with factor VIIa (P=0.02). Thrombosis occurred in one (11%) infant. Six (33%) infants died within 72 h of treatment, and overall mortality was 10/18 (56%). CONCLUSION: Treatment with factor VIIa at doses of 90 mcg kg(-1) improved coagulation studies and decreased the need for plasma transfusions in a group of critically ill infants without significant risk. Factor VIIa may be an effective addition to current treatment modalities for refractory hemorrhage in infants.

Does IVIg administration yield improved immune function in very premature neonates?

Intravenous immunoglobulin (IVIg) has been evaluated as an adjunctive therapy for neonatal sepsis with modest clinical success despite strong biological plausibility. Multiple factors contribute to this outcome, but perhaps none greater than the limited immune system function in newborns, especially in the very premature neonates. For very premature neonates (<30 weeks gestational age), understanding the effects of IVIg on specific immature immune system functions is particularly relevant given their preponderance to develop sepsis and therefore potentially benefit from IVIg-mediated immunoenhancement. Here, we review the available evidence for enhanced immune function after IVIg administration in very premature neonates and highlight areas for future research.

Long-term morbidities associated with vocal cord paralysis after surgical closure of a patent ductus arteriosus in extremely low birth weight infants.

OBJECTIVE: Determine associations between left vocal cord paralysis (LVCP) and poor respiratory, feeding and/or developmental outcomes in extremely low birth weight (ELBW) infants following surgical closure of a patent ductus arteriosus (PDA). STUDY DESIGN: ELBW infants who underwent PDA ligation between January 2004 and December 2006 were identified. We compared infants with and without LVCP following ligation to determine relationships between LVCP and respiratory morbidities, feeding and growth difficulties and neurodevelopmental impairment at 18 to 22-month follow-up. Student's t-test, Fisher's exact test and multivariable regression analyses were used to determine associations. RESULT: In all, 60 ELBW infants with a mean gestational age of 25 weeks and mean birth weight of 725 g had a PDA surgically closed. Twenty-two of 55 survivors (40%) were diagnosed with LVCP post-operatively. Infants with LVCP were significantly more likely to develop bronchopulmonary dysplasia (82 vs 39%, P=0.002), reactive airway disease (86 vs 33%, P<0.0001), or need for gastrostomy tube (63 vs 6%, P<0.0001). CONCLUSION: LVCP as a complication of surgical ductal ligation in ELBW infants is associated with persistent respiratory and feeding problems. Direct laryngoscopy should be considered for all infants who experience persistent respiratory and/or feeding difficulties following PDA ligation.

Prevalence of renal anomalies after urinary tract infections in hospitalized infants less than 2 months of age.

OBJECTIVE: Our aim was to determine the incidence of anatomical abnormalities after a urinary tract infection (UTI) in infants <2 months of age hospitalized in the neonatal intensive care unit (NICU). STUDY DESIGN: This was a retrospective, single-center cohort study of infants <2 months of age in the NICU with a UTI and documented renal imaging. RESULT: We identified 141 infants with UTIs. The mean gestational age and birth weight were 28 weeks and 1254 g, respectively. The most commonly identified pathogen was coagulase-negative Staphylococcus (28%, 44 of 156). A major abnormality was found on at least one imaging study for 4% (5 of 118) of infants. Major abnormalities were noted on 4% (5 of 114) of renal ultrasounds and 2% (2 of 82) of voiding cystourethrography examinations. CONCLUSION: Among infants in the NICU <2 months of age at the time of a UTI, the prevalence of major anatomical abnormalities is <5%.

Transpyloric tube feeding in very low birthweight infants with suspected gastroesophageal reflux: impact on apnea and bradycardia.

OBJECTIVE: Our aim was to assess the safety and efficacy of transpyloric tube feeding as a therapeutic option to reduce apnea and bradycardia in hospitalized very low birthweight (VLBW) infants with clinical signs suggestive of gastroesophageal reflux (GER). STUDY DESIGN: This was a retrospective single-center cohort study of VLBW infants hospitalized from 2001 to 2004 with signs of GER who received transpyloric enteral tube feedings. Apnea (>10 s) and bradycardia (<100 bpm) episodes were compared before and after the initiation of transpyloric feedings. The Wilcoxon signed-rank test was used to compare differences between cardiorespiratory episodes before and after treatment at 1-day and combined 3-day intervals. Events recorded to assess the safety of transpyloric feedings included death, sepsis and necrotizing enterocolitis (NEC). RESULTS: A total of 72 VLBW infants with a median birthweight of 870 g (ranging from 365 to 1435 g) and gestational age of 26 weeks (from 23 to 31 weeks) were identified. The median weight at initiation of transpyloric feedings was 1297 g (from 820 to 3145 g) and infants received transpyloric feeds for a median duration of 18 days (from 1 to 86 days). After the initiation of transpyloric feedings, a reduction in apnea episodes from 4.0 to 2.5 (P=0.02) and a decrease in bradycardia episodes from 7.2 to 4.5 (P<0.001) was observed when comparing the total number of episodes for the 3 days before and after treatment. Five (6.9%) of the infants developed NEC while receiving transpyloric feedings. None of the infants receiving human milk (P=0.07) and 36% of those receiving hydrolysate-based formula (P<0.01) during transpyloric feeds developed NEC. No infants had late-onset culture-proven sepsis. Seven (9.7%) infants died before hospital discharge. CONCLUSIONS: Transpyloric feedings, especially when limited to human milk, may safely reduce episodes of apnea and bradycardia in preterm infants with suspected GER. Prospective randomized studies are needed to determine the biological impact of bypassing the stomach, as well as the safety and efficacy of this intervention. The results of such studies could modify the current prevailing safety concerns regarding transpyloric feeding in this population.

Vocal fold paralysis following surgical ductal closure in extremely low birth weight infants: a case series of feeding and respiratory complications.

Surgical closure of a patent ductus arteriosus (PDA) continues to be a frequent procedure among extremely preterm infants. Recent evidence indicates surgical closure is associated with worse outcomes than after medical closure. Left vocal fold paralysis is a known complication of this surgery, but there is little information available on the impact of this specific complication on long-term outcomes of these infants. In this case series, we describe the clinical course of three sets of multiple births, in which at least one infant underwent surgical closure of the PDA and subsequently developed feeding and/or breathing difficulties due to left vocal fold paralysis, and compare to their siblings who did not sustain this complication. The case series suggests that some long-term morbidities associated with surgical closure of the PDA may be attributable to this specific complication.

Congenital diaphragmatic hernia: a systematic review and summary of best-evidence practice strategies.

OBJECTIVES: Recent reports suggest that specific care strategies improve survival of infants with congenital diaphragmatic hernia (CDH). This review presents details of care from centers reporting high rates of survival among CDH infants. STUDY DESIGN: We conducted a MEDLINE search (1995 to 2006) and searched all citations in the Cochrane Central Register of Controlled Trials. Studies were included if they contained reports of >20 infants with symptomatic CDH, and >75% survival of isolated CDH. RESULT: Thirteen reports from 11 centers met inclusion criteria. Overall survival, including infants with multiple anomalies, was 603/763 (79%; range: 69 to 93%). Survival for isolated CDH was 560/661 (85%; range: 78 to 96%). The frequency of extracorporeal membrane oxygenation (ECMO) use for isolated CDH varied widely among reporting centers 251/622 (40%; range: 11 to 61%), as did survival for infants with isolated CDH placed on ECMO: 149/206 (73%; range: 33 to 86%). There was no suggestion of benefit from use of antenatal glucocorticoids given after 34 weeks gestation or use of postnatal surfactant. Low mortality was frequently attributed to minimizing lung injury and adhering to center-specific criteria for ECMO. CONCLUSION: Use of strategies aimed at minimizing lung injury, tolerance of postductal acidosis and hypoxemia, and adhering to center-specific criteria for ECMO were strategies most consistently reported by successful centers. The literature lacks randomized clinical trials of these or other care strategies in this complex patient population; prospective studies of safety and long-term outcome are needed.

Caspofungin for the treatment of azole resistant candidemia in a premature infant.

Candidemia is common in extremely low birth weight infants and is associated with substantial mortality and morbidity. Treatment options have traditionally been limited to amphotericin B deoxycholate or fluconazole. We present a case of a premature infant with persistent candidemia despite antifungal treatment that responded to therapy with caspofungin, an echinocandin antifungal. The infant's Candida isolate developed resistance to azoles during fluconazole administration and also suffered from severe hypercalcemia during the initiation of caspofungin therapy.