Anticoagulation practices associated with bleeding and thrombosis in pediatric extracorporeal membrane oxygenation; a multi-center secondary analysis.

To determine associations between anticoagulation practices and bleeding and thrombosis during pediatric extracorporeal membrane oxygenation (ECMO), we performed a secondary analysis of prospectively collected data which included 481 children (<19 years), between January 2012 and September 2014. The primary outcome was bleeding or thrombotic events. Bleeding events included a blood product transfusion >80 ml/kg on any day, pulmonary hemorrhage, or intracranial bleeding, Thrombotic events included pulmonary emboli, intracranial clot, limb ischemia, cardiac clot, and arterial cannula or entire circuit change. Bleeding occurred in 42% of patients. Five percent of subjects thrombosed, of which 89% also bled. Daily bleeding odds were independently associated with day prior activated clotting time (ACT) (OR 1.03, 95% CI= 1.00, 1.05, p=0.047) and fibrinogen levels (OR 0.90, 95% CI 0.84, 0.96, p <0.001). Thrombosis odds decreased with increased day prior heparin dose (OR 0.88, 95% CI 0.81, 0.97, p=0.006). Lower ACT values and increased fibrinogen levels may be considered to decrease the odds of bleeding. Use of this single measure, however, may not be sufficient alone to guide optimal anticoagulation practice during ECMO.

Microglial MyD88 signaling regulates acute neuronal toxicity of LPS-stimulated microglia in vitro.

Although the role of microglial activation in neural injury remains controversial, there is increasing evidence for a detrimental effect in the immature brain, which may occur in response to release of neurotoxic substances including pro-inflammatory cytokines. However, the signaling mechanisms involved in microglial-induced neuronal cell death are unclear. Microglia isolated from the brains of wild-type (WT) or MyD88 knockout (KO) mice were exposed to PBS or the TLR4-ligand LPS (100 ng/mL) for 2, 6, 14, or 24 h, and the microglia-conditioned medium (MCM) collected. Detection of multiple inflammatory molecules in MCM was performed using a mouse 22-plex cytokine microbead array kit. Primary neuronal cultures were supplemented with the 14 or 24 h MCM, and the degree of neuronal apoptosis examined after exposure for 24 h. Results showed a rapid and sustained elevation in multiple inflammatory mediators in the MCM of WT microglia exposed to LPS, which was largely inhibited in MyD88 KO microglia. There was a significant increase in apoptotic death measured at 24 h in cultured neurons exposed to CM from either 14 or 24 h LPS-stimulated WT microglia (p<.05 vs. WT control). By contrast, there was no increase in apoptotic death in cultured neurons exposed to CM from 14 or 24 h LPS-stimulated MyD88 KO microglia (p=.15 vs. MyD88 KO control). These data suggest that MyD88-dependent activation of microglia by LPS causes release of factors directly toxic to neurons.

Endogenous alpha2-adrenergic receptor-mediated neuroprotection after severe hypoxia in preterm fetal sheep.

Central alpha-adrenergic receptor activity is important for fetal adaptation to hypoxia before birth. It is unclear whether it is also important during recovery. We therefore tested the hypothesis that an infusion of the specific alpha(2)-adrenergic receptor antagonist idazoxan (1 mg/kg/h i.v.) from 15 min to 4 h after profound hypoxia induced by 25 min umbilical cord occlusion in fetal sheep at 70% of gestation (equivalent to the 28-32 weeks in humans) would increase neural injury. After 3 days' recovery, idazoxan infusion was associated with a significant increase in neuronal loss in the hippocampus (P<0.05), expression of cleaved caspase-3 (P<0.05), and numbers of activated microglia (P<0.05). There was no significant effect on other neuronal regions or on loss of O4-positive premyelinating oligodendrocytes in the subcortical white matter. Idazoxan was associated with an increase in evolving epileptiform electroencephalographic (EEG) transient activity after occlusion (difference at peak 2.5+/-1.0 vs. 11.7+/-4.7 counts/min, P<0.05) and significantly reduced average spectral edge frequency, but not EEG intensity, from 54 until 72 h after occlusion (P<0.05). Hippocampal neuronal loss was correlated with total numbers of epileptiform transients during idazoxan infusion (P<0.01; r(2)=0.7). In conclusion, endogenous inhibitory alpha(2)-adrenergic receptor activation after severe hypoxia appears to significantly limit evolving hippocampal damage in the immature brain.

Fish functional traits are affected by hydrodynamics at small spatial scale.

The Mediterranean damselfish Chromis chromis is a species with a broad distribution found both in the Mediterranean Sea and Eastern Atlantic as far south as the coast of Angola. We hypothesized that the species may have significant functional morphological plasticity to adapt along a gradient of environmental conditions. It is a non-migratory zooplanktivorous species and spends the daytime searching for food in the middle of the water column. Therefore, local hydrodynamics could be one of the environmental factors affecting traits of C. chromis with repercussions at the population level. We compared the body condition, individual growth and body shapes of damselfish collected under two different hydrodynamic conditions (low ∼10 cm s(-1) vs. high ∼20 cm s(-1)). Specimens showed higher body condition under high-hydrodynamics, where conditions offered greater amounts of food, which were able to support larger individuals. Individuals smaller than 60-mm were more abundant under low-hydrodynamics. Morphometric analysis revealed that high-hydrodynamics were favored by fish with a more fusiform body shape and body traits developed for propellant swimming.

Characterization of recombinant soybean leghemoglobin a and apolar distal histidine mutants.

The cDNA for soybean leghemoglobin a (Lba) was cloned from a root nodule cDNA library and expressed in Escherichia coli. The crystal structure of the ferric acetate complex of recombinant wild-type Lba was determined at a resolution of 2.2 A. Rate constants for O2, CO and NO binding to recombinant Lba are identical with those of native soybean Lba. Rate constants for hemin dissociation and auto-oxidation of wild-type Lba were compared with those of sperm whale myoglobin. At 37 degrees C and pH 7, soybean Lba is much less stable than sperm whale myoglobin due both to a fourfold higher rate of auto-oxidation and to a approximately 600-fold lower affinity for hemin. The role of His61(E7) in regulating oxygen binding was examined by site-directed mutagenesis. Replacement of His(E7) with Ala, Val or Leu causes little change in the equilibrium constant for O2 binding to soybean Lba, whereas the same mutations in sperm whale myoglobin cause 50 to 100-fold decreases in K(O2). These results show that, at neutral pH, hydrogen bonding with His(E7) is much less important in regulating O2 binding to the soybean protein. The His(E7) to Phe mutation does cause a significant decrease in K(O2) for Lba, apparently due to steric hindrance of the bound ligand. The rate constants for O2 dissociation from wild-type and native Lba decrease significantly with decreasing pH. In contrast, the O2 dissociation rate constants for mutants with apolar E7 residues are independent of pH, suggesting that hydrogen bonding to the distal histidine residue in the native protein is enhanced under acid conditions. All of these results support the hypothesis that the high affinity of Lba for oxygen and other ligands is determined primarily by enhanced accessibility and reactivity of the heme group.

Current concepts in brain resuscitation.

In spite of the tremendous amount of effort and money put forth to reduce morbidity and mortality associated with global cerebral ischemia, the outlook for patients suffering an ischemic insult remains dismal. The lack of a sufficient substrate supply during the period of ischemia as well as the production of toxic metabolites in response to ischemia have been incriminated as key factors causing brain damage. As discussed in this article, modes of therapy have included efforts to minimize the duration of ischemia (eg, effective cardiopulmonary resuscitation, hemodilution, heparinization, calcium antagonists) and decrease the production of toxic metabolites (eg, barbiturates, calcium antagonists). Although the barbiturates have also been proposed to decrease the metabolic needs during ischemia, they have no therapeutic value for global cerebral ischemia. The initial evaluation of the calcium antagonists has been more promising.

Linked Records of Children with Traumatic Brain Injury. Probabilistic Linkage without Use of Protected Health Information.

OBJECTIVE: Record linkage may create powerful datasets with which investigators can conduct comparative effectiveness studies evaluating the impact of tests or interventions on health. All linkages of health care data files to date have used protected health information (PHI) in their linkage variables. A technique to link datasets without using PHI would be advantageous both to preserve privacy and to increase the number of potential linkages. METHODS: We applied probabilistic linkage to records of injured children in the National Trauma Data Bank (NTDB, N = 156,357) and the Pediatric Health Information Systems (PHIS, N = 104,049) databases from 2007 to 2010. 49 match variables without PHI were used, many of them administrative variables and indicators for procedures recorded as International Classification of Diseases, 9th revision, Clinical Modification codes. We validated the accuracy of the linkage using identified data from a single center that submits to both databases. RESULTS: We accurately linked the PHIS and NTDB records for 69% of children with any injury, and 88% of those with severe traumatic brain injury eligible for a study of intervention effectiveness (positive predictive value of 98%, specificity of 99.99%). Accurate linkage was associated with longer lengths of stay, more severe injuries, and multiple injuries. CONCLUSION: In populations with substantial illness or injury severity, accurate record linkage may be possible in the absence of PHI. This methodology may enable linkages and, in turn, comparative effectiveness studies that would be unlikely or impossible otherwise.

Potential neuroprotective strategies for perinatal infection and inflammation.

Preterm born infants have high rates of brain injury, leading to motor and neurocognitive problems in later life. Infection and resulting inflammation of the fetus and newborn are highly associated with these disabilities. However, there are no established neuroprotective therapies. Microglial activation and expression of many cytokines play a key role in normal brain function and development, as well as being deleterious. Thus, treatment must achieve a delicate balance between possible beneficial and harmful effects. In this review, we discuss potential neuroprotective strategies targeting systemic infection or the resulting systemic and central inflammatory responses. We highlight the central importance of timing of treatment and the critical lack of studies of delayed treatment of infection/inflammation.

Gypsies and acute medical intervention.

Recently, a 7-month-old, terminally ill Gypsy infant was admitted to a pediatric intensive care unit. Treating this child and her extended family was a challenging experience during which numerous culture-related problems were encountered. The Gypsy approach to acute medical care consisted of the presence of a large extended family unit, the lack of decision making by the patient's parents, and several different Gypsy traditions. There were diverse, and often derogatory, reactions and prejudices from the hospital staff. After interviewing family members, this family's needs were easier to understand, and interaction with them in culturally relevant terms was possible. When dealing with Gypsy families, identification of the responsible elder male members of the family, establishment of firm lines of communication with essential family members and the parents, and education of the medical staff concerning Gypsies are recommended.

Effect of seating position and restraint use on injuries to children in motor vehicle crashes.

OBJECTIVE: To determine the effect of restraint use and seating position on injuries to children in motor vehicle crashes, with stratification by area of impact. METHODS: Children <15 years old involved in serious automobile crashes in Utah from 1992 through 1996 were identified from statewide motor vehicle crash records. Serious crashes are defined as those resulting in occupant injuries with broken bones or significant bleeding or property damage exceeding $750. Probabilistic methods were used to link these records with hospital records. Analysis used logistic regression controlling for age, restraint use, occupant seating position, and type of crash. RESULTS: We studied 5751 children and found 53% were rear seat passengers. More than 40% were unrestrained. Sitting in the rear seat offered a significant protective effect (adjusted odds ratio: 1.7; 95% confidence interval: 1.6-2.0), and restraint use enhanced this effect (adjusted odds ratio: 2.7; 95% confidence interval: 2.4-3.1). Mean hospital charges were significantly greater for front seat passengers. CONCLUSIONS: Rear seat position during a motor vehicle crash provides a significant protective effect, restraint use furthers this effect, and usage rates of restraint devices are low. The rear seat protective effect is in addition to and independent of the protection offered from restraints.

Age-related changes in chest geometry during cardiopulmonary resuscitation.

We studied alterations of chest geometry during conventional cardiopulmonary resuscitation in anesthetized immature swine. Pulsatile force was applied to the sternum in increments to determine the effects of increasing compression on chest geometry and intrathoracic vascular pressures. In 2-wk- and 1-mo-old piglets, permanent changes in chest shape developed due to incomplete recoil of the chest along the anteroposterior axis, and large intrathoracic vascular pressures were generated. In 3-mo-old animals, permanent chest deformity did not develop, and large intrathoracic vascular pressures were not produced. We propose a theoretical model of the chest as an elliptic cylinder. Pulsatile displacement along the minor axis of an ellipse produces a greater decrease in cross-sectional area than displacement of a circular cross section. As thoracic cross section became less circular due to deformity, greater changes in thoracic volume, and hence pressure, were produced. With extreme deformity at high force, pulsatile displacement became limited, diminishing pressure generation. We conclude that changes in chest geometry are important in producing intrathoracic intravascular pressure during conventional cardiopulmonary resuscitation in piglets.

Age-related effects of compression rate and duration in cardiopulmonary resuscitation.

The effects of various compression rate and duration combinations on chest geometry and cerebral perfusion pressure during cardiopulmonary resuscitation (CPR) were studied in immature swine. Pentobarbital-anesthetized 2- and 8-wk-old piglets received CPR after ventricular fibrillation. At compression rates of 40, 60, 80, 100, 120, and 150/min, duty cycle (compression duration/total cycle time) was increased from 10 to 80% by 10% increments. Mean aortic and sagittal sinus pressures, pulsatile displacement, and deformity of the anterior chest wall were measured. Increasing duty cycle increased cerebral perfusion pressure until chest relaxation time was compromised. Inadequate chest recoil, development of static chest deformation, and limitation of pulsatile chest wall movement occurred in both age groups when relaxation time was very short (150-200 ms in 2-wk-old piglets, 250-300 ms in 8-wk-old piglets). These changes in chest geometry correlated with deterioration of cerebral perfusion pressure only in 8-wk-old piglets. In the younger group, perfusion pressures plateaued but did not deteriorate. These data emphasize the importance of duty cycle in generating cerebral perfusion pressure and indicate that younger animals can tolerate high compression rates except at extremely long duty cycles.

Albuterol in acute bronchiolitis--continued therapy despite poor response?

To determine whether clinicians continue to treat acute bronchiolitis with nebulized albuterol despite lack of clinical improvement after such treatment, we reviewed the medical records of 90 randomly selected infants and children with the primary diagnosis of that disorder who were treated in this 232-bed tertiary care children's hospital. Clinical improvement and no clinical improvement were defined as improvement and lack of improvement, respectively, in air movement, wheezing, retractions, oxygen saturation, work of breathing, and respiratory rate after administration of nebulized albuterol. Response to nebulized albuterol was determined from explicit written documentation in the medical records. Of 68 children who received nebulized albuterol in the emergency department, 52% had written documentation indicating no clinical improvement; however, 94% had admission orders to continue the therapy. Within 12 hours after admission, 61% were again noted to have no clinical improvement with nebulized albuterol. Eighty-seven percent of nonresponders continued to receive albuterol throughout hospitalization, and 54% continued to receive it after discharge. Continuing therapy despite lack of response resulted in unnecessary medical expenses.

Intracranial pressure monitoring in severe pediatric near-drowning.

Between April 1979 and April 1981, 20 near-drowned children admitted to Childrens Hospital of Los Angeles with a Glasgow coma score of 3 underwent intracranial pressure (ICP) monitoring and brain resuscitative therapy. By the 3rd hospital day, 14 patients had developed ICP elevation above 20 torr, and 11 of these had sustained intracranial hypertension above 30 torr. Ten of these children died, and 4 remain in a persistent vegetative state. Of 6 patients whose ICP never exceeded 20 torr, 3 recovered completely, 1 died, and 2 remain without any cognitive function. The salvage rate for patients with normal ICP after near-drowning accidents is significantly better than that for patients in whom the ICP is elevated (P = 0.017). Intracranial hypertension is associated with a uniformly bad outcome and is frequent in patients who die or suffer permanent, severe central nervous system damage after near-drowning.

Ecstasy intoxication: an overlap between serotonin syndrome and neuroleptic malignant syndrome.

3,4-Methylenedioxymethamphetamine (MDMA), also known as "ecstasy" is a popular recreational drug with potential for abuse. Although its neurotoxic effects have been established in animal studies, the acute and long-term effects of this serotonergic agent in humans are still unknown. We describe a 19-year-old woman with overlapping symptoms of neuroleptic malignant syndrome and serotonin syndrome after a single exposure to MDMA. We also review 15 other cases reported in the literature to draw attention to the serious neurotoxicity, including fatal outcomes, caused by the use of this increasingly popular, illicit drug.

Bedside transpyloric tube placement in the pediatric intensive care unit.

BACKGROUND: The purpose of this study was to demonstrate the feasibility of placing transpyloric feeding tubes at the bedside without fluoroscopy in critically ill pediatric patients. METHODS: The patient population consisted of 90 patients (ages 1 week to 15 years, median age 9 months) admitted to a 26-bed pediatric intensive care unit in a university-affiliated pediatric hospital. Patient weights ranged from 2.4 to 100 kg with a median weight of 7.5 kg. Seventy-six patients were endotracheally intubated and mechanically ventilated; one patient had a tracheotomy. A total of 24 patients were pharmacologically paralyzed; 38 patients were receiving catecholamine infusions, and 17 patients had intracranial monitoring devices in place. All had concurrent nasogastric suctioning. Nonweighted Silicone Rubber 6F or 8F nasoenteric tubes were inserted at the bedside using metoclopramide, air insufflation and positioning to achieve transpyloric passage. Blue-dyed water was instilled in 58 patients to test for reflux and confirm transpyloric position. RESULTS: Successful nonfluoroscopic bedside transpyloric (duodenal or jejunal) tube placement was verified radiographically in 84 (93%) patients; seven of these patients were less than 4 weeks of age. One patient had blue dye in the nasogastric fluids, consistent with duodenogastric reflux or failure of transpyloric passage. The abdominal radiographs confirmed the results of the blue dye test in all 58 patients. There were six (6.7%) unsuccessful attempts at transpyloric bedside tube placement: four were a result of hemodynamic instability, one was a result of oropharyngeal trauma, and one was due to intestinal malrotation. The average time for placement was 15 minutes with a range of 5 to 45 minutes. No complications from tube placement were observed. CONCLUSIONS: Bedside placement of transpyloric feeding tubes is a safe and effective method to institute enteral feedings in critically ill pediatric patients.

Early enteral feeding in the pediatric intensive care unit.

BACKGROUND: The purpose of this study was to evaluate the feasibility and safety of early enteral feedings of critically ill pediatric patients. METHODS: The subject population of 42 critically ill patients ranged in age from 5 days to 18 years (mean 5.8 years), mean weight 17 kg. Transpyloric nasoenteric tubes were placed in all patients by a nonfluoroscopic bedside technique. All subjects were mechanically ventilated; 32 (76%) were on one or more vasoactive medications. Six (15%) patients were fed for more than 13 days while on vasoactive support and pharmacological paralysis. RESULTS: There were no documented complications of early enteral feeding, including aspiration. All patients were able to achieve caloric goals within 48 hours of beginning enteral feedings. All patients developed regular stool patterns despite periodic absence of bowel sounds. Enteral feedings replaced 256 days of total parenteral nutrition. Estimated patient charge savings averaged $425 for each day of enteral feedings. CONCLUSIONS: Early enteral feedings are feasible, well tolerated, and cost effective in critically ill pediatric patients.

Critical pathways for postoperative care after simple congenital heart surgery.

OBJECTIVE: To evaluate the clinical, financial, and parent/patient satisfaction impact of critical pathways on the postoperative care of pediatric cardiothoracic patients with simple congenital heart lesions. STUDY DESIGN: Critical pathways were developed by pediatric intensive care nurses and implemented under the direction of pediatric cardiothoracic surgeons. PATIENTS AND METHODS: Critical pathways were used during a 12-month study on 46 postoperative patients with simple repair of atrial septal defect (ASD), coarctation of the aorta (CoA), and patent ductus arteriosus (PDA). Using the study criteria, a control group of 58 patients was chosen from 1993. Prospective and control group data collected included postoperative intubation time, total laboratory tests, arterial blood gas utilization, morphine utilization, time in the pediatric intensive care unit, total hospital stay, total hospital charges, total hospital cost, and complications. Variances from the critical pathway and satisfaction data were also recorded for study patients. RESULTS: Resource utilization was reduced after implementation of critical pathways. Significant reductions were seen in total hours in the pediatric intensive care unit, total number of laboratory tests, postoperative intubation times, arterial blood gas utilization, morphine utilization, length of hospitalization (ASD, 4.9 to 3.1 days; CoA, 5.2 to 3.2 days; and PDA, 4.1 to 1.4 days; all P < 0.05), total hospital charges (ASD, $16,633 to $13,627; CoA, $14,292 to $8319; and PDA, $8249 to $4216; all P < 0.05), and total hospital costs. There was no increase in respiratory complications or other complications. Patients and families were generally satisfied with their hospital experience, including analgesia and length of hospitalization. CONCLUSIONS: Implementation of critical pathways reduced resource utilization and costs after repair of three simple congenital heart lesions, without obvious complications or patient dissatisfaction.

Cerebral vascular diseases.

Strokes remain an important cause of mortality and morbidity despite recent advances in neurologic intensive care. Although support of ventilation and circulation improves the outcome for stroke patients, the efficacy of cerebral resuscitative measures such as hyperventilation, osmotherapy, fluid restriction, steroids, intracranial pressure control, and barbiturates remains unproven. Current specific therapies (anticoagulation, surgery) are useful in carefully selected patients. New therapies now being researched include fluorocarbons, narcotic antagonists, and calcium blockers.

Analyses of nuclear ldhA gene and mtDNA control region sequences of Atlantic northern bluefin tuna populations.

There has been considerable debate about whether the Atlantic northern bluefin tuna exist as a single panmictic unit. We have addressed this issue by examining both mitochondrial DNA control region nucleotide sequences and nuclear gene ldhA allele frequencies in replicate size or year class samples of northern bluefin tuna from the Mediterranean Sea and the northwestern Atlantic Ocean. Pairwise comparisons of multiple year class samples from the 2 regions provided no evidence for population subdivision. Similarly, analyses of molecular variance of both mitochondrial and ldhA data revealed no significant differences among or between samples from the 2 regions. These results demonstrate the importance of analyzing multiple year classes and large sample sizes to obtain accurate estimates when using allele frequencies to characterize a population. It is important to note that the absence of genetic evidence for population substructure does not unilaterally constitute evidence of a single panmictic population, as genetic differentiation can be prevented by large population sizes and by migration.