Synthesis and anticonvulsant activity of some tetracyclic indole derivatives.

Several related series of cycloalkyl[4,5]pyrrolo[3,2,1-ij]quinolines 7a-g, 8a-c, 10a-3, and 16a-f and indolo[3,2,1-hi]indoles 22a-c and 23a,b were synthesized and tested for anticonvulsant activity. The key preparative step, a Fischer indole reaction between a bicyclic hydrazine and a cyclic ketone, gave the compounds in 34-96% yield. The products were tested in rat maximal electroshock for anticonvulsant activity. Several compounds showed good activity, with 6-[(dimethylamino)methyl]-4,5,6,8,9,10-hexahydrocyclopenta[4,5]pyrrolo[3,2,1-ij]quinoline (7d) and N-methyl-4,5,6,8,9,10,11,12-octahydrocyclohepta[4,5]pyrrolo[3,2,1-ij]quinoline- 6-carboxamide (10c) having ED50's of 12.5 and 12.9 mg/kg po, respectively.

Angiotensin converting enzyme inhibitors: N-substituted monocyclic and bicyclic amino acid derivatives.

The synthesis of N-(3-mercaptopropionyl)-N-arylglycines (14a-x),- N-arylalanines (15a,b),-N-cycloalkylglycines (16a-k), and -1,2,3,4-tetrahydroisoquinoline-3-carboxylic acids (17a-d), -1,2,3,4-tetrahydroquinoline-2-carboxylic acids (18a-f), and -indoline-2-carboxylic acids (19a-k) is described. In vitro inhibition of angiotensin converting enzyme (ACE) is reported for each compound, and the structure--activity relationship for each series is discussed. The in vivo inhibition of ACE and antihypertensive effects of representative compounds from each series are discussed. The most potent compound, 19d, had an in vitro ACE IC50 of 2.6 X 10(-9) M and lowered blood pressure in spontaneous hypertensive rats 85 mm at a dose of 10 mg/kg po.

Soluble fas levels correlate with multiple organ dysfunction severity, survival and nitrate levels, but not with cellular apoptotic markers in critically ill patients.

Apoptosis is a mode of programmed cell death (PCD). Transduction of apoptotic signals results in cellular suicide. Organ specific apoptosis has been proposed as a factor in multiple organ dysfunction syndrome (MODS). Fas is a widely occurring apoptotic signal receptor molecule expressed by almost any type of cell, which is also released in a soluble circulating form (circulating fas, sfas). In this exploratory study, we investigated the association of sfas with severity, survival, known mediators of multiple organ dysfunction, and cellular apoptotic markers on peripheral blood mononuclear cells (PBMC) in a group of 35 patients with MODS and in 35 matched controls. Critically ill patients with MODS had significantly elevated sfas levels compared to controls over time (P < .001). Increased serum concentration of circulating fas was associated with increased severity of multiple organ dysfunction. Non-survivors exhibited significantly higher sfas levels compared to survivors (P < .01) and increasing sfas was inversely associated with the likelihood of survival (P < .05). Circulating fas levels correlated highly with serum nitrate concentration, but not with fas and fasL expression on PBMC of critically ill patients. TNF-alpha and IL-6, although they appear to be mediators of both apoptosis and MODS, had no association with sfas. These results are suggestive of the need for further investigation on the role of apoptotic signaling in the development of MODS. They also suggest a potential prognostic value of sfas for SIRS/MODS clinical outcomes.

The effect of saline lavage prior to suctioning.

OBJECTIVE: To determine the effect on oxygen saturation of instilling a saline bolus into artificial airways prior to suctioning, as measured by pulse oximeter. DESIGN: Quasi-experimental, single-case, counterbalanced design. SETTING: The surgical, medical and coronary intensive care units of a federal, teaching medical center. SUBJECTS: Subjects were 40 men, more than 40 years old, in need of intensive care nursing and mechanical ventilation. INTERVENTIONS: Subjects were suctioned as needed for 24 hours. A 5-mL saline bolus was instilled every other time the subject was suctioned. Outcome measurements were done immediately before and after suctioning and at 1-minute intervals for 5 minutes after suctioning. MAIN OUTCOME MEASURES: Noninvasive oxygen saturation values. RESULTS: The instillation of a saline bolus was found to have an adverse effect on oxygen saturation that worsened over time. Significant changes in oxygen saturation as a result of saline bolus instillation were found at 2,3,4 and 5 minutes after instillation. CONCLUSIONS: These results indicate that instilling saline prior to suctioning has an adverse effect on oxygen saturation. These results support the recommendation that the practice of instilling saline prior to suctioning should be abandoned as a routine procedure. More study is needed to investigate whether a specific group of patients may actually benefit from this procedure.

Instillation of normal saline before suctioning in patients with pulmonary infections: a prospective randomized controlled trial.

OBJECTIVE: To determine the effect of instillation of normal saline before suctioning on oxygen saturation, heart rate, and blood pressure in patients with pulmonary infections. METHODS: A prospective randomized controlled trial was conducted in the surgical, medical, and burn/trauma ICUs of an academic medical center. Eighteen men and 11 women (mean age = 60 years) receiving mechanical ventilation who met the criteria for pulmonary infection were randomly assigned to 2 groups. One group had instillation of a 5-mL bolus of normal saline before suctioning; the other did not. Suctioning was done as needed during an 8-to 12-hour period. Oxygen saturation, heart rate, and blood pressure were measured noninvasively immediately before and after suctioning, at 1-minute intervals for 5 minutes after suctioning, and at 10 minutes after suctioning. RESULTS: Instillation of normal saline had an adverse effect on oxygen saturation, which worsened over time. Differences in saturation between the 2 groups were significant at 4, 5, and 10 minutes after suctioning. Differences in heart rate and blood pressure were not significant. CONCLUSION: Instillation of normal saline before suctioning has an adverse effect on oxygen saturation and should not be used routinely in patients receiving mechanical ventilation who have pulmonary infection.

Development of a model of advanced practice.

BACKGROUND: The acute care nurse practitioner role is relatively new and not yet clearly defined. Our institution is in the first phase of a role delineation study that includes model development, validity testing, model revision, and dissemination. OBJECTIVES: To identify domains of practice, activities within each domain of practice, and common conceptual strands that cut across each domain, and to synthesize this information into a usable format to guide practice and role development. METHODS: A nonexperimental study design was used, including review of literature, expert consultation, brainstorming, and review of practice. RESULTS: The patient is central to the model. The identified domains of practice include direct comprehensive care, support of systems, education, research, and publication, and professional leadership. The conceptual strands include empowerment, collaboration, and scholarship. A continuum of experience from novice to expert was also identified within each domain. CONCLUSIONS: The development of the model is the first and most important phase in the role-delineation process. We believe that the model is accurate but still in need of testing. Nevertheless, our model can be used to guide institutions and individual practitioners.

Advanced practice nursing role delineation in acute and critical care: application of the strong model of advanced practice.

PURPOSE: This purpose of this study was to differentiate between the roles of clinical nurse specialists and acute care nurse practitioners. BACKGROUND AND SIGNIFICANCE: Hypothesized blending of the clinical nurse specialist and acute care nurse practitioner roles is thought to result in an acute care clinician who integrates the clinical skills of the nurse practitioner with the systems knowledge, educational commitment, and leadership ability of the clinical nurse specialist. Ideally, this role blending would facilitate excellence in both direct and indirect patient care. The Strong Model of Advanced Practice, which incorporates practice domains of direct comprehensive care, support of systems, education, research, and publication and professional leadership, was tested to search for practical evidence of role blending. METHODS: This descriptive, exploratory, pilot study included subjects (N = 18) solicited from an academic medical center and from an Internet advanced practice listserv. Questionnaires included self-ranking of expertise in practice domains, as well as valuing of role-related tasks. Content validity was judged by an expert panel of advanced practice nurses. RESULTS: Analyses of descriptive statistics revealed that clinical nurse specialists, who had more experience both as registered nurses and in the advanced practice nurse role, self-ranked their expertise higher in all practice domains. Acute care nurse practitioners placed higher importance on tasks related to direct comprehensive care, including conducting histories and physicals, diagnosing, and performing diagnostic procedures, whereas clinical nurse specialists assigned greater importance to tasks related to education, research, and leadership. CONCLUSIONS: Levels of self-assessed clinical expertise as well as valuing of role-related tasks differed among this sample of clinical nurse specialists and acute care nurse practitioners. Groundwork has been laid for continuing exploration into differentiation in advanced practice nursing roles. IMPLICATIONS: As the clinical nurse specialist role changes and the acute care nurse practitioner role emerges, it is imperative that advanced practice nurses describe their contribution to health care. Associating advanced practice nursing activities with outcomes will help further characterize these 2 advanced practice roles.

The systemic inflammatory response, sepsis, and multiple organ dysfunction: new definitions for an old problem.

Sepsis is one of the leading causes of morbidity and mortality in the United States. Until recently, there was much variation in the definition and descriptions of sepsis. This article outlines the report of the consensus conference between the Society of Critical Care Medicine and the American College of Chest Physicians, which established recommendations for the terminology to be used when describing sepsis. An overview of the epidemiology of sepsis and the current state-of-the-art therapy are also provided.

An educational model for the acute care nurse practitioner.

As new opportunities for acute care nurse practitioners (ACNP) evolve, there is increasing recognition of the need to distinguish between the knowledge base and the role functions generic to all advanced practice nurses, and the knowledge base specific to different areas of clinical specialization. This necessitates differentiating between converging core curriculum elements and merging the roles of advanced practice nurses. This article presents an educational model for the ACNP.

Systemic inflammatory response syndrome, sepsis, and nutritional support.

This article reviews the metabolic alterations that occur in SIRS and sepsis and the management of these patients nutritionally. Practical clinical assessment parameters that can be used by the critical care nurse to determine the nutritional and metabolic needs of the patient are presented. Issues related to enteral and parenteral routes of delivery are presented, and a discussion of disease-specific nutritional formulas is included. An understanding of the determination of metabolic and nutrition needs and the provision of adequate support to meet those needs are vital to the care of the hypermetabolic septic patient.

A review of normal saline instillation: implications for practice.

Nurses commonly use normal saline instillation (NSI) as a component of the suctioning procedure. The current research on NSI has not clearly identified many positive aspects of the procedure. Much of the research suggests it may actually be harmful. There has been little investigation into the reasons NSI is used. It is presumed that NSI is used to increase secretion removal when patients have thick endotracheal secretions due to inadequate humidity to the airway. Nurses need to be aware of the potential negative effects of routine NSI as well as alternative methods for maintaining adequate airway humidification.

Humor won, humor too: a model to incorporate humor into the healthcare setting.

The benefits of using humor in health care include stress reduction and improved psychological well-being for patients and the nursing staff. The authors discuss model to incorporate humor into a specific health-care setting, and include a detailed description of two humor programs: the Chuckle Wagon and Nursing Humor Resource Center.

Humor won, humor too: a model to incorporate humor into the healthcare setting (revised)

The benefits of using humor in health care include stress reduction and improved psychological well-being for patients and the nursing staff. The authors discuss a model to incorporate humor into a specific healthcare setting, and include a detailed description of two humor programs: the Chuckle Wagon and Nursing Humor Resource Center.

A review of disease-specific formulas.

Critical illness frequently leads to organ dysfunction. Nutritional support of individual organ function is an evolving area of nutritional support. Within the past several years, there was an increase in the number of nutritional products reported to improve organ function. In this article, the authors review disease/organ-specific nutritional support, including the theory behind therapy and the empiric data supporting or refuting these theories. It is hoped that this article will aid practitioners in their nutritional management of patients with organ dysfunction.

Neutralizing ageism in critical care via outcomes research.

Ageism, as a mind-set, amplifies a belief that intensive care for the elderly is ineffectual. However, there are little data to support the notion that advanced chronological age alone predicts unfavorable outcomes in response to intensive care. A lack of outcome data, combined with ageism, may place older patients at risk for rationing of intensive care. Currently, neither public policy nor cultural norms directly support a limitation in services to the elderly. However, as pressure to reduce health care costs increases, critically ill elderly patients may be targeted for rationing. In this context, outcomes research involving elderly populations is crucial. The purpose of this report is to explicate the risk of ageism in the delivery of intensive care and to describe methods for implementing outcomes assessment for critically ill elderly patients as an essential element in a continuum of care.

Does programmed cell death (apoptosis) play a role in the development of multiple organ dysfunction in critically ill patients? a review and a theoretical framework.

OBJECTIVES: To critically review the current understanding of the pathophysiologic events leading to the development of secondary multiple organ dysfunction (MODS) in critical illness and to examine the role of apoptosis (programmed cell death) as a mechanism involved in the progression of MODS. DATA SOURCES: Research and review articles published since 1982 on the pathophysiology of MODS, particularly the role of cytokines, reactive oxygen species, heat shock proteins, and apoptosis. Research and review articles on the physiology of apoptosis. Articles include human/animal and in vitro/in vivo studies. DATA EXTRACTION: The most prevalent mediating factors of MODS were examined for their potential to induce apoptosis, as reported in the literature. The combination of several of the above factors was also examined in terms of apoptosis-triggering potential. DATA SYNTHESIS: Specific pathophysiologic conditions related to the onset of MODS have been shown to affect apoptotic rates in organ tissue cells and their respective endothelial cells in animal and in vitro models. These conditions include the following: a) increased release of inflammation-related cytokines; b) increased production of oxygen free radicals associated with ischemia/reperfusion injury and states of low tissue perfusion; c) expression and release of heat shock proteins from tissue cells and the liver; d) elevated glucocorticoid concentrations after adrenal cortex activation; and e) release of bacterial products into the systemic circulation. CONCLUSION: The most important MODS-related pathophysiologic conditions known to date have been shown to affect programmed cell death rates in almost all cell types. Organ-specific cell death involving both parenchymal and microvasculature endothelial cells is conceivably underlying organ dysfunction. The hypothesis that increased apoptotic rates are involved in organ dysfunction may provide a unifying theory for the pathophysiology of MODS.

Serum leptin levels are higher but are not independently associated with severity or mortality in the multiple organ dysfunction/systemic inflammatory response syndrome: a matched case control and a longitudinal study.

OBJECTIVE: Hypercatabolism and immune dysfunction are closely associated with the development of systemic inflammatory response--multiple organ dysfunction (SIRS/MODS) in critical illness. It remains unclear however, whether leptin, an adipocyte-derived hormone whose levels are influenced by several cytokines and which regulates immune function, food-intake and energy expenditure is independently related to the development of and/or severity and mortality from SIRS/MODS. DESIGN AND PATIENTS: To assess the role of leptin in SIRS/MODS we performed a matched case control and a longitudinal study (14 days) in 35 critically ill patients with SIRS/MODS and 35 matched controls. RESULTS: Baseline leptin levels were positively associated with body mass index (BMI) and TNF-alpha (P < 0.01) in patients and with IGF-1 and IL-6 levels (P < 0.05) in controls. Furthermore, leptin levels exhibited a progressive increase from the first to the last day of the study and although baseline levels were not different, peak leptin levels as well as leptin levels on the last day of the study were significantly higher in cases than in controls (P < 0.05). TNF-alpha levels, IL-6 and cortisol levels were also higher, whereas IGF-1 levels were lower in cases (P < 0.05). To assess whether leptin levels are independently associated with SIRS/MODS we performed multivariate logistic regression analysis which revealed that leptin up-regulation in cases is mediated by elevated TNF-alpha and cortisol levels. Finally, there was no independent association between leptin and survival in this group of critically ill patients. CONCLUSION: We conclude that cytokines and cortisol upregulate leptin levels, which may contribute to the development of the hypercatabolism, wasting and immune dysfunction but leptin levels are not independently associated with severity or mortality of patients with systemic inflammatory response-multiple organ dysfunction.