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Biomedical subjects

Katherine J Deans

Publications and source records attributed to Katherine J Deans.

14 recordsLinked to original sources
PubMed2005

Hemolysis-associated endothelial dysfunction mediated by accelerated NO inactivation by decompartmentalized oxyhemoglobin.

During intravascular hemolysis in human disease, vasomotor tone and organ perfusion may be impaired by the increased reactivity of cell-free plasma hemoglobin (Hb) with NO. We experimentally produced acute intravascular hemolysis in a canine model in order to test the hypothesis that low levels of decompartmentalized or cell-free plasma Hb will severely reduce NO bioavailability and produce vasomotor instability. Importantly, in this model the total intravascular Hb level is unchanged; only the compartmentalization of Hb within the erythrocyte membrane is disrupted. Using a full-factorial design, we demonstrate that free water-induced intravascular hemolysis produces dose-dependent systemic vasoconstriction and impairs renal function. We find that these physiologic changes are secondary to the stoichiometric oxidation of endogenous NO by cell-free plasma oxyhemoglobin. In this model, 80 ppm of inhaled NO gas oxidized 85-90% of plasma oxyhemoglobin to methemoglobin, thereby inhibiting endogenous NO scavenging by cell-free Hb. As a result, the vasoconstriction caused by acute hemolysis was attenuated and the responsiveness to systemically infused NO donors was restored. These observations confirm that the acute toxicity of intravascular hemolysis occurs secondarily to the accelerated dioxygenation reaction of plasma oxyhemoglobin with endothelium-derived NO to form bioinactive nitrate. These biochemical and physiological studies demonstrate a major role for the intact erythrocyte in NO homeostasis and provide mechanistic support for the existence of a human syndrome of hemolysis-associated NO dysregulation, which may contribute to the vasculopathy of hereditary, acquired, and iatrogenic hemolytic states.

Animals↗
PubMed2005

Novel therapies for sepsis: a review.

BACKGROUND: Over the past 30 years, efforts have been made to identify therapeutic targets in the host response to infection. METHODS: A review of the randomized controlled clinical sepsis trials and meta-analyses of glucocorticoids, mediator-specific anti-inflammatory agents, and anticoagulant agents was performed. RESULTS: The effects of glucocorticoids in sepsis appear to be dose-dependent, with high doses decreasing survival and low doses improving survival. As a class, the mediator-specific anti-inflammatory agents have a small beneficial effect on survival; however, no single agent has demonstrated significant benefit. The treatment effects of these agents appear to be related to the patient's risk of death. As a class, the anticoagulant agents do not improve survival; however, the efficacy of these agents may have been confounded by concurrent heparin therapy. Activated protein C demonstrated a beneficial effect on survival that was dependent on severity of illness. CONCLUSION: Trials of agents directed at altering the host's response during sepsis have had variable results, and it appears that several different factors may alter the efficacy of these agents.

Animals↗
PubMed2004

Differing effects of epinephrine, norepinephrine, and vasopressin on survival in a canine model of septic shock.

During sepsis, limited data on the survival effects of vasopressors are available to guide therapy. Therefore, we compared the effects of three vasopressors on survival in a canine septic shock model. Seventy-eight awake dogs infected with differing doses of intraperitoneal Escherichia coli to produce increasing mortality were randomized to receive epinephrine (0.2, 0.8, or 2.0 microg.kg(-1).min(-1)), norepinephrine (0.2, 1.0, or 2.0 microg.kg(-1).min(-1)), vasopressin (0.01 or 0.04 U/min), or placebo in addition to antibiotics and fluids. Serial hemodynamic and biochemical variables were measured. Increasing doses of bacteria caused progressively greater decreases in survival (P <0.06), mean arterial pressure (MAP) (P <0.05), cardiac index (CI) (P <0.02), and ejection fraction (EF) (P=0.02). The effects of epinephrine on survival were significantly different from those of norepinephrine and vasopressin (P=0.03). Epinephrine had a harmful effect on survival that was significantly related to drug dose (P=0.02) but not bacterial dose. Norepinephrine and vasopressin had beneficial effects on survival that were similar at all drug and bacteria doses. Compared with concurrent infected controls, epinephrine caused greater decreases in CI, EF, and pH, and greater increases in systemic vascular resistance and serum creatinine than norepinephrine and vasopressin. These epinephrine-induced changes were significantly related to the dose of epinephrine administered. In this study, the effects of vasopressors were independent of severity of infection but dependent on the type and dose of vasopressor used. Epinephrine adversely affected organ function, systemic perfusion, and survival compared with norepinephrine and vasopressin. In the ranges studied, norepinephrine and vasopressin have more favorable risk-benefit profiles than epinephrine during sepsis.

Animals↗
PubMed2004

Meta-analysis: the effect of steroids on survival and shock during sepsis depends on the dose.

BACKGROUND: Previous meta-analyses demonstrated that high-dose glucocorticoids were not beneficial in sepsis. Recently, lower-dose glucocorticoids have been studied. PURPOSE: To compare recent trials of glucocorticoids for sepsis with previous glucocorticoid trials. DATA SOURCES: Systematic MEDLINE search for studies published between 1988 and 2003. STUDY SELECTION: Randomized, controlled trials of sepsis that examined the effects of glucocorticoids on survival or vasopressor requirements. DATA EXTRACTION: Two investigators independently collected data on patient and study characteristics, treatment interventions, and outcomes. DATA SYNTHESIS: The 5 included trials revealed a consistent and beneficial effect of glucocorticoids on survival (I2 = 0%; relative benefit, 1.23, [95% CI, 1.01 to 1.50]; P = 0.036) and shock reversal (I2 = 0%; relative benefit, 1.71 [CI, 1.29 to 2.26]; P < 0.001). These effects were the same regardless of adrenal function. In contrast, 8 trials published before 1989 demonstrated a survival disadvantage with steroid treatment (I2 = 14%; relative benefit, 0.89 [CI, 0.82 to 0.97]; P = 0.008). In comparison with the earlier trials, the more recent trials administered steroids later after patients met enrollment criteria (median, 23 hours vs. <2 hours; P = 0.02), for longer courses (6 days vs. 1 day; P = 0.01), and in lower total dosages (hydrocortisone equivalents, 1209 mg vs. 23 975 mg; P = 0.01) to patients with higher control group mortality rates (mean, 57% vs. 34%; P = 0.06) who were more likely to be vasopressor-dependent (100% vs. 65%; P = 0.03). The relationship between steroid dose and survival was linear, characterized by benefit at low doses and increasing harm at higher doses (P = 0.02). LIMITATIONS: We could not analyze time-related improvements in medical care and potential bias secondary to nonreporting of negative study results. CONCLUSIONS: Although short courses of high-dose glucocorticoids decreased survival during sepsis, a 5- to 7-day course of physiologic hydrocortisone doses with subsequent tapering increases survival rate and shock reversal in patients with vasopressor-dependent septic shock.

Adrenal Insufficiency↗
PubMed2004

Foramen of Morgagni hernia: changes in diagnosis and treatment.

BACKGROUND: Foramen of Morgagni hernias are uncommon diaphragmatic hernias for which there are limited reported data. The purpose of this study is to report a recent case series of foramen of Morgagni hernias in the context of new diagnostic and treatment modalities. METHODS: A retrospective chart review was performed over a 15-year period, from 1987 to 2001. Twelve patients who had a foramen of Morgagni hernia repaired at our hospital were identified, and data from these patients were collected. RESULTS: The average age at treatment was 45 years, with 50% of patients being asymptomatic. Radiographic evaluation included computed tomography scans in two thirds of the patients with a 100% sensitivity for diagnosis. All hernias were right-sided, and the most common contents of the hernias were omentum and colon. The transabdominal route was the preferred surgical approach. Thoracoscopy was used in 2 patients to further characterize a mediastinal mass. Two patients underwent laparoscopic repair. Postoperative complications were infrequent, and there were no recurrences during a 6-month to 10-year follow-up. CONCLUSIONS: The emergence of highly accurate diagnostic computed tomography scans combined with less invasive surgical techniques utilizing laparoscopy and thoracoscopy has aided in the treatment of foramen of Morgagni hernias over the last 15 years.

Adult↗
PubMed2004

Recombinant human activated protein C in sepsis: assessing its clinical use.

Based on the results of the phase III PROWESS trial, recombinant human activated protein C (rhAPC) was approved by the Food and Drug Administration (FDA) for use in severely septic patients. Concerns regarding rhAPC's inconsistent effects, incomplete understanding of its mechanism of action, and its safety in particular subgroups were raised during the FDA's evaluation. This study attempts to assess the cost-effectiveness rhAPC by comparing its effects during recent clinical use to its prior phase III trial testing and by considering other potentially less expensive treatments with effects that may overlap those of rhAPC. In patients with similar numbers of injured organs, mortality rates may be higher with rhAPC during clinical use compared with the phase III trial. There may also be an increased risk of hemorrhage and other adverse events that necessitate early discontinuation of treatment. Many of the patients receiving rhAPC during clinical use may have otherwise been excluded from its phase III trial testing. Data from several recent phase III trials as well as a recent meta-analysis suggest that heparin and physiologic dose steroids offer substantially less expensive alternatives to rhAPC. Further phase IV testing will be required to confirm such possibilities.

APACHE↗
PubMed2004

Activated protein C in sepsis: emerging insights regarding its mechanism of action and clinical effectiveness.

PURPOSE OF REVIEW: Dysregulation of endogenous coagulant and anticoagulant systems is now believed to play an important role in the pathogenesis of sepsis and septic shock. Reductions in host activated protein C levels and resultant microvascular thrombosis provided a basis for the use of recombinant human activated protein C in sepsis. Although controversial, the findings from an initial phase III trial testing this agent resulted in its approval for use in patients with severe sepsis and high risk of death. This review highlights emerging insights into the biology of protein C and activated protein C in sepsis, summarizes additional analysis growing out of the phase III trial testing recombinant human activated protein C, and assesses the cost-effectiveness that the clinical use of the agent has had thus far. RECENT FINDINGS: Binding of activated protein C to the endothelial cell protein C receptor is recognized to result in a growing number of actions including increased activity of activated protein C itself and inhibition of both nuclear factor-kappaB, a central regulator in the host inflammatory response, and apoptosis. Additional analysis of the original phase III trial testing recombinant human activated protein C appears to emphasize one of the US Food and Drug Administration's original concerns regarding an association between severity of sepsis and this agent's effects. Postmarketing analysis and growing experience with other anticoagulant agents and corticosteroids in sepsis raise questions regarding the ultimate cost-effectiveness of activated protein C. SUMMARY: The protein C pathway is important both to coagulant and inflammatory pathways during sepsis. Based on emerging investigations, its actions appear to be increasingly complex ones. Despite potentially promising results in an initial phase III trial, the role of recombinant human activated protein C in the treatment of septic patients must continue to be evaluated.

Blood Coagulation↗
PubMed2004

Defining the standard of care in randomized controlled trials of titrated therapies.

PURPOSE OF REVIEW: To discuss the appropriate standard of care in randomized controlled trials of titrated therapies in critically ill patients. RECENT FINDINGS: The debate over the appropriate standard of care in randomized controlled trials was sparked by the Acute Respiratory Distress Syndrome Network trial of low tidal volume ventilation. In this trial, patients were randomized to either low or traditional tidal volume ventilation, and the investigators reported that low tidal volume ventilation significantly improved survival in patients with acute respiratory distress syndrome. However, it was argued that the control group used in this trial was not reflective of current practice patterns and that the improvement in survival may have been derived from patients in the control group being placed at increased risk. This debate forced intensivists to consider what defines an appropriate standard-of-care control group in randomized controlled trials of titrated therapies. If titrated therapies are to be studied safely, the mechanism behind the titration must be understood and incorporated into the control group. Failure to include a comparator group receiving current practice creates a study design that may jeopardize patient safety because there is no control group representing probable patient outcome outside of the trial. Additionally, randomizing patients to the extremes of a range of care without incorporation of a current practice control group prevents the investigators from making valid recommendations for changing current practice. SUMMARY: The incorporation of current practice patterns into randomized controlled trials of titrated therapies is essential for producing generalizable results and safeguarding patients.

Decision Making↗