Pharmacologic management of neonatal abstinence syndrome in a community hospital.

Neonatal abstinence syndrome has become a growing concern in infants born to substance-abusing mothers in the State of Florida. At Sarasota Memorial Hospital in Sarasota, FL, methadone and morphine treatment strategies have been formulated to manage symptomatic neonates after birth. We report our findings over a 5-year period utilizing each of these protocols in a community hospital setting.

Extremely Preterm Neonate with a Tracheobronchial Foreign Body: A Case Report.

We report the case of an approximately 27-week gestational-age preterm infant admitted on the day of life number four for evaluation of a foreign body noted on serial chest X-rays. CT of the chest revealed a foreign body present in the trachea, extending from just above the tracheal bifurcation deep into the posterior basilar segment of the right lower lobe. Endoscopic removal of the foreign body revealed a portion of the plastic sheath of the stylet used during intubation. We also provide a brief review of the relevant literature.

Congenital Mastocytosis: Case Report and Review of the Literature.

Mastocytosis is a rare infiltrative disorder characterized by mast cell proliferation within the skin and various extra-cutaneous organ systems. We report the case of a full-term neonate admitted to the neonatal intensive care unit for evaluation of diffuse skin lesions on her face, trunk and extremities. Initially, the lesions appeared to be consistent with a blueberry muffin rash. However, over a period of days the lesions became vesicular and changed in shape and number. The neonate underwent evaluation for infective etiologies, skin biopsy of the lesions, and flow cytometry analysis of the peripheral blood. The surgical pathology examination of the skin biopsy demonstrated mast cells consistent with a diagnosis of cutaneous mastocytosis. A review of relevant literature is also provided.

Neutrophil-specific chemokines are produced by astrocytic cells but not by neuronal cells.

BACKGROUND: Neutrophils have a central role in the inflammatory conditions of the central nervous system (CNS). ELR chemokines direct neutrophil migration, but the source of chemokines in the CNS is unclear. We quantified chemokine production using cell-line models of astrocytic and neuronal cells, specifically NT2.N cells, a human line with characteristics of immature neurons, and NT2.A cells, a line with characteristics of astrocytes. OBJECTIVE: In NT2.N and NT2.A cells, and their parent cell line NT2, we sought to: (1) quantify ELR chemokines, (2) determine receptor (CXCR-1 and CXCR-2) expression, and (3) measure the function of the chemokines generated from these cells. DESIGN/METHODS: NT2 cells were differentiated into NT2.N cells and NT2.A cells with all trans retinoic acid and mitosis inhibitors. Chemokine concentrations in culture supernatants were determined by ELISA. Immunofluorescence was used to detect CXCR-1 and CXCR-2. RT-PCR was used to determine chemokine and chemokine receptor mRNA. Chemotaxis assays were used to assess function. RESULTS: ELR chemokines were not detected in supernatants of NT2 or NT2.N cells, although mRNA for GRO-gamma/CXCL3 was found in both. In contrast, in NT2.A cells, mRNA and protein were present for GCP-2/CXCL6, GRO-alpha/CXCL1, GRO-gamma/CXCL3, and IL-8/CXCL8. CXCR-1 and CXCR-2 were expressed on NT2, NT2.N, and NT2.A cells detected by immunofluorescent staining and RT-PCR. Supernatants of NT2.A cells resulted in neutrophil chemotactic function of 30.5 +/- 3.9%, greater than NT2 cells (12.3 +/- 1.6%, mean +/- SEM, P < 0.01). CONCLUSIONS: We speculate that astrocytes are a source of ELR chemokines in the human CNS and that neurons and astrocytes can respond to those chemokines.

Developmental expression of chemokine receptor genes in the human fetus.

BACKGROUND: Chemokines induce cell motility during embryogenesis by activating specific receptors. While the orchestration of organogenesis is complex and requires the interaction of many morphoregulatory molecules that lead to coordinated organ development, limited knowledge exists regarding the human developmental biology of chemokines and their receptors. Such information on chemokine receptor expression could potentially enhance our understanding of organogenesis in the normal human fetus. AIM: To determine the distribution of the CXC receptors (CXCR-1, CXCR-2, CXCR-3, and CXCR-4) and SDF-1 in human fetuses. SUBJECTS: Tissues from human fetuses 12-15 weeks (n = 5) and 16-19 weeks (n = 5) gestation were studied. OUTCOME MEASURES: Reverse transcription-PCR was performed to simultaneously determine the gene expression of CXCR-1-4 and SDF-1, and immunohistochemical staining of non-hematopoietic tissues was used to determine the specific cellular proteins. RESULTS: CXCR-1-4 and SDF-1 mRNA were present in every tissue examined. The expression of CXCR-3 in kidney, liver, and brain was dependent upon gestational age. CXCR-1-4 protein was expressed in non-hematopoietic cells in the brain, heart, intestine, and kidney. CONCLUSIONS: CXCR-1-4 and SDF-1 genes are widely expressed in the normal human fetus. This suggests that these gene products could influence fetal development.

Enteral administration of a simulated amniotic fluid to very low birth weight neonates.

OBJECTIVE: To reduce feeding intolerance among very low birth weight neonates. STUDY DESIGN: A total of 10 neonates with birth weights of 750 to 1250 g were given oral-gastric boluses (2.5 ml/kg every 3 hours) of a solution patterned after amniotic fluid. When milk feedings were begun the milk was mixed with the test solution. The solution was given at a constant daily dose of 20 ml/kg/day while the volumes of milk feedings were gradually increased. When milk feedings reached 80 ml/kg/day the test solution was discontinued. A comparison group consisted of neonates who met study criteria but were cared for during the period immediately preceding the study. The outcome was the number of calories taken enterally over the first 21 days of life. RESULTS: The test solution was begun an average of 27 hours after birth (range, 4 to 45). In the test group the first milk feedings were introduced 74 hours after birth (range, 18 to 144), which was similar to the time milk was introduced in the comparison subjects (79 hours; range, 18 to 168). After milk feedings were started, the test patients had a total of four NPO days (0.4 NPO days per patient) during their first 21 days, while the comparison group had 34 NPO days (3.4 NPO days per patient). During the first 14 days of life the test solution recipients had a median of 26.5 enteral cal/kg/day (range, 4.3 to 68.9), while the comparison neonates had 8.5 (range, 0.2 to 25; p < 0.05). During the first 21 days of life the test solution recipients had a median of 56.9 enteral cal/kg/day (range, 11.5 to 89.4), while the comparison neonates had 19.2 (range, 0.9 to 52.8; p < 0.05). CONCLUSION: In all, 10 VLBW infants tolerated the test solution for periods up to 14 days with no significant adverse effects. A randomized trial to determine whether this solution reduces feeding intolerance among VLBW neonates should be conducted.

Effect of administering recombinant erythropoietin to women with postpartum anemia: a meta-analysis.

OBJECTIVES: Recombinant erythropoietin (rEpo) has been administered to women with postpartum anemia in an attempt to accelerate their increase in hemoglobin concentration and reduce postpartum transfusions. However, it is not clear whether such an approach can be supported by evidence and should be generally recommended. STUDY DESIGN AND METHODS: Medical and scientific literature from January 1990 to December 2002 was searched and studies that reported the administration of rEpo to women with postpartum anemia were evaluated. RESULTS: Eight evaluated studies reported an aggregate of 480 women; 300 rEpo recipients and 180 controls. Significant diversity in design was observed in rEpo dose, route of rEpo administration, iron supplementation, and baseline hemoglobin. No significant safety concerns were reported. In all five studies where it was reported, 4 to 7 days after beginning treatment, greater increases in hemoglobin concentration were observed among the rEpo recipients than among the controls. However, heterogeneity of results (Q-test statistic, p<0.01) indicated that it was not appropriate to apply summary statistics. The effect of rEpo on postpartum transfusion rate was not measurable by summary statistics because of the limited number of transfusions given (no transfusions among the 300 rEpo recipients vs two transfusions among the 180 controls). CONCLUSION: Administration of rEpo to women with postpartum anemia appears to be safe, and is associated with a trend toward a faster increase in hemoglobin concentration. However, its efficacy in terms of diminishing postpartum transfusions is unproven.

Effect of beginning recombinant erythropoietin treatment within the first week of life, among very-low-birth-weight neonates, on "early" and "late" erythrocyte transfusions: a meta-analysis.

OBJECTIVES: Erythrocyte transfusions to neonates can be categorized as "early" if given during the first 3 weeks of life and "late" if given thereafter. We used a meta-analysis to determine whether recombinant erythropoietin (rEpo) administration to very-low-birth-weight (VLBW, <1500 g) neonates, beginning in the first week of life, reduces either "early" or "late" transfusions. STUDY DESIGN AND METHODS: Studies that used a randomized, placebo-controlled, double-masked design were deemed acceptable. We identified 12 acceptable, relevant, clinical trials. Additional data not provided in the publications were obtained from two of the authors. RESULTS: The acceptable studies involved an aggregate of 561 rEpo and 529 placebo recipients. If rEpo was begun in the first week of life, the summary odds ratio (OR) for receiving any transfusion ("early" or "late") was 0.52, 95% confidence interval (CI): 0.34 to 0.79 (p=0.001). The OR for receiving an "early" transfusion was 0.54 (95% CI: 0.25 to 1.15; p=0.055), and the OR for receiving a "late" transfusion was 0.56 (95% CI: 0.37 to 0.83; p=0.036). Heterogeneity among studies was too great to estimate the effect of rEpo on the number of transfusions received or the volume of blood transfused (p<0.001 for the Q-test statistic). Subgroup analysis suggested that when rEpo is begun in the first week of life, neonates 1000 to 1500 g and >29 weeks are more likely to completely avoid transfusion than are extremely low-birth-weight (ELBW, <1000 g) neonates. No dose-response relationship was apparent between rEpo dose or iron dose and transfusion. No difference was apparent depending on whether the rEpo was given subcutaneously vs intravenously. CONCLUSION: If rEpo is begun in the first week of life, a moderate reduction can be expected (p=0.001) in the proportion of VLBW neonates transfused. Reduction is less significant in "early" transfusion (p=0.055) than in "late" transfusion (p=0.036). Such treatment is not likely to eliminate transfusions among ELBW neonates completely.

Persistent perianal abscess in early infancy as a presentation of autoimmune neutropenia.

Autoimmune neutropenia of infancy is a primary, usually self-limiting, antineutrophil autoimmune phenomenon seen in infancy and early childhood. These infants are at a higher risk of infection, and early detection, particularly with the availability of newer therapeutic options such as hematopoietic growth factors, can allow close follow-up and, if needed, treatment. We report two infants with autoimmune neutropenia who presented with a persistent perianal abscess, which has not been documented previously in this population.

Tolerance of an enterally administered simulated amniotic fluid-like solution by neonates recovering from surgery for congenital bowel abnormalities.

OBJECTIVE: We report a single-centered, Phase I pilot trial, testing the enteral administration of an experimental amniotic fluid-like solution to 10 neonates who were otherwise "NPO" following surgery for congenital bowel abnormalities. The overall hypothesis was that the trophic effect of the solution on intestinal villi would facilitate advancement to full enteral feedings. The specific hypothesis tested in this pilot trial was that the solution would be tolerated. STUDY DESIGN: Ten neonates who were NPO following surgery for congenital bowel abnormalities, were studied before any "trophic" feedings were begun. Each received an experimental, sterile, isotonic, amniotic fluid-like solution at a dose of 20 ml/kg/day enterally. When milk feedings were begun they were mixed with the experimental solution. Increases in the volume of milk feedings occurred at the discretion of the neonatologist and surgeon, and the experimental solution was discontinued any time the neonatologist or surgeon felt it was not tolerated, or when 100 ml of milk feedings/kg/day was achieved. We quantified the amount and character of emesis, stools, and gastric residuals, measured abdominal girth and blood pressure, looked for skin rashes, and sought any signs of intolerance or adverse events. We recorded the days to achieve milk feedings of 20, 50, 100, and 120 ml/kg/day and length of hospital stay. RESULTS: The experimental solution was begun 4 to 32 days after surgery, invariably prior to the institution of "trophic" milk feedings. All subjects completed the doses with no evidence of intolerance. All achieved 100 ml/kg of milk feedings 14 days, or fewer, following institution of the experimental solution (mean 11.1 days, range, 3 to 14). All lived and were discharged home 20.2 days (range, 8 to 42) after the experimental solution was begun. CONCLUSIONS: In this pilot trial involving 10 neonates who had surgery for congenital bowel abnormalities, the enteral administration of a sterile, isotonic, amniotic fluid-like solution was tolerated.

A neonate with severe thrombocytopenia and radio-ulnar synostosis.

Bone marrow failure syndromes can be associated with abnormalities of the forearms. We observed a neonate with congenital thrombocytopenia who had bilateral radio-ulnar synostosis and fifth finger clinodactly. We performed an evaluation of the mechanism causing the thrombocytopenia using a combination of direct and indirect measures of thrombopoiesis. These tests indicated decreased platelet production. This entity of congenital hyporegenerative thrombocytopenia with bilateral radio-ulnar synostosis and fifth-finger clinodactly is an uncommon but easily recognizable form of congenital amegakaryocytic thrombocytopenia (CAMT). This entity can be distinguished from the TAR syndrome (thrombocytopenia and absent radii) by the distinctive orthopedic issues, different underlying genetic mutations, and a more worrisome prognosis for CAMT than for TAR.

Tolerance of a sterile isotonic electrolyte solution containing select recombinant growth factors in neonates recovering from necrotizing enterocolitis.

OBJECTIVE: To assess the tolerance of a sterile isotonic electrolyte solution containing select recombinant growth factors enterally administered in neonates who were NPO because of necrotizing enterocolitis (NEC). STUDY DESIGN: A phase I trial was accomplished among 30 neonates. Patients received 5, 10, or 20 mL enterally of the study solution/kg/day divided into every 3-hour dosing, for 3 days prior to when feedings of milk were to resume. The occurrence of emesis, gastric residuals, diarrhea, bloody stools, abdominal distention, skin rashes and death were sought. RESULTS: Gestational ages ranged from 25.2 to 41.1 weeks. A total of 16 neonates had Stage IA NEC, six Stage IB, and eight Stage IIA. The solution was well tolerated in all 30; none developed diarrhea, guaiac positive or bloody stools, or abdominal distention. Administration of the solution was not prematurely discontinued in any infant. Two neonates died secondary to late-onset sepsis remote from the study period. CONCLUSIONS: Enteral administration of a sterile isotonic electrolyte solution containing select recombinant growth factors was well tolerated by neonates with NEC.

Congenital neutropenia.

The term "congenital neutropenia" signifies neutropenia that is present at birth. It includes a wide variety of disorders, some transient and others life long. Some varieties of congenital neutropenia are mild, with blood neutrophil concentrations below normal but not low enough to constitute a significant host defense deficiency. Other varieties of congenital neutropenia are characterized by low blood neutrophil concentrations and a predisposition to repeated infections.

Hematopoietic growth factors in neonatal medicine: the use of enterally administered hematopoietic growth factors in the neonatal intensive care unit.

The practice of complete bowel rest in prematurely delivered neonates and those who have undergone surgery for congenital anomalies of the gastrointestinal (GI) tract is common in neonatal intensive care units (NICU). However, increased recognition of the critical role of growth factors in GI development suggests that this practice might be modified to include the administration of synthetic amniotic fluid-like solutions designed to bridge the neonate between their intra-uterine environment and that of the NICU. This article reviews advances in administering synthetic amniotic fluid-like solutions in the NICU.

Immune neutropenia in the neonate.

Immune-mediated neonatal neutropenias include alloimmune neonatal neutropenia, neonatal autoimmune neutropenia, and autoimmune neutropenia of infancy. These disorders have remained somewhat nebulous entities with difficulties persisting in both clinical identification and laboratory confirmation. A review of these disorders is presented, with basic information on the neutrophil antigen systems, pathophysiologic mechanisms, laboratory diagnosis, and therapeutic options.

Recent advances in neonatal pharmacotherapy.

OBJECTIVE: To provide commentary and reviews and brief discussions in controversial or innovative recent advances in neonatal pharmacotherapy. To discuss cutting edge drug delivery systems that may become useful in neonatal drug delivery in the future. DATA SOURCES: Articles were identified through searches of MEDLINE (1990-October 2005), key articles in the authors' files, and in some cases, through data generated and/or published by the author of a particular topic. DATA SELECTION: Article selection and relevance to the topics under discussion was determined by individual authors. DATA SYNTHESIS: Therapeutic strategies addressed in this review include the use of hematopoietic growth factors including a simulated amniotic fluid preparation containing these growth factors for neonates with selected gastrointestinal problems, erythropoietin for neuroprotection following perinatal asphyxia, drug therapy advances in treatment of patent ductus arteriosus (PDA), evaluation of advances in transdermal drug delivery, and its potential application to neonates and advances in the treatment of persistent pulmonary hypertension (PPHN) of the newborn. CONCLUSIONS: Despite being over 30 years old, the practice of neonatology is as much of an art as a science. Advances in the basic science research have improved our understanding of use of pharmacologic agents in the premature and full-term neonate including drug disposition pathways. Expanding our knowledge on issues such as physiology of hematopoietic factors, the pharmacologic responses of conditions such as PDA and PPHN, and newer technologies for drug administration, as well as other pharmacologic responses in the neonate are vital in the development of safe and efficacious treatments for neonates. Many questions remain unanswered, and every clinician must make an effort to contribute to the knowledge and understanding of pharmacotherapy in this patient population.

The effects and comparative differences of neutrophil specific chemokines on neutrophil chemotaxis of the neonate.

Neutrophil specific chemokines are potent chemoattractants for neutrophils. IL-8/CXCL8 is the most extensively studied member of this group, and its concentrations increase during inflammatory conditions of the newborn infant including sepsis and chronic lung disease. A significant amount of information exists on the effects of IL-8/CXCL8 on neutrophil chemotaxis of neonates, but little is known about the other neutrophil specific chemokines. The aim of this study was to determine the relative potency of the neutrophil specific chemokines on chemotaxis of neonatal neutrophils and to compare this effect with the effect on adult neutrophils. Neutrophils were isolated from cord blood or healthy adult donors and incubated in a Neuroprobe chemotaxis chamber. Chemokine concentrations ranging from 1-1000 ng/mL were used. Differences in chemotactic potency existed among the seven neutrophil specific chemokines. Specifically, at 100 ng/mL, the order was IL-8/CXCL8>GRO-alpha/CXCL1>GCP-2/CXCL6>NAP-2/CXCL7>ENA-78/CXCL5>GRO-gamma/CXCL2>GRO-beta/CXCL3. This pattern was observed for adult and neonatal neutrophils. We conclude that (1) neutrophils from cord blood exhibit the same pattern of potency for each ELR chemokine as neutrophils from adults, and (2) migration of neonatal neutrophils is significantly less than that of adults at every concentration examined except the lowest (1 ng/mL).

IL-8/CXC ligand 8 survives neonatal gastric digestion as a result of intrinsic aspartyl proteinase resistance.

The human fetus and neonate swallow biologically significant quantities of IL-8/CXC ligand 8 (CXCL8) in amniotic fluid and breast milk, and this remains measurable through simulated neonatal gastric and proximal intestinal digestions. We sought to confirm the structural and functional integrity of IL-8/CXCL8 in digestates and determine the mechanisms underlying this protease resistance. We observed that in comparison with BSA, IL-8/CXCL8 is highly resistant to pepsin and can be detected intact in assays for structural, immunologic, and functional integrity. In a computational molecular docking simulation, IL-8/CXCL8 was observed to fit poorly in the pepsin active site. On the basis of simulated mutation analyses, we hypothesized that this protease resistance is due to disulfide bond-related tertiary folding in IL-8/CXCL8. This was confirmed on chemical reduction of these groups.

Use of myeloid colony-stimulating factors in neonates with septicemia.

Bacterial sepsis is a major cause of neonatal morbidity and mortality. Successful management of neonatal sepsis requires early diagnosis, appropriate antimicrobial treatment, and aggressive intensive care. However, even when steps are taken appropriately, mortality rates can be high, particularly among certain subgroups, such as extremely preterm neonates and neonates with neutropenia. Multiple factors contribute to the increased susceptibility of neonates to infection, including developmental quantitative and qualitative neutrophil defects. Studies of infected animal and human neonates suggest that the use of recombinant human granulocyte colony stimulating factor (rhG-CSF) or recombinant human granulocyte macrophage colony stimulating factor (rhGM-CSF) can partially counterbalance these defects and thereby reduce morbidity and mortality. However, the body of clinical evidence is currently not sufficient to recommend rhG-CSF or rhGM-CSF administration confidently as routine adjunctive treatment for neonates with sepsis.

ELR+ CXC chemokines in human milk.

CXC chemokines bearing the glutamic acid-leucine-arginine (ELR) motif are crucial mediators in neutrophil-dependent acute inflammation. Interestingly, however, Interleukin (IL)-8/CXC ligand (CXCL) 8 is expressed in human milk in biologically significant concentrations, and may play a local maturational role in the developing human intestine. In this chemokine subfamily, there are six other known peptides beside IL-8/CXCL8, all sharing similar effects on neutrophil chemotaxis and angiogenesis. In this study, we measured the concentrations of these chemokines in human milk, sought their presence in human mammary tissue by immunohistochemistry, and confirmed chemokine expression in cultured human mammary epithelial cells (HMECs). Each of the seven ELR(+) CXC chemokines was measurable in milk, and except for NAP-2/CXCL7, these concentrations were higher than serum. The concentrations were higher in colostrum (except for GRO-beta/CXCL2 and NAP-2/CXCL7), and correlated negatively with time elapsed postpartum. IL-8/CXCL8, GRO-gamma/CXCL3, and ENA-78/CXCL5 concentrations were higher in preterm milk. There was intense immunoreactivity in mammary epithelial cells for all ELR(+) CXC chemokines, and the intensity of staining was higher in breast tissue with lactational changes. The supernatants from confluent HMEC cultures also contained measurable concentrations of all the seven ELR(+) CXC chemokines. These results confirm that all ELR(+) CXC chemokines are actively secreted by the mammary epithelial cells into human milk. Further studies are needed to determine if these chemokines share with IL-8/CXCL8 the protective effects on intestinal epithelial cells.