Life-Threatening Bleeding in Children: A Prospective Observational Study.

OBJECTIVES: The purpose of our study was to describe children with life-threatening bleeding. DESIGN: We conducted a prospective observational study of children with life-threatening bleeding events. SETTING: Twenty-four childrens hospitals in the United States, Canada, and Italy participated. SUBJECTS: Children 0-17 years old who received greater than 40 mL/kg total blood products over 6 hours or were transfused under massive transfusion protocol were included. INTERVENTIONS: Children were compared according bleeding etiology: trauma, operative, or medical. MEASUREMENTS AND MAIN RESULTS: Patient characteristics, therapies administered, and clinical outcomes were analyzed. Among 449 enrolled children, 55.0% were male, and the median age was 7.3 years. Bleeding etiology was 46.1% trauma, 34.1% operative, and 19.8% medical. Prior to the life-threatening bleeding event, most had age-adjusted hypotension (61.2%), and 25% were hypothermic. Children with medical bleeding had higher median Pediatric Risk of Mortality scores (18) compared with children with trauma (11) and operative bleeding (12). Median Glasgow Coma Scale scores were lower for children with trauma (3) compared with operative (14) or medical bleeding (10.5). Median time from bleeding onset to first transfusion was 8 minutes for RBCs, 34 minutes for plasma, and 42 minutes for platelets. Postevent acute respiratory distress syndrome (20.3%) and acute kidney injury (18.5%) were common. Twenty-eight-day mortality was 37.5% and higher among children with medical bleeding (65.2%) compared with trauma (36.1%) and operative (23.8%). There were 82 hemorrhage deaths; 65.8% occurred by 6 hours and 86.5% by 24 hours. CONCLUSIONS: Patient characteristics and outcomes among children with life-threatening bleeding varied by cause of bleeding. Mortality was high, and death from hemorrhage in this population occurred rapidly.

Are pediatric critical care medicine fellowships teaching and evaluating communication and professionalism?

OBJECTIVES: To describe the teaching and evaluation modalities used by pediatric critical care medicine training programs in the areas of professionalism and communication. DESIGN: Cross-sectional national survey. SETTING: Pediatric critical care medicine fellowship programs. SUBJECTS: Pediatric critical care medicine program directors. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Survey response rate was 67% of program directors in the United States, representing educators for 73% of current pediatric critical care medicine fellows. Respondents had a median of 4 years experience, with a median of seven fellows and 12 teaching faculty in their program. Faculty role modeling or direct observation with feedback were the most common modalities used to teach communication. However, six of the eight (75%) required elements of communication evaluated were not specifically taught by all programs. Faculty role modeling was the most commonly used technique to teach professionalism in 44% of the content areas evaluated, and didactics was the technique used in 44% of other professionalism content areas. Thirteen of the 16 required elements of professionalism (81%) were not taught by all programs. Evaluations by members of the healthcare team were used for assessment for both competencies. The use of a specific teaching technique was not related to program size, program director experience, or training in medical education. CONCLUSIONS: A wide range of techniques are currently used within pediatric critical care medicine to teach communication and professionalism, but there are a number of required elements that are not specifically taught by fellowship programs. These areas of deficiency represent opportunities for future investigation and improved education in the important competencies of communication and professionalism.

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 mug/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.

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.

Histamine 2 receptor antagonists vs intravenous proton pump inhibitors in a pediatric intensive care unit: a comparison of gastric pH.

PURPOSE: The aim of this study was to assess gastric pH in critically ill pediatric patients receiving intravenous stress ulcer medication. MATERIALS AND METHODS: A prospective study was done in 48 patients with a gastric tube in place who were receiving either ranitidine or a proton pump inhibitor and no enteral nutrition. Daily peak and trough gastric pHs were measured. RESULTS: The median age was 7 years 5 months (range, 1 month to 19 years), the median weight was 31 kg (range, 3-130 kg), and the median pediatric risk of mortality 2 (PRISM2) score was 12.5 (range, 0-31). All patients were intubated and 8 received dialysis. The average trough pH was 4.4 +/- 1.6 in the ranitidine group, 4.9 +/- 1.8 in the once daily proton pump inhibitor group, and 5.0 +/- 1.2 in the twice daily proton pump inhibitor group (P = .16). The average peak pH was 5.3 +/- 1.8 in the ranitidine group, 5.9 +/- 1.6 in the once daily proton pump inhibitor group, and 6.0 +/- 1.0 in the twice daily proton pump inhibitor group (P = .06). Three (10%) of 28 trough pH measurements in the twice daily proton pump inhibitor group were more acidic than 4 vs 24 (40%) of 60 in the ranitidine group, and 22 (40%) of 56 in the once daily proton pump inhibitor group (P = .02). One (4%) of 27 peak pH measurements in the twice daily proton pump inhibitor group were more acidic than 4 vs 13 (20%) of 61 in the ranitidine group, and 9 (16%) of 56 in the once daily proton pump inhibitor group (P = .12). Three patients (6%; 95% confidence interval, 0.51%-16%) developed upper gastrointestinal bleeding, and 4 patients (8%; 95% confidence interval, 0%-13%) developed ventilator-acquired pneumonia. CONCLUSIONS: Many critically ill pediatric patients receiving stress ulcer prophylaxis have a trough or peak gastric pH more acidic than 4.

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.

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 for 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.

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.

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.

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.

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.

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.

A pilot trial comparing cerebral perfusion pressure-targeted therapy to intracranial pressure-targeted therapy in children with severe traumatic brain injury.

OBJECT: The authors sought to compare cerebral perfusion pressure (CPP)- with intracranial pressure (ICP)-targeted therapy in children with severe traumatic brain injury (TBI). METHODS: A randomized controlled trial was developed to assess CPP and ICP therapies in 17 children (range 15 months-15 years of age) with poststabilization Glasgow Coma Scale (GCS) scores of less than or equal to 8 who were admitted to a pediatric intensive care unit at a Level I trauma center. Goals in the ICP group were to maintain ICP lower than 20 mm Hg and CPP higher than 50 mm Hg. In the CPP group, goals were to maintain CPP higher than 70 mm Hg for patients at least 2 years old and higher than 60 mm Hg for patients younger than 2 years of age. The study outcomes were death or functional outcome at 1 year postinjury. The median GCS scores in the CPP group (12 patients) and the ICP group (five patients) were 6 and 7, respectively. In the CPP group, two patients died, one was lost to follow up, four were unimpaired, and five had mild impairment. In the ICP group, all patients survived; one was lost to follow up, two had mild impairment, and two had hemiparesis and moderate impairment. There were four unimpaired survivors in the CPP arm compared with none in the ICP arm (p = 0.08). CONCLUSIONS: The CPP method appears to be safe, although this feasibility study does not establish that the CPP therapy is superior to ICP therapy.

Implications for matrix metalloproteinases as modulators of pediatric lung disease.

Matrix metalloproteinases (MMPs) are a large family (>20) of cation-dependent proteinases believed to be important modulators of normal human lung development and potentially harmful mediators of lung damage. Little is known about MMP production and secretion by the lung during childhood or how alterations in MMP levels may be involved in lung damage. We examined endotracheal aspirates from children (<19 years) without lung disease for the presence of MMP activity. Only gelatinase activity was detectable, and inhibitor profiles suggest they represented one or more MMPs. Comparison of gelatinase activity, MMP expression, and MMP activity in children without pulmonary disease with children who required mechanical ventilation for respiratory failure show: 1) gelatinase activity was approximately five- to sixfold higher in respiratory failure; 2) MMP-7, MMP-8, and MMP-9 concentrations and MMP-8 and MMP-9 activities were markedly elevated in respiratory failure; and 3) MMP-7, MMP-8, and MMP-9 levels were significantly correlated in children with lung disease. These studies provide compelling evidence that specific MMPs are present in the diseased lung and may participate in the pathogenesis of pediatric respiratory failure.

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.

Metalloproteinase and growth factor interactions: do they play a role in pulmonary fibrosis?

Chronic lung disease due to interstitial fibrosis can be a consequence of acute lung injury and inflammation. The inflammatory response is mediated through the migration of inflammatory cells, actions of proinflammatory cytokines, and the secretion of matrix-degrading proteinases. After the initial inflammatory insult, successful healing of the lung may occur, or alternatively, dysregulated tissue repair can result in scarring and fibrosis. On the basis of recent insights into the mechanisms underlying acute lung injury and its long-term consequences, data suggest that proteinases, such as the matrix metalloproteinases (MMPs), may not only be involved in the breakdown and remodeling that occurs during the injury but may also cause the release of growth factors and cytokines known to influence growth and differentiation of target cells within the lung. Through the release of and activation of fibrosis-promoting cytokines and growth factors such as transforming growth factor-beta1, tumor necrosis factor-alpha, and insulin-like growth factors by MMPs, we propose that these metalloproteinases may be integral to the initiation and progression of pulmonary fibrosis.