Biomedical subjects

Keith R Walley

Publications and source records attributed to Keith R Walley.

34 records · Page 2Linked to original sources

PubMed2004

Neutrophil apoptosis in preeclampsia, do steroids confound the relationship?

AIM: To investigate the influence of maternal corticosteroid administration on neutrophil apoptosis in early onset preeclampsia. METHODS: We investigated five groups: early onset preeclampsia (EOPET, <34 weeks, n = 10); late-onset preeclampsia (LOPET, > or =34 weeks, n = 7); normotensive intrauterine growth restriction (nIUGR, n = 11); normal pregnancy (NPC, n = 22); and non-pregnancy (n = 10). We examined, by flow cytometry, spontaneous neutrophil apoptosis after 18 h culture (hypodiploid DNA, Annexin V binding, propidium iodide [PI] permeability). RESULTS: For the 10 women with EOPET exposed to betamethasone in the previous 48 h, we found that neutrophil apoptosis was not inappropriately inhibited, in contrast to our previous findings in women not thus exposed. Neither LOPET nor nIUGR differed from normal pregnancy. CONCLUSION: Betamethasone alters the rate of spontaneous neutrophil apoptosis in EOPET. The anti-inflammatory influence of betamethasone may explain some of the differences between our previous and present findings with respect to neutrophil apoptosis in EOPET. Corticosteroids ameliorate the course of antenatal and postnatal preeclampsia. These results may reflect the mechanisms that underlie the transient improvements seen with antenatal dexamethasone use.

Adult↗

PubMed2004

Microarray genotyping resource to determine population stratification in genetic association studies of complex disease.

We have developed a robust microarray genotyping chip that will help advance studies in genetic epidemiology. In population-based genetic association studies of complex disease, there could be hidden genetic substructure in the study populations, resulting in false-positive associations. Such population stratification may confound efforts to identify true associations between genotype/haplotype and phenotype. Methods relying on genotyping additional null single nucleotide polymorphism (SNP) markers have been proposed, such as genomic control (GC) and structured association (SA), to correct association tests for population stratification. If there is an association of a disease with null SNPs, this suggests that there is a population subset with different genetic background plus different disease susceptibility. Genotyping over 100 null SNPs in the large numbers of patient and control DNA samples that are required in genetic association studies can be prohibitively expensive. We have therefore developed and tested a resequencing chip based on arrayed primer extension (APEX) from over 2000 DNA probe features that facilitate multiple interrogations of each SNP, providing a powerful, accurate, and economical means to simultaneously determine the genotypes at 110 null SNP loci in any individual. Based on 1141 known genotypes from other research groups, our GC SNP chip has an accuracy of 98.5%, including non-calls.

Animals↗

PubMed2003

Three-dimensional capillary geometry in gut tissue.

Accurate characterization of capillary geometry is of the utmost importance for physiological tissue studies such as oxygen transport. We show that 3D microscopy can be used to measure tissue capillary geometry both in normal and disease states. We imaged fluorescently labeled gut mucosa capillary beds of three control rats and three rats 4 hours after i.p. injection of 9 mg/kg endotoxin. We used serial optical sectioning microscopy coupled with deconvolution to reconstruct 3D capillary geometry. Theoretical point spread functions accounting for depth into the specimen resulted in better reconstructions than experimentally measured point spread functions. We next derived the distribution of the shortest distances to the nearest capillary from all extravascular tissue voxels. In normal rats the shortest-distance distributions were remarkably constant despite widely varying capillary geometry. Furthermore, the mean of the shortest-distance distributions increased significantly for endotoxemic rats (4.8+/-0.4 microm) compared to controls (4.3+/-0.3 microm, P<0.05). Hence, serial sectioning microscopy provides an accurate venue for measuring physiologically relevant 3D capillary structure.

Algorithms↗

PubMed2003

Role of platelet activating factor in cardiac dysfunction, apoptosis and nitric oxide synthase mRNA expression in the ischemic-reperfused rabbit heart.

BACKGROUND: The role of platelet activating factor (PAF) and nitric oxide in myocardial ischemia-reperfusion (MIR) injury and the interrelationship of the two mediators is poorly understood. The contribution of PAF to apoptosis during MIR has not been studied. OBJECTIVES: To determine the contribution of PAF to ex vivo cardiac dysfunction during the initial 5 h of postischemia reperfusion, to determine the contribution of PAF to inducible nitric oxide synthase (NOS) and endothelial NOS mRNA expression during MIR, and to determine whether PAF contributes to apoptosis during MIR. METHODS: Isolated blood-perfused rabbit hearts underwent 30 min of global ischemia and 5 h reperfusion. Animals were divided into four groups, which received either PAF antagonist TCV-309 or vehicle before ischemia, or were sham operated (heart perfusion only), or were control (no heart perfusion). RESULTS: Administration of the PAF antagonist significantly improved myocardial contractility (614 mmHg/s versus 308 mmHg/s, positive dP/dt, P<0.0001) and coronary vascular flow rate (5.5 mL/min versus 3.9 mL/min, P<0.01) during reperfusion compared with untreated animals (values at 5 h reperfusion). Treatment with PAF antagonist significantly increased mRNA expression of endothelial NOS (2.8 versus 1.3 ratio, P<0.05) compared with the untreated group. PAF antagonist reduced procaspase-3 cleavage (66 versus 108 ratio, P<0.05) and DNA fragmentation (8.2 versus 11.0 positive cells per field) compared with untreated animals. CONCLUSIONS: PAF antagonism with TCV-309 protected against myocardial contractile depression and coronary vasoconstriction during the initial 5 h reperfusion. PAF may play a role in the regulation of endothelial NOS mRNA expression and contribute to apoptosis during ischemia-reperfusion in the heart.

Animals↗

PubMed2003

The evaluation and management of shock.

Shock is an emergency that requires continuous bedside evaluation, resuscitation, and re-evaluation. The initial bedside examination allows the clinician to determine whether the patient exhibits a clinical picture that is consistent with hypovolemic, cardiogenic, or vasodilatory shock. The primary survey dictates urgent initial resuscitation that usually consists of intubation, ventilation, and volume support. Vasoactive therapy is started when the patient is well volume-resuscitated and consists of inotropic support for cardiogenic shock and pressor therapy for vasodilatory shock. The secondary survey is helpful in revealing the cause of shock and necessary to institute early definitive therapy. Early shock has a hemodynamic component, which is often easily reversed. Septic shock and prolonged shock from any cause has an inflammatory component, which is not easily reversed and leads to multiple-system organ failure (MSOF) and death. Success in treatment of shock depends on early recognition of shock and the rapid tempo of resuscitation of its hemodynamic component to prevent or minimize the inflammatory component.

Critical Illness↗

PubMed2003

Albumin resuscitation increases cardiomyocyte contractility and decreases nitric oxide synthase II expression in rat endotoxemia.

OBJECTIVE: Hypotension and hypoperfusion during septic shock may contribute to tissue hypoxia and the intramyocardial inflammatory response that results in myocardial dysfunction. Therefore, we hypothesized that crystalloid or colloid resuscitation may alter myocardial dysfunction. DESIGN: Randomized, controlled, prospective animal study. SETTING: University animal laboratory. SUBJECTS: Sprague-Dawley rats (250-300 g, n = 6/group). INTERVENTIONS: Rats received an intraperitoneal injection of 10 mg/kg lipopolysaccharide or control. One hour later, rats were randomized to intravenous resuscitation and received either 30 mL/kg normal saline, 10 mL/kg 10% pentastarch, 10 mL/kg 5% rat albumin, or no volume. MEASUREMENTS AND MAIN RESULTS: We measured fractional shortening of cardiomyocytes isolated 5 hrs after lipopolysaccharide or control injection. In separate identical experiments, we measured myocardial interleukin-6, macrophage inhibitory protein-2, and nitric oxide synthase II protein and messenger RNA expression. Control fractional shortening of 24.1 +/- 2.2% was decreased by lipopolysaccharide to 18.8 +/- 1.2% (p <.001). Volume resuscitation after lipopolysaccharide significantly improved fractional shortening (p <.001). In particular, albumin resuscitation increased fractional shortening to 23.5 +/- 0.9%, which was more than either saline (fractional shortening 20.1 +/- 1.7%,p <.01) or pentastarch (fractional shortening 21.4 +/- 0.9%,p <.01). Myocardial macrophage inhibitory protein-2 protein and interleukin-6 and macrophage inhibitory protein-2 messenger RNA expression and neutrophil content were elevated following lipopolysaccharide (p <.05) but were not altered by volume resuscitation. Myocardial nitric oxide synthase II protein and messenger RNA expression increased following lipopolysaccharide (p <.01) and decreased with albumin resuscitation. CONCLUSIONS: We conclude that following lipopolysaccharide injection, volume resuscitation improves cardiomyocyte fractional shortening. Albumin resuscitation is particularly beneficial in preventing reduced cardiomyocyte contractility, and this benefit may be related to an albumin-induced reduction in nitric oxide synthase II protein and messenger RNA expression following endotoxin injection.

Albumins↗

PubMed2003

Severe acute respiratory distress syndrome (SARS): a critical care perspective.

OBJECTIVE: To review the epidemiology, clinical features, etiology, diagnosis, and management of severe acute respiratory syndrome (SARS) from a critical care perspective. DATA SOURCES: A MEDLINE search was performed using the following terms: severe acute respiratory syndrome and SARS virus. Additional information and references were obtained from the Web sites for the Centers for Disease Control and Prevention, World Health Organization, and Health Canada. STUDY SELECTION: Recent case series were used to develop a review of the epidemiology, clinical features, outcomes, and management of patients with SARS from an intensive care unit (ICU) perspective. This was supplemented by epidemiology information obtained from other Web-based sources. Recent published studies describing the etiology of SARS were also included. DATA SYNTHESIS: SARS has rapidly spread from Southeast Asia to numerous countries, including Canada and the United States. A new coronavirus has been isolated and detected from many affected patients. The mortality rate worldwide is approximately 10.5%. From five cohorts, the ICU admission rate ranged from 20% to 38%. Fifty-nine percent to 100% of the ICU patients required mechanical ventilatory support. The mortality rate of SARS patients admitted to the ICU ranged from 5% to 67%. The most common clinical symptoms and signs are fever, cough, dyspnea, myalgias, malaise, and inspiratory crackles. Common laboratory abnormalities included mild leukopenia, lymphopenia, and increased aspartate transaminase, alanine transaminase, lactic dehydrogenase, and creatine kinase. The chest radiograph pattern ranged from focal infiltrates to diffuse airspace disease. Management consisted of isolation, strict respiratory and contact precautions, ventilatory support as needed, empiric broad-spectrum antibiotics, ribavirin, and corticosteroids. Predictors of mortality included advanced age, the presence of comorbidities, and a high lactic dehydrogenase or high neutrophil count at admission. CONCLUSIONS: SARS is a highly contagious, infectious process that can advance to significant hypoxemic respiratory failure requiring ICU monitoring and support. Early recognition is critical for effective management and containment of this disease.

Adult↗

PubMed2003

Acute hypervolaemia improves arterial oxygen pressure in athletes with exercise-induced hypoxaemia.

The aim of this study was to determine the effect of acute plasma volume expansion on arterial blood-gas status during 6.5 min strenuous cycling exercise comparing six athletes with and six athletes without exercise-induced arterial hypoxaemia (EIAH). We hypothesized that plasma volume expansion could improve arterial oxygen pressure in a homogeneous sample of athletes - those with EIAH. In this paper we have extended the analysis and results of our recently published surprising findings that lengthening cardiopulmonary transit time did not improve arterial blood-gas status in a heterogeneous sample of endurance cyclists. One 500 ml bag of 10 % Pentastarch (infusion condition) or 60 ml 0.9 % saline (placebo) was infused prior to exercise in a randomized, double-blind fashion on two different days. Power output, cardiac output, oxygen consumption and arterial blood gases were measured during strenuous exercise. Cardiac output and oxygen consumption were not affected by acute hypervolaemia. There were group x condition interaction effects for arterial oxygen pressure and alveolar-arterial oxygen pressure difference, suggesting that those with hypoxaemia experienced improved arterial oxygen pressure (+4 mmHg) and lower alveolar-arterial oxygen pressure difference (-2 mmHg) with infusion. In conclusion, acute hypervolaemia improves blood-gas status in athletes with EIAH. The impairment of gas exchange occurs within the first minute of exercise, and is not impaired further throughout the remaining duration of exercise. This suggests that arterial oxygen pressure is only minimally mediated by cardiac output.

Acute Disease↗

PubMed2003

Bad medicine: low-dose dopamine in the ICU.

Low-dose dopamine administration (ie, doses < 5 microg/kg/min) has been advocated for 30 years as therapy in oliguric patients on the basis of its action on dopaminergic renal receptors. Recently, a large, multicenter, randomized, controlled trial has demonstrated that low-dose dopamine administered to critically ill patients who are at risk of renal failure does not confer clinically significant protection from renal dysfunction. In this review, we present the best evidence and summarize the effects of low-dose dopamine infusion in critically ill patients. We review the history and physiology of low-dose dopamine administration and discuss the reasons why dopamine is not clinically effective in the critically ill. In addition to the lack of renal efficacy, we present evidence that low-dose dopamine administration worsens splanchnic oxygenation, impairs GI function, impairs the endocrine and immunologic systems, and blunts ventilatory drive. We conclude that there is no justification for the use of low-dose dopamine administration in the critically ill.

Animals↗

PubMed2003

Genetic polymorphisms in sepsis and septic shock: role in prognosis and potential for therapy.

Genetic epidemiologic studies suggest a strong genetic influence on the outcome from sepsis, and genetics may explain the wide variation in the individual response to infection that has long puzzled clinicians. Several candidate genes have been identified as important in the inflammatory response and investigated in case-controlled studies, including the tumor necrosis factor (TNF)-alpha and TNF-beta genes, positioned next to each other within the cluster of human leukocyte antigen class III genes on chromosome 6. Other candidate genes for sepsis and septic shock include the interleukin (IL)-1 receptor antagonist gene, the heat shock protein gene, the IL-6 gene, the IL-10 gene, the CD-14 gene, the Toll-like receptor (TLR)-4 gene, and the TLR-2 gene, to name a few. In this review, we summarize the evidence for a genetic susceptibility to development of sepsis and death from sepsis, discuss design of clinical genetics studies relevant to the study of complex disorders, consider the candidate genes likely to be involved in the pathogenesis of sepsis, and discuss the potential for targeted therapy of sepsis and septic shock based on genetic variability.

Acute-Phase Proteins↗

PubMed2002

Improved arterial oxygenation with biologically variable or fractal ventilation using low tidal volumes in a porcine model of acute respiratory distress syndrome.

We compared biologically variable ventilation (V (bv); n = 9) with control mode ventilation (V (c); n = 8) at low tidal volume (VT)--initial 6 ml/kg--in a porcine model of acute respiratory distress syndrome (ARDS). Hemodynamics, respiratory gases, airway pressures, and VT data were measured. Static P-V curves were generated at 5 h. Interleukin (IL)-8 and IL-10 were measured in serum and tracheal aspirate. By 5 h, higher Pa(O(2)) (173 +/- 30 mm Hg versus 119 +/- 23 mm Hg; mean +/- SD; p < 0.0001 group x time interaction [G x T]), lower shunt fraction (6 +/- 1% versus 9 +/- 3%; p = 0.0026, G x T) at lower peak airway pressure (21 +/- 2 versus 24 +/- 1 cm H(2)O; p = 0.0342; G x T) occurred with V (bv). IL-8 concentrations in tracheal aspirate and wet:dry weight ratios were inversely related; p = 0.011. With V (c), IL-8 concentrations were 3.75-fold greater at wet:dry weight ratio of 10. IL-10 concentrations did not differ between groups. In both groups, ventilation was on the linear portion of the P-V curve. With V (bv), VT variability demonstrated an inverse power law indicating fractal behavior. In this model of ARDS, V (bv) improved Pa(O(2)) at lower peak airway pressure and IL-8 levels compared with V (c).

Analysis of Variance↗

PubMed2002

Pro/con clinical debate: are steroids useful in the management of patients with septic shock?

Decision-making in the intensive care unit is often very difficult. Although we are encouraged to make evidence-based decisions, this may be difficult for a number of reasons. To begin with, evidence may not exist to answer the clinical question. Second, when there is evidence it may not be applicable to the patient in question or the clinician may be reluctant to apply it to the patient based on a number of secondary issues such as costs, premorbid condition or possible complications. Finally, emotions are often highly charged when caring for patients that have a significant chance of death, and care-givers as well as families are frequently prepared to take chances on a therapy whose benefit is not entirely clear. Steroid use in septic shock is an example of a therapy that makes some sense but has conflicting support in the literature. In this issue of Critical Care Forum, the two sides of this often heated debate are brought to the forefront in an interesting format.

Adrenal Cortex Hormones↗

PubMed2002

Beneficial effects of short-term vasopressin infusion during severe septic shock.

BACKGROUND: Septic shock is associated with vasopressin deficiency and a hypersensitivity to its exogenous administration. The goal of the current study was to determine whether short-term vasopressin infusion in patients experiencing severe septic shock has a vasopressor sparing effect while maintaining hemodynamic stability and adequate end-organ perfusion. METHODS: Patients experiencing septic shock that required high-dose vasopressor support were randomized to a double-blinded 4-h infusion of either norepinephrine (n = 11) or vasopressin (n = 13), and open-label vasopressors were titrated to maintain blood pressure. To assess end-organ perfusion, urine output and creatinine clearance, gastric mucosal carbon dioxide tension, and electrocardiogram ST segment position were measured. RESULTS: Patients randomized to norepinephrine went from a median prestudy norepinephrine infusion of 20.0 microg/min to a blinded infusion of 17.0 mug/min at 4 h, whereas those randomized to vasopressin went from a median prestudy norepinephrine infusion of 25.0 microg/min to 5.3 microg/min at 4 h (P < 0.001). Mean arterial pressure and cardiac index were maintained in both groups. Urine output did not change in the norepinephrine group (median, 25 to 15 ml/h) but increased substantially in the vasopressin group (median, 32.5 to 65 ml/h; P < 0.05). Similarly, creatinine clearance did not change in the norepinephrine group but increased by 75% in the vasopressin group (P < 0.05). Gastric mucosal carbon dioxide tension and electrocardiogram ST segments did not change significantly in either group. CONCLUSIONS: The authors conclude that short-term vasopressin infusion spared conventional vasopressor use and improved some measures of renal function in patients with severe septic shock.

Aged↗

PubMed2002

Activated protein C in normal human pregnancy and pregnancies complicated by severe preeclampsia: a therapeutic opportunity?

OBJECTIVES: Given the efficacy and safety of recombinant human activated protein C (rhAPC) in the systemic inflammatory response syndrome, this study was designed to review the evidence for a role for APC in the pathogenesis of preeclampsia. Preeclampsia is a proinflammatory and procoagulant state, and it is a pregnancy-specific condition that mimics the systemic inflammatory response syndrome. rhAPC reduces mortality in patients with systemic inflammatory response syndrome and could potentially have a role as disease-modifying therapy in preeclampsia. To determine which patients would be offered rhAPC, the literature pertaining to fetal/neonatal outcomes for preeclampsia remote from term, transplacental transport of protein C, and pregnancy experience with the compound were reviewed. DATA SOURCES: MEDLINE, review papers, hand searches of relevant nonindexed journals, and the bibliographies of relevant textbooks and articles reviewed. STUDY SELECTION: Randomized controlled trials were considered to provide the best quality of clinical data. Case-control series were considered over uncontrolled data. Some data were not available in the published literature (e.g., neonatal outcomes at various gestational ages and birthweights after a hypertensive pregnancy; and transplacental transfer of protein C), and these data were determined by us. DATA EXTRACTION: Data were extracted by systematic review onto data collection sheets. Because of the quality of the data, this review is primarily qualitative. DATA SYNTHESIS: APC levels fall during normal gestation, returning to normal values by 6 wks postpartum. Limited data suggest that early onset preeclampsia is a state of further, and inappropriate, reduction in APC. Preeclampsia resembles systemic inflammatory response syndrome in this regard. After hypertensive pregnancies, neonates have a 50% chance of intact survival if delivered after 27 + 0 wks of gestation with a birthweight of >600 g. It would seem ethical to offer women with preeclampsia with <50% chance of intact perinatal survival novel and potentially disease-modifying therapy such as rhAPC, especially as there is no transplacental transfer of protein C. Limited evidence would support the use of rhAPC in women with severe postpartum preeclampsia. CONCLUSIONS: Sufficient data exist to support the use of rhAPC in phase II clinical studies for women with either early onset preeclampsia or severe or deteriorating postpartum disease.

Case-Control Studies↗

PubMed2002

Circulating white blood cells affect red cell pulmonary transit times in endurance athletes during intense exercise.

PURPOSE: The aim of this study was to determine the relationship between the right-to-left ventricular red cell pulmonary transit times (PTT) during intense exercise and circulating white blood cell (WBC) counts in highly trained endurance athletes. We postulated that high levels of WBCs preexercise would slow PTT. Eleven endurance-trained athletes (VO2max = 69.6 +/- 7.7 mL.kg-1.min-1; weight = 75.0 +/- 6.2 kg; height = 181.0 +/- 7.1 cm) performed 6.5 min constant-load, near-maximal cycling exercise (approximately 92% VO2max) on two different days. Preexercise WBC counts were measured in arterial blood drawn from the radial artery 30 min before exercise. PTT was measured during the 3rd min of exercise by first-pass radionuclide cardiography using centroid and deconvolution analysis, whereas cardiac output (Q) was measured during the last 2.5 min of exercise via a count-based ratio method from the MUGA technique. RESULTS: Combined mean PTT from both deconvolution and centroid analysis at minute three of exercise was 2.45 +/- 0.21 s, whereas the preexercise WBC count was 5.3 +/- 1.6 x 109.L-1. Cardiopulmonary blood volume at minute three of exercise was 1.22 +/- 0.13 L, VO2 was 4.58 +/- 0.44 L.min-1, and Q was 30.2 +/- 4.2 L.min-1. We found that PTT was negatively correlated with circulating WBC (r = -0.61; adjusted r2 = 0.30; P = 0.04; N = 11) but not with the dispersion (spread) of transit times around the mean (r = 0.19; P = 0.57). CONCLUSION: This suggests that athletes with higher circulating numbers of WBCs preexercise have faster (shorter) red cell transit times through the lung during intense exercise.

Cardiac Output↗

PubMed2002

Lack of agreement between thermodilution and fick cardiac output in critically ill patients.

STUDY OBJECTIVE: s: Individual comparison of cardiac output via intermittent thermodilution and Fick technique over a wide range of cardiac outputs. DESIGN: Prospective clinical investigation. SETTING: Multidisciplinary ICUs of two teaching hospitals in Vancouver, British Columbia. PARTICIPANTS: Eighteen critically ill patients who had pulmonary and systemic arterial catheters and in whom active support was being withdrawn. INTERVENTIONS: Measurement of thermodilution cardiac output and calculation of Fick cardiac output while support was withdrawn. Active support was withdrawn in a three-step process: removal of vasopressors followed by decrease in fraction of inspired oxygen to 0.21, and finally removal of mechanical ventilation. MEASUREMENTS AND RESULTS: Simultaneous Fick and thermodilution cardiac outputs were obtained over a wide range. Fick calculated cardiac outputs were obtained using the Fick equation with oxygen uptake (O(2)) being measured with indirect calorimetry. O(2) determinations were made using five measurements over 5 min, with the mean being used for subsequent analysis. Thermodilution cardiac outputs were determined by the mean of five measurements, with the first being discarded. Coefficient of variation was calculated for the O(2) and thermodilution cardiac outputs. One hundred thirty-six simultaneous cardiac outputs were obtained in 18 patients with a mean APACHE (acute physiology and chronic health evaluation) II score of 25.5. The range of cardiac outputs was 1.39 to 16.95 L/min. Linear regression analysis found a good correlation of the data sets, with an R of 0.85. Bias and precision calculations found a bias of - 0.17 L/min with the upper and lower limits of agreement being 2.96 L/min and - 3.30 L/min, respectively. In patients with high cardiac outputs (> 7 L/min), the bias was - 1.90 with the limits of agreement being 1.87 L/min and - 5.67 L/min. The coefficient of variation for O(2) was 4.6% and for thermodilution cardiac output was 7.75%. CONCLUSIONS: There was good consistency of each of the measurements with a low coefficient of variation. The bias for the whole group was small, but the limits of agreement extended into a clinically relevant area, resulting in a lack of agreement. In patients with high cardiac outputs, the Fick tended to consistently produce higher cardiac outputs compared to thermodilution, suggesting a systematic error.

Adult↗