Soft [beta]-adrenoceptor agonists for topical use in psoriasis

Psoriasis is characterised by epidermal proliferation and inflammation resulting in the appearance of elevated erythematous plaques. The ratio of c~AMP/c~GMP is decreased in psoriatic skin and when the epidermal cell surface receptors are stimulated by β-adrenergic agonists, intracellular ATP is transformed into c-AMP, thus restoring the c~AMP/c~GMP levels. This thesis describes a series of β-adrenoceptor agonists for topical delivery based upon the soft-drug approach. Soft drugs are defined as biologically active, therapeutically useful chemical compounds (drugs) characterised by a predictable and controllable In vivo destruction (metabolism) to non-toxic moieties. after they achieve their therapeutic role, The N-substituent can accommodate a broad range of structures and here the alkoxycarbonylethyl group has been used to provide metabolic susceptability. The increased polarity of the dihydroxy acid, expected after metabolic conversion of the soft~drug, ethyl N-[2'-(3',4'-dihydroxyphenyl)-2'-hydroxyethyl]-3- aminopropionate, should eliminate agonist activity. Further. to prevent oxidation and enhance topical delivery, the catechol hydroxyl groups have been esterified to produce a pro-soft-drug which generates the soft-drug in enzymic systems. The chemical hydrolysis of the pro-soft-drug proceeded via the formation of the dlpivaloyloxy acid and it failed to generate the active dihydroxy ester soft-drug. In contrast, in the presence of porcine liver carboxyesterase, the hydrolysis of the pro-soft drug proceeded via the formation of the required active soft-drug. This compound, thus, has the appropnate kinetic features to enable it to be evaluated further as a drug for the treatment of psoriasis. The pH rate-profile for the hydrolysis of soft-drug indicated a maximum stability at pH ∼ 4.0. The individual rate constants for the degradation and the pKa were analysed by nonlinear regression. The pKa of 7.40 is in excellent agreement with that determined by direct titration (7.43) and indicates that satisfactory convergence was achieved. The soft-drug was poorly transported across a silicone membrane; it was also air-sensitive due to oxidation of the catechol group. The transport of the pro-soft-drug was more efficient and, over the donor pH range 3-8, increased with pH. At lower values, the largely protonated species was not transported. However, above pH 7. chemical degradation was rapid so that a donor pH of 5-6 was optimum. The β-adrenergic agonist activity of these compounds was tested in vitro by measuring chronotropic and inotropic responses in the guinea pig atria and relaxation of guinea pig trachea precontracted with acetylcholine (10-3 M). The soft~drug was a full agonist on the tracheal preparation but was less potent than isoprenaline. Responses of the soft~drug were competitively antagonised by propranolol (10-6 M). The soft~drug produced an increase in force and rate of the isolated atrial preparatIon. The propyl analogue was equally potent with ED50 of 6.52 x 10-7 M. In contrast, at equivalent doses, the dihydroxy acid showed no activity; only a marginal effect was observed on the tracheal preparation. For the pro~soft-drug, responses were of slow onset, in both preparations, with a slowly developing relaxatlon of the tracheal preparatlon at high concentrations (10-5 M). This is consistent with in vitro results where the dipivaloyl groups are hydrolysed more readily than the ethyl ester to gIve the active soft-drug. These results confirm the validity tif the pro-soft-drug approach to the deUvery of β-adrenoceptor agonists.

A novel actuated digit with tactile feedback for clinical applications

This thesis describes the work carried out on the development of a novel digit actuator system with tactile perception feedback to a user and demonstrated as a master-slave system. For the tactile surface of the digit, contrasting sensor elements of resistive strain gauges and optical fibre Bragg grating sensors were evaluated. A distributive tactile sensing system consisting of optimised neural networking schemes was developed, resulting in taxonomy of artificial touch. The device is suitable for use in minimal invasive surgical (MIS) procedures as a steerable tip and a digit constructed wholly from polymers makes it suitable for use in Magnetic Resonance Imaging (MRI) environments enabling active monitoring of the patient during a procedure. To provide a realistic template of the work the research responded to the needs of two contrasting procedures: palpation of the prostate and endotracheal intubation in anaesthesia where the application of touch sense can significantly assist navigation. The performance of the approach was demonstrated with an experimental digit constructed for use in the laboratory in phantom trials. The phantom unit was developed to resemble facets of the clinical applications and digit system is able to evaluate reactive force distributions acting over the surface of the digit as well as different descriptions of contact and motion relative to the surface of the lumen. Completing control of the digit is via an instrumented glove, such that the digit actuates in sympathy with finger gesture and tactile information feedback is achieved by a combination of the tactile and visual means.

Does Obesity Affect Outcomes in Children Admitted from Trauma Centers?

Introduction and Research Objectives: Pediatric obesity has reached epidemic proportions in the United States. In the critical care setting, obesity has yet to be fully studied. We sought to evaluate the effects of obesity in children who are admitted to a hospital from trauma centers using Kid's Inpatient Database (KID) during 2009. Methods: The study examined inpatient admissions from pediatric trauma patients in 2009 using the Kids´ Inpatient Database (KID). Patients (n=27599) were selected from the KID based on Age (AGE>1) and Admission Type (ATYPE=5) and assessed on Race, Sex, Length of Stay (LOS), Number of Diagnoses and Procedures, Severity of Illness (SOI), Risk of Mortality (ROM), Co-morbidities, and Intubation by comparing obese and non-obese cohorts. Chi-square test and student t-test were used to analyze the data. All variables were weighted to get national estimates. Results: The overall prevalence of obesity (those coded as having obesity as co-morbidity) was 1.6% with significantly higher prevalence among Blacks (1.8%), Hispanics (2.3%), and Native Americans (4.1%; p<0.001). Obesity was more prevalent among females (2.4% vs 1.2%; p<.001). Overall mortality in the cohort was 4.8%. Obesity was significantly lower among children who died during hospitalization (0.5% vs 1.6%; p<0.002). However, obese children had significantly longer LOS, greater number of diagnoses, more procedures and greater than expected loss of function due to SOI when compared with nonobese cohort (p<.001). Deficiency anemia, diabetes, hypertension, liver disease, and fluid and electrolyte disorders are all strongly associated with the presence of obesity (p<.005). The rate of intubation is similar between obese and non-obese cohorts. Conclusion: Our study using KID national database found that obese children who are admitted from trauma centers have a higher morbidity and LOS but lower mortality. Racial and gender inequalities of obesity prevalence is consistent with previous reports.

Does Obesity Affect Outcomes In Children Admitted From Trauma Centers?

Introduction and Research Objectives: Pediatric obesity has reached epidemic proportions in the United States. In the critical care setting, obesity has yet to be fully studied. We sought to evaluate the effects of obesity in children who are admitted to a hospital from trauma centers using Kid's Inpatient Database (KID) during 2009. Methods: The study examined inpatient admissions from pediatric trauma patients in 2009 using the Kids´ Inpatient Database (KID). Patients (n=27599) were selected from the KID based on Age (AGE>1) and Admission Type (ATYPE=5) and assessed on Race, Sex, Length of Stay (LOS), Number of Diagnoses and Procedures, Severity of Illness (SOI), Risk of Mortality (ROM), Co-morbidities, and Intubation by comparing obese and non-obese cohorts. Chi-square test and student t-test were used to analyze the data. All variables were weighted to get national estimates. Results:The overall prevalence of obesity (those coded as having obesity as co-morbidity) was 1.6% with significantly higher prevalence among Blacks (1.8%), Hispanics (2.3%), and Native Americans (4.1%; p Conclusion: Our study using KID national database found that obese children who are admitted from trauma centers have a higher morbidity and LOS but lower mortality. Racial and gender inequalities of obesity prevalence is consistent with previous reports.

Avaliação da eficácia da implementação de um pacote de medidas na prevenção de pneumonia associada à ventilação mecânica em unidade de terapia intensiva adulta

Background: Ventilator-associated pneumonia (VAP) is a health care related infection and the second leading cause of nosocomial infections linked to morbidity and mortality rates. Therefore, the implementation of care guideline protocols has become necessary for critically ill patients in ICUs in order to provide adequate treatment. Objective: To assess the impact of a package called FAST HUG in PAV ; analyze the risk factors for occurrence of VAP in adult patients at an ICU of a private hospital ; analyze the clinical characteristics of patients who were or were not submitted to the FAST HUG ; analyze the etiology of microorganisms related to EPI ; determine the cost of hospitalization in patients with pneumonia and in patients who received the FAST HUG.Methods: The study was performed in a private hospital that has an 8-bed ICU. It was divided into two phases: before implementing FAST HUG, from August 2011 to August 2012 and after the implementation of FAST HUG, from September 2012 to December 2013. An individual form for each patient in the study was filled out by using information taken electronically from the hospital medical records. The following data for each patient was obtained: age, gender, reason for hospitalization, the use of three or more types of antibiotics, length of stay, intubation time and progress. Findings: After the implementation of FAST HUG, there was an observable decrease in the occurrence of VAP (p <0.01), as well as a reduction in mortality rates (p <0.01). It also shows that the intervention performed in the study resulted in a significant reduction in ICU hospital costs (p <0.05).Conclusion: The implementation of FAST HUG reduced the cases of VAP. Thus, decreasing costs, reducing mortality rates and length of stay, which therefore resulted in an improvement to the overall quality of care.

Weaning from ventilation

Aims/purpose: Getting off the ventilator is an important patient-centred outcome for patients with acute respiratory failure. It signifies an improvement in patient condition, enables easier communication, reduces fear and anxiety and consequently a reduced requirement for sedatives. Weaning from ventilation therefore is a core ICU nursing task that is addressed in this presentation.
Presentation description: There are different schools of thought on when ventilator weaning begins including: (a) from intubation with titration of support; and (b) only when the patient’s condition improves. There are also different schools of thought on how to wean including gradual reductions in ventilator support to: (a) a low level consistent with extubation; or (b) to a level to attempt a spontaneous breathing trial followed by extubation if successful. Regardless of the approach, what is patient-relevant is the need to determine early when the patient may be ‘ready’ to discontinue ventilation. This time point can be assessed using simple criteria and should involve all ICU staff to the level of their experience. This presentation challenges the notion that only senior nurses or nurses with a ‘weaning course’ should be involved in the weaning process and proposes opportunities for engaging nurses with all levels of experience.
Conclusion: An ICU nursing taskforce that is focused and engaged in determining patient readiness for weaning can make a strong contribution to patient-relevant outcomes.

Congenital nasolacrimal duct obstruction:Comparison of two different treatment algorithms

Purpose: To clarify the most appropriate treatment regimen for congenital nasolacrimal duct obstruction (CNLDO). Methods: A retrospective observational analysis was performed of patients undergoing probing with or without intubation to treat CNLDO in a single institution (Royal Victoria Hospital, Belfast) from 2006 to 2011. Results: Based on exclusion criteria, 246 eyes of 177 patients (aged 0 to 9.8 years with a mean age of 2.1 years) were included in this study: 187 (76%) eyes had successful outcome at first intervention with primary probing, whereas 56 (23%) eyes underwent secondary intervention. There were no significant differences by gender, age, or obstruction complexity between the successful and unsuccessful patients with first intervention. For those patients requiring secondary intervention, 16 of 24 (67%) eyes had successful probing, whereas 22 of 24 (92%) had successful intubation. Patients with intubation as a secondary procedure were significantly more likely to have a successful outcome (P = .037). Statistical analysis was performed using the Fisher's exact test and Barnard's exact test. Conclusions: Primary probing for CNLDO has a high success rate that is not adversely affected by increasing age. This study also indicates that if initial probing is unsuccessful, nasolacrimal intubation rather than repeat probing yields a significantly higher success rate.

CURB-65 and Other Markers of Illness Severity in Community-Acquired Pneumonia Among HIV-Positive Patients

As the relative burden of community-acquired bacterial pneumonia among HIV-positive patients increases, adequate prediction of case severity on presentation is crucial. We sought to determine what characteristics measurable on presentation are predictive of worse outcomes. We studied all admissions for community-acquired bacterial pneumonia over one year at a tertiary centre. Patient demographics, comorbidities, HIV-specific markers and CURB-65 scores on Emergency Department presentation were reviewed. Outcomes of interest included mortality, bacteraemia, intensive care unit admission and orotracheal intubation. A total of 396 patients were included: 49 HIV-positive and 347 HIV-negative. Mean CURB-65 score was 1.3 for HIV-positive and 2.2 for HIV-negative patients (p < 0.0001), its predictive value for mortality being maintained in both groups (p = 0.03 and p < 0.001, respectively). Adjusting for CURB-65 scores, HIV infection by itself was only associated with bacteraemia (adjusted odds ratio [AOR] 7.1, 95% CI [2.6-19.5]). Patients with < 200 CD4 cells/µL presented similar CURB-65 adjusted mortality (aOR 1.7, 95% CI [0.2-15.2]), but higher risk of intensive care unit admission (aOR 5.7, 95% CI [1.5-22.0]) and orotracheal intubation (aOR 9.1, 95% CI [2.2-37.1]), compared to HIV-negative patients. These two associations were not observed in the > 200 CD4 cells/µL subgroup (aOR 2.2, 95% CI [0.7-7.6] and aOR 0.8, 95% CI [0.1-6.5], respectively). Antiretroviral therapy and viral load suppression were not associated with different outcomes (p > 0.05). High CURB-65 scores and CD4 counts < 200 cells/µL were both associated with worse outcomes. Severity assessment scales and CD4 counts may both be helpful in predicting severity in HIV-positive patients presenting with community-acquired bacterial pneumonia.

Non-invasive monitoring of changes in exhaled markers of airway inflammation in Thoroughbred racehorses

Exhaled breath (EB) and exhaled breath condensate (EBC) contain numerous volatile gases and a wide-array of non-volatile compounds, several of which have been investigated as markers of lower airway inflammation in human and veterinary medicine and have been used to diagnose and monitor diseases associated with pulmonary inflammation. The identification of reliable biomarkers within EB and EBC is an active research focus with the common goal of establishing non-invasive and repeatable assessment of respiratory health and disease in mammals. The application of EB and EBC analysis holds considerable appeal in the investigation of respiratory disease in Thoroughbred racehorses, as inflammatory airway disease (IAD) is a common cause for poor performance in this population of animals. This study documented that EB and EBC samples can be safely collected from Thoroughbred racehorses in their own environment, without adverse effect or interference with the horse’s training regimen. The use of off-line collection and analysis of exhaled gases via chemiluminescence is suitable for the measurement of exhaled carbon monoxide, but is not appropriate for analyzing exhaled nitric oxide in horses. Significant changes in the concentration of exhaled CO and the pH of EBC occurred in response to strenuous exercise and when exercising in different environmental temperatures. Exhaled CO was associated with tracheal mucus score (and the number of neutrophils in the mucus) and EBC pH was significantly different in horses with evidence of neutrophilic IAD compared to horses without IAD. Numerous physiological and environmental variables were identified as confounding factors in the assessment of both exhaled CO and EBC pH, with respiratory rate prior to EB collection, and during EBC collection, consistently identified as an explanatory variable influencing the concentration of exhaled biomarkers. Further studies in EB and EBC analysis in horses need to focus on objectively accounting for key respiratory dynamics during sample collection.

Unexpected Complication of a Multinodular Goitre

Multinodular goitre is the most common thyroid gland disorder. It can cause hyperthyroidism and mechanical complaints such as tracheal compression or dysphagia. We report a unique case of a patient with a toxic multinodular goitre presenting with a deep venous thrombosis of the left arm due to direct local compression of blood flow.

Antibiotics resistance of Stenotrophomonas maltophilia strains isolated from various clinical specimens.

Background: A limited number of antibiotics are recommended for the therapy of Stenotrophomonas maltophilia infections due to therapy difficulties caused by its numerous mechanisms of resistance. Objectives: In this study conducted over a period of approximately 5 years we aimed to determine resistance rates of S. maltphilia based on drug classification recommended by Clinical and Laboratory Standards Institute. Methods: A total of 118 S. maltphilia strains isolated from various clinical specimens between January 2006 and June 2012 were included in the study. BD Phoenixautomated microbiology system (Becton Dickinson, USA) was utilized for species level identification and antibiotic susceptibility testing. Results: Sixty seven of S. maltphilia strains were isolated from tracheal aspirate isolates, 17 from blood, 10 from sputum, 10 from wound and 14 from other clinical specimens. Levofloxacin was found to be the most effective antibiotic against S. maltphilia strains with resistance rate of 7.6%. The resistance rates to other antibiotics were as follows: chloramphenicol 18.2%, trimethoprim-sulfamethoxazole 20.3% and ceftazidime 72%. Conclusion: The study revealed that S. maltphilia is resistant to many antibiotics. The treatment of infections caused by S. maltphilia should be preferred primarily as levofloxacin, chloramphenicol, and TMP-SXT, respectively.

CURB-65 and other markers of illness severity in community-acquired pneumonia among HIV-positive patients

Introduction: As the relative burden of community-acquired bacterial pneumonia among HIV-positive patients increases, adequate prediction of case severity on presentation is crucial. We sought to determine what characteristics measurable on presentation are predictive of worse outcomes. Methods: We studied all admissions for community-acquired bacterial pneumonia over 1 year at a tertiary centre. Patient demographics, comorbidities, HIV-specific markers and CURB-65 scores on Emergency Department presentation were reviewed. Outcomes of interest included mortality, bacteraemia, intensive care unit admission and orotracheal intubation. Results: A total of 396 patients were included, 49 HIV positive and 347 HIV negative. Mean CURB-65 score was 1.3 for HIV-positive and 2.2 for HIV-negative patients (p<0.0001), its predictive value for mortality being maintained in both groups (p¼0.03 and p<0.001, respectively). Adjusting for CURB-65 scores, HIV infection by itself was only associated with bacteraemia (adjusted odds ratio 7.1 CI 95% [2.6–19.5]). Patients with<200 CD4 cells/mL presented similar CURB- 65 adjusted mortality (adjusted odds ratio 1.7 CI 95% [0.2–15.2]), but higher risk of intensive care unit admission (adjusted odds ratio 5.7 CI 95% [1.5–22.0]) and orotracheal intubation (adjusted odds ratio 9.1 CI 95% [2.2–37.1]), compared to HIV-negative patients. These two associations were not observed in the>200 CD4 cells/mL subgroup (adjusted odds ratio 2.2 CI 95% [0.7–7.6] and adjusted odds ratio 0.8 CI 95% [0.1–6.5] respectively). Antiretroviral therapy and viral load suppression were not associated with different outcomes (p>0.05). Conclusions: High CURB-65 scores and CD4 counts<200 cells/mL were both associated with worse outcomes. Severity assessment scales and CD4 counts may both be helpful in predicting severity in HIV-positive patients presenting with community-acquired bacterial pneumonia.

Intubação Endotraqueal – Um Dilema na Assistência Pré-hospitalar

A intubação endotraqueal (IET), no pré-hospitalar, é considerada o “gold standard” na manutenção da via aérea de modo a fornecer a ventilação e oxigenação à pessoa em situação crítica, no entanto, está associada a várias complicações e riscos. Com este trabalho de revisão sistemática da literatura pretendeu-se compreender a relação entre a IET em emergência pré-hospitalar e o prognóstico da pessoa em situação crítica, colocando a seguinte questão: “Qual o impacto da intubação endotraqueal, em emergência pré-hospitalar, no prognóstico clínico do doente?”. Este trabalho de investigação iniciou-se com uma pesquisa da literatura de língua inglesa e portuguesa, nas bases de dados científicas MEDLINE, CINAHL, MedicLatina e Nursing and Allied Health Collection num horizonte temporal entre 2010 e 2014. A evidência destaca que a realização da intubação endotraqueal, no pré-hospitalar, está associada a piores taxas de reanimação cardiorrespiratória, ao aumento das taxas de mortalidade e ao aumento das comorbilidades. Estas conclusões reforçam a discussão em torno da prática da IET no pré-hospitalar e sensibilizam os profissionais de saúde para a limitação desta prática a casos em que exista indicação clínica segura.

Tracheostomy in Pediatric Intensive Care Unit: When and Where?

Background: Tracheostomy was first observed in Egyptian drawings in 3600 BC and performed frequently during the 1800’s diphtheria epidemic. Objectives: The aim of this study was to elucidate the indications, complications, mortality rate, and the effect of pediatric tracheostomy on length of PICU or hospital stay. Materials and Methods: Demographic characteristics, diagnosis at admission, duration of ventilation of 152 patients were analyzed retrospectively. Results: The most common tracheostomy indication was prolonged intubation. The mean duration of mechanical ventilation before tracheostomy was 23.8 days. Forty five percent of the tracheostomy procedures were performed at bedside. Neither the place nor the age had any effect on the development of complications (P = 0.701, P = 0.622). The procedure enabled 62% of the patients to be discharged from hospital. Conclusions: Tracheostomy facilitates discharge and weaning of mechanical ventilation. Although the timing of tracheostomy has to be determined for each individual patient, three weeks of ventilation seems to be a suitable period for tracheostomy. Tracheostomy can be performed at bedside safely but patient selection should be made carefully.

Comparison of Complications and Efficacy of NIPPV and Nasal CPAP in Preterm Infants With RDS

Background: Respiratory distress syndrome (RDS) is one of the most common diseases in neonates admitted to NICU. For this important cause of morbidity and mortality in preterm neonates, several treatment methods have been used. To date, non-invasive methods are preferred due to fewer complications. Objectives: Herein, two non-invasive methods of ventilation support are compared: NCPAP vs. NIPPV. Patients and Methods: This is a randomized clinical trial. Premature neonates with less than 34 weeks gestation, suffering from RDS entered the study, including 151 newborns admitted to Vali-Asr NICU during 2012-2013. Most of these patients received surfactant as early rescue via INSURE method and then randomly divided into two NCPAP (73 neonates) and NIPPV (78 neonates) groups. Both early and late complications are compared including extubation failure, hospital length of stay, GI perforation, apnea, intraventricular hemorrhage (IVH) and mortality rate. Results: The need for re-intubation was 6% in NIPPV vs. 17.6% in NCPAP group, which was statistically significant (P = 0.031). The length of hospital stay was 23.92 ± 13.5 vs. 32.61 ± 21.07 days in NIPPV and NCPAP groups, respectively (P = 0.002). Chronic lung disease (CLD) was reported to be 4% in NCPAP and 0% in NIPPV groups (P = 0.035). The most common complication occurred in both groups was traumatization of nasal skin and mucosa, all of which fully recovered. Gastrointestinal perforation was not reported in either group. Conclusions: This study reveals the hospital length of stay, re-intubation and BPD rates are significantly declined in neonates receiving NIPPV as the treatment for RDS.