Lee P. Skrupky

Persistent lymphopenia after diagnosis of sepsis predicts mortality.

ABSTRACT Objective: The objective of this study was to determine whether persistent lymphopenia on the fourth day following the diagnosis of sepsis predicts mortality. Methods: This was a single-center, retrospective cohort study of 335 adult patients with bacteremia and sepsis admitted to a large university-affiliated tertiary care hospital between January 1, 2010, and July 31, 2012. All complete blood cell count profiles during the first 4 days following the diagnosis of sepsis were recorded. The primary outcome was 28-day mortality. Secondary outcomes included development of secondary infections, 1-year mortality, and hospital and intensive care unit lengths of stay. Results: Seventy-six patients (22.7%) died within 28 days. Lymphopenia was present in 28-day survivors (median, 0.7 × 103 cells/&mgr;L; interquartile range [IQR], 0.4–1.1 × 103 cells/&mgr;L) and nonsurvivors (median, 0.6 × 103 cells/&mgr;L; IQR, 0.4–1.1 × 103 cells/&mgr;L) at the onset of sepsis and was not significantly different between the groups (P = 0.35). By day 4, the median absolute lymphocyte count was significantly higher in survivors compared with nonsurvivors (1.1 × 103 cells/&mgr;L [IQR, 0.7–1.5 × 103 cells/&mgr;L] vs. 0.7 × 103 cells/&mgr;L [IQR, 0.5–1.0 × 103 cells/&mgr;L]; P < 0.0001). Using logistic regression to account for potentially confounding factors (including age, Acute Physiology and Chronic Health Evaluation II score, comorbidities, surgical procedure during the study period, and time until appropriate antibiotic administration), day 4 absolute lymphocyte count was found to be independently associated with 28-day survival (adjusted odds ratio, 0.68 [95% confidence interval, 0.51–0.91]) and 1-year survival (adjusted odds ratio, 0.74 [95% confidence interval, 0.59–0.93]). Severe persistent lymphopenia (defined as an absolute lymphocyte count of 0.6 × 103 cells/&mgr;L or less on the fourth day after sepsis diagnosis) was associated with increased development of secondary infections (P = 0.04). Conclusions: Persistent lymphopenia on the fourth day following the diagnosis of sepsis predicts early and late mortality and may serve as a biomarker for sepsis-induced immunosuppression.

Advances in the Management of Sepsis and the Understanding of Key Immunologic Defects

Anesthesiologists are increasingly confronting the difficult problem of caring for patients with sepsis in the operating room and in the intensive care unit. Sepsis occurs in more than 750,000 patients in the United States annually and is responsible for more than 210,000 deaths. Approximately 40% of all intensive care unit patients have sepsis on admission to the intensive care unit or experience sepsis during their stay in the intensive care unit. There have been significant advances in the understanding of the pathophysiology of the disorder and its treatment. Although deaths attributable to sepsis remain stubbornly high, new treatment algorithms have led to a reduction in overall mortality. Thus, it is important for anesthesiologists and critical care practitioners to be aware of these new therapeutic regimens. The goal of this review is to include practical points on important advances in the treatment of sepsis and provide a vision of future immunotherapeutic approaches.

A comparison of ventilator-associated pneumonia rates as identified according to the National Healthcare Safety Network and American College of Chest Physicians criteria.

Objective:The objective of this study was to compare the observed rates of ventilator-associated pneumonia when using the National Healthcare Safety Network vs. the American College of Chest Physicians criteria. Design:Prospective, observational cohort study. Setting:A 1250-bed academic tertiary care medical center. Patients:Adult medical and surgical intensive care unit patients requiring mechanical ventilation for >48 hrs. Interventions:None. Measurements and Main Results:Patients were prospectively and independently screened for ventilator-associated pneumonia from January 2009 to January 2010 using the National Healthcare Safety Network and American College of Chest Physicians criteria. All American College of Chest Physicians classifications, including the corresponding radiographs and laboratory data, were prospectively reviewed by one of the investigators (JD) and confirmed by a second investigator (MHK). All National Healthcare Safety Network classifications were administratively determined using the hospitals infection prevention surveillance system. Over 1 yr, 2060 patients met the inclusion criteria. Of these, 83 patients (4%) had ventilator-associated pneumonia according to the American College of Chest Physicians criteria as compared with 12 patients (0.6%) using the National Healthcare Safety Network criteria. The corresponding rates of ventilator-associated pneumonia were 8.5 vs. 1.2 cases per 1,000 ventilator days, respectively. Agreement of the two sets of criteria was marginal (&kgr; statistic, 0.26). Cultures were positive in 88% of ventilator-associated pneumonias in the American College of Chest Physicians group as compared to 92% in the National Healthcare Safety Network group. Conclusions:There is poor agreement between clinical and administrative surveillance methods for the diagnosis of ventilator-associated pneumonia. Although there may be some benefit to using more stringent criteria for surveillance of ventilator-associated pneumonia, use of the administratively applied National Healthcare Safety Network criteria may significantly underestimate the scope of the clinical problem.

Ventilator-associated tracheobronchitis in a mixed surgical and medical ICU population.

BACKGROUND Ventilator-associated tracheobronchitis (VAT) is considered an intermediate condition between bacterial airway colonization and ventilator-associated pneumonia (VAP). The purpose of this prospective cohort study was to further characterize VAT in terms of incidence, etiology, and impact on patient outcomes. METHODS Patients intubated for >48 h in the surgical and medical ICUs of Barnes-Jewish Hospital were screened daily for the development of VAT and VAP over 1 year. Patients were followed until hospital discharge or death, and patient demographics, causative pathogens, and clinical outcomes were recorded. RESULTS A total of 28 patients with VAT and 83 with VAP were identified corresponding to frequencies of 1.4% and 4.0%, respectively. VAP was more common in surgical than medical ICU patients (5.3% vs 2.3%; P<.001), but the occurrence of VAT was similar between surgical and medical patients (1.3% vs 1.5%; P=.845). VAT progressed to VAP in nine patients (32.1%) despite antibiotic therapy. There was no significant difference in hospital mortality between patients with VAP and VAT (19.3% vs 21.4%; P=.789). VAT was caused by a multidrug-resistant (MDR) pathogen in nine cases (32.1%). CONCLUSION VAT occurs less commonly than VAP but at a similar incidence in medical and surgical ICU patients. VAT frequently progressed to VAP, and patients diagnosed with VAT had similar outcomes to those diagnosed with VAP, suggesting that antimicrobial therapy is appropriate for VAT. VAT is also frequently caused by MDR organisms, and this should be taken into account when choosing antimicrobial therapy.

Comparison of Bivalirudin and Argatroban for the Management of Heparin-Induced Thrombocytopenia

Study Objectives. To compare the effectiveness of bivalirudin and argatroban in achieving anticoagulation goals and to compare clinical outcomes assessing the safety and efficacy in patients with known or suspected heparin‐induced thrombocytopenia (HIT).

Heparin or 0.9% sodium chloride to maintain central venous catheter patency: A randomized trial

Objective:To compare heparin (3 mL, 10 units/mL) and 0.9% sodium chloride (NaCl, 10 mL) flush solutions with respect to central venous catheter lumen patency. Design:Single-center, randomized, open label trial. Setting:Medical intensive care unit and Surgical/Burn/Trauma intensive care unit at Barnes-Jewish Hospital, St. Louis, MO. Patients:Three hundred forty-one patients with multilumen central venous catheters. Patients with at least one lumen with a minimum of two flushes were included in the analysis. Interventions:Patients were randomly assigned within 12 hrs of central venous catheter insertion to receive either heparin or 0.9% sodium chloride flush. Measurements and Main Results:The primary outcome was lumen nonpatency. Secondary outcomes included the rates of loss of blood return, inability to infuse or flush through the lumen (flush failure), heparin-induced thrombocytopenia, and catheter-related blood stream infection. Assessment for patency was performed every 8 hrs in lumens without continuous infusions for the duration of catheter placement or discharge from intensive care unit. Three hundred twenty-six central venous catheters were studied yielding 709 lumens for analysis. The nonpatency rate was 3.8% in the heparin group (n = 314) and 6.3% in the 0.9% sodium chloride group (n = 395) (relative risk 1.66, 95% confidence interval 0.86–3.22, p = .136). The Kaplan-Meier analysis for time to first patency loss was not significantly different (log rank = 0.093) between groups. The rates of loss of blood return and flush failure were similar between the heparin and 0.9% sodium chloride groups. Pressure-injectable central venous catheters had significantly greater rates of nonpatency (10.6% vs. 4.3%, p = .001) and loss of blood return (37.0% vs. 18.8%, p <.001) compared to nonpressure-injectable catheters. The frequencies of heparin-induced thrombocytopenia and catheter-related blood stream infection were similar between groups. Conclusion:0.9% sodium chloride and heparin flushing solutions have similar rates of lumen nonpatency. Given potential safety concerns with the use of heparin, 0.9% sodium chloride may be the preferred flushing solution for short-term use central venous catheter maintenance.

Prolonged Infusion Antibiotics for Suspected Gram-Negative Infections in the ICU: A Before-After Study

BACKGROUND: β-Lactam antibiotics demonstrate time-dependent killing. Prolonged infusion of these agents is commonly performed to optimize the time the unbound concentration of an antibiotic remains greater than the minimum inhibitory concentration and decrease costs, despite limited evidence suggesting improved clinical results. OBJECTIVE: To determine whether prolonged infusion of β-lactam antibiotics improves outcomes in critically ill patients with suspected gram-negative infection. METHODS: We conducted a single-center, before-after, comparative effectiveness trial between January 2010 and January 2011 in the intensive care units at Barnes-Jewish Hospital, an urban teaching hospital affiliated with the Washington University School of Medicine in St. Louis, MO. Outcomes were compared between patients who received standardized dosing of meropenem, piperacillin-tazobactam, or cefepime as an intermittent infusion over 30 minutes (January 1, 2010, to June 30, 2010) and patients who received prolonged infusion over 3 hours (August 1, 2010, to January 31, 2011). RESULTS: A total of 503 patients (intermittent infusion, n = 242; prolonged infusion, n = 261) treated for gram-negative infection were included in the clinically evaluable population. Approximately 50% of patients in each group received cefepime and 20% received piperacillin-tazobactam. More patients in the intermittent infusion group received meropenem (35.5% vs 24.5%; p = 0.007). Baseline characteristics were similar between groups, with the exception of a greater occurrence of chronic obstructive pulmonary disease (COPD) in the intermittent infusion group. Treatment success rates in the clinically evaluable group were 56.6% for intermittent infusion and 51.0% for prolonged infusion (p = 0.204), and in the microbiologically evaluable population, 55.2% for intermittent infusion and 49.5% for prolonged infusion (p = 0.486). Fourteen-day, 30-day, and inhospital mortality rates in the clinically evaluable population for the intermittent and prolonged infusion groups were 13.2% versus 18.0% (p = 0.141), 23.6% versus 25.7% (p = 0.582), and 19.4% versus 23.0% (p = 0.329). CONCLUSIONS: Routine use of prolonged infusion of time-dependent antibiotics for the empiric treatment of gram-negative bacterial infections offers no advantage over intermittent infusion antibiotic therapy with regard to treatment success, mortality, or hospital length of stay. These results were confirmed after controlling for potential confounders in a multivariate analysis.

The presence of hypothermia within 24 hours of sepsis diagnosis predicts persistent lymphopenia.

Objective:To determine whether hypothermia within 24 hours of sepsis diagnosis is associated with development of persistent lymphopenia, a feature of sepsis-induced immunosuppression. Design:Retrospective cohort study. Setting:A 1,200-bed university-affiliated tertiary care hospital. Patients:Adult patients diagnosed with bacteremia and sepsis within 5 days of hospital admission between January 1, 2010, and July 31, 2012. Interventions:None. Measurements and Main Results:Leukocyte counts were recorded during the first 4 days following sepsis diagnosis. Persistent lymphopenia was defined as an absolute lymphocyte count less than 1.2 cells/&mgr;L × 103 present on the fourth day after diagnosis. Of the 445 patients with sepsis included, hypothermia developed in 64 patients (14.4%) (defined as a body temperature < 36.0°C) within 24 hours of sepsis diagnosis. Hypothermia was a significant independent predictor of persistent lymphopenia (adjusted odds ratio, 2.70 [95% CI, 1.10, 6.60]; p = 0.03) after accounting for age, disease severity, comorbidities, source of bacteremia, and type of organism. Compared with the nonhypothermic patients, hypothermic patients had higher 28-day (50.0% vs 24.9%, p < 0.001) and 1-year mortality (60.9% vs 47.0%, p = 0.001). Conclusions:Hypothermia is associated with higher mortality and an increased risk of persistent lymphopenia in patients with sepsis, and it may be an early clinical predictor of sepsis-induced immunosuppression.

Optimizing sustained use of sedation in mechanically ventilated patients: focus on safety.

Optimizing sustained use of ICU sedation in mechanically ventilated patients requires careful consideration of drug-specific characteristics (E.G. pharmacokinetics), consideration of potential adverse effects in susceptible patients, and utilization of sedation-minimizing strategies. In the era of anxiolytic dosing protocols adjusted to specific patient behaviors as defined by sedation scales in conjunction with daily interruption, midazolam is a reasonable option for long-term sedation. Propofol is an appealing agent for ICU sedation due to its pharmacokinetic profile and a reduced propensity to result in prolonged sedation. However, care should be taken to monitor for potential devastating adverse effects including hypertriglyceridemia and propofol-related infusion syndrome (PRIS). Dexmedetomidine unreliably provides adequate sedation at doses currently approved by the FDA, though upward titration of dexmedetomidine coupled with rescue benzodiazepines and/or fentanyl appears to be safe and comparable to benzodiazepines in the achievement of light to moderate Richmond Agitation Sedation Scale (RASS) goals. Clinicians should closely monitor patients receiving dexmedetomidine for hemodynamic-altering bradycardia. Strategies that promote frequent patient assessment with corresponding sedative dose minimization have demonstrated the benefits of limiting oversedation. Implementation of a sedation protocol requires careful consideration of ICU resources and staffing such that efforts made are sustainable and will be safe and effective for the patient population affected.

Inadequate Source Control and Inappropriate Antibiotics are Key Determinants of Mortality in Patients with Intra-Abdominal Sepsis and Associated Bacteremia

BACKGROUND Patients with intra-abdominal sepsis and associated bacteremia have a high mortality rate. However, outcomes studies in this population are limited, in part because of the small numbers of such patients. The objective of this study was to describe characteristics of critically ill patients with secondary blood stream infection (BSI) of intra-abdominal origin and identify predictors of mortality. METHODS This retrospective, single-center study evaluated patients admitted between January 2005 and January 2011 with bacteremia because of an intra-abdominal source. Patients were included if they met criteria for severe sepsis based on International Classification of Diseases, 9th Revision (ICD 9) codes for acute organ dysfunction, had a positive blood culture, had at least one ICD 9 code indicative of an intra-abdominal process, and had a confirmed or clinically suspected intra-abdominal infection (IAI) within 72 h of the blood culture. Chart review was performed to confirm the presence of these criteria and also the absence of any other potential source of bacteremia. Data were collected on patient demographics, BSI source, source control procedure details, microorganisms isolated, and antibiotics administered. Multivariable logistic regression analysis was performed to identify independent predictors of mortality. RESULTS Three hundred six patients with BSI were identified, of which 108 episodes were deemed to be of intra-abdominal origin. Gram-negative organisms comprised 43% of blood isolates, followed by gram-positives (33%), anaerobes (14%), and yeast (9%). Appropriate antimicrobial therapy was administered in 71% of patients. The overall mortality rate was 27.8%. As compared with survivors, non-survivors were older, more likely to have underlying COPD or asthma, and have renal or metabolic failure (p<0.05 for all). Among non-survivors, adequate source control was obtained less frequently (64% vs. 91%, p=0.002) and median time to appropriate antibiotics was longer (23 h vs. 4 h, p=0.004). Logistic regression analysis revealed inadequate source control (p=0.002) and inappropriate antibiotics (p=0.016) to be independently associated with mortality. CONCLUSIONS Critically ill patients with a BSI of abdominal origin are at high risk for mortality. Failure to achieve adequate source control and administration of inappropriate antibiotics were independent predictors of mortality. Thus, these represent potential opportunities to impact outcomes in patients with complicated IAI.