Epidemiology of pediatric severe sepsis and septic shock in Turkey: Prevalence, Results and Treatments Study.

AIM: This study was aimed at characterizing the prevalence, management, and outcomes of pediatric severe sepsis and septic shock in tertiary pediatric intensive care units (PICUs) in Turkey. METHODS: A point prevalence study was conducted on five days over the course of one year in 29 PICUs in Turkey. Outcomes included severe sepsis and septic shock point prevalence, therapies used, duration of PICU stay, and mortality at day 28. RESULTS: Of the 1757 children who were admitted to the PICU during the study period, 141 (8.0%) children met the consensus criteria for severe sepsis and 23 (1.3%) children met the criteria for septic shock. Pediatric severe sepsis and septic shock accounted for 8% and 1.3% of all PICU admissions, respectively. The median age of the patients was 2.6 years (interquartile range (IQR), 0.7-8.6 years). Enteral nutrition (79.3%) was preferred compared to parenteral nutrition (31.1%) for the first 3 days after PICU admission. A total of 39 patients died while in the PICU, for a 23.8% mortality rate, which did not vary by age. CONCLUSION: The mortality rate was similar to that in other studies. Hematologic-immunologic comorbidity, parenteral nutrition and the use of vasoactive drugs were independently associated with mortality.

Erythropoietin prevents lymphoid apoptosis but has no effect on survival in experimental sepsis.

BACKGROUND: Lymphoid apoptosis in sepsis is associated with poor outcome, and prevention of apoptosis frequently improves survival in experimental models of sepsis. Recently, erythropoietin (EPO) was shown to protect against lipopolysaccharide (LPS)-induced mortality. As cecal ligation and puncture (CLP) is a clinically more relevant model of sepsis, we evaluated the effect of EPO on CLP-induced lymphoid tissue apoptosis and mortality. METHODS: Young Wistar rats were subjected to polymicrobial sepsis by CLP. EPO (5,000 U/kg intraperitoneal) was administered 30 min before CLP and then 1 and 4 h after CLP. Spleen, thymus, and small intestine were harvested at 24 h and assessed for apoptosis by terminal deoxynucleotidyl transferase nick-end labeling (TUNEL) and caspase-3 staining. A separate group of animals was followed up for mortality. RESULTS: Splenic, thymic, and intestinal apoptosis was increased after CLP; administration of EPO significantly decreased apoptosis as determined by TUNEL and caspase-3 staining. Final survival in the CLP mortality study was 30% in both saline and EPO groups. CONCLUSION: Our results provide the first evidence that EPO attenuates lymphoid apoptosis in the CLP model of sepsis. However, EPO is not associated with a survival benefit in the CLP model of sepsis.

Hyperferritinemia in the critically ill child with secondary hemophagocytic lymphohistiocytosis/sepsis/multiple organ dysfunction syndrome/macrophage activation syndrome: what is the treatment?

INTRODUCTION: Hyperferritinemia is associated with increased mortality in pediatric sepsis, multiple organ dysfunction syndrome (MODS), and critical illness. The International Histiocyte Society has recommended that children with hyperferritinemia and secondary hemophagocytic lymphohistiocytosis (HLH) or macrophage activation syndrome (MAS) should be treated with the same immunosuppressant/cytotoxic therapies used to treat primary HLH. We hypothesized that patients with hyperferritinemia associated secondary HLH/sepsis/MODS/MAS can be successfully treated with a less immunosuppressant approach than is recommended for primary HLH. METHODS: We conducted a multi-center cohort study of children in Turkish Pediatric Intensive Care units with hyperferritinemia associated secondary HLH/sepsis/MODS/MAS treated with less immunosuppression (plasma exchange and intravenous immunoglobulin or methyl prednisolone) or with the primary HLH protocol (plasma exchange and dexamethasone or cyclosporine A and/or etoposide). The primary outcome assessed was hospital survival. RESULTS: Twenty-three children with hyperferritinemia and secondary HLH/sepsis/MODS/MAS were enrolled (median ferritin = 6341 µg/dL, median number of organ failures = 5). Univariate and multivariate analyses demonstrated that use of plasma exchange and methyl prednisolone or intravenous immunoglobulin (n = 17, survival 100%) was associated with improved survival compared to plasma exchange and dexamethasone and/or cyclosporine and/or etoposide (n = 6, survival 50%) (P = 0.002). CONCLUSIONS: Children with hyperferritinemia and secondary HLH/sepsis/MODS/MAS can be successfully treated with plasma exchange, intravenous immunoglobulin, and methylprednisone. Randomized trials are required to evaluate if the HLH-94 protocol is helpful or harmful compared to this less immune suppressive and cytotoxic approach in this specific population.

A survey of pediatric intensive care services in Turkey.

The aim of this study was to describe and assess the structure, organization, and staffing of pediatric intensive care services in Turkey. A survey was sent to major university and government hospitals. Out of the 40 hospitals stating to provide pediatric intensive care, 34 responded to the survey (85% response rate). In the majority (81.2%) of hospitals, pediatric intensive care was provided in single room units or within the pediatric ward. Unit size ranged from 1-16 beds with an average of 6.8 +/- 4.2 operational beds per unit. Much of the equipment and a sufficient number of specialists for pediatric intensive care unit (PICU) care were present in the surveyed hospitals. However, only 12 units had a pediatric intensivist on staff and few had special PICU nurses. Many hospitals in Turkey already have various equipment and specialists needed to support pediatric intensive care. Expansion of services and improved care could be achieved if more pediatric intensivists and nurses could be provided and services concentrated in fully equipped tertiary centers.

RNA interference in neuroscience.

One of the most exciting findings in recent years has been the discovery of RNA interference (RNAi). RNAi is an important system that allows sequence-specific gene silencing through targeted degradation of mRNA by cognate double-stranded RNA (dsRNA). RNAi plays a role in endogenous cellular processes, such as developmental control and heterochromatin formation, and serves as an antiviral defense mechanism. Recent findings suggest that RNAi and related pathways are involved in protecting the genome against instabilities caused by transposons and repetitive sequences. Several rapidly developing RNAi methodologies provide a new approach for elucidation of gene functions. RNAi technology is also currently being evaluated as a potentially useful method to develop highly specific dsRNA-based gene-silencing therapeutics. In this paper, we review the use of RNAi in neuroscience research and as a possible therapeutic tool for treatment of neurological diseases.

Erythropoietin as a novel neuroprotectant.

PURPOSE: To provide an overview of the current knowledge on neuroprotective properties of Erythropoietin (Epo), mechanisms by which Epo produces neuroprotection, and signaling pathways regulated by Epo in the nervous system. METHODS: The Medline database was searched for articles on the neuroprotective properties of Epo. Experimental and clinical studies were systematically reviewed. RESULTS: In addition to promoting the survival, proliferation, and differentiation of immature erythroid cells, Epo and the Epo receptor (EpoR) have recently been shown to exist and function in the nervous system. The Epo/EpoR system plays a critical role in neurodevelopment and neuroprotection. Epo ameliorates or prevents neuronal injury by neuroprotective, anti-apoptotic, anti-inflammatory, anti-oxidant, angiogenic, neurogenic and neurotrophic effects in cell culture and animal models of neurological diseases. The clinical effectiveness of recombinant human Epo in ischemic stroke in human patients has also been reported recently. CONCLUSION: Recent studies suggest that Epo is a potential novel neurotherapeutic agent and further clinical studies are warranted.

Erythropoietin improves long-term spatial memory deficits and brain injury following neonatal hypoxia-ischemia in rats.

It is well known that neonatal hypoxic-ischemic brain injury leads to mental retardation and deficits in cognitive abilities such as learning and memory in human beings. The ameliorative effect of erythropoietin (Epo) on experimental hypoxic-ischemic brain injury in neonatal rats has been recently reported. However, the effect of Epo on cognitive abilities in the hypoxic-ischemic brain injury model is unknown. The aim of this study is to investigate the effects of Epo on learning-memory, behavior and neurodegeneration induced by hypoxia-ischemia. Seven days old Wistar Albino rat pups have been used in the study (n = 28). Experimental groups in the study were: (1) saline-treated hypoxia-ischemia group, (2) Epo-treated (i.p., 1000 U/kg) hypoxia-ischemia group, (3) sham-operated group, (4) control group. In hypoxia-ischemia groups, left common carotid artery was ligated permanently on the seventh postnatal day. Two hours after the procedure, hypoxia (92% nitrogen and 8% oxygen) was induced for 2.5 h. Epo was administered as a single dose immediately after the hypoxia period. When pups were 22 days old, learning experiments were performed using Morris water maze. On the 20th week, when brain development is accepted to be complete, learning experiments were repeated. Rats were then perfused and brains removed for macroscopic and microscopic evaluation. Epo treatment immediately after hypoxic-ischemic insult significantly improved long-term neurobehavioral achievements when tested during the subsequent phase of brain maturation and even into adulthood. Histopathological evaluation demonstrated that Epo also significantly diminished brain injury and spared hippocampal CA1 neurons. In conclusion, Epo administrated as a single dose immediately after neonatal hypoxic-ischemic insult provides benefit over a prolonged period in the still developing rat brain. Since the wide use of Epo in premature newborns, this agent may be potentially beneficial in treating asphyxial brain damage in the perinatal period.

Erythropoietin and the nervous system.

Erythropoietin (Epo) is a hematopoietic growth factor and cytokine which stimulates erythropoiesis. In recent years, Epo has been shown to have important nonhematopoietic functions in the nervous system. Nonerythropoietic actions of Epo include a critical role in the development, maintenance, protection and repair of the nervous system. A wide variety of experimental studies have shown that Epo and its receptor are expressed in the nervous system and Epo exerts remarkable neuroprotection in cell culture and animal models of nervous system disorders. In this review, we summarize the current knowledge on the neurotrophic and neuroprotective properties of Epo, the mechanisms by which Epo produces neuroprotection and the signal transduction systems regulated by Epo in the nervous system.

Multiple erythematous nodules and ecthyma gangrenosum as a manifestation of Pseudomonas aeruginosa sepsis in a previously healthy infant.

Pseudomonas aeruginosa septicemia is rare in healthy infants and children. Also not common, dermatologic manifestations such as ecthyma gangrenosum and indurated erythematous nodular lesions may be the first signs of pseudomonas infection, or may appear later in the course of the disease. Peripheral facial paralysis and mastoiditis are also rare and serious complications of acute otitis media caused by P. aeruginosa. We report a previously healthy 6-month-old boy who had an uncommon presentation and rare complications during the course of P. aeruginosa sepsis.

Polyethylene skin wrapping accelerates recovery from hypothermia in very low-birthweight infants.

BACKGROUND: Thermal management of the very low-birthweight (VLBW) infant is a cornerstone of neonatology because thermal stress is an important determinant of survival. This prospective study was designed to determine the effects of polyethylene occlusive skin wrapping on heat loss in VLBW infants admitted to the neonatal intensive care unit (NICU) promptly after birth. METHODS: Thirty consecutively inborn infants weighing <1500 g were allocated to a wrap or non-wrap group within an incubator after admission to the NICU. Axillary and incubator temperatures were taken on arrival at 1 and 2 h. RESULTS: Infants in the wrap group reached a normal axillary temperature faster then non-wrap infants and required lower incubator temperatures. CONCLUSIONS: Polyethylene film wrapping effectively helps to correct hypothermia in VLBW infants admitted to the NICU.

Erythropoietin downregulates bax and DP5 proapoptotic gene expression in neonatal hypoxic-ischemic brain injury.

BACKGROUND: Perinatal asphyxia is an important cause of neonatal mortality and subsequent serious sequelae such as motor and cognitive deficits and seizures. The ameliorative effect of erythropoietin (Epo) on experimental hypoxic-ischemic brain injury in neonatal rats has been recently reported. Recent studies also confirm the antiapoptotic effect of Epo in a variety of in vitro and in vivo neuronal injury models including hypoxic-ischemic brain injury. However, molecular mechanisms of Epo protection and antiapoptotic effect in this model are unclear. Epo may exert its antiapoptotic effect via the differential regulation of the expression of genes involved in the apoptotic process. OBJECTIVES: Thus, in the present study, we studied the effects of systemically administered Epo on antiapoptotic (bcl-2, bcl-XL), proapoptotic (bax and DP5) gene expression following hypoxic-ischemic brain injury in neonatal rats. METHODS: Seven- day-old Wistar rat pups were divided into three groups: control group (n=15), saline-treated group (n=17), and Epo-treated group (n=18). Rat pups were subjected to left carotid artery occlusion followed by 2.5 h of hypoxic exposure. Epo-treated group received an intraperitoneal injection of recombinant human Epo at a dose of 1,000 units/kg, saline-treated group received an intraperitoneal injection of saline at the same volume of Epo. Forty-eight hours after hypoxia, 3 animals in each group were killed for histopathological evaluation. To detect DNA fragmentation in cell nuclei, terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling reaction was applied. Bcl-2 and bax protein expression were also analyzed with immunohistochemistry. For reverse transcriptase-polymerase chain reaction (RT-PCR) analysis, rats were sacrificed 4, 12, and 24 h after hypoxia. Bcl-2, bcl-XL, bax, and DP5 mRNA expression were analyzed by RT-PCR. RESULTS: Epo significantly prevented hypoxia-ischemia-induced bax and DP5 mRNA upregulation in brain tissue. Epo did not show any effect on bcl-XL transcription altered by injury. However, Epo reversed injury-induced downregulation in bcl-2 transcription. Modulating effects of Epo on bcl-2 and bax protein expression were also revealed by immunohistochemistry. CONCLUSIONS: These results suggest that Epo exerts a neuroprotective effect against hypoxic-ischemic brain injury, at least partially, via the differential regulation of the expression of genes involved in apoptotic process.

Effects of childhood bronchiectasis on cardiac functions.

BACKGROUND: Bronchiectasis is still a widespread disease in developing countries. It is an important cause of mortality and morbidity. The information on cardiac involvement in bronchiectasis is limited. However, cor pulmonale is common in patients with chronic lung disease, such as cystic fibrosis. METHODS: We utilized echocardiography and exercise tests, along with clinical scoring, chest radiograph scoring, and pulmonary function tests in 21 patients to determine whether detectable changes in cardiac functions were present, and the nature of their relationship to the underlying disease severity. RESULTS: The ventricular systolic functions were preserved in all patients. Some of the patients had changes in left ventricular diastolic function indices, characterized by abnormal Ewave/Awave (E/A) ratios or isovolumetric relaxation time values. Isovolumetric relaxation time but not E/A ratios was found to have a significant negative correlation with the clinical score. In addition, exercise capacity was decreased in bronchiectatic children. Most of the patients stopped the exercise test due to exhaustion before reaching maximum heart rate. CONCLUSION: Left ventricular diastolic functions are affected in bronchiectasis, and the performance of patients is dependent on their pulmonary status. This is the first study demonstrating the cardiac effects of bronchiectasis according to our survey of the published literature.