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Timothy G Buchman

Publications and source records attributed to Timothy G Buchman.

48 records · Page 3Linked to original sources
PubMed2002

Inhibition of intestinal epithelial apoptosis and survival in a murine model of pneumonia-induced sepsis.

CONTEXT: Increased intestinal epithelial apoptosis is present in both human autopsy studies and animal models of sepsis. Whether altering gut apoptosis decreases mortality in sepsis induced by pathogenic bacteria outside the gut is unknown. OBJECTIVE: To determine if decreasing levels of intestinal cell death improves survival in a murine model of Pseudomonas aeruginosa pneumonia-induced sepsis. DESIGN AND MATERIALS: Prospective study in which transgenic mice that overexpress the antiapoptotic protein Bcl-2 in their intestinal epithelium (n = 25) and control littermates (n = 26) were subjected to intratracheal injection of P aeruginosa. MAIN OUTCOME MEASURES: Survival at 7 postoperative days, compared between the 2 groups. Secondary outcomes included quantification of gut epithelial apoptosis. RESULTS: Survival in transgenic mice that overexpress Bcl-2 in the intestinal epithelium was 40% (10/25) compared with 4% (1/26) in control littermates 7 days after intratracheal injection of P aeruginosa (P =.001), with differences in survival noted within 24 hours of surgery. Overexpression of Bcl-2 was associated with a decrease in gut epithelial apoptosis demonstrated by active caspase 3 staining, the terminal deoxynucleotidyltransferase-mediated dUTP nick end-labeling assay, and hematoxylin-eosin staining. CONCLUSIONS: In this murine model, inhibiting gut epithelial apoptosis by overexpression of Bcl-2 was associated with a survival advantage in P aeruginosa pneumonia-induced sepsis. These results suggest that intestinal epithelial apoptosis may play a role in sepsis-related mortality.

Animals↗
PubMed2002

The frequency and effects of cytochrome P450 (CYP) 2C9 polymorphisms in patients receiving warfarin.

BACKGROUND: Warfarin sodium (warfarin) is commonly prescribed in surgical practice. Warfarin use is complicated by an unpredictable dose response that may be due in part to genetically determined differences in metabolic capacity. To better understand the interaction between genotype and response to warfarin therapy, we determined the frequency and functional effects of polymorphisms of the predominant cytochrome P450 subfamily responsible for warfarin metabolism (eg, CYP2C9) in an ethnically defined U.S. patient population. DESIGN: Patients requiring chronic anticoagulation with warfarin sodium (warfarin) were recruited over an 11-month period (June 1999 through May 2000) from the inpatient and outpatient divisions of a tertiary care medical center in this prospective observational study. Clinical and demographic information was collected and CYP2C9 genotype was determined. RESULTS: One hundred fifty-three patients receiving warfarin therapy for at least four weeks and comprising two ethnic groups [33 African Americans (22%) and 120 Caucasians (78%)] were genotyped. The mean weekly warfarin dose (+/-SEM) for all patients [36.9 (+/- 1.5) mg] was not influenced by gender [85 males (56%), 68 females (44%)] or ethnicity (p>0.05 for both), but was significantly affected by age (p = 0.006 for weight adjusted warfarin dose). The frequencies of CYP polymorphisms were as follows: 2C9*2 (24/153) 15.7%, 2C9*3 (23/153) 15.0%. There were no gender differences in polymorphism frequency (CYP2C9*2 frequency = (13/ 85) 15.3% in males, (12/68) 17.6% in females, p=0.74; CYP2C9*3 frequency = (15/85) 17.6% in males and (8/68) 11.8% in females, p = 0.38). CYP polymorphisms were much less common in African Americans than Caucasians [(5/33) 15.2% versus (47/120) 39.2%, respectively p = 0.05)]. Patients with CYP polymorphisms (2C9*2, 2C9*3) had significantly lower warfarin doses compared to patients with wild-type genotypes [30.6 (+/- 2.5) mg versus 40.1 (+/- 1.7) mg, p = 0.0021] . Stepwise backward regression analysis suggested a moderate ability to predict warfarin dose based on CYP genotype (r2 = 0.26), p < 0.01). CONCLUSIONS: CYP2C9 polymorphisms are common, associated with significant reductions in warfarin dose, and partly account for interpatient variability in warfarin sensitivity. As interactions between genetic factors and other variables that influence warfarin effect are more completely understood, CYP analysis may prove a useful adjunct for increasing the safety and efficacy of this agent.

Black or African American↗
PubMed2002

Template-directed dye-terminator incorporation with fluorescence polarization detection for analysis of single nucleotide polymorphisms implicated in sepsis.

Sepsis continues to be a common source of morbidity and mortality in critically ill patients. Single nucleotide polymorphisms (SNPs) present in genes encoding inflammatory mediators have been associated with predisposition and outcome in this syndrome. The use of high throughput SNP analysis in large epidemiological studies is necessary to more fully understand the genetic underpinnings of this disease. We adapted template-directed dye-terminator incorporation with fluorescence polarization detection (TDI-FP) to the analysis of eight SNPs implicated in mediating the sepsis syndrome: TNF-alpha (-308), TNF-alpha (-238), TNF-beta (+250), IL-1beta (+3953), IL-6 (-174), IL-10 (-592), plasminogen activator inhibitor-1 (PAI-1 (-675)), and TLR4 299 (+1032). Optimization of PCR, amplicon purification, and template-directed dye-terminator incorporation reactions were necessary to achieve acceptable performance characteristics for these assays. Sequence validated samples served as controls. Using this method we were able to assign genotype in 99.3% of assays and identified 64 unique genotypes in samples obtained from 90 individuals. TDI-FP is a flexible and robust method of SNP detection that can be optimized in a systematic fashion. This method has potential advantages compared with other high throughput genotyping techniques and appears well suited to clinical situations requiring analysis of large numbers of samples.

Cytokines↗
PubMed2002

Effect of an education program on decreasing catheter-related bloodstream infections in the surgical intensive care unit.

OBJECTIVE: The purpose of the study was to determine whether an education initiative aimed at improving central venous catheter insertion and care could decrease the rate of primary bloodstream infections. DESIGN: Pre- and postintervention observational study. SETTING: Eighteen-bed surgical/burn/trauma intensive care unit (ICU) in an urban teaching hospital. PATIENTS: A total of 4,283 patients were admitted to the ICU between January 1, 1998, and December 31, 2000. INTERVENTIONS: A program primarily directed toward registered nurses was developed by a multidisciplinary task force to highlight correct practice for central venous catheter insertion and maintenance. The program consisted of a 10-page self-study module on risk factors and practice modifications involved in catheter-related infections as well as a verbal in-service at staff meetings. Each participant was required to take a pretest before taking the study module and an identical test after its completion. Fact sheets and posters reinforcing the information in the study module were also posted throughout the ICU. MEASUREMENTS AND MAIN RESULTS: Seventy-four primary bloodstream infections occurred in 6874 catheter days (10.8 per 1000 catheter days) in the 18 months before the intervention. After the implementation of the education module, the number of primary bloodstream infections fell to 26 in 7044 catheter days (3.7 per 1000 catheter days), a decrease of 66% (p < .0001). The estimated cost savings secondary to the decreased infection rate for the 18 months after the intervention was between $185,000 and $2.808 million. CONCLUSIONS: A focused intervention primarily directed at the ICU nursing staff can lead to a dramatic decrease in the incidence of primary bloodstream infections. Educational programs may lead to a substantial decrease in cost, morbidity, and mortality attributable to central venous catheterization.

Catheterization, Central Venous↗
PubMed2002

Overexpression of Bcl-2 in the intestinal epithelium improves survival in septic mice.

OBJECTIVES: The aim of this study was to determine whether decreasing intestinal epithelial apoptosis in sepsis would alter mortality rates. The roles of the antiapoptotic protein Bcl-2 and the "executioner" protease caspase-3 in sepsis-induced gut cell death also were evaluated. DESIGN: Prospective, randomized, controlled trial. SETTING: Animal laboratory in an academic medical center. INTERVENTIONS: Transgenic mice that overexpress Bcl-2 throughout the small intestinal epithelium (n = 23) and littermate controls (n = 27) were subjected to cecal ligation and puncture (CLP) and followed for 8 days to assess survival. A second group of transgenic (n = 15) and littermate animals (n = 15) were subjected to CLP and were killed between 16 and 48 hrs postoperatively to assess for intestinal apoptosis and active caspase-3 staining. MEASUREMENTS AND MAIN RESULTS: Survival of transgenic animals was 83% 8 days after CLP compared with 44% for littermate controls (p < .005). Survival curves between the two groups of animals began diverging within 24 hrs. Overexpression of Bcl-2 was associated with a significant decrease in apoptosis between 16 and 24 hrs post-CLP (p < .05) as well as decreased staining for active caspase-3. CONCLUSIONS: Decreasing intestinal epithelial cell death via overexpression of Bcl-2 improves survival in septic mice. The gut may play a central role in the pathophysiology of sepsis.

Animals↗
PubMed2002

Sedation modulates recognition of novel stimuli and adaptation to regular stimuli in critically ill adults.

BACKGROUND: Responsiveness of critically ill patients is affected by disease and by therapy. Subjective tests of responsiveness (e.g., modified Ramsay score) reflect global integrity of a response arc that includes transduction, perception, classification, and an overt response. The performance of individual components is usually not assessed. OBJECTIVE: To determine whether an association exists among sedative medications and the brain's component information processing and adaptive abilities. DESIGN: Initial observational study of a convenience sample. SETTING: A surgical intensive care unit of a university hospital. PATIENTS: A total of 22 endotracheally intubated, mechanically ventilated patients chemically sedated with narcotics and a benzodiazepine (n = 12), or narcotics and propofol (n = 10) using sedation protocols. INTERVENTIONS: None. MEASUREMENTS AND FINDINGS: Patients were presented flashes of light and pulses of sound at fixed or random intervals. Patients receiving low doses of fentanyl and propofol adapted to stimuli presented at fixed intervals and retained the response to novelty. Patients receiving higher doses of those medications did not respond to novelty and responded to stimuli presented at fixed intervals as if they were novel. Patients receiving fentanyl and benzodiazepines had generally weaker responses to all stimuli. Moreover, their responses to fixed and random stimuli were similar. At low doses, the patients retained responses to novelty and adapted to fixed, whereas at higher doses the opposite was observed: the response to novelty was lost and the patients responded to fixed stimuli as if they were novel. These observations suggest that the sedative medications generally accelerate the physiologic decay of stimuli as they engage the brain's information processing and adaptive abilities and further suggest that different sedative medications may have different effects on the brain. CONCLUSIONS: Commonly administered sedative medications may alter the brain's biophysical state and thereby modulate specific aspects of the brain's information processing and adaptive functions. These functions can be interrogated even when the patient is seemingly unresponsive. If this observation is confirmed in subsequent prospective controlled randomized trials, electrophysiologic interrogation of the brain's information processing and adaptive capacities could serve as an adjunct to clinical assessment of responsiveness and management of sedative medications.

Adolescent↗
PubMed2002

Sepsis gene expression profiling: murine splenic compared with hepatic responses determined by using complementary DNA microarrays.

OBJECTIVE: DNA microarrays allow genome-wide assessment of changes in relative messenger RNA abundance and thus can be used to monitor changes in gene expression. The aim of this series of experiments was to gain experience in sepsis gene expression profiling in a well-accepted model of murine polymicrobial abdominal sepsis and begin characterizing (in the parlance of genomics) the sepsis "transcriptome." DESIGN: Prospective animal study. SETTING: University-based animal research facility.SUBJECTS C57BL/6 mice. INTERVENTIONS: After induction of general anesthesia, cecal ligation and puncture were performed to induce peritonitis and polymicrobial sepsis. The control group had sham laparotomy only. Three samples of spleen and liver were collected from septic and sham animals at 24 hrs after laparotomy. Changes in expression were measured for 588 annotated mouse genes by using a commercially available complementary DNA microarray kit. MEASUREMENTS AND MAIN RESULTS: Broad-scale gene expression profiles were characterized for septic liver and spleen and compared with sham controls. The analytical tools used included commercially available software packages and a novel analysis program. Very little overlap was observed in the septic gene expression profiles of these two organs. Most of the genes identified have previously been linked to regulation of the inflammatory response; importantly, however, some have not. In addition, hierarchical cluster analysis showed that cecal ligation and puncture at 24 hrs induced coordinate expression of genes that alter cell signaling and survival pathways in spleen, consistent with previously published reports of sepsis-induced splenocyte apoptosis. The current limitations of microarray analysis as reflected in these studies are also discussed. CONCLUSIONS: Microarray technology provides a powerful new tool for rapidly analyzing tissue-specific changes in gene expression induced by sepsis in animal models. To our knowledge, these data constitute the first report on the use of microarrays to determine the sepsis transcriptome.

Animals↗
PubMed2002

Heart rate variability in critical illness and critical care.

Although the rhythm of a healthy heart is clinically described as regular, the rate is variable. Studies of diverse populations have led to several generalizations about heart rate variability (HRV): (1) HRV is physiologic and normally declines with age, (2) acute changes in HRV are associated with several disease processes that require critical care, (3) measures of HRV can be used to describe the status of critically ill patients, and (4) measures of HRV can be used to predict events subsequent to at least one type of critical illness, myocardial infarction. This brief review considers the mechanisms underlying HRV, the measures that are used to describe HRV, and recent information regarding the use of HRV measures as predictive tools in critical care. The reviewers' opinion is that real-time analysis of HRV in critical illness may provide caregivers with additional information about patient status, effects of intervention, and prognosis.

Age Factors↗
PubMed2002

Coagulation inhibitors in the treatment of sepsis.

Despite advances in supportive care, sepsis and septic shock continue to be major causes of morbidity and mortality in critically ill patients. The lack of efficacy of anti-inflammatory drugs in patients with sepsis has shifted interest toward developing alternative treatments. The observation that clotting system activation may in part underlie the physiological derangements of sepsis has resulted in efforts to target the clotting cascade as a therapeutic strategy. Anticoagulants have been shown to ameliorate physiological derangements and improve survival in animal sepsis models. Three agents have undergone extensive study in humans: recombinant human activated protein C (rhAPC, drotrecogin-alpha), antithrombin III (ATIII) and tissue factor pathway inhibitor (TFPI). While a recent Phase III study of rhAPC suggests a survival benefit in patients with sepsis, major concerns about this trial include the manner in which the study was conducted, the potential toxicity of rhAPC and the questionable efficacy of this agent in patients with low mortality risk. Further clinical testing of rhAPC appears to be necessary to better define the target population most appropriate for its use. In contrast, a large Phase III study of high dose ATIII in patients with sepsis failed to show a treatment benefit with this agent. Finally, while TFPI has undergone extensive preclinical and Phase II testing, the results of Phase III studies have not been published. In summary, while coagulation inhibitors may ultimately have a therapeutic role in selected subgroups of patients with sepsis, the efficacy and safety of this class of agents remain to be proven.

Anticoagulants↗
PubMedDate not supplied

Computerized content analysis of conversational interactions.

The emotional impact of illness sustained by patients, their families, and friends is increasingly recognized as an important dimension of clinical evaluation and intervention. This study first attempted to extend a computerized technique of measuring the magnitude of mental events from a content analysis of speech initially designed for use on single verbal samples or verbal texts to the analysis of conversational interactions. The study then applied this method of extended measurement to conversations concerning seriously ill surgical patients. The authors' objective was to develop a graphic method that illustrates the neuropsychological interchanges occurring in these conversations. Speech samples were recorded during discussions among nurses, surgeons, intensivists, and family members involved in the care and treatment of seriously ill patients hospitalized in the surgical intensive care unit at Barnes-Jewish Hospitals associated with Washington University School of Medicine, St. Louis, Missouri. These samples then were transcribed into computer-readable text files and divided into utterances: uninterrupted speech by a single individual. The utterances were assigned numeric scores by a computer program on each of 14 validated content analysis scales measuring various neuropsychological dimensions. The scores are presented graphically in chronological sequence to illustrate the emotional interactions in these conversations. The graphic representations depicting sequences of computerized content analysis-derived scores for the mental reactions of the speakers in such conversations provide insights into the psychodynamics occurring in such stressful situations.

Adaptation, Psychological↗
PubMedDate not supplied

Use of clonidine to decrease intestinal fluid losses in patients with high-output short-bowel syndrome.

BACKGROUND: Some patients who have short bowel syndrome (SBS) have high intestinal outputs, which increases the risk of dehydration and fluid-electrolyte abnormalities and impairs quality of life. METHODS: We evaluated the use of clonidine, an alpha2-adrenergic receptor agonist, in 2 patients with SBS and high intestinal outputs, who were refractory to conventional therapy with antidiarrheal and antisecretory agents (loperamide, belladonna, opiates, somatostatin, histamine2 receptor antagonists and proton pump inhibitors). The first patient (case 1) was a 29-year-old woman who had 175 cm of small bowel anastamosed to 8 cm of descending colon, ending in a colostomy. The second patient (case 2) was a 22-year-old man who had 30 cm of jejunum anastomosed to 30 cm of sigmoid colon and rectum. RESULTS: The addition of clonidine, 0.1 mg per os (PO) 2 times per day, to the treatment regimen of case 1 decreased her ostomy output from approximately 4 L/day to approximately 1 L/day, eliminating the need for parenteral nutrition and fluids and decreasing the need for opiate therapy. The addition of clonidine, 0.2 mg PO 2 times per day in case 2 resulted in decreased rectal outputs from approximately 4 L/day to approximately 1.5 L/day. CONCLUSIONS: These results demonstrate that clonidine can effectively reduce intestinal fluid and electrolyte losses and should be considered as an additional treatment option in patients with SBS and high intestinal outputs.

Adrenergic alpha-Agonists↗