Edmund F. LaGamma

“Proactive” Management of Percutaneously Inserted Central Catheters Results in Decreased Incidence of Infection in the ELBW Population

OBJECTIVE: Extremely low birth weight (ELBW) infants often acquire catheter-related infections (CRIs) when a percutaneously inserted central catheter (PICC) is used for parenteral nutrition or drug administration. Our objective was to compare the incidence of CRIs after we established a “PICC Maintenance Team” for the proactive management — compared to expectant management — of these lines.STUDY DESIGN: We did a prospective collection and analysis of catheter-related sepsis data over a 15-month period from February 1, 1998 through May 1, 1999. Eligible patients included all neonates weighing <1000 g at birth.RESULTS: There was a significantly decreased incidence of CRIs, to a rate of 7.1%, or 5.1/1000 catheter days (p<0.05).CONCLUSION: “Proactive” management of PICC, significantly reduced the incidence of CRIs. The reduction in infection rate is estimated to save 180 hospitalized patient days/100 very low birth weight neonates, with a concomitant savings in morbidity and medical expense.

Characterization of Acute Brain Injuries and Neurobehavioral Profiles in a Rabbit Model of Germinal Matrix Hemorrhage

Background and Purpose— Germinal matrix hemorrhage-intraventricular hemorrhage (GMH-IVH) is the most common neurological problem of premature infants and has enormous financial and social impact. Despite this, there is no standardized animal model of IVH depicting acute brain injuries. Methods— We delivered rabbit-pups prematurely at 29-day gestation by C-section, administered intraperitoneal glycerol to the pups at 3-hour postnatal age to induce IVH, and evaluated the brain for evidence of injuries. Results— About 80% of glycerol-treated pups developed gross IVH. We found greater neutrophil and microglia infiltration around the ventricles (periventricular zone) in pups with IVH than in controls. We noted more apoptosis and neuronal degeneration in the periventricular zone than in the neocortex in pups with IVH, but not in controls. There was evidence of axonal damage revealed by β-amyloid precursor protein and neurofilament immunolabeling. Neurobehavioral testing showed that pups with IVH were more wobbly with lesser capability to walk on inclination than pups without IVH. There was no evidence of acute systemic toxicity in the glycerol-treated pups. An evaluation of autopsy materials from premature infants revealed similar evidence of apoptosis and cellular infiltration in the periventricular zone in cases with IVH, but not in cases without IVH—suggesting clinical relevance of the model. Conclusion— The study provides an instructive animal model of IVH with evidence of acute brain injuries that can be used to evaluate strategies in prevention of IVH and acute posthemorrhagic complications.

Astrocyte End-Feet in Germinal Matrix, Cerebral Cortex, and White Matter in Developing Infants

Astrocyte end-feet ensheathe blood vessels in the brain and are believed to provide structural integrity to the cerebral vasculature. We sought to determine in developing infants whether the coverage of blood vessels by astrocyte end-feet is decreased in germinal matrix (GM) compared with cerebral cortex and white matter (WM), which may cause fragility of the GM vasculature. Therefore, we evaluated the perivascular coverage by astrocyte end-feet in these areas. We double-labeled the brain sections with astroglial markers [glial fibrillary acidic protein (GFAP), aquaporin-4 (AQP4), and S-100β] and a vascular marker, laminin. Perivascular coverage by GFAP+ astrocyte end-feet increased consistently as a function of gestational age (GA) in cortex and WM from 19 to 40 wk. Compared with GFAP, AQP4+ astrocyte end-feet developed at an earlier GA, ensheathing about 63% of blood vessels for 23–40 wk in cortex, WM, and GM. Coverage by GFAP+ perivascular end-feet was decreased in GM compared with cortex and WM from 23 to 34 wk. There was no difference in the coverage by AQP4+ end-feet among the three areas in these infants. The expression of AQP4, a water channel molecule, in the astrocyte end-feet was not significantly different between premature and mature infants, suggesting similar risk of brain edema in preterm and term infants in pathologic conditions. More importantly, the lesser degree of GFAP expression in astrocyte end-feet of GM compared with cortex and WM may reflect a cytoskeletal structural difference that contributes to the fragility of GM vasculature and propensity to hemorrhage.

Neuroprotection in a rabbit model of intraventricular haemorrhage by cyclooxygenase-2, prostanoid receptor-1 or tumour necrosis factor-alpha inhibition

Intraventricular haemorrhage is a major complication of prematurity that results in neurological dysfunctions, including cerebral palsy and cognitive deficits. No therapeutic options are currently available to limit the catastrophic brain damage initiated by the development of intraventricular haemorrhage. As intraventricular haemorrhage leads to an inflammatory response, we asked whether cyclooxygenase-2, its derivative prostaglandin E2, prostanoid receptors and pro-inflammatory cytokines were elevated in intraventricular haemorrhage; whether their suppression would confer neuroprotection; and determined how cyclooxygenase-2 and cytokines were mechanistically-linked. To this end, we used our rabbit model of intraventricular haemorrhage where premature pups, delivered by Caesarian section, were treated with intraperitoneal glycerol at 2 h of age to induce haemorrhage. Intraventricular haemorrhage was diagnosed by head ultrasound at 6 h of age. The pups with intraventricular haemorrhage were treated with inhibitors of cyclooxygenase-2, prostanoid receptor-1 or tumour necrosis factor-α; and cell-infiltration, cell-death and gliosis were compared between treated-pups and vehicle-treated controls during the first 3 days of life. Neurobehavioural performance, myelination and gliosis were assessed in pups treated with cyclooxygenase-2 inhibitor compared to controls at Day 14. We found that both protein and messenger RNA expression of cyclooxygenase-2, prostaglandin E2, prostanoid receptor-1, tumour necrosis factor-α and interleukin-1β were consistently higher in the forebrain of pups with intraventricular haemorrhage relative to pups without intraventricular haemorrhage. However, cyclooxygenase-1 and prostanoid receptor 2-4 levels were comparable in pups with and without intraventricular haemorrhage. Cyclooxygenase-2, prostanoid receptor-1 or tumour necrosis factor-α inhibition reduced inflammatory cell infiltration, apoptosis, neuronal degeneration and gliosis around the ventricles of pups with intraventricular haemorrhage. Importantly, cyclooxygenase-2 inhibition alleviated neurological impairment, improved myelination and reduced gliosis at 2 weeks of age. Cyclooxygenase-2 or prostanoid receptor-1 inhibition reduced tumour necrosis factor-α level, but not interleukin-1β. Conversely, tumour necrosis factor-α antagonism did not affect cyclooxygenase-2 expression. Hence, prostanoid receptor-1 and tumour necrosis factor-α are downstream to cyclooxygenase-2 in the inflammatory cascade induced by intraventricular haemorrhage, and cyclooxygenase-2-inhibition or suppression of downstream molecules--prostanoid receptor-1 or tumour necrosis factor-α--might be a viable neuroprotective strategy for minimizing brain damage in premature infants with intraventricular haemorrhage.

Analysis of lymphocyte proliferative response subpopulations in very low birth weight infants and during the first 8 weeks of life.

ABSTRACT: Cell-mediated immunity is not well characterized in very low birth weight infants, and abnormalities may represent a significant vulnerability to infection. This report describes 165 serial studies in 58 infants between 700 and 1300 g birth weight during the first 8 wk of life. Two ml of blood were drawn at 2-wk intervals to measure T cell numbers and subsets and response to phytohemagglutinin (PHA). Overall, lymphocyte proliferation to PHA averaged 17,264 cpm, significantly less than the adult control (23,566 cpm). T cell numbers and subsets were CD3 62% (adult controls 75%), CD4 45% (49%), and CD8 18.6% (27%). Values at birth were lower as all parameters increased for at least the first 4 wk of life: PHA at birth was 15,464 cpm, CD3 48%, CD4 37%, and CD8 13%. Because of the lymphocytosis of premature infants, the absolute numbers of total T cells and subsets were within the normal adult range despite less than 50% of the mono-nuclear cells at birth being T cells. A study of five infants demonstrated an average of 52% B7+ cells at birth showing that the number of B cells at birth was increased approximately 10-fold over the control number in adults. Clinical correlation showed that the increases in both the % CD8 and the absolute number of CD8+ lymphocytes after birth were correlated with both the occurrence of sepsis and the number of red cell transfusions. In summary this study assessed lymphocyte subsets in a sizeable number of very low birth weight infants serially during the first 8 wk of life including lymphocyte function using isolated mononuclear cells. It demonstrated that premature infants are different from adults controls and full term newborns in: 1) having decreased lymphocyte proliferative response to PHA, 2) having lower % CD3 and CD8, and 3) having an increased number of B cells at birth.

Maturational changes in laminin, fibronectin, collagen IV, and perlecan in germinal matrix, cortex, and white matter and effect of betamethasone

Germinal matrix is selectively vulnerable to hemorrhage in premature infants, and use of prenatal betamethasone is associated with a lower occurrence of germinal matrix hemorrhage. Because the major components of extracellular matrix of the cerebral vasculature—laminin, fibronectin, collagen IV, and perlecan—provide structural stability to blood vessels, we examined whether the expression of these molecules was decreased in the germinal matrix and affected by betamethasone. In both human fetuses and premature infants, fibronectin was significantly lower in the germinal matrix than in the cortical mantle or white matter anlagen. Conversely, laminin α1 gene expression was greater in the human germinal matrix compared with the cortical mantle or white matter. Expression of α1‐ and α2(IV) collagen chains increased with advancing gestational age. Low‐dose prenatal betamethasone treatment enhanced fibronectin level by 1.5–2‐fold whereas a high dose reduced fibronectin expression by 2‐fold in rabbit pups. Because fibronectin provides structural stability to the blood vessels, its reduced expression in the germinal matrix may contribute to the fragility of germinal matrix vasculature and the propensity to hemorrhage in premature neonates.

Delivery of gastroschisis patients before 37 weeks of gestation is associated with increased morbidities

BACKGROUND Despite advances in the care of neonates with gastroschisis, patients present with significant morbidities. Preterm delivery of neonates with gastroschisis is often advocated to avoid the intestinal damage that may be sustained with prolonged exposure to amniotic fluid. However, preterm delivery may impose additional morbidities to this disease process. METHODS We conducted a retrospective review of patients with gastroschisis born from 1989 to 2007. Demographic and clinical data were collected. Preterm healthy neonates, with gestational age from 26 to 36 weeks, were used as controls. RESULTS Preterm infants with gastroschisis had a 14 times higher risk for any of the recorded morbidities. As compared to term neonates with gastroschisis, preterm neonates with gastroschisis had a higher rate of sepsis, longer duration to reach full enteral feedings, and longer length of stay. Although the preterm infants with gastroschisis were less likely to be small for gestational age at birth, they were as likely as the term infants with gastroschisis to have failure to thrive at discharge and had a greater drop in weight percentile during hospitalization. CONCLUSIONS Preterm delivery should be avoided because there is no clear benefit to the gut in avoiding derivative injuries. Meticulous attention should be given to the nutritional needs of patients with gastroschisis.

Hemophagocytic lymphohistiocytosis presenting with thrombocytopenia in the newborn.

Hemophagocytic lymphohistiocytosis (HLH) may present with thrombocytopenia during the newborn period. Three neonates (one term and two preterm) presented during the newborn period with thrombocytopenia. Transient recovery occurred in two newborns. The diagnosis of HLH was made after the recurrence of thrombocytopenia and the clinical symptoms at 5 and 7 weeks. The third infant was a premature baby diagnosed at 8 days of age after manifesting the clinical and laboratory features of HLH. All three neonates were treated with chemotherapy and responded well. After hematologic and clinical remission was achieved, the two newborns received hematopoietic stem cell transplantation from allogeneic donors. The third neonate is currently receiving chemotherapy. Persistent or recurrent thrombocytopenia of undetermined cause during the neonatal period should raise the suspicion of HLH, even though other symptoms or signs are not yet evident.

Compliance with prophylaxis for respiratory syncytial virus infection in a home setting

Background. Respiratory syncytial virus (RSV) is the most common respiratory pathogen in infancy and childhood. Objective. To compare the compliance and biologic efficacy of a home health care agency dosing-compliance program to treatment provided in a physician’s office setting during a single RSV season (November to May). Methods. AAP guidelines were used to identify neonates who were eligible for RSV prophylaxis before discharge from a neonatal intensive care unit setting. Parents were asked to choose to receive the recommended treatment for their child either in their pediatrician’s office setting or through a sequence of periodic nursing visits to their home. All home health care records were reviewed for demographics, number of doses received and hospitalization rate. Pediatricians office records were surveyed by telephone interview of their office staff and parents. Compliance data were calculated based on actual monthly injections given during the RSV season. Results. We followed prospectively 1446 infants who received palivizumab during a single RSV season (November 1, 2000 through April 30, 2001). Of these infants 67% (969 of 1446) received their monthly injections in the home setting where 98% of the doses were given on schedule. In contrast 477 infants (33%) received their injections in a pediatrician’s office (parent’s choice) with a compliance of only 89% for completion of all recommended doses (P < 0.001 vs. home setting). There were 9 RSV hospitalizations (0.93%) in the home setting group and 8 RSV hospitalizations (3.57%) in the office setting (P < 0.001). More parents indicated that the in-home prophylaxis program was more convenient than was true for those receiving treatment in the physician’s office setting (P < 0.01). Conclusions. Better compliance with home injections was associated with a decrease in the hospitalization rate for RSV with a higher degree of parental satisfaction.

Stereospecific Regulation of Tyrosine Hydroxylase and Proenkephalin Genes by Short-Chain Fatty Acids in Rat PC12 Cells

Circulating short-chain fatty acids (SCFAs) are primarily derived from bacterial fermentation of carbohydrates in the colon where they function as physiologic modulators of epithelial cell maturation. Butyrate has been shown to induce tyrosine hydroxylase, the rate-limiting enzyme of catecholamine synthesis, and enkephalin neuropeptide gene transcription, suggesting a role in perinatal sympathoadrenal stress-adaptation. We sought to determine whether there were SCFA structural requirements for this effect. Nine biologically relevant SCFAs and butyrate derivatives were tested in an in vitro model (PC12, rat pheochromocytoma cells) for their ability to regulate neurotransmitter-related gene expression. Our results revealed that among all the studied SCFAs, only propionate and butyrate increased tyrosine hydroxylase and proenkephalin mRNA levels. The functional activity was selective to the carbon atom chain length and associated with the presence of an ethyl moiety in the carbon atom backbone chain. Modifications or absence of this domain affected the gene induction response, suggesting a receptor-mediated mechanism(s). Moreover, propionate, butyrate, and the drug 4-phenyl-butyrate were each shown to regulate transmitter genes via at least three independent mechanisms: histone hyperacetylation, cAMP signaling, or peroxisome proliferator-activated receptor gamma–mediated pathways. Thus, the biologic impact of SCFAs on catecholaminergic and opioid systems depend on the activation of SCFA-specific, dose-specific, and gene-specific molecular mechanisms. We speculate that 1) circulating levels of SCFAs may influence sympathoadrenal transmitter biosynthesis and hence whole animal stress-adaptive responsiveness after birth, and 2) the adverse effects of antibiotics on delayed acquisition of postnatal gut flora may affect this apparent evolutionary advantage of gut colonization.