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Biomedical subjects

Timothy G Buchman

Publications and source records attributed to Timothy G Buchman.

At least 19 recordsLinked to original sources
PubMed2006

Molecular diagnostics in sepsis: from bedside to bench.

BACKGROUND: Based on recent in vitro data, we tested the hypothesis that microarray expression profiles can be used to diagnose sepsis, distinguishing in vivo between sterile and infectious causes of systemic inflammation. STUDY DESIGN: Exploratory studies were conducted using spleens from septic patients and from mice with abdominal sepsis. Seven patients with sepsis after injury were identified retrospectively and compared with six injured patients. C57BL/6 male mice were subjected to cecal ligation and puncture, or to IP lipopolysaccharide. Control mice had sham laparotomy or injection of IP saline, respectively. A sepsis classification model was created and tested on blood samples from septic mice. RESULTS: Accuracy of sepsis prediction was obtained using cross-validation of gene expression data from 12 human spleen samples and from 16 mouse spleen samples. For blood studies, classifiers were constructed using data from a training data set of 26 microarrays. The error rate of the classifiers was estimated on seven de-identified microarrays, and then on a subsequent cross-validation for all 33 blood microarrays. Estimates of classification accuracy of sepsis in human spleen were 67.1%; in mouse spleen, 96%; and in mouse blood, 94.4% (all estimates were based on nested cross-validation). Lists of genes with substantial changes in expression between study and control groups were used to identify nine mouse common inflammatory response genes, six of which were mapped into a single pathway using contemporary pathway analysis tools. CONCLUSIONS: Sepsis induces changes in mouse leukocyte gene expression that can be used to diagnose sepsis apart from systemic inflammation.

Adolescent↗
PubMed2006

A new safety event reporting system improves physician reporting in the surgical intensive care unit.

BACKGROUND: Medical errors are common, and physicians have notably been poor medical error reporters. In the SICU, reporting was generally poor and reporting by physicians was virtually nonexistent. This study was designed to observe changes in error reporting in an SICU when a new card-based system (SAFE) was introduced. STUDY DESIGN: Before implementation of the SAFE reporting system, education was given to all SICU healthcare providers. The SAFE system was introduced into the SICU for a 9-month period from March 2003 through November 2003, to replace an underused online system. Data were collected from the SAFE card reports and the online reporting systems during introduction, removal, and reimplementation of these cards. Reporting rates were calculated as number of reported events per 1,000 patient days. RESULTS: Reporting rates increased from 19 to 51 reports per 1,000 patient days after the SAFE cards were introduced into the ICU (p</= 0.001). Physician reporting increased most, rising from 0.3 to 5.8 reports per 1,000 patient days; nursing reporting also increased from 18 to 39 reports per 1,000 patient days (both p</=0.001). When the SAFE cards were removed, physician reporting declined to 0 reports per 1,000 patient days (p=0.01) and rose to 8.1 (p=0.001) when the cards were returned, similar to nursing results. A higher proportion of physician reports were events that caused harm compared with no effect (p < 0.05). CONCLUSIONS: A card reporting system, combined with appropriate education, improved overall reporting in the SICU, especially among physician providers. Nurses were more likely to use reporting systems than were physicians. Physician reports were more likely to be of events that caused harm.

Adult↗
PubMed2006

The relationship between the surgeon and the intensivist in the surgical intensive care unit.

When a patient enters the intensive care unit, the admitting surgeon also enters a new environment. In some hospitals, the surgical intensive care unit (SICU) is "closed"--critical care providers manage care; in others the unit is "open," and the admitting surgeon is in charge. A third system is the "mixed" model of ICU administration; a collaborative approach. This article addresses concerns and conflicts that frequently arise between admitting surgeons and intensivists. It is written from the perspective of two surgeon-intensivists who have been in both roles. Recent behavioral and social research on ICU conflicts and their resolution is reviewed, and and new strategies for conflict resolution are also presented.

Clinical Protocols↗
PubMed2006

Genetic research and testing in critical care: surrogates' perspective.

OBJECTIVE: Genetic testing is increasingly a component of clinical research in critical illness and has potential for integration into routine care. This study explored the perspectives of surrogate decision-makers (SDMs) for acutely ill patients with respect to social, legal, and ethical aspects of genetic testing. SETTING: Medical and surgical intensive care units in an urban tertiary care hospital. INTERVENTION: Questionnaires administered to SDMs for critically ill patients over a 12-month period. MEASUREMENTS AND MAIN RESULTS: A majority of eligible SDMs participated (117/146; 80.8%). SDMs were more likely to permit genetic testing for purposes of diagnosing a treatable life-threatening disease (114/117; 97.4%) or chronic disease (111/117; 94.9%) than for an untreatable life-threatening illness (95/117; 81.2%) (p < .001). SDMs were receptive to testing to explain familial traits (112/117; 95.7%) or ethnic traits (105/117; 89.7%) (p = .131). SDMs were concerned about potential for economic discrimination, with a majority expressing reluctance to permit testing if employers (93/117; 79.5%), health insurers (90/117; 76.9%), or life insurers (92/117; 78.6%) could access results. There was a greater willingness to allow participation in studies in which data were collected anonymously (90/117; 76.9%) vs. nonanonymously (75/117; 64.1%) (p = .04). Finally, SDMs placed greater trust in universities and nonprofit organizations (107/117; 91.4%) than either the federal government (75/117; 64.1%) or pharmaceutical companies (46/117; 39.3%) to perform genetic research (p < .01). CONCLUSIONS: SDMs expressed concerns regarding economic discrimination, confidentiality of data, and trust in entities conducting clinical investigation that may represent barriers both to performing studies in which genetic information is collected and to implementation of gene-based technologies in the critical care environment.

Biomedical Research↗
PubMed2005

Efficacy and safety of an insulin infusion protocol in a surgical ICU.

BACKGROUND: Hyperglycemia is associated with complications in the surgical intensive care unit. The purpose of this study was to determine the efficacy and safety of nurse-driven insulin infusion protocols in lowering blood glucose (BG) in critical illness. STUDY DESIGN: All patients in a 24-bed surgical intensive care unit who required i.v. insulin infusions during 3 noncontiguous 6-month periods from 2002 to 2004 were evaluated. In the preintervention phase, 71 patients received a physician-initiated insulin infusion without a developed protocol. They were compared with 95 patients who received a nurse-driven insulin infusion protocol with a target BG of 120 to 150 mg/dL and to 119 patients who received a more stringent protocol with a target BG of 80 to 110 mg/dL. RESULTS: There was a stepwise decrease in average daily BG levels, from 190 to 163 to 132 mg/dL (p < 0.001). The less stringent protocol decreased the time to achieve a BG level < 150 mg/dL from 14.1 to 7.4 hours compared with physician-driven management (p < 0.05) resulting in similar time on an insulin infusion (53 versus 48 hours). The more intensive protocol brought BG levels < 150 mg/dL in 7.2 hours and < 111 mg/dL in 13.6 hours, but increased the length of time a patient was on an insulin infusion to 77 hours. The incidence of severe hypoglycemia (BG < 40 mg/dL) was statistically similar between the groups, ranging between 1.1% and 3.4%. CONCLUSIONS: Implementation of a nurse-driven protocol led to more rapid and more effective BG control in critically ill surgical patients compared with physician management. Tighter BG control can be obtained without a significant increase in hypoglycemia, although this is associated with increased time on an insulin infusion.

Adult↗
PubMed2005

Early antibiotic administration but not antibody therapy directed against IL-6 improves survival in septic mice predicted to die on basis of high IL-6 levels.

Elevated interleukin (IL)-6 levels correlate with increased mortality following sepsis. IL-6 levels >14,000 pg/ml drawn 6 h after cecal ligation and puncture (CLP) are associated with 100% mortality in ND4 mice, even if antibiotic therapy is initiated 12 h after septic insult. Our first aim was to see whether earlier institution of antibiotic therapy could improve overall survival in septic mice and rescue the subset of animals predicted to die on the basis of high IL-6 levels. Mice (n = 184) were subjected to CLP, had IL-6 levels drawn 6 h later, and then were randomized to receive imipenem, a broad spectrum antimicrobial agent, beginning 6 or 12 h postoperatively. Overall 1-wk survival improved from 25.5 to 35.9% with earlier administration of antibiotics (P < 0.05). In mice with IL-6 levels >14,000 pg/ml, 25% survived if imipenem was started at 6 h, whereas none survived if antibiotics were started later (P < 0.05). On the basis of these results, we examined whether targeted antibody therapy could improve survival in mice with elevated IL-6 levels. A different cohort of mice (n = 54) had blood drawn 6 h after CLP, and then they were randomized to receive either monoclonal anti-IL-6 IgG or irrelevant rat IgG. Anti-IL-6 antibody failed to improve either overall survival or outcome in mice with IL-6 levels >14,000 pg/ml. These results demonstrate that earlier systemic therapy can improve outcome in a subset of mice predicted to die in sepsis, but we are unable to demonstrate any benefit in similar animals using targeted therapy directed at IL-6.

Animals↗
PubMed2005

Iron dysregulation combined with aging prevents sepsis-induced apoptosis.

BACKGROUND: Sepsis, iron loading, and aging cause independent increases in gut epithelial and splenic apoptosis. It is unknown how their combination will affect apoptosis and systemic cytokine levels. MATERIALS AND METHODS: Hfe-/- mice (a murine homologue of hemochromatosis) abnormally accumulate iron in their tissues. Aged (24-26 months) or mature (16-18 months) Hfe-/- mice and wild type (WT) littermates were subjected to cecal ligation and puncture (CLP) or sham laparotomy. Intestine, spleen, and blood were harvested 24 h later and assessed for apoptosis and cytokine levels. RESULTS: Gut epithelial and splenic apoptosis were low in both aged septic and sham Hfe-/- mice, regardless of the amount of iron in their diet. Mature septic WT mice had increased apoptosis compared to age-matched sham WT mice. Mature septic Hfe-/- mice had similar levels of intestinal cell death to age-matched septic WT mice but higher levels of splenic apoptosis. Apoptosis was significantly lower in septic aged Hfe-/- mice than septic mature Hfe-/- animals. Interleukin-6 was elevated in septic aged Hfe-/- mice compared to sham mice. CONCLUSIONS: Although sepsis, chronic iron dysregulation, and aging each increase gut and splenic apoptosis, their combination yields cell death levels similar to sham animals despite the fact that aged Hfe-/- mice are able to mount an inflammatory response following CLP and mature Hfe-/- mice have elevated sepsis-induced apoptosis. Combining sepsis with two risk factors that ordinarily increase cell death and increase mortality in CLP yields an apoptotic response that could not have been predicted based upon each element in isolation.

Aging↗
PubMed2005

Mechanisms of decreased intestinal epithelial proliferation and increased apoptosis in murine acute lung injury.

OBJECTIVES: The aim of this study was to determine the effects of acute lung injury on the gut epithelium and examine mechanisms underlying changes in crypt proliferation and apoptosis. The relationship between severity and timing of lung injury to intestinal pathology was also examined. DESIGN: Randomized, controlled study. SETTING: University research laboratory. SUBJECTS: Genetically inbred mice. INTERVENTIONS: Following induction of acute lung injury, gut epithelial proliferation and apoptosis were assessed in a) C3H/HeN wild-type and C3H/HeJ mice, which lack functional Toll-like receptor 4 (n = 17); b) C57Bl/6 mice that received monoclonal anti-tumor necrosis factor-alpha or control antibody (n = 22); and c) C57Bl/6 wild-type and transgenic mice that overexpress Bcl-2 in their gut epithelium (n = 21). Intestinal epithelial proliferation and death were also examined in animals with differing degrees of lung inflammation (n = 24) as well as in a time course analysis following a fixed injury (n = 18). MEASUREMENTS AND MAIN RESULTS: Acute lung injury caused decreased proliferation and increased apoptosis in crypt epithelial cells in all animals studied. C3H/HeJ mice had higher levels of proliferation than C3H/HeN animals without additional changes in apoptosis. Anti-tumor necrosis factor-alpha antibody had no effect on gut epithelial proliferation or death. Overexpression of Bcl-2 did not change proliferation despite decreasing gut apoptosis. Proliferation and apoptosis were not correlated to severity of lung injury, as gut alterations were lost in mice with more severe acute lung injury. Changes in both gut epithelial proliferation and death were apparent within 12 hrs, but proliferation was decreased 36 hrs following acute lung injury while apoptosis returned to normal. CONCLUSIONS: Acute lung injury causes disparate effects on crypt proliferation and apoptosis, which occur, at least in part, through differing mechanisms involving Toll-like receptor 4 and Bcl-2. Severity of lung injury does not correlate with perturbations in proliferation or death in the gut epithelium, and acute lung injury-induced changes in intestinal epithelial proliferation persist longer than those in apoptosis.

Animals↗
PubMed2005

Relationship between tracheostomy timing and duration of mechanical ventilation in critically ill patients.

OBJECTIVE: Tracheostomy practice in the setting of critical illness is controversial because evidence demonstrating unequivocal benefit is lacking. We undertook this study to determine the relationship between tracheostomy timing and duration of mechanical ventilation, intensive care unit length of stay, and hospital length of stay and to evaluate the relative influence of clinical and nonclinical factors on tracheostomy practice. DESIGN: Analysis of Project Impact, a multi-institutional critical care administrative database. SETTING: Medical school. PATIENTS: Data from 43,916 patients were reviewed. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Tracheostomy was performed in 2,473 (5.6%) of 43,916 patients analyzed. Tracheostomy patients had a higher survival rate than nontracheostomy patients (78.1 vs. 71.7%, p < .001) and underwent this procedure following a median (25th-75th percentile) of 9.0 (5.0-14.0) days of ventilatory support. Tracheostomy frequency and timing varied significantly comparing patient, intensive care unit, and hospital characteristics (p < .05 for all). Tracheostomy timing correlated significantly with duration of mechanical ventilation (r = .690), intensive care unit (r = .610), and hospital length of stay (r = .341, p < .001 for all). At most, 22% of patients were supported via tracheostomy at any given time. Although a minority, tracheostomy patients accounted for 26.2%, 21.0%, and 13.5% of all ventilator, intensive care unit, and hospital days, respectively. CONCLUSIONS: Although practice varies substantially, tracheostomy timing appears significantly associated with duration of mechanical ventilation, intensive care unit length of stay, and hospital length of stay. These findings emphasize the need for an adequately supported multiple-center trial to better define patient selection for tracheostomy and to test the hypothesis that timing of this procedure influences clinically important outcomes.

Critical Care↗
PubMed2005

RNAi.

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Animals↗
PubMed2005

Evaluation of the applicability, efficacy, and safety of a thromboembolic event prophylaxis guideline designed for quality improvement of the traumatically injured patient.

BACKGROUND: Thromboembolic events (TE) such as deep venous thrombosis (DVT) and pulmonary embolism (PE) are common after trauma. Our Trauma Practice Management Committee developed an evidence-based DVT/PE prophylaxis guideline using a modified Delphi approach to standardize care and reduce TE rates. Our objective was to evaluate the applicability, efficacy, and safety of this guideline in the traumatized patient, especially those admitted first to the intensive care unit (ICU). METHODS: We developed a risk-stratified DVT/PE prophylaxis guideline incorporating specific injuries, pertinent history, and physiologic parameters, favoring aggressive therapy in those at highest risk of dying from a PE. We prospectively collected data using this guideline in all patients admitted to the trauma or orthopedic-trauma services that were expected to stay for more than 48 hours (March-December 2003). Comparison was made with historical controls. Data collected included DVT, PE, prophylaxis level chosen, inferior vena cava filters, admission service and location, TRISS scores, length of stay, outcomes, adverse events, and specific risk factors. RESULTS: TE rates after implementation of the guideline were lower than historical controls for all patients (1.9% vs. 1.0%, p = 0.059) and for patients admitted first to the ICU (6.3% vs. 2%, p = 0.018). Completed sheets were collected for 46% of the targeted population. No bleeding events caused by guideline anticoagulation were noted, and one death occurred after inferior vena cava filter placement. Nine of the 12 TEs in the treatment group were in patients with spine or closed-head injury, delaying chemical prophylaxis. CONCLUSION: Form-based, risk-adjusted prophylaxis against TE leads to lower TE rates in a general and orthopedic ICU trauma population. Protocol compliance should be enforced.

Clinical Protocols↗
PubMed2004

Differential modulation of endotoxin responsiveness by human caspase-12 polymorphisms.

Caspases mediate essential key proteolytic events in inflammatory cascades and the apoptotic cell death pathway. Human caspases functionally segregate into two distinct subfamilies: those involved in cytokine maturation (caspase-1, -4 and -5) and those involved in cellular apoptosis (caspase-2, -3, -6, -7, -8, -9 and -10). Although caspase-12 is phylogenetically related to the cytokine maturation caspases, in mice it has been proposed as a mediator of apoptosis induced by endoplasmic reticulum stress including amyloid-beta cytotoxicity, suggesting that it might contribute to the pathogenesis of Alzheimer's disease. Here we show that a single nucleotide polymorphism in caspase-12 in humans results in the synthesis of either a truncated protein (Csp12-S) or a full-length caspase proenzyme (Csp12-L). The read-through single nucleotide polymorphism encoding Csp12-L is confined to populations of African descent and confers hypo-responsiveness to lipopolysaccharide-stimulated cytokine production in ex vivo whole blood, but has no significant effect on apoptotic sensitivity. In a preliminary study, we find that the frequency of the Csp12-L allele is increased in African American individuals with severe sepsis. Thus, Csp12-L attenuates the inflammatory and innate immune response to endotoxins and in doing so may constitute a risk factor for developing sepsis.

Africa↗
PubMed2004

The impact of bedside behavior on catheter-related bacteremia in the intensive care unit.

HYPOTHESIS: The success of an educational program in July 1999 that lowered the catheter-related bloodstream infection (CRBSI) rate in our intensive care unit (ICU) 3-fold is correlated with compliance with "best-practice" behaviors. DESIGN: Before-after trial. SETTING: Surgical ICU in a referral hospital. PATIENTS: A random sample underwent bedside audits of central venous catheter care (n = 187). All ICU admissions during a 39-month period (N = 4489) were prospectively followed for bacteremia. INTERVENTIONS: On the basis of audit results in December 2000, a behavioral intervention was designed to improve compliance with evidenced-based guidelines of central venous catheter management. MAIN OUTCOME MEASURES: Compliance with practices known to decrease CRBSI. Secondary outcome was CRBSI rate on all ICU patients. RESULTS: Multiple deficiencies were identified on bedside audits 18 months after the previous educational program. After the implementation of a separate behavioral intervention in July 2001, a second set of bedside audits in December 2001 demonstrated improvements in documenting the dressing date (11% to 21%; P<.001) and stopcock use (70% to 24%; P<.001), whereas nonsignificant trends were observed in hand hygiene (17% to 30%; P>.99) and maximal sterile barrier precautions (50% to 80%; P =.29). Appropriate practice was observed before and after the behavioral intervention in catheter site placement, dressing type, absence of antibiotic ointment, and proper securing of central venous catheters. Thirty-two CRBSIs occurred in 9353 catheter-days 24 months before the behavioral intervention compared with 17 CRBSIs in 6152 catheter-days during the 15 months after the intervention (3.4/1000 to 2.8/1000 catheter-days; P =.40). CONCLUSIONS: Although a previous educational program decreased the CRBSI rate, this was associated with only modest compliance with best practice principles when bedside audits were performed 18 months later. A behavioral intervention improved all identified deficiencies, leading to a nonsignificant decrease in CRBSIs.

Adult↗
PubMed2004

Treatment of hypophosphatemia using a protocol based on patient weight and serum phosphorus level in a surgical intensive care unit.

BACKGROUND: Hypophosphatemia may cause organ derangements in the surgical intensive care unit. The purpose of this study was to determine the impact of a repletion protocol for hypophosphatemia based on admission weight and phosphorus level. STUDY DESIGN: All patients who presented to an 18-bed surgical intensive care unit with a serum phosphorus level of 2.2 mg/dL or less or who received phosphorus supplementation despite having normal levels were identified. In the preintervention phase between January and June 2001, 137 patients were retrospectively identified who met these criteria. A protocol was then designed giving a single intravenous dose of phosphorus based on weight and serum phosphorus. Repletion was given with sodium or potassium phosphorus based on presupplementation levels. After protocol implementation 141 patients met these criteria between September 2001 and February 2002, and treatment and postrepletion levels were followed prospectively. RESULTS: A total of 47 patients were repleted before the intervention with adequate followup and 22 (47%) attained a normal level. Supplementation success was 53% in moderate hypophosphatemia (2.2 mg/dL or less) and 27% in severe hypophosphatemia (less than 1.5 mg/dL). After protocol implementation, 111 patients were repleted with 84 (76%) correcting to a normal level (p = 0.002 compared with retrospective patients). Success was 78% in moderate hypophosphatemia and 62% in severe hypophosphatemia. Inappropriate supplementation of normal phosphorus levels decreased from 51 to 16 patients after protocol implementation. CONCLUSIONS: A protocol based on weight and serum levels successfully treated both moderate and severe hypophosphatemia in the majority of critically ill patients. Protocol implementation also decreased unnecessary supplementation of normal phosphorus levels.

Adult↗
PubMed2004

High-dose exogenous iron following cecal ligation and puncture increases mortality rate in mice and is associated with an increase in gut epithelial and splenic apoptosis.

OBJECTIVES: Despite having dysregulated iron metabolism, critically ill patients may receive exogenous iron for the treatment of anemia. Iron is associated with increased tissue apoptosis and may facilitate bacterial growth. We hypothesized that exogenous iron administration given after the onset of sepsis would lead to increased mortality rate. To discriminate between elevated cell death and bacterial overgrowth as potential mediators of mortality, we examined gut epithelial and lymphocyte apoptosis and systemic bacterial counts in animals given iron supplementation after the onset of sepsis. DESIGN: Prospective, randomized, controlled study. SETTING: Animal laboratory in a university medical center. SUBJECTS: Male C57BL/6 mice, 6-10 wks old. INTERVENTIONS: C57BL/6 mice were subjected to cecal ligation and puncture (CLP), a well-accepted model of intra-abdominal sepsis, followed by daily subcutaneous injections of either 1 mL of iron dextran (5 mg/mL) or 0.9% NaCl for a total of five doses. Animals (n = 78) were followed for survival for 8 days. Separate cohorts (n = 76) were killed 24 or 48 hrs after cecal ligation and puncture or sham laparotomy and were assayed for gut epithelial and splenic apoptosis as well as for quantitative blood cultures. MEASUREMENTS AND MAIN RESULTS: Eight-day survival was 7% in animals that received iron and 26% in mice that received 0.9% NaCl (p < .005). Iron supplementation after cecal ligation and puncture increased apoptosis by both active caspase 3 and hematoxylin and eosin staining in both the intestinal epithelium and spleen at 24 hrs (p < .05). Iron supplementation after sham laparotomy did not cause mortality or elevated apoptosis. Quantitative blood cultures revealed no detectable differences between septic animals that received iron and those that received 0.9% NaCl. CONCLUSIONS: High-dose iron supplementation with iron dextran after the onset of sepsis significantly increases mortality rate in this animal model. Iron-induced mortality may be mediated by an increase in gut epithelial and splenic apoptosis, whereas severity of bacteremia does not appear to play a causative role.

Anemia, Iron-Deficiency↗