ACCM/PALS haemodynamic support guidelines for paediatric septic shock: an outcomes comparison with and without monitoring central venous oxygen saturation

Introduction: The ACCM/PALS guidelines address early correction of paediatric septic shock using conventional measures. In the evolution of these recommendations, indirect measures of the balance between systemic oxygen delivery and demands using central venous or superior vena cava oxygen saturation ( ScvO(2) >= 70%) in a goal-directed approach have been added. However, while these additional goal-directed endpoints are based on evidence-based adult studies, the extrapolation to the paediatric patient remains unvalidated. Objective: The purpose of this study was to compare treatment according to ACCM/PALS guidelines, performed with and without ScvO(2) goal-directed therapy, on the morbidity and mortality rate of children with severe sepsis and septic shock. Design, participants and interventions: Children and adolescents with severe sepsis or fluid-refractory septic shock were randomly assigned to ACCM/PALS with or without ScvO(2) goal-directed resuscitation. Measurements: Twenty-eight-day mortality was the primary endpoint. Results: Of the 102 enrolled patients, 51 received ACCM/PALS with ScvO(2) goal-directed therapy and 51 received ACCM/PALS without ScvO(2) goal-directed therapy. ScvO(2) goal-directed therapy resulted in less mortality ( 28-day mortality 11.8% vs. 39.2%, p = 0.002), and fewer new organ dysfunctions ( p = 0.03). ScvO(2) goal-directed therapy resulted in more crystalloid ( 28 ( 20-40) vs. 5 ( 0-20) ml/kg, p < 0.0001), blood transfusion ( 45.1% vs. 15.7%, p = 0.002) and inotropic ( 29.4% vs. 7.8%, p = 0.01) support in the first 6 h. Conclusions: This study supports the current ACCM/PALS guidelines. Goal-directed therapy using the endpoint of a ScvO(2) = 70% has a significant and additive impact on the outcome of children and adolescents with septic shock.

Outflow occlusion for circulatory arrest in dogs

The purpose of this study was to evaluate the possibility of producing circulatory arrest by occlusion of the pulmonary trunk as an alternative to the venous inflow occlusion through the left hemithorax. Eight healthy mongrel dogs were divided in two groups. Group I underwent 4 minutes of outflow occlusion and Group II was submitted to 8 minutes of circulatory arrest. Outflow occlusion was performed through left thoracotomy and pericardiotomy by passing a Rumel tourniquet around the pulmonary trunk. Physical examination, electrocardiography, echocardiography, blood gas analyses, hemodynamic, and oxygen transport variables were obtained before and after the procedure. The dogs from Group I did not have any clinical, electrocardiographic, echocardiographic, or hemo-dynamic abnormalities after anesthetic recover. In the Group II, only one dog survived, which had no clinical, electrocardiographic, or echocardiographic abnormalities. In this last dog, just after releasing the occlusion, it was detected increases in the following parameters: heart rate (HR), systolic, diastolic and mean arterial blood pressure (SAP; DAP; MAP), pulmonary artery pressure (PAP), pulmonary wedge pressure (PWP), central venous pressure (CVP), cardiac output (CO), systolic index (SI), cardiac index (CI), left and right ventricular stroke work (LVSW; RVSW), oxygen delivery index (DO2), oxygen consumption index (VO2), and oxygen extraction (O2 ext). Moreover, the oxygen content of arterial and mixed venous blood (CaO2; CvO2), and the arterial and mixed venous partial pressure of oxygen (PaO2; PvO2) were decreased 5 minutes after circulatory arrest. Outflow occlusion is a feasible surgical procedure for period of 4 minutes of circulatory arrest.

Minimum alveolar concentrations and hemodynamic effects of two different preparations of sevoflurane in pigs

BACKGROUND: Original sevoflurane (Sevo A) is made with water, while a generic sevoflurane (Sevocris) is produced with propylene glycol as a stabilizing additive. We investigated whether the original and generic sevoflurane preparations differed in terms of their minimum alveolar concentration (MAC) values and hemodynamic effects. METHODS: Sixteen pigs weighing 31.6±1.8 kg were randomly assigned to the Sevo A or Sevocris groups. After anesthesia induction via mask with the appropriate sevoflurane preparation (6% in 100% oxygen), the MAC was determined for each animal. Hemodynamic and oxygenation parameters were measured at 0.5 MAC, 1 MAC and 1.5 MAC. Histopathological analyses of lung parenchyma were performed. RESULTS: The MAC in the Sevo A group was 4.4±0.5%, and the MAC in the Sevocris group was 4.1±0.7%. Hemodynamic and metabolic parameters presented significant differences in a dose-dependent pattern as expected, but they did not differ between groups. Cardiac indices and arterial pressures decreased in both groups when the sevoflurane concentration increased from 0.5 to 1 and 1.5 MAC. The oxygen delivery index (DO2I) decreased significantly at 1.5 MAC. CONCLUSION: Propylene glycol as an additive for sevoflurane seems to be as safe as a water additive, at least in terms of hemodynamic and pulmonary effects.

Effects of Fluid Resuscitation on Cardiovascular Performance After Posttraumatic Pneumonectomy

Background: Several factors have been implicated in the high-mortality rate of posttraumatic pneumonectomy. In this study, we evaluated the hemodynamic and echocardiographic changes induced by pneumonectomy and fluid resuscitation after hemorrhagic shock. Methods: Fourteen dogs were bled to a target mean arterial pressure of 40 mmHg. The animals were assigned to two groups: control (no fluid resuscitation) and lactated Ringer`s (3 x shed blood volume). The left pulmonary hilum was cross clamped, and the animals were observed for 60 minutes. Systemic hemodynamics was evaluated using Swan-Ganz, arterial catheter, and ultrasonic flow probe. Systemic O(2)-derived variables were calculated. Ejection fraction was determined by two-dimensional echocardiography. Results: Fluid resuscitation improved the mean arterial pressure and systemic oxygen delivery. After pneumonectomy, no significant increase in right ventricular pressure was observed in the LR group. No signs of major ventricular dilation or changes in arterial oxygenation were observed. Conclusion: Our data suggest that pneumonectomy is not associated with early pulmonary hypertension; gentle fluid resuscitation improves cardiovascular performance and is not associated with an increase in right ventricular pressure.

Short-Term Effects of Hydroxyethylstarch Resuscitation on Systemic and Regional Hemodynamics and Metabolism in a Brain-Dead Canine Model

Background. Hydroxyethylstarch (HES) is a synthetic polymer of glucose that has been suggested for therapeutic use in long-term plasma expansion. The aim of this study was to test the hypothesis that the infusion of a small volume of HES may provide benefits in systemic and regional hemodynamics and metabolism in a brain-dead canine model compared with large volume crystalloid resuscitation. Methods. Fourteen mongrel dogs were subjected to a brain-death protocol by consecutive insufflations of a balloon catheter in the epidural space. One hour after induction of brain-death, the animals were randomly assigned to two groups: NS (0.9% NaCl, 33mL/kg), and HES (6% HES 450/0.7, 17mL/Kg). Systemic and regional hemodynamics were evaluated using Swan-Ganz, ultrasonic flowprobes, and arterial catheters. Serial blood samples were collected for blood gas, electrolyte, and serum chemistry analysis. Systemic, hepatic, and splanchnic O(2)-derived variables were also calculated. Results. Epidural balloon insufflations induced a significant increase in mean arterial pressure, cardiac output (MAP and CO, respectively), regional blood flow, and systemic vascular resistance. Following the hyperdynamic phase, severe hypotension with normalization of systemic and regional blood flow was observed. Fluid resuscitation induced a prompt increase in MAP, CO, and portal vein blood flow, and a significant reduction in systemic and pulmonary vascular resistance. There were no differences between groups in metabolic indices, liver function tests (LFTs), or renal function tests. HES was more effective than NS in restoring cardiac performance in the first 2h after fluid resuscitation (P < 0.05). Both tested solutions partially and temporarily restored systemic and regional oxygen delivery. Conclusion. Small volumes of 6% HES 450/0.7 improved cardiovascular performance and provided the same regional hemodynamic and metabolic benefits of large volumes of isotonic crystalloid solutions. (C) 2011 Elsevier Inc. All rights reserved.

Photocytotoxic activity of a nitrosyl phthalocyanine ruthenium complex - A system capable of producing nitric oxide and singlet oxygen

The synthesis, structural aspects, pharmacological assays, and in vitro photoinduced cytotoxic properties of [Ru(NO)(ONO)(pc)] (pc = phthalocyanine) are described. Its biological effect on the B16F10 cell line was studied in the presence and absence of visible light irradiation. At comparable irradiation levels, [Ru(NO) (ONO)(pc)] was more effective than [Ru(pc)] at inhibiting cell growth, suggesting that occurrence of nitric oxide release following singlet oxygen production upon light irradiation may be an important mechanism by which the nitrosyl ruthenium complex exhibits enhanced biological activity in cells. Following visible light activation, the [Ru(NO)(ONO)(pc)] complex displayed increased potency in B16F10 cells upon modifications to the photoinduced dose; indeed, enhanced potency was detected when the nitrosyl ruthenium complex was encapsulated in a drug delivery system. The liposome containing the [Ru(NO)(ONO)(pc)] complex was over 25% more active than the corresponding ruthenium complex in phosphate buffer solution. The activity of the complex was directly proportional to the ruthenium amount present inside the cell, as determined by inductively coupled plasma mass spectroscopy. Flow cytometry analysis revealed that the photocytotoxic activity was mainly due to apoptosis. Furthermore, the vasorelaxation induced by [Ru(NO)(ONO)(pc)], proposed as NO carrier, was studied in rat isolated aorta. The observed vasodilation was concentration-dependent. Taken together, the present findings demonstrate that the [Ru(NO)(ONO)(pc)] complex induces vascular relaxation and could be a potent anti-tumor agent. Nitric oxide release following singlet oxygen production upon visible light irradiation on a nitrosyl ruthenium complex produces two radicals and may elicit phototoxic responses that may find useful applications in photodynamic therapy. Crown Copyright (C) 2011 Published by Elsevier Inc. All rights reserved.

Iontophoretic transport of zinc phthalocyanine tetrasulfonic acid as a tool to improve drug topical delivery

Phthalocyanines have been used as systemic photosensitizers because of their high affinity towards tumour tissue, and the high rates of reactive oxygen species produced when they are irradiated during photodynamic therapy. However, the topical administration of these compounds is limited by their large size, poor hydrosolubility and ionic character. This study aimed to investigate the iontophoretic delivery of charged zinc phthalocyanine tetrasulfonic acid (ZnPcS(4)) from a hydrophilic gel to different skin layers by means of in-vitro and in-vivo studies. Six hours of passive administration was insufficient for ZnPcS(4) to cross the stratum corneum (SC) and to reach the epidermis and dermis. No positive effect was reached when anodal iontophoresis was performed, showing that the drug-electrode attraction effect was higher than the electro-osmosis contribution at a pH of 5.5. Cathodal iontophoresis, however, was able to transport significant amounts of the drug to the viable epidermis. In addition, the absence of NaCl in the formulation significantly increased (by five-fold) the amount of ZnPcS(4) that crossed the SC and accumulated in the epidermis and dermis. It was possible to visualize the drug accumulation in the follicle openings and in the epidermis, even after SC removal. In-vivo experiments in rat skin showed that these results were maintained in an in-vivo model, even with only 15 min of iontophoresis. In addition, confocal analysis of the treated skin showed a homogeneous distribution of ZnPcS(4) in the viable epidermis after this short period of cathodal iontophoresis. Anti-Cancer Drugs 22:783-793 (C) 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Retrograde delivery of photosensitizer (TPPp-O-beta-GluOH)(3) selectively potentiates its photodynamic activity

Photodynamic therapy involves administration of a photosensitizing drug and its subsequent activation by visible light of the appropriate wavelength. Several approaches to increasing the specificity of photosensitizers for cancerous tissues and, in particular, through their conjugation to ligands that are directed against tumor-associated antigens have been investigated. Here, we have studied the delivery of the photocytotoxic porphyrin compound TPP(p-O-beta-D-GluOH)(3) into tumor cells that overexpress the glycosphingolipid Gb3, using the Gb3-binding nontoxic B-subunit of Shiga toxin (STxB) as a vector. To allow for site-directed chemical coupling, an STxB variant carrying a free sulfhydryl moiety at its C-terminal end has been used. Binding affinity, cellular uptake, singlet oxygen quantum yield, and phototoxicity of the conjugate have been examined. Despite some effect of coupling on both the photophysical properties of TPP(p-O-beta-D-GluOH)(3) and the affinity of STxB for its receptor, the conjugate exhibited a higher photocytotoxic activity than the photosensitizer alone and was exquisitely selective for Gb3-expressing tumor cells. Furthermore, our data strongly suggest that STxB-mediated retrograde delivery of the photosensitizer to the biosynthetic/secretory pathway is critical for optimal cytotoxic activity. In conclusion, a strong rationale for using retrograde delivery tools such as STxB in combination with photosensitizing agents for the photodynamic therapy of tumors is presented.

Polímeros sintéticos biodegradáveis: matérias-primas e métodos de produção de micropartículas para uso em drug delivery e liberação controlada

Micropartículas produzidas a partir de polímeros sintéticos têm sido amplamente utilizadas na área farmacêutica para encapsulação de princípios ativos. Essas micropartículas apresentam as vantagens de proteção do princípio ativo, mucoadesão e gastrorresistência, melhor biodisponibilidade e maior adesão do paciente ao tratamento. Além disso, utiliza menores quantidade de princípio ativo para obtenção do efeito terapêutico proporcionando diminuição dos efeitos adversos locais, sistêmicos e menor toxidade. Os polímeros sintéticos empregados na produção das micropartículas são classificados biodegradáveis ou não biodegradáveis, sendo os biodegradáveis mais utilizados por não necessitam ser removidos cirurgicamente após o término de sua ação. A produção das micropartículas poliméricas sintéticas para encapsulação tanto de ativos hidrofílicos quanto hidrofóbicos pode ser emulsificação por extração e/ou evaporação do solvente; coacervação; métodos mecânicos e estão revisados neste artigo evidenciando as vantagens, desvantagens e viabilidade de cada metodologia. A escolha da metodologia e do polímero sintético a serem empregados na produção desse sistema dependem da aplicação terapêutica requerida, bem como a simplicidade, reprodutibilidade e factibilidade do aumento de escala da produção.

Natural rubber latex used as drug delivery system in guided bone regeneration (GBR)

In this work, we propose natural rubber latex (NRL) membranes as a protein delivery system. For this purpose Bovine Serum Albumin (BSA) was incorporated into the latex solution for in vitro protein delivery experiments. Different polymerization temperatures were used, from -10 to 27 °C, in order to control the membrane morphology. These membranes were characterized by Scanning Electron Microscopy (SEM), Atomic Force Microscopy (AFM), as well as the Lowry Method to measure the BSA release. SEM and AFM microscopy analysis showed that the number, size and distribution of pores in NRL membranes can be varied, as well as its overall morphology. We have found that the morphology of the membrane is the predominant factor for higher protein release, compared with pore size and number of pores. Results demonstrated that the best drug-delivery system was the membrane polymerized at RT (27 °C), which does release 66% of its BSA content for up to 18 days. Our results indicate that NRLb could be used in the future as an active membrane that could accelerate bone healing in GBR.

Influência do local de nascimento e do transporte sobre a morbimortalidade de recém-nascidos prematuros

OBJETIVO: Verificar a influência do local de nascimento e do transporte sobre a morbimortalidade de recém-nascidos prematuros na Região Sul do Brasil. MÉTODOS: Estudo de coorte com recém-nascidos prematuros transferidos para a unidade de tratamento intensivo de referência (grupo transporte = 61), tendo sido acompanhados até a alta. Os dados sobre o atendimento no hospital de origem e transporte foram obtidos no momento da internação. Esse grupo foi comparado com neonatos da maternidade de referência, pareados por idade gestacional (grupo controle = 123), tendo como desfecho primário o óbito e desfechos secundários as alterações da glicemia, temperatura e saturação de oxigênio no momento da internação e a incidência de enterocolite necrosante, displasia broncopulmonar e sepses. Na associação entre as variáveis e o desfecho, foi utilizado o risco relativo. Foi adotado um nível de significância de α = 5% e β = 90%. RESULTADOS: A distância média percorrida foi de 91 km. A idade gestacional média foi de 34 semanas. Entre os recém-nascidos transferidos, 23% (n = 14) não tiveram atendimento pediátrico na sala de parto. No transporte, 33% dos recém-nascidos foram acompanhados por pediatra, e os equipamentos utilizados foram: incubadora (57%), bomba de infusão (13%), oxímetro (49%) e aparelho para aferição da glicemia (21%). O grupo transporte apresentou maior incidência de hiperglicemia, risco relativo (RR) = 3,2 (2,3-4,4), hipoglicemia, RR = 2,4 (1,4-4,0), hipertermia, RR = 2,5 (1,6-3,9), e hipoxemia, RR = 2,2 (1,6-3,0). Foram observados 18% de óbitos no grupo dos transferidos e 8,9% no grupo controle, RR = 2,0 (1,0-2,6). CONCLUSÕES: A pesquisa expõe deficiências no atendimento e transporte dos recém-nascidos, sendo necessária uma melhor organização do atendimento perinatal e do transporte na região nordeste do Rio Grande do Sul.

Socioeconomic Differences in Preferences and Willingness-to-Pay for Insulin Delivery Systems in Type 1 and Type 2 Diabetes

Background: An evaluation of patients' preferences is necessary to understand the demand for different insulin delivery systems. The aim of this study was to investigate the association between socioeconomic status (SES) and patients' preferences and willingness to pay (WTP) for various attributes of insulin administration for diabetes management. Methods: We conducted a discrete choice experiment (DCE) to determine patients' preferences and their WTP for hypothetical insulin treatments. Both self-reported annual household income and education completed were used to explore differences in treatment preferences and WTP for different attributes of treatment across different levels of SES. Results: The DCE questionnaire was successfully completed by 274 patients. Overall, glucose control was the most valued attribute by all socioeconomic groups, while route of insulin delivery was not as important. Patients with higher incomes were willing to pay significantly more for better glucose control and to avoid adverse events compared to lower income groups. In addition, they were willing to pay more for an oral short-acting insulin ($Can 71.65 [95% confidence interval, $40.68, $102.62]) compared to the low income group ($Can 9.85 [95% confidence interval, 14.86, 34.56; P < 0.01]). Conversely, there were no differences in preferences when the sample was stratified by level of education. Conclusions: This study revealed that preferences and WTP for insulin therapy are influenced by income but not by level of education. Specifically, the higher the income, the greater desire for an oral insulin delivery system, whereas an inhaled route becomes less important for patients.

Preliminary biocompatibility investigation of magnetic albumin nanosphere designed as a potential versatile drug delivery system

Background: The magnetic albumin nanosphere (MAN), encapsulating maghemite nanoparticles, was designed as a magnetic drug delivery system (MDDS) able to perform a variety of biomedical applications. It is noteworthy that MAN was efficient in treating Ehrlich's tumors by the magnetohyperthermia procedure. Methods and materials: In this study, several nanotoxicity tests were systematically carried out in mice from 30 minutes until 30 days after MAN injection to investigate their biocompatibility status. Cytometry analysis, viability tests, micronucleus assay, and histological analysis were performed. Results: Cytometry analysis and viability tests revealed MAN promotes only slight and temporary alterations in the frequency of both leukocyte populations and viable peritoneal cells, respectively. Micronucleus assay showed absolutely no genotoxicity or cytotoxicity effects and histological analysis showed no alterations or even nanoparticle clusters in several investigated organs but, interestingly, revealed the presence of MAN clusters in the central nervous system (CNS). Conclusion: The results showed that MAN has desirable in vivo biocompatibility, presenting potential for use as a MDDS, especially in CNS disease therapy.

Signatures of oxygen on Cu(3)Au(100): From isolated impurity to oxide regimes

We analyze the scanning tunneling microscopy (STM) signatures for the O/Cu(3)Au(100) surface from the low-coverage (isolated impurity) to high-coverage (oxide) regimes. First-principles calculations show that oxygen signatures switch from dark to bright spots as the oxygen coverage increases. This behavior is nicely traced back to a change in the oxygen orbital character of the Fermi-level electronic states. Our results allow for the chemical identification by STM of oxygen and copper atoms in the fully ordered O/Cu(3)Au(100)-c(2x2) surface.