Tjasa Hranjec

Aggressive versus conservative initiation of antimicrobial treatment in critically ill surgical patients with suspected intensive-care-unit-acquired infection: a quasi-experimental, before and after observational cohort study

BACKGROUND Antimicrobial treatment in critically ill patients can either be started as soon as infection is suspected or after objective data confirm an infection. We postulated that delaying antimicrobial treatment of patients with suspected infections in the surgical intensive care unit (SICU) until objective evidence of infection had been obtained would not worsen patient mortality. METHODS We did a 2-year, quasi-experimental, before and after observational cohort study of patients aged 18 years or older who were admitted to the SICU of the University of Virginia (Charlottesville, VA, USA). From Sept 1, 2008, to Aug 31, 2009, aggressive treatment was used: patients suspected of having an infection on the basis of clinical grounds had blood cultures sent and antimicrobial treatment started. From Sept 1, 2009, to Aug 31, 2010, a conservative strategy was used, with antimicrobial treatment started only after objective findings confirmed an infection. Our primary outcome was in-hospital mortality. Analyses were by intention to treat. FINDINGS Admissions to the SICU for the first and second years were 762 and 721, respectively, with 101 patients with SICU-acquired infections during the aggressive year and 100 patients during the conservative year. Compared with the aggressive approach, the conservative approach was associated with lower all-cause mortality (13/100 [13%] vs 27/101 [27%]; p=0·015), more initially appropriate therapy (158/214 [74%] vs 144/231 [62%]; p=0·0095), and a shorter mean duration of therapy (12·5 days [SD 10·7] vs 17·7 [28·1]; p=0·0080). After adjusting for age, sex, trauma involvement, acute physiology and chronic health evaluation (APACHE) II score, and site of infection, the odds ratio for the risk of mortality in the aggressive therapy group compared with the conservative therapy group was 2·5 (95% CI 1·5-4·0). INTERPRETATION Waiting for objective data to diagnose infection before treatment with antimicrobial drugs for suspected SICU-acquired infections does not worsen mortality and might be associated with better outcomes and use of antimicrobial drugs. FUNDING National Institutes of Health.

Hypocaloric compared with eucaloric nutritional support and its effect on infection rates in a surgical intensive care unit: a randomized controlled trial

BACKGROUND Proper caloric intake goals in critically ill surgical patients are unclear. It is possible that overnutrition can lead to hyperglycemia and an increased risk of infection. OBJECTIVE This study was conducted to determine whether surgical infection outcomes in the intensive care unit (ICU) could be improved with the use of hypocaloric nutritional support. DESIGN Eighty-three critically ill patients were randomly allocated to receive either the standard calculated daily caloric requirement of 25-30 kcal · kg(-1) · d(-1) (eucaloric) or 50% of that value (hypocaloric) via enteral tube feeds or parenteral nutrition, with an equal protein allocation in each group (1.5 g · kg(-1) · d(-1)). RESULTS There were 82 infections in the hypocaloric group and 66 in the eucaloric group, with no significant difference in the mean (± SE) number of infections per patient (2.0 ± 0.6 and 1.6 ± 0.2, respectively; P = 0.50), percentage of patients acquiring infection [70.7% (29 of 41) and 76.2% (32 of 42), respectively; P = 0.57], mean ICU length of stay (16.7 ± 2.7 and 13.5 ± 1.1 d, respectively; P = 0.28), mean hospital length of stay (35.2 ± 4.9 and 31.0 ± 2.5 d, respectively; P = 0.45), mean 0600 glucose concentration (132 ± 2.9 and 135 ± 3.1 mg/dL, respectively; P = 0.63), or number of mortalities [3 (7.3%) and 4 (9.5%), respectively; P = 0.72]. Further analyses revealed no differences when analyzed by sex, admission diagnosis, site of infection, or causative organism. CONCLUSIONS Among critically ill surgical patients, caloric provision across a wide acceptable range does not appear to be associated with major outcomes, including infectious complications. The optimum target for caloric provision remains elusive.

Donor Age Is Associated With Chronic Allograft Vasculopathy After Adult Heart Transplantation: Implications for Donor Allocation

BACKGROUND Chronic allograft vasculopathy (CAV) is a major cause of long-term complications and mortality after heart transplantation. Although recipient factors have been implicated, little is known of the role of donor factors in CAV development. We sought to identify donor factors associated with development of CAV after heart transplantation. METHODS We reviewed the United Network for Organ Sharing heart transplant database from August 1987 to May 2008. Univariate and multivariate analyses were performed to assess the association between donor variables and the onset of CAV for adult recipients. Donor age was matched to recipient age and analyzed with respect to development of CAV. RESULTS Of the 39,704 recipients, a total of 11,714 (29.5%) experienced CAV. Multivariate analysis demonstrated seven donor factors as independent predictors of CAV: age, ethnicity, sex, weight, history of diabetes, hypertension, and tobacco use. When matching young donors (0 to 19.9 years) and old donors (> or =50 years) to each recipient age group, older donors (> or =50 years) conferred a higher risk of developing CAV. Further modeling demonstrated that for each recipient group, older donor age (> or =50 years) conferred a higher risk of CAV development compared with younger donor age (0 to 19.9 years; p < 0.0001). CONCLUSIONS Donor factors including sex, hypertension, diabetes, and tobacco use are independently associated with recipient CAV. Older donor age confers a greater risk of CAV development regardless of the age of the recipient. A heightened awareness for the development of CAV is warranted when using older donors in adult cardiac transplantation, in particular with recipients 40 years of age or older.

Surgical Site Infection Prevention: How We Do It

BACKGROUND Efforts to prevent surgical site infection (SSI) employ methods that are valid scientifically, but each institution and each surgeon also incorporates methods believed to be useful although this has not been proved by clinical trials. METHODS The surgical literature was reviewed, as were practices at the University of Virginia that the authors believe are of value for the prevention of SSI. RESULTS Preventive antibiotics are established measures. A case can be made for increasing the dose in patients with a large body mass, and antibiotics probably should be re-administered during procedures lasting longer than 3 h. Chlorhexidine showers for the patient are not proven; however, they are inexpensive and of potential benefit. Hair removal is always done with clippers and in the operating room at the time of the procedure. No scientific case can be made specifically for using antiseptic at the surgical site before the incision. Keeping the blood glucose concentration and the core body temperature near normal probably are important, but how close to normal is unclear. Transfusion enhances SSI, but leukocyte reduction of transfused blood may be of benefit. Some evidence supports the value of antibacterial suture in preventing SSI. CONCLUSIONS Many proven and potentially valid methods are employed to prevent SSI. Coordinated and standardized protocols with good data collection can assist the multi-disciplinary efforts to reduce SSI within the unique practices of a given institution.

Tissue-derived proinflammatory effect of adenosine A2B receptor in lung ischemia–reperfusion injury

OBJECTIVE Ischemia-reperfusion injury after lung transplantation remains a major source of morbidity and mortality. Adenosine receptors have been implicated in both pro- and anti-inflammatory roles in ischemia-reperfusion injury. This study tests the hypothesis that the adenosine A(2B) receptor exacerbates the proinflammatory response to lung ischemia-reperfusion injury. METHODS An in vivo left lung hilar clamp model of ischemia-reperfusion was used in wild-type C57BL6 and adenosine A(2B) receptor knockout mice, and in chimeras created by bone marrow transplantation between wild-type and adenosine A(2B) receptor knockout mice. Mice underwent sham surgery or lung ischemia-reperfusion (1 hour ischemia and 2 hours reperfusion). At the end of reperfusion, lung function was assessed using an isolated buffer-perfused lung system. Lung inflammation was assessed by measuring proinflammatory cytokine levels in bronchoalveolar lavage fluid, and neutrophil infiltration was assessed via myeloperoxidase levels in lung tissue. RESULTS Compared with wild-type mice, lungs of adenosine A(2B) receptor knockout mice were significantly protected after ischemia-reperfusion, as evidenced by significantly reduced pulmonary artery pressure, increased lung compliance, decreased myeloperoxidase, and reduced proinflammatory cytokine levels (tumor necrosis factor-α; interleukin-6; keratinocyte chemoattractant; regulated on activation, normal T-cell expressed and secreted; and monocyte chemotactic protein-1). Adenosine A(2B) receptor knockout → adenosine A(2B) receptor knockout (donor → recipient) and wild-type → adenosine A(2B) receptor knockout, but not adenosine A(2B) receptor knockout → wild-type, chimeras showed significantly improved lung function after ischemia-reperfusion. CONCLUSIONS These results suggest that the adenosine A(2B) receptor plays an important role in mediating lung inflammation after ischemia-reperfusion by stimulating cytokine production and neutrophil chemotaxis. The proinflammatory effects of adenosine A(2B) receptor seem to be derived by adenosine A(2B) receptor activation primarily on resident pulmonary cells and not bone marrow-derived cells. Adenosine A(2B) receptor may provide a therapeutic target for prevention of ischemia-reperfusion-related graft dysfunction in lung transplant recipients.

Donor factors are associated with bronchiolitis obliterans syndrome after lung transplantation.

BACKGROUND Bronchiolitis obliterans syndrome (BOS) is the major hurdle preventing long-term success in lung transplantation, and is the primary reason for the 50% 5-year survival. Recipient and perioperative risk factors have been investigated in BOS, but less is known about donor factors. Therefore, we investigated what donor factors are important in the development of BOS. METHODS We performed a retrospective review of the United Network for Organ Sharing lung transplant database from 1987 to 2008. Lung transplant recipients had yearly follow-up. Donor factors were evaluated for their influence on BOS development. Kaplan-Meier plots of BOS-free survival were compared for each donor factor and a multivariate Cox proportional hazard model for BOS was created with donor factors. RESULTS A total of 17,222 lung transplant recipients were identified; 6,991 recipients had sufficient follow-up BOS data. Of these recipients 57% (n = 3,984) developed BOS within 5 years. Recipients who received lungs from donors who were younger, without an active pulmonary infection, or those without current tobacco use had longer BOS-free survival. Recipients who received lungs with higher partial pressures of oxygen in arterial blood (Pao(2)) developed more BOS (p < 0.0001). Donor high Pao(2), older age, and current tobacco use were independent predictors of BOS in lung transplant recipients. CONCLUSIONS Donor factors and donor management strategies are important contributors to development of recipient BOS. Identification of these factors may help limit BOS and may identify recipients at high risk. Surprisingly, high Pao(2) in the donor is an independent predictor of BOS development.

Diagnosis-Dependent Relationships between Cytokine Levels and Survival in Patients Admitted for Surgical Critical Care

BACKGROUND Death after trauma, infection, or other critical illness has been attributed to unbalanced inflammation, in which dysregulation of cytokines leads to multiple organ dysfunction and death. We hypothesized that admission cytokine profiles associated with death would differ based on admitting diagnosis. STUDY DESIGN This 5-year study included patients admitted for trauma or surgical intensive care for more than 48 hours at 2 academic, tertiary care hospitals between October 2001 and May 2006. Cytokine analysis for interleukin (IL)-1, -2, -4, -6, -8, -10, -12, interferon-gamma, and tumor necrosis factor (TNF)-alpha was performed using ELISA on specimens drawn within 72 hours of admission. Mann-Whitney U test was used to compare median admission cytokine levels between alive and deceased patients. Relative risks and odds of death associated with admission cytokines were generated using univariate analysis and multivariate logistic regression models, respectively. RESULTS There were 1,655 patients who had complete cytokine data: 290 infected, nontrauma; 343 noninfected, nontrauma; and 1,022 trauma. Among infected patients, nonsurvivors had higher median admission levels of IL-2, -8, -10, and granulocyte macrophage-colony stimulating factor; noninfected, nontrauma patients had higher IL-6, -8, and IL-10; and nonsurviving trauma patients had higher IL-4, -6, -8, and TNF-alpha. IL-4 was the most significant predictor of death and carried the highest relative risk of dying in trauma patients, and IL-8 in nontrauma, noninfected patients. In infected patients, no cytokine independently predicted death. CONCLUSIONS Cytokine profiles of certain disease states may identify persons at risk of dying and allow for selective targeting of multiple cytokines to prevent organ dysfunction and death.

Identification of risk factors for the development of clostridium difficile-associated diarrhea following treatment of polymicrobial surgical infections

Objective:To identify risk factors for Clostridium difficile-associated diarrhea (CDAD) in surgical patients following treatment of polymicrobial infections. Summary Background Data:Infections among surgical patients are frequently anaerobic or mixed aerobic-anaerobic infections and are therefore subject to polymicrobial antibiotic coverage, including metronidazole. While multiple antibiotics are known to contribute to the development of CDAD, the role of preventive antibiotics is unproven. Methods:An 11-year dataset of consecutive infections treated in surgical patients at a single hospital was reviewed. All intra-abdominal, surgical site, or skin/skin structure infections were identified. Each infection was evaluated for antibiotic coverage and subsequent CDAD. Antibiotic usage was assessed using &khgr;2 analysis. A multiple logistic regression was used to identify independent predictors of CDAD. Results:A total of 4178 intra-abdominal, surgical site, or skin/skin structure infections were identified. Of these infections, 98 were followed by CDAD. Only carbapenem use affected the incidence of CDAD: 3.5% of infections treated with a carbapenem were followed by CDAD, whereas only 2.1% of infections treated without carbapenems were followed by CDAD (P = 0.04). Metronidazole had no association with future CDAD. Only age and Acute Physiology and Chronic Health Evaluation II (APACHE II) score were independently associated with CDAD by multiple logistic regression analysis. Conclusions:Older patients with a high severity of illness are at greatest risk for developing CDAD following treatment of polymicrobial infections. No specific antibiotic class, including fluoroquinolones, is associated with an increased incidence of CDAD in this population. Although use of metronidazole in the treatment of polymicrobial infections is appropriate for anaerobic coverage, it does not reduce the risk of future CDAD.

Permissive Hypercapnia in the Management of Congenital Diaphragmatic Hernia: Our Institutional Experience

BACKGROUND Congenital diaphragmatic hernia (CDH) is a potentially lethal anomaly associated with pulmonary hypoplasia and persistent pulmonary hypertension. Permissive hypercapnia is a strategy designed to reduce lung injury from mechanical ventilation in infants. It has been shown to be a potentially superior method of ventilator management for patients with CDH. In 2001, the Divisions of Neonatology and Pediatric Surgery at the University of Virginia Childrens Hospital established permissive hypercapnia as the management strategy for treatment of CDH. We hypothesized that permissive hypercapnia would be associated with improved outcomes in this patient population. STUDY DESIGN This retrospective review compares outcomes of infants treated for CDH in the extracorporeal membrane oxygenation (ECMO) era before and after initiation of permissive hypercapnia at a single institution. Outcomes were compared using univariate statistical analysis. RESULTS Ninety-one patients were available for analysis and were divided into 2 groups: 42 (Group 1) treated before and 49 (Group 2) treated after implementation of permissive hypercapnia. Survival was higher in Group 2 (85.8% vs 54.8%; p = 0.001; relative risk [RR] 3.17). Morbidity was lower in Group 2 and approached statistical significance (65.3% vs 83.3%; p = 0.052). Patients in Group 2 were repaired later, had a lower rate of ECMO use, and were extubated earlier. There was no difference in hospital stay. CONCLUSIONS The use of permissive hypercapnia for infants with CDH was associated with decreased mortality, a longer period of ventilation before repair with a shorter period of ventilation after repair, a lower rate of ECMO use, and no lengthening of hospital stay. Permissive hypercapnia remains the standard of care for ventilation of infants with CDH at our institution.

Sex- and Diagnosis-dependent Differences in Mortality and Admission Cytokine Levels Among Patients Admitted for Intensive Care*

Objectives:To investigate the role of sex on cytokine expression and mortality in critically ill patients. Design:A cohort of patients admitted to were enrolled and followed over a 5-year period. Setting:Two university-affiliated hospital surgical and trauma ICUs. Patients:Patients 18 years old and older admitted for at least 48 hours to the surgical or trauma ICU. Interventions:Observation only. Measurements and Main Results:Major outcomes included admission cytokine levels, prevalence of ICU-acquired infection, and mortality during hospitalization conditioned on trauma status and sex. The final cohort included 2,291 patients (1,407 trauma and 884 nontrauma). The prevalence of ICU-acquired infection was similar for men (46.5%) and women (44.5%). All-cause in-hospital mortality was 12.7% for trauma male patient and 9.1% for trauma female patient (p = 0.065) and 22.9% for nontrauma male patients and 20.6% for nontrauma female patients (p = 0.40). Among trauma patients, logistic regression analysis identified female sex as protective for all-cause mortality (odds ratio, 0.57). Among trauma patients, men had significantly higher admission serum levels of interleukin-2, interleukin-12, interferon-&ggr;, and tumor necrosis factor-&agr;, and among nontrauma patients, men had higher admission levels of interleukin-8 and tumor necrosis factor-&agr;. Conclusions:The relationship between sex and outcomes in critically ill patients is complex and depends on underlying illness. Women appear to be better adapted to survive traumatic events, while sex may be less important in other forms of critical illness. The mechanisms accounting for this gender dimorphism may, in part, involve differential cytokine responses to injury, with men expressing a more robust proinflammatory profile.