Joshua A. Doherty

The Importance of Fluid Management in Acute Lung Injury Secondary to Septic Shock

BACKGROUND Recent studies have suggested that early goal-directed resuscitation of patients with septic shock and conservative fluid management of patients with acute lung injury (ALI) can improve outcomes. Because these may be seen as potentially conflicting practices, we set out to determine the influence of fluid management on the outcomes of patients with septic shock complicated by ALI. METHODS A retrospective analysis was performed at Barnes-Jewish Hospital (St. Louis, MO) and in the medical ICU of Mayo Medical Center (Rochester, MN). Patients hospitalized with septic shock were enrolled into the study if they met the American-European Consensus definition of ALI within 72 h of septic shock onset. Adequate initial fluid resuscitation (AIFR) was defined as the administration of an initial fluid bolus of >or= 20 mL/kg prior to and achievement of a central venous pressure of >or= 8 mm Hg within 6 h after the onset of therapy with vasopressors. Conservative late fluid management (CLFM) was defined as even-to-negative fluid balance measured on at least 2 consecutive days during the first 7 days after septic shock onset. RESULTS The study cohort was made up of 212 patients with ALI complicating septic shock. Hospital mortality was statistically lowest for those achieving both AIFR and CLFM and higher for those achieving only CLFM, those achieving only AIFR, and those achieving neither (17 of 93 patients [18.3%] vs 13 of 31 patients [41.9%] vs 30 of 53 patients [56.6%] vs 27 of 35 [77.1%], respectively; p < 0.001). CONCLUSIONS Both early and late fluid management of septic shock complicated by ALI can influence patient outcomes.

Septic Shock Attributed to Candida Infection: Importance of Empiric Therapy and Source Control

BACKGROUND Delayed treatment of candidemia has previously been shown to be an important determinant of patient outcome. However, septic shock attributed to Candida infection and its determinants of outcome have not been previously evaluated in a large patient population. METHODS A retrospective cohort study of hospitalized patients with septic shock and blood cultures positive for Candida species was conducted at Barnes-Jewish Hospital, a 1250-bed urban teaching hospital (January 2002-December 2010). RESULTS Two hundred twenty-four consecutive patients with septic shock and a positive blood culture for Candida species were identified. Death during hospitalization occurred among 155 (63.5%) patients. The hospital mortality rate for patients having adequate source control and antifungal therapy administered within 24 hours of the onset of shock was 52.8% (n = 142), compared to a mortality rate of 97.6% (n = 82) in patients who did not have these goals attained (P < .001). Multivariate logistic regression analysis demonstrated that delayed antifungal treatment (adjusted odds ratio [AOR], 33.75; 95% confidence interval [CI], 9.65-118.04; P = .005) and failure to achieve timely source control (AOR, 77.40; 95% CI, 21.52-278.38; P = .001) were independently associated with a greater risk of hospital mortality. CONCLUSIONS The risk of death is exceptionally high among patients with septic shock attributed to Candida infection. Efforts aimed at timely source control and antifungal treatment are likely to be associated with improved clinical outcomes.

Quality of traditional surveillance for public reporting of nosocomial bloodstream infection rates.

CONTEXT Central line-associated bloodstream infection (BSI) rates, determined by infection preventionists using the Centers for Disease Control and Prevention (CDC) surveillance definitions, are increasingly published to compare the quality of patient care delivered by hospitals. However, such comparisons are valid only if surveillance is performed consistently across institutions. OBJECTIVE To assess institutional variation in performance of traditional central line-associated BSI surveillance. DESIGN, SETTING, AND PARTICIPANTS We performed a retrospective cohort study of 20 intensive care units among 4 medical centers (2004-2007). Unit-specific central line-associated BSI rates were calculated for 12-month periods. Infection preventionists, blinded to study participation, performed routine prospective surveillance using CDC definitions. A computer algorithm reference standard was applied retrospectively using criteria that adapted the same CDC surveillance definitions. MAIN OUTCOME MEASURES Correlation of central line-associated BSI rates as determined by infection preventionist vs the computer algorithm reference standard. Variation in performance was assessed by testing for institution-dependent heterogeneity in a linear regression model. RESULTS Forty-one unit-periods among 20 intensive care units were analyzed, representing 241,518 patient-days and 165,963 central line-days. The median infection preventionist and computer algorithm central line-associated BSI rates were 3.3 (interquartile range [IQR], 2.0-4.5) and 9.0 (IQR, 6.3-11.3) infections per 1000 central line-days, respectively. Overall correlation between computer algorithm and infection preventionist rates was weak (ρ = 0.34), and when stratified by medical center, point estimates for institution-specific correlations ranged widely: medical center A: 0.83; 95% confidence interval (CI), 0.05 to 0.98; P = .04; medical center B: 0.76; 95% CI, 0.32 to 0.93; P = .003; medical center C: 0.50, 95% CI, -0.11 to 0.83; P = .10; and medical center D: 0.10; 95% CI -0.53 to 0.66; P = .77. Regression modeling demonstrated significant heterogeneity among medical centers in the relationship between computer algorithm and expected infection preventionist rates (P < .001). The medical center that had the lowest rate by traditional surveillance (2.4 infections per 1000 central line-days) had the highest rate by computer algorithm (12.6 infections per 1000 central line-days). CONCLUSIONS Institutional variability of infection preventionist rates relative to a computer algorithm reference standard suggests that there is significant variation in the application of standard central line-associated BSI surveillance definitions across medical centers. Variation in central line-associated BSI surveillance practice may complicate interinstitutional comparisons of publicly reported central line-associated BSI rates.

Empiric Combination Antibiotic Therapy Is Associated with Improved Outcome against Sepsis Due to Gram-Negative Bacteria: a Retrospective Analysis

ABSTRACT The optimal approach for empirical antibiotic therapy in patients with severe sepsis and septic shock remains controversial. A retrospective cohort study was conducted in the intensive care units of a university hospital. The data from 760 patients with severe sepsis or septic shock associated with Gram-negative bacteremia was analyzed. Among this cohort, 238 (31.3%) patients received inappropriate initial antimicrobial therapy (IIAT). The hospital mortality rate was statistically greater among patients receiving IIAT compared to those initially treated with an appropriate antibiotic regimen (51.7% versus 36.4%; P < 0.001). Patients treated with an empirical combination antibiotic regimen directed against Gram-negative bacteria (i.e., β-lactam plus aminoglycoside or fluoroquinolone) were less likely to receive IIAT compared to monotherapy (22.2% versus 36.0%; P < 0.001). The addition of an aminoglycoside to a carbapenem would have increased appropriate initial therapy from 89.7 to 94.2%. Similarly, the addition of an aminoglycoside would have increased the appropriate initial therapy for cefepime (83.4 to 89.9%) and piperacillin-tazobactam (79.6 to 91.4%). Logistic regression analysis identified IIAT (adjusted odds ratio [AOR], 2.30; 95% confidence interval [CI] = 1.89 to 2.80) and increasing Apache II scores (1-point increments) (AOR, 1.11; 95% CI = 1.09 to 1.13) as independent predictors for hospital mortality. In conclusion, combination empirical antimicrobial therapy directed against Gram-negative bacteria was associated with greater initial appropriate therapy compared to monotherapy in patients with severe sepsis and septic shock. Our experience suggests that aminoglycosides offer broader coverage than fluoroquinolones as combination agents for patients with this serious infection.

Methicillin-resistant Staphylococcus aureus sterile-site infection : The importance of appropriate initial antimicrobial treatment

Objective:The first goal of this investigation was to determine the rate of appropriate initial antimicrobial administration to patients with methicillin-resistant Staphylococcus aureus (MRSA) sterile-site infections. Our second goal was to evaluate the influence of appropriate initial treatment of MRSA sterile-site infection on outcome. Design:A retrospective, single-center, observational cohort study. Setting:Barnes-Jewish Hospital, a 1200-bed urban teaching facility. Patients:Adult patients requiring hospitalization identified to have an MRSA sterile-site infection. Interventions:Retrospective data collection from automated hospital and pharmacy databases. Measurements and Main Results:Five hundred forty-nine patients with S. aureus sterile site infections were identified during a 3-yr period (January 2002 through December 2004). One hundred twenty-seven (23.1%) died during hospitalization. Hospital mortality was statistically greater for patients receiving inappropriate initial antimicrobial treatment (n = 380) within 24 hrs of a positive culture than for those receiving appropriate initial treatment (n = 169) (26.1% vs. 16.6%; p = .015). Multiple logistic regression analysis identified inappropriate initial antimicrobial treatment (adjusted odds ratio [AOR], 1.92; 95% confidence interval [CI], 1.48–2.50; p = .0134), vasopressor administration (AOR, 5.49; 95% CI, 4.08–7.38; p < .001), and increasing age (1-yr increments) (AOR, 1.03; 95% CI, 1.02–1.04; p < .001) as independent determinants of hospital mortality. Conclusions:Inappropriate initial antimicrobial treatment of MRSA sterile-site infections is common and is associated with an increased risk of hospital mortality. Appropriate antimicrobial treatment of MRSA sterile-site infections may be maximized by increased use of initial empirical antimicrobial treatment regimens targeting MRSA in patients at risk for this infection until organism identification and susceptibility become known. LEARNING OBJECTIVESOn completion of this article, the reader should be able to: Explain the impact of appropriate initial antimicrobial treatment for methicillin-resistant Staphylococcus aureus (MRSA) sterile site infections. List examples of “sterile sites” used. Use this information in a clinical setting. Dr. Kollef has disclosed that he is/was the recipient of grant/research funds from Merck, Elan, Pfizer, and Bard. All remaining authors have disclosed that they have no financial relationships with or interests in any commercial companies pertaining to this educational activity. Lippincott CME Institute, Inc., has identified and resolved all faculty conflicts of interest regarding this educational activity. Visit the Critical Care Medicine Web site (www.ccmjournal.org) for information on obtaining continuing medical education credit.

Inappropriate antibiotic therapy in Gram-negative sepsis increases hospital length of stay.

Objectives:To describe the impact of initially inappropriate antibiotic therapy on hospital length of stay in Gram-negative severe sepsis and septic shock. Design:Retrospective cohort. Setting:Academic urban hospital. Patients:Patients with Gram-negative bacteremia (primary or secondary, nosocomial or non-nosocomial) and severe sepsis or septic shock. Interventions:None. Measurements and Main Results:We defined initially inappropriate antibiotic therapy as occurring when the patient either was not administered an antibiotic within 24 hrs of sepsis onset or was treated with an antibiotic to which the culprit pathogen was resistant in vitro. The cohort included 760 subjects (mean age 59.3 ± 16.3 yrs, mean Acute Physiology and Chronic Health Evaluation II score 23.7 ± 6.7). More than half of infections were nosocomial (55.1%), and Escherichia coli represented the most common pathogen (n = 225). Pseudomonas species were isolated in 17.4% of patients. Nearly one-third of patients (31.3%) received initially inappropriate antibiotic therapy. Patients administered initially inappropriate antibiotic therapy were more likely to have a nosocomial infection, to have underlying cancer or diabetes or both, to require chronic hemodialysis, and to undergo mechanical ventilation. Those administered initially inappropriate antibiotic therapy also faced higher inhospital mortality. The unadjusted median length of stay after sepsis onset in those administered initially inappropriate antibiotic therapy was 11 days compared to 9 days in those treated appropriately (p = .028 by log-rank test). In a Cox model controlling for the multiple confounders noted, initially inappropriate antibiotic therapy independently correlated with continued hospitalization (adjusted hazard ratio 1.19, 95% confidence interval 1.01–1.40, p = .044). Adjusting for these covariates indicated that initially inappropriate antibiotic therapy independently increased the median attributable length of stay by 2 days. Conclusions:Initially inappropriate antibiotic therapy occurs in one-third of persons with severe sepsis and septic shock attributable to Gram-negative organisms. Beyond its impact on mortality, initially inappropriate antibiotic therapy is significantly associated with length of stay in this population. Efforts to decrease rates of initially inappropriate antibiotic therapy may serve to improve hospital resource use by leading to shorter overall hospital stays.

Hospital-wide impact of a standardized order set for the management of bacteremic severe sepsis

Objective:To evaluate the hospital-wide impact of a standardized order set for the management of bacteremic severe sepsis on processes of medical care and patient outcomes. Design:Retrospective, before and after study design. Setting:Barnes-Jewish Hospital, a 1200-bed academic medical center. Patients:Bacteremic patients with severe sepsis (200 from the 18-month before period and 200 from the 18-month after period). Interventions:Hospital-wide implementation of a standardized order set for the management of bacteremic severe sepsis. Measurements and Main Results:A total of 400 patients with bacteremia and severe sepsis were selected at random within the specified time periods. Patients in the after group received more intravenous fluids in the first 12 hours after onset of hypotension (1627 ± 1862 mL vs. 2054 ± 2237 mL; p = 0.04) and were more likely to receive appropriate initial antibiotic therapy (53.0% vs. 65.5%, p = 0.01). In-hospital mortality was statistically decreased in the after group (55.0% vs. 39.5%, p < 0.01), as was the hospital length of stay (28.7 ± 30.1 days vs. 22.4 ± 20.9 days; p = 0.02). Compared with the before group, the after group had reduced occurrence of renal failure (49.0% vs. 36.0%, p < 0.01), cardiovascular failure (70.5% vs. 57.0%, p < 0.01), and were less likely to require vasopressors after initial fluid resuscitation (68.5% vs. 52.5%, p < 0.01). Conclusions:The implementation of a hospital-wide standardized order set for the management of bacteremic severe sepsis was associated with greater fluid administration, improved antibiotic therapy, decreased incidence of organ failure, and improved survival.

Clostridium difficile-associated disease and mortality among the elderly critically ill.

Objective:To describe the epidemiology of and to develop a simple 30-day mortality clinical decision rule among critically ill patients ≥65 yrs. Increasing incidence of hospitalizations with and emergence of hypervirulent epidemic strains have made Clostridium difficile-associated disease an important public health concern. Advanced age is a risk factor for development of and death from Clostridium difficile-associated disease. Intensive care unit patients with Clostridium difficile-associated disease have a high mortality, but neither the burden of nor risk factors for death among the elderly intensive care unit patients with Clostridium difficile-associated disease are well understood. Design:Secondary analysis of a retrospective cohort study. Setting:All intensive care units at a single academic institution. Patients:A total of 278 critically ill patients with Clostridium difficile-associated disease; n = 148 aged ≥65 yrs. Interventions:None in addition to routine intensive care unit care. Measurements and Main Results:Univariate analyses were performed to compare characteristics and outcomes of the elderly vs. the younger groups, and elderly 30-day survivors with nonsurvivors. Multivariable logistic regression model was developed with 30-day mortality as a dependent variable. Covariates retained in the model were assigned weighted points to develop a 30-day mortality prediction score. Area under the receiver operating characteristics curve and cross-validation analyses evaluated the score characteristics. Elderly patients were 68% more likely to experience 30-day mortality than the younger group. Absence of chronic respiratory disease (R), age 75+ yrs (A), septic shock (S), and Acute Physiology and Chronic Health Evaluation II score 20+ (A) comprised the RASA score, whose receiver operating characteristics was 0.740; 95% Confidence Interval was 0.663–0.817. Conclusions:Elderly patients represent approximately 50% of intensive care unit patients with Clostridium difficile-associated disease and have a higher 30-day mortality than younger patients. A simple prediction rule incorporating determinants of 30-day mortality easily available at the bedside may aid in optimizing treatment decisions in this growing population.

Gram-negative bacteraemia in non-ICU patients: factors associated with inadequate antibiotic therapy and impact on outcomes

BACKGROUND A considerable number of gram-negative bacteraemias occur outside intensive care units (ICUs). Inadequate antibiotic therapy in ICUs has been associated with adverse outcomes; however, there are no prospective studies in non-ICU patients. METHODS A 6 month (1 August 2006-31 January 2007), prospective cohort study of non-ICU patients with gram-negative bacteraemia in a tertiary-care hospital was performed. Inadequate empirical antibiotic therapy was defined as no antibiotic or starting a non-susceptible antibiotic within 24 h after the initial positive blood culture. RESULTS Two hundred and fifty non-ICU patients had gram-negative bacteraemia. The mean age was 56.4 (+/-16.1) years. The predominant bacteria in monomicrobial infections were Escherichia coli (24%), Klebsiella pneumoniae (18%) and Pseudomonas aeruginosa (8%). Sixty-one (24%) patients had polymicrobial bacteraemia. Seventy patients (28%) required ICU transfer and 35 (14%) died. Seventy-nine (31.6%) received inadequate empirical antibiotic therapy. These patients were more likely to have a hospital-acquired infection [odds ratio (OR) = 1.99, 95% confidence interval (CI) = 1.11-3.56, P = 0.02] and less likely to have E. coli monomicrobial bacteraemia [OR 0.40 (95% CI 0.19-0.86), P = 0.02]. There were no differences in occurrence of sepsis [72 (91.1%) patients with inadequate versus 159 (93.0%) with adequate therapy; P = 0.6], ICU transfer [20 (25.3%) versus 50 (29.2%); P = 0.5], post-bacteraemia length of stay (median = 6.8 versus 6.1 days; P = 0.09) or death [11 (13.9%) versus 24 (14.0%); P = 1.0]. CONCLUSIONS Nearly one-third of the non-ICU patients with gram-negative bacteraemia received inadequate empirical antibiotic therapy. There was no difference in adverse outcomes between patients receiving inadequate or adequate therapy in this study.

Resistance to empiric antimicrobial treatment predicts outcome in severe sepsis associated with gram‐negative bacteremia

BACKGROUND Gram-negative bacteria are an important cause of severe sepsis. Recent studies have demonstrated reduced susceptibility of Gram-negative bacteria to currently available antimicrobial agents. METHODS We performed a retrospective cohort study of patients with severe sepsis who were bacteremic with Pseudomonas aeruginosa, Acinetobacter species, or Enterobacteriaceae from 2002 to 2007. Patients were identified by the hospital informatics database and pertinent clinical data (demographics, baseline severity of illness, source of bacteremia, and therapy) were retrieved from electronic medical records. All patients were treated with antimicrobial agents within 12 hours of having blood cultures drawn that were subsequently positive for bacterial pathogens. The primary outcome was hospital mortality. RESULTS A total of 535 patients with severe sepsis and Gram-negative bacteremia were identified. Hospital mortality was 43.6%, and 82 (15.3%) patients were treated with an antimicrobial regimen to which the causative pathogen was resistant. Patients infected with a resistant pathogen had significantly greater risk of hospital mortality (63.4% vs 40.0%; P < 0.001). In a multivariate analysis, infection with a pathogen that was resistant to the empiric antibiotic regimen, increasing APACHE II scores, infection with Pseudomonas aeruginosa, healthcare-associated hospital-onset infection, mechanical ventilation, and use of vasopressors were independently associated with hospital mortality. CONCLUSIONS In severe sepsis attributed to Gram-negative bacteremia, initial treatment with an antibiotic regimen to which the causative pathogen is resistant was associated with increased hospital mortality. This finding suggests that rapid determination of bacterial susceptibility could influence treatment choices in patients with severe sepsis potentially improving their clinical outcomes.