Margaret K. Winkler

Exploring the interface between metallo-proteinase activity and growth factor and cytokine bioavailability.

Metallo-proteinases are implicated in many processes involved in tissue remodeling, cell motility, morphogenesis, and cell and organ growth and differentiation. Recent data suggest that several members of the metzincin family including the matrix metallo-proteinases (MMPs), adamalysin-related proteinases, and the newly described pappalysins, are intimately involved in the activation and/or release of cytokines and growth factors. We review how metzincins, working through unique mechanisms, influence the extracellular milieu of several important cytokines and growth factors including transforming growth factor-beta (TGF-beta), TNF-alpha, IGFs and HB-epidermal growth factor (EGF). Because metzincins can modulate the bioavailability of these peptides, they may serve as unique target molecules to control cytokine and growth factor action in the extracellular environment.

Oral and nasal enteral tube placement errors and complications in a pediatric intensive care unit

Objective: To report five cases of errors in the placement of oral/nasal enteral tubes in a pediatric intensive care unit, and to review literature on placement techniques and complication rates. Design: Case series and review of the literature. Setting: A 19-bed pediatric intensive care unit in a tertiary care pediatric hospital. Patients: A 14-yr-old male with respiratory distress following a near drowning, a 10-yr-old male with recurrent acute lymphocytic leukemia and Pneumocystis carinii pneumonia, a 16-yr-old female with complex congenital heart disease and respiratory failure, a 16-yr-old male with status asthmaticus, and a 2-yr-old male with congenital heart disease. Interventions: None. Main Results: Five cases of enteral tube placement errors occurred in our combined medical-surgical pediatric critical care unit within the past year. All five resulted in placement of the feeding tube in the respiratory tract, four occurred despite the presence of cuffed endotracheal tubes. Three of the five patients had subsequent worsening of their respiratory status. One developed a pneumothorax, one developed pulmonary hemorrhage, and one developed an increased oxygen requirement. Conclusions: Patients in the pediatric intensive care unit may have characteristics that place them at an increased risk for misplacement of oral or nasal enteral tubes into the respiratory tract. Placement of enteral tubes into the respiratory tract may cause serious morbidity and possibly mortality. Checking the placement of enteral tubes with traditional methods does not prevent misplacement in the respiratory tree, and new techniques should be considered.

Transforming growth factor–beta inhibition of cytokine-induced vascular cell adhesion molecule-1 expression in human astrocytes

Leukocyte transmigration across the blood‐brain barrier (BBB) is a cardinal feature of central nervous system (CNS) inflammation. Astrocytes form an integral part, both structurally and functionally, of the BBB. Vascular cell adhesion molecule‐1 (VCAM‐1), a member of the immunoglobulin gene superfamily, is involved in extravasation into inflamed tissues and activation of T‐lymphocytes. In this study, we investigated the role of TGF‐β, an immunosuppressive cytokine, in regulating cytokine‐induced VCAM‐1 expression in astrocytes. Human astroglioma cell lines and primary human fetal astrocytes were examined for VCAM‐1 gene expression after treatment with proinflammatory cytokines (TNF‐α, IL‐1β, IFN‐γ) in the absence or presence of TGF‐β. Astroglioma cell lines as well as primary human fetal astrocytes expressed low levels of VCAM‐1 constitutively, and the proinflammatory cytokines induced marked increases in VCAM‐1 expression, particularly TNF‐α and IL‐1β. The inclusion of TGF‐β1 or TGF‐β2 with the proinflammatory cytokines inhibited VCAM‐1 gene expression to varying degrees (33–93%) in all the astroglioma cell lines and primary fetal cells. These results indicate that TGF‐β is an important regulator of cytokine induced VCAM‐1 expression on astrocytes and may prove useful clinically in controlling CNS inflammation. GLIA 22:171–179, 1998.

Pediatric off-label use of recombinant factor VIIa.

OBJECTIVE. Our goal was to report our institutional experience with recombinant factor VIIa for the treatment and/or prevention of bleeding in nonhemophiliac children. METHODS. This was a retrospective case series in a tertiary pediatric referral hospital. RESULTS. During 1999–2006, 135 patients received recombinant factor VIIa for off-label use. The median number of doses was 2; the median dose was 88 μg/kg. The most common diagnoses among patients receiving recombinant factor VIIa were disseminated intravascular coagulation/sepsis (28), surgical bleeding (19), procedural prophylaxis (16), and trauma (15). The median volume of blood products administered 24 hours before recombinant factor VIIa treatment was 29.7 vs 11.7 mL/kg 24 hours after treatment. Only 1 high-risk patient had significant bleeding after receiving prophylactic recombinant factor VIIa before an invasive procedure. Nonsurvivors had significantly increased incidence of multiple organ dysfunction syndrome (75%) compared with survivors (23%). The largest group of patients (n = 28) received recombinant factor VIIa for bleeding and/or coagulopathy because of disseminated intravascular coagulation; the mortality in this group was 26 (93%) of 28. Eleven patients received multiple doses of recombinant factor VIIa to treat bleeding complications after hematopoietic stem cell transplant, without improvement in blood use. Mortality in medical patients was 58% vs 16% in surgical patients. Three patients had significant thrombotic adverse events after receiving recombinant factor VIIa, resulting in 2 deaths and 1 leg amputation. CONCLUSIONS. Off-label use of recombinant factor VIIa significantly decreases blood-product administration; surgical patients had control of life-threatening bleeding with low associated mortality. Prophylactic recombinant factor VIIa may be effective in preventing bleeding if given before invasive procedures in children at high risk. Prolonged use of recombinant factor VIIa for bleeding complications after hematopoietic stem cell transplant is not effective in preventing packed red blood cell transfusion. Presence of disseminated intravascular coagulation and mulitorgan dysfunction syndrome may help predict futility of recombinant factor VIIa treatment. Off-label use of recombinant factor VIIa is associated with thromboembolic events in children.

Early Developmental Changes in IGF-I, IGF-II, IGF Binding Protein-1, and IGF Binding Protein-3 Concentration in the Cerebrospinal Fluid of Children

IGF-I and IGF-II are ubiquitously expressed growth factors that have profound effects on the growth and differentiation of many cell types and tissues, including cells of the CNS. In biologic fluids, most IGFs are bound to one of six IGF binding proteins (IGFBPs 1–6). Increasing evidence strongly supports a role for IGF-I in CNS development, as it promotes neuronal proliferation and survival. However, little is known about IGF-I and its homolog IGF-II and their carrier proteins, IGFBPs, during the neonatal period in which brain size increases dramatically, myelination takes place, and neurons show limited capacity to proliferate. Herein, we have determined the concentrations of IGF-I, IGF-II, IGFBP-1, and IGFBP-3 in cerebral spinal fluid (CSF) samples that were collected from children who were 1 wk to 18 y of age. The concentrations of IGF-I, IGFBP-1, and IGFBP-3 in CSF from children <6 mo of age were significantly higher than in older children, whereas IGF-II was higher in the older group. This is in contrast to what is observed in the peripheral circulation, where IGF-I and IGFBP-3 are low at birth and rise rapidly during the first year, reaching peak levels during puberty. Higher concentrations of IGF-I, IGFBP-1, and IGFBP-3 in the CSF of very young children suggest that these proteins might participate in the active processes of myelination and synapse formation in the developing nervous system. We propose that IGF-I and certain IGFBPs are likely necessary for normal CNS development during critical stages of neonatal brain growth and development.

Severe invasive community-associated methicillin-resistant Staphylococcus aureus infections in previously healthy children.

Objective: An increase in community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) infections has been reported in the literature. Most severe, life-threatening infections were previously thought to be associated with chronically ill or frail patients. Our pediatric intensive care unit (PICU) has seen a recent dramatic increase in primary, severe invasive CA-MRSA infections in healthy children. Design/Setting: A retrospective chart review of all previously healthy patients admitted to our 19-bed combined medical-surgical PICU with a primary diagnosis of severe invasive, culture-proven CA-MRSA disease during the past 6 years. Results: Eleven previously healthy patients were admitted to our PICU with severe, primary, invasive CA-MRSA infections from March 2006 through September 2007, in contrast to no patients meeting these criteria in the preceding 5 years. The mortality rate was 27%, compared with an overall PICU mortality rate during the study period of <7%. The mean PICU length of stay of these patients was 14.9 days, compared with an average PICU length of stay of 2.4 days. Despite initiation of treatment with vancomycin at admission to the PICU in all but one case, patients took a mean of 5.7 days to convert to negative blood cultures. Eight patients had bacteremia longer than 4 days. Six of the patients developed bilateral necrotizing pneumonia requiring prolonged mechanical ventilation. Conclusions: Severe CA-MRSA infections in healthy children are increasing at an alarming rate in our institution. This acute rise in incidence, coupled with an alarmingly high associated mortality rate, raises important questions about the initial empirical antibiotic therapy we use in caring for patients presenting with suspected life-threatening CA-MRSA disease. Vancomycin monotherapy may not be adequate treatment for severe CA-MRSA infections.

The use of enteral naloxone to treat opioid-induced constipation in a pediatric intensive care unit.

Objective: To describe the effects of enteral naloxone used to treat opioid-induced constipation in pediatric intensive care patients. Design: Retrospective chart review. Setting: Pediatric intensive care unit. Patients: Twenty-three patients who received opioid therapy and enteral naloxone in our institution from January 2003 to February 2004 were compared with a randomly sampled control group matched for age, weight, sex, and length of stay who received opioids but had not received enteral naloxone. Interventions: None. Measurements: Daily stool output, daily opiate usage, nutrition, adjuvant laxative use, and side effects were assessed. Results: Patients stayed an average of 5 days (range, 0–13 days) in the pediatric intensive care unit before enteral administration of naloxone was instituted and received it for an average of 9 consecutive days (range, 3–30 days). Mean stool output for study patients before administration of enteral naloxone was 0.14 ± 0.38 stools per day, whereas after its initiation it was 1.60 ± 1.14 stools per day (p < .001). However, two patients developed significant opiate withdrawal symptoms after receiving enteral naloxone. The average stool output for control patients was 0.53 ± 1.21 stools per day. Conclusions: Enteral naloxone may be effective in increasing stool output in opioid-induced constipation but carries the risk of introducing withdrawal symptoms. Further studies are needed to evaluate this agent for opioid-induced constipation in the intensive care unit.

Fatal Hypermagnesemia Caused by an Epsom Salt Enema: A Case Illustration

The authors describe a case of fatal hypermagnesemia caused by an Epsom salt enema. A 7-year-old male presented with cardiac arrest and was found to have a serum magnesium level of 41.2 mg/dL (33.9 mEq/L) after having received an Epsom salt enema earlier that day. The medical history of Epsom salt, the common causes and symptoms of hypermagnesemia, and the treatment of hypermagnesemia are reviewed. The easy availability of magnesium, the subtle initial symptoms of hypermagnesemia, and the need for education about the toxicity of magnesium should be of interest to physicians.

Deep Sedation With Propofol in Patients With Rett Syndrome

Herein we present the largest retrospective case-control series of deep sedation in patients with Rett syndrome, including discussion of the unique aspects of Rett syndrome that make these patients at high risk of sedation. Twenty-one patients with Rett syndrome and 21 control patients who received propofol for deep sedation to facilitate lumbar puncture were compared. Patients with Rett syndrome required significantly less propofol than control patients when standardized for weight and the duration of the procedure (P = .004). Seven of the 21 patients with Rett syndrome compared with none of the control patients experienced a serious adverse event, most of which were due to prolonged apnea (P = .004). All adverse events were transient, and all patients returned to their baseline after the procedure was completed. Sedation of patients with Rett syndrome is associated with a relatively high rate of complications and should not be done without appropriate personnel available who recognize the risks of sedating this unique population. (J Child Neurol 2006;21:210—213; DOI 10.2310/7010.2006.00051).

The use of recombinant factor VIIa in a patient with Noonan syndrome and life-threatening bleeding.

Objective: To present a case report of a patient with Noonan syndrome who developed life-threatening gastrointestinal bleeding shortly after cardiac surgery that was successfully treated with recombinant factor VIIa. Design: Case report. Setting: Pediatric intensive care unit of a children’s hospital. Patient: Ten-month-old with Noonan syndrome and massive gastrointestinal bleeding resulting in severe hypovolemic shock. Interventions: Recombinant factor VIIa was used in this patient’s severe bleeding associated with Noonan syndrome after no other supportive measures were successful. Measurements and Main Results: Recombinant Factor VIIa significantly decreased the patient’s bleeding and allowed his hypovolemic shock to improve. Ultimately, the patient made a complete recovery. Conclusions: Noonan syndrome has a constellation of both cardiac and noncardiac malformations including an increased risk of bleeding, and recombinant factor VIIa is an important agent in the treatment of significant bleeding.