C5a-mediated neutrophil dysfunction is RhoA-dependent and predicts infection in critically ill patients.

Critically ill patients are at heightened risk for nosocomial infections. The anaphylatoxin C5a impairs phagocytosis by neutrophils. However, the mechanisms by which this occurs and the relevance for acquisition of nosocomial infection remain undetermined. We aimed to characterize mechanisms by which C5a inhibits phagocytosis in vitro and in critically ill patients, and to define the relationship between C5a-mediated dysfunction and acquisition of nosocomial infection. In healthy human neutrophils, C5a significantly inhibited RhoA activation, preventing actin polymerization and phagocytosis. RhoA inhibition was mediated by PI3Kδ. The effects on RhoA, actin, and phagocytosis were fully reversed by GM-CSF. Parallel observations were made in neutrophils from critically ill patients, that is, impaired phagocytosis was associated with inhibition of RhoA and actin polymerization, and reversed by GM-CSF. Among a cohort of 60 critically ill patients, C5a-mediated neutrophil dysfunction (as determined by reduced CD88 expression) was a strong predictor for subsequent acquisition of nosocomial infection (relative risk, 5.8; 95% confidence interval, 1.5-22; P = .0007), and remained independent of time effects as assessed by survival analysis (hazard ratio, 5.0; 95% confidence interval, 1.3-8.3; P = .01). In conclusion, this study provides new insight into the mechanisms underlying immunocompromise in critical illness and suggests novel avenues for therapy and prevention of nosocomial infection.

Reducing ventilator-associated pneumonia in intensive care: impact of implementing a care bundle.

OBJECTIVES: Ventilator-associated pneumonia is the most common intensive care unit-acquired infection. Although there is widespread consensus that evidenced-based interventions reduce the risk of ventilator-associated pneumonia, controversy has surrounded the importance of implementing them as a "bundle" of care. This study aimed to determine the effects of implementing such a bundle while controlling for potential confounding variables seen in similar studies. DESIGN: A before-and-after study conducted within the context of an existing, independent, infection surveillance program. SETTING: An 18-bed, mixed medical-surgical teaching hospital intensive care unit. PATIENTS: All patients admitted to intensive care for 48 hrs or more during the periods before and after intervention. INTERVENTIONS: A four-element ventilator-associated pneumonia prevention bundle, consisting of head-of-bed elevation, oral chlorhexidine gel, sedation holds, and a weaning protocol implemented as part of the Scottish Patient Safety Program using Institute of Health Care Improvement methods. MEASUREMENTS AND MAIN RESULTS: Compliance with head-of-bed elevation and chlorhexidine gel were 95%-100%; documented compliance with "wake and wean" elements was 70%, giving overall bundle compliance rates of 70%. Compared to the preintervention period, there was a significant reduction in ventilator-associated pneumonia in the postintervention period (32 cases per 1,000 ventilator days to 12 cases per 1,000 ventilator days; p<.001). Statistical process control charts showed the decrease was most marked after bundle implementation. Patient cohorts staying ≥6 and ≥14 days had greater reduction in ventilator-associated pneumonia acquisition and also had reduced antibiotic use (reduced by 1 and 3 days; p=.008/.007, respectively). Rates of methicillin-resistant Staphylococcus aureus acquisition also decreased (10% to 3.6%; p<.001). CONCLUSIONS: Implementation of a ventilator-associated pneumonia prevention bundle was associated with a statistically significant reduction in ventilator-associated pneumonia, which had not been achieved with earlier ad hoc ventilator-associated pneumonia prevention guidelines in our unit. This occurred despite an inability to meet bundle compliance targets of 95% for all elements. Our data support the systematic approach to achieving high rates of process compliance and suggest systematic introduction can decrease both infection incidence and antibiotic use, especially for patients requiring longer duration of ventilation.

Induction drug and outcome of patients admitted to the intensive care unit after emergency laparotomy.

BACKGROUND AND OBJECTIVE: Etomidate is often used to induce anaesthesia in sick patients owing to its relative cardiovascular stability. However, etomidate affects adrenal cortical activity, and there is concern that this could impair outcome in patients undergoing emergency surgery. METHODS: We retrospectively analysed data from 176 patients admitted to an ICU after emergency laparotomy. We retrieved ASA status, surgical diagnosis, induction drug use, blood pressure before and after induction and any vasopressor administration, steroid and vasopressor therapy in ICU and patient outcome. Choice of induction drug was at the discretion of the attending anaesthetist. RESULTS: The drugs (numbers of patients) used to induce anaesthesia were etomidate (52), thiopental (90), propofol (16), midazolam (12) and ketamine (4). Fifty-two patients (30%) died in hospital. ASA status was the only independent predictor of hospital outcome (P < 0.001). Choice of induction drug was related to ASA status. As ASA status worsened, the likelihood of using etomidate or midazolam/ketamine increased (P = 0.001). We found no association between etomidate and dying in hospital, though our study might not have had sufficient power to show a difference between induction drugs. The relative risks [95% confidence interval (CI)] of dying in hospital were etomidate 1.16 (0.72-1.87), thiopental 0.82 (0.52-1.30), propofol 0.40 (0.11-1.49) and midazolam/ketamine 1.84 (1.09-3.12). Vasopressor and steroid therapy in the ICU was not related to induction drug. The risk of developing hypotension at induction or of receiving vasopressor to treat hypotension was least with etomidate. CONCLUSION: We found no evidence that etomidate is associated with worse outcome than thiopental or propofol in patients undergoing emergency laparotomy, but we cannot be certain that etomidate is well tolerated in this group of patients. More data are required to address this issue definitively.

Patients with hip fracture admitted to critical care: epidemiology, interventions and outcome.

INTRODUCTION: Although there is much current debate about the use of critical care to enhance peri-operative care of patients with hip fracture there are limited supporting data. We investigated the epidemiology, critical care interventions and outcomes of patients with hip fracture admitted to a large UK critical care unit. PATIENTS AND METHODS: We reviewed all patients with hip fracture (excluding those with multiple trauma, and those with femoral shaft or peri-prosthetic fracture) who were admitted to our critical care unit during a four year period. We recorded patient characteristics, reason for admission to critical care, interventions and organ support performed, and patient outcome. RESULTS: We identified 99 patients with a mean age of 81 years; this represented 1% of patients admitted to critical care, and 2.4% of patients with hip fracture admitted to hospital during the study period. Fifty-two patients required no organ support; 19 received only respiratory support, 13 only cardiovascular support, 12 received both respiratory and cardiovascular support, and 3 received respiratory, cardiovascular and renal support. Outcome worsened as the level of organ support increased (p=0.01). Fifteen patients died in critical care, acute hospital mortality was 33% and 1-year mortality was 54%. No patient for whom admission was planned before surgery died in critical care and the 30-day mortality for this group was 13%. Outcome was related to the time between surgery and critical care admission: patients admitted before surgery or longer than 2 days after surgery had worse outcomes (p=0.001). The reason for admission to critical care also influenced outcome: patients with sepsis had poor outcome with one-third dying in critical care and a further one-third not surviving to hospital discharge. CONCLUSIONS: The major determinants of outcome in this population were reason for admission, and timing of admission to critical care. One year survival was better than that for unselected patients aged >80 years admitted to critical care. Admission to critical care and use of enhanced peri-operative care for selected hip fracture patients is entirely appropriate and beneficial.

Early lactate clearance in septic patients with elevated lactate levels admitted from the emergency department to intensive care: time to aim higher?

PURPOSE: Septic patients with hyperlactatemia have increased mortality rates, irrespective of hemodynamic and oxygen-derived variables. The aims of the study are the following: (1) to ascertain whether lactate clearance (LC) (percentage change in lactate over unit time) predicts mortality in septic patients admitted to intensive care directly from the emergency department and (2) to calculate the optimal "cut-off" value for mortality prediction. METHODS: Three-year retrospective observational study of consecutive patients with severe sepsis and septic shock admitted to intensive care from the emergency department of a tertiary UK hospital. We calculated 6-hour LC, performed receiver operating characteristic analyses to calculate optimal cut-off values for initial lactate and LC, dichotomized patients according to the LC cut-off, and calculated hazard ratios using a Cox proportional hazards model. RESULTS: One hundred six patients were identified; 78, after exclusions. Lactate clearance was independently associated with 30-day mortality (P<.04); optimal cut-off, 36%. Mortality rates were 61.1% and 10.7% for patients with 6-hour LC 36% or less and greater than 36%, respectively. Hazard ratio for death with LC 36% or less was 7.33 (95% confidence interval, 2.17-24.73; P<.001). CONCLUSIONS: Six-hour LC was independently associated with mortality, and the optimal cut-off value was 36%, significantly higher than previously reported. We would support further research investigating this higher LC as a distinct resuscitation end point in patients with severe sepsis and septic shock.