Jian Shou

Does de-escalation of antibiotic therapy for ventilator-associated pneumonia affect the likelihood of recurrent pneumonia or mortality in critically ill surgical patients?

BACKGROUND Ventilator-associated pneumonia (VAP) is a leading cause of mortality in critically ill patients. Although previous studies have shown that de-escalation therapy (DT) of antibiotics may decrease costs and the development of resistant pathogens, minimal data have shown its effect in surgical patients or in any patients with septic shock. We hypothesized that DT for VAP was not associated with an increased rate of recurrent pneumonia (RP) or mortality in a high acuity cohort of critically ill surgical patients. METHODS All surgical intensive care unit (SICU) patients from January 2005 to May 2007 with VAP diagnosed by quantitative bronchoalveolar lavage with a positive threshold of 10,000 CFU/mL were identified. Data collected included age, gender, Acute Physiologic and Chronic Health Evaluation Score III (A3), type of bacterial or other pathogen, antibiotics used for initial and final therapy, mortality, RP, and appropriateness of initial therapy (AIT). Patients were designated as receiving AIT, DT, or escalation of antibiotic therapy based on microbiology for their VAP. RESULTS One hundred thirty-eight of 1,596 SICU patients developed VAP during the study period (8.7%). For VAP patients, the mean Acute Physiologic and Chronic Health Evaluation III score was 82.7 points with a mean age of 63.8 years. The RP rate was 30% and did not differ between patients receiving DT (27.3%) and those who did not receive DT (35.1%). Overall mortality was 37% (55% predicted by A3 norms) and did not differ between those receiving DT (33.8%) or not (42.1%). The most common pathogens for primary VAP were methicillin-resistant Staphylococcus aureus (14%), Escherichia coli (11%), and Pseudomonas aeruginosa (9%) whereas P. aeruginosa was the most common pathogen in RP. The AIT for all VAP was 93%. De-escalation of therapy occurred in 55% of patients with AIT whereas 8% of VAP patients required escalation of antibiotic therapy. The most commonly used initial antibiotic choice was vancomycin/piperacillin-tazobactam (16%) and the final choice was piperacillin-tazobactam (20%). Logistic regression demonstrated no specific parameter correlated with development of RP. Higher A3 (Odds ratio, 1.03; 95% confidence interval, 1.01-1.05) was associated with mortality whereas lack of RP (odds ratio, 0.31; 95% confidence interval, 0.12-0.80), and AIT reduced mortality (odds ratio, 0.024; 95% confidence interval, 0.007-0.221). Age, gender, individual pathogen, individual antibiotic regimen, and the use of DT had no effect on mortality. CONCLUSION De-escalation therapy did not lead to RP or increased mortality in critically ill surgical patients with VAP. De-escalation therapy was also shown to be safe in patients with septic shock. Because of its acknowledged benefits and lack of demonstrable risks, de-escalation therapy should be used whenever possible in critically ill patients with VAP.

Defining the current negative appendectomy rate: For whom is preoperative computed tomography making an impact?

BACKGROUND Historically, the negative appendectomy rate (NAR) for patients operated on for acute appendicitis (AA) has exceeded 20%. We sought to define the current NAR with increased use of computed tomography (CT) and laparoscopy. METHODS Records of 1425 consecutive patients undergoing appendectomy for suspicion of AA during the past 7 years at a single institution were reviewed. The NAR was calculated and compared with earlier data from this institution (1995-1999). Statistical methods included the Fisher exact test and the Student t test; differences of P < .05 were considered statistically significant. RESULTS The overall NAR was 7.65% compared to 16.3% over the period 1995-1999 (P = .0001), without a change in the perforation rate. Concurrently, the rate of preoperative CT increased from 32% to 95%. CT was associated with a lesser NAR only among adult females (7.6% vs 20.8%, P = .005) but not among adult males or children. No difference in NAR was noted in comparing laparoscopic and open appendectomy. Patients without AA had a greater mean duration of symptoms and lower white blood cell count at presentation than those with AA. Most patients undergoing negative appendectomy had a CT, and more than 50% had CT interpretations that were positive for, or could not exclude, AA. CONCLUSIONS The NAR in our hospital has decreased progressively to approximately 5%. Although preoperative CT is used in almost all patients, it is only associated with a lesser NAR among adult females. False-positive CTs may contribute to the residual NAR, and further data are needed to determine whether subgroups of male or pediatric patients benefit from preoperative CT.

Randomized, double-blind, placebo-controlled trial of effects of enteral iron supplementation on anemia and risk of infection during surgical critical illness.

BACKGROUND Critical illness is characterized by hypoferremia, iron-deficient erythropoiesis (IDE), and anemia. The relative risks and benefits of iron supplementation in this setting are unknown. METHODS Anemic, critically ill surgical patients with an expected intensive care unit length of stay (ULOS) >or= 5 days were randomized to either enteral iron supplementation (ferrous sulfate 325 mg three times daily) or placebo until hospital discharge. Outcomes included hematocrit, iron markers (i.e., serum concentrations of iron, ferritin, and erythrocyte zinc protoporphyrin [eZPP]), red blood cell (RBC) transfusion, transfusion rate (mL RBC/study day), nosocomial infection, antibiotic days, study length of stay (LOS), ULOS, and death. Iron-deficient erythropoiesis was defined as an elevated eZPP concentration. RESULTS Two hundred patients were randomized; 97 received iron, and 103 received placebo. Socio-demographics, baseline acuity, hematocrit, and iron markers were similar in the two groups. No differences were observed between the iron and placebo groups with respect to either hematocrit or iron markers following up to 28 days. However, patients treated with iron were significantly less likely to receive an RBC transfusion (29.9% vs. 44.7%, respectively; p = 0.03) and had a significantly lower transfusion rate (22.0 mL/day vs. 29.9 mL/day; p = 0.03). Subgroup analysis revealed that these differences were observed in patients with baseline IDE only. Iron and placebo groups did not differ with respect to incidence of infection (46.8% vs. 48.9%; p = 0.98), antibiotic days (14 vs. 16; p = 0.45), LOS (14 vs. 16 days; p = 0.24), ULOS (12 vs. 14 days; p = 0.69), or mortality rate (9.4% vs. 9.9%; p = 0.62). CONCLUSIONS Enteral iron supplementation of anemic, critically ill surgical patients does not increase the risk of infection and may benefit those with baseline IDE by decreasing the risk of RBC transfusion. A trial comparing enteral and parenteral iron supplementation in this setting is warranted (ClinicalTrials.gov number, NCT00450177).

Glucocorticoids mediate macrophage dysfunction in protein calorie malnutrition.

BACKGROUND In hospitalized patients protein calorie malnutrition substantially increases the incidence of infection and death. Protein calorie malnutrition results in significant macrophage dysfunction. Whether a primary nutrient deficit or elevated glucocorticoids levels mediate this dysfunction is unclear. The aim of this study was to evaluate the neuroendocrine response to protein calorie malnutrition and its effects on macrophage function. METHODS By use of a murine model of protein calorie malnutrition, mice were randomized to (1) a standard 24% casein diet (control), (2) protein-free diet (PFD), (3) PFD in adrenalectomized mice, (4) PFD plus the glucocorticoid receptor antagonist RU486 (10 mg/kg), or (5) a standard 24% casein diet plus a 50 mg corticosterone pellet implanted subcutaneously for 7 days. Mice were killed after 7 days, and body weight and serum albumin and corticosterone levels were measured. Peritoneal macrophages were obtained, and stimulated superoxide and interleukin-6 productions were measured. RESULTS Protein calorie malnutrition significantly impaired macrophage function and elevated serum glucocorticoid levels. Blocking the stress corticosterone response with adrenalectomy or using RU486 to block corticosterone receptors prevented the impairment of macrophage function without restoring nutritional indexes (body weight and serum albumin level). Administration of glucocorticoids via a subcutaneous pellet reproduced macrophage impairment without leading to nutritional deficits. CONCLUSIONS The neuroendocrine systemic response to protein calorie malnutrition with elevated serum corticosterone levels is a major determinant of macrophage dysfunction in protein calorie malnutrition.

Beneficial effect of enteral glycine in intestinal ischemia/reperfusion injury

It has been shown in vitro that glycine can protect renal tubules and hepatocytes from hypoxic injury. Glycine also attenuates ischemic injury in transplanted livers. The present study investigated the effect of enteral glycine in a murine model of ischemia/reperfusion injury of the small intestine. Mice (n = 12 in each group) were randomized to receive two gastric gavages of either a 20% glycine (Gly) or 23% balanced amino acid (AA) solution with a 6-hour interval between each gavage. One hour after the second gavage, mice underwent superior mesenteric artery clamping for 20 minutes. The clamp was then released for reperfusion. Another group of mice (n = 8) underwent a sham operation and served as additional control animals. Six hours after ischemia/reperfusion, the mice were killed in order to assess the intestinal injury (intestinal protein content, mucosal disaccharidase activity, and intestinal histologic findings) and the systemic consequences (bacterial translocation, serum interleukin-6, and lung myeloperoxidase activity). A second set of mice (n = 55) underwent identical gavages and ischemia/reperfusion and they were followed for survival. Compared to AA, enteral glycine administered prior to intestinal ischemia/reperfusion injury significantly preserved mucosal indices and intestinal histology and decreased lung myeloperoxidase activity. Survival was also significantly increased in animals receiving glycine compared to AA control mice. These data suggest that enteral glycine supplementation may be beneficial in attenuating intestinal ischemia/reperfusion injury and its related systemic effects in this murine model.

Decreasing magnitude of multiple organ dysfunction syndrome despite increasingly severe critical surgical illness: a 17-year longitudinal study.

BACKGROUND Multiple organ dysfunction syndrome (MODS) remains prevalent and the leading cause of mortality in the surgical intensive care unit (ICU). Improvements in ICU care in the last 10 years (e.g., tight glycemic control, activated protein C, fewer transfusions causing fewer nosocomial infections) may have decreased the incidence, magnitude, and mortality of MODS, as hypothesized in this study. METHODS Longitudinal 17-year prospective study of 11,314 ICU patients (academic/tertiary unit, Level I trauma center), 5,157 (45.5%) of whom developed any degree of MODS (Marshall score, cumulative). Data collected included Admission Acute Physiology and Chronic Health Evaluation (APACHE)-II and APACHE-III scores, MOD score (MODsc), hospital mortality, and the incidence and magnitude of MODS. The ratio of MODsc: APACHE III was calculated. Analyses (X +/- SEM, chi2, repeated-measures ANOVA, linear and polynomial regression, c-statistic) were performed for calendar-year intervals beginning in 1990 through 2006. RESULTS Among MODS patients, the mean MODsc was 6.3 +/- 0.1 points, and the mortality rate was 22%. The APACHE III score increased significantly (p < 0.0001) over time, but the mortality rate was unchanged (r2 = 0.02). Adjusted for illness severity (MODsc:A3), the magnitude of MODS decreased significantly (p < 0.0001) during the time period. CONCLUSIONS Despite significant increases in admission APACHE III score over 17 years, the adjusted magnitude of MODS (MODsc:A3) decreased. Given the strong association between MODS and mortality for critically ill surgical patients, it is likely that the unchanged risk-adjusted mortality observed over time is due to the reduced magnitude of MODS.

Higher Body Mass Index Predicts Need for Insulin but Not Hyperglycemia, Nosocomial Infection, or Death in Critically Ill Surgical Patients

BACKGROUND Strict glycemic control in critically ill patients has been an important advance in surgical critical care, as hyperglycemia is associated with a higher likelihood of death, complications, and nosocomial infections. Insulin resistance is particularly common in obese patients, but the impact of body mass index (BMI) on insulin requirements, ability to achieve euglycemia, and infectious outcomes in critically ill surgical patients has not been studied. We hypothesized that obese patients would not incur a higher likelihood of infection if euglycemia was maintained. METHODS Admissions to the surgical intensive care unit (ICU) from October 1, 2004, to October 31, 2006, were identified. Necessary data were available for 946 patients. The main predictor variable was BMI, which was analyzed as both a continuous and a five-level categorical variable. Data on insulin requirements as well as glycemic control were captured. The main outcome variable was the occurrence of at least one nosocomial infection. Additional outcomes were dysfunction of at least one organ system at any time during surgical ICU admission, quantified using the Multiple Organ Dysfunction Score, as well as the ICU length of stay and death. All statistical analyses were performing using SPSS version 11 for Macintosh. RESULTS Both the need for insulin infusion (p = 0.0001) and the mean insulin units/day among patients receiving infusions (p = 0.03) increased significantly with increasing BMI. However, periods of euglycemia were similar among BMI groups. A total of 152 patients (16.1%) incurred at least one nosocomial infection, for a total of 169 infections. The majority (n = 107; 63.3%) were ventilator-associated pneumonias. Neither infection (p = 0.99), organ dysfunction (p = 0.14), ICU length of stay (p = 0.22), nor mortality rate (p = 0.09) differed significantly by BMI group. The need for an insulin infusion was associated significantly with nosocomial infection (p = 0.0001). Additional predictors of infection were a higher Acute Physiology and Chronic Health Evaluation (APACHE) III score (p < 0.0001), age-adjusted APACHE III score (p < 0.0001), and emergency admission (0.001). After controlling for the need for an insulin infusion, BMI was not associated with infection. CONCLUSIONS Increasing BMI was associated significantly with insulin resistance. Despite insulin resistance, however, obese patients did not incur longer periods of hyperglycemia. Outcomes that have been associated consistently with glycemic control, such as nosocomial infection and mortality rate, did not differ according to BMI. These data suggest that BMI is not associated with infection during critical illness, and that this absence of an association may be influenced at least partially by the ability to maintain similar glycemic control in obese and non-obese patients.

Efficacy of Therapy with Recombinant Human Activated Protein C of Critically Ill Surgical Patients with Infection Complicated by Septic Shock and Multiple Organ Dysfunction Syndrome

BACKGROUND Septic shock causing or complicating critical surgical illness results in high mortality. Drotrecogin alfa (activated), known also as recombinant human activated protein C (rhAPC) has become controversial as therapy, owing to persisting questions of efficacy and safety. We hypothesized rhAPC to be effective therapy for critically ill surgical patients with septic shock. METHODS Open-label therapy with rhAPC (by predefined criteria) of 108 critically ill surgical patients. Treated patients were matched individually in prospect for age, gender, Acute Physiology and Chronic Health Evaluation (APACHE)-II and -III scores, site of infection, and organism (0-2 points each, maximum 12 points) with 108 patients from our 15,000-patient surgical intensive care unit database who did not receive rhAPC. No match was accepted if <6 points. Multiple organ dysfunction (MOD) scores and data regarding cortisol concentrations, bleeding complications, and transfusion requirements were collected. The primary endpoint was 28-day mortality, with mortality for hospitalization and resolution of organ dysfunction as secondary endpoints. Statistical analyses included ANOVA, c statistic, binary logistic regression, and Kaplan-Meier time-to-event and Cox proportional hazards analyses; α=0.05. RESULTS The mean match score was 9.2±0.1 points (range, 6-12 points). Patients were well matched by all criteria, including baseline MOD score (9.5±0.7 vs. 9.8±0.3 points, p=0.66). Mean age was 68.1±1.1 years (p=0.49), Mean APACHE-III score was 99.6±1.5 points (p=0.87). Mean time to rhAPC administration was 25±3 h. Survival at 28 days after rhAPC was 71.3% vs. 49.1% (p=0.001); hospital survival was 57.4% vs. 40.7% (p=0.02). By logistic regression, rhAPC therapy resulted in improved 28-day survival (OR 2.57, 95% CI 1.46-4.52, p=0.001) (model χ2 11.244, p=0.001); and hospital survival (OR 1.96, 95% CI 1.14-3.36, p=0.015) (model χ2 6.03, p=0.014). The MOD score decreased significantly (p=0.012) during rhAPC therapy. CONCLUSION Therapy with rhAPC appeared to improve survival in surgical ICU patients with life-threatening infection characterized by septic shock and organ dysfunction.

Contemporary predictors of conversion from laparoscopic to open appendectomy.

BACKGROUND We defined the contemporary conversion rate from laparoscopic appendectomy (LA) to open appendectomy and identified pre-operative factors associated with conversion. METHODS Retrospective review of 941 consecutive LAs performed for suspected acute appendicitis in a single urban university hospital between 2000 and 2007. Patient characteristics, clinical features, physical examination findings, laboratory values, computed tomography (CT) findings, surgeon identity, operative findings, and pathologic results were assessed. Categorical variables were compared in patients undergoing LA and those in whom conversion was necessary using the Fisher exact test; the Student t-test was used to compare continuous variables. Multivariable analysis was performed with binomial logistic regression. Statistical significance was established at α = 0.05. RESULTS The overall conversion rate was 4.1% and did not change significantly over the course of the study. By univariable analysis, conversion was significantly associated with older age, male gender, American Society of Anesthesiologists (ASA) score >2 points, longer duration of symptoms, rigidity on physical examination, increased percentage of neutrophils on admission white blood cell differential count, extraluminal air on CT, inexperience of the attending surgeon with LA, retrocecal location of the appendix, gross necrosis or perforation, murky or purulent ascites, and microscopic evidence of perforation. By multivariable analysis, advanced age (hazard ratio [HR] 1.02 per year; 95% confidence interval [CI] 1.01-1.04, p = 0.02), ASA score >2 points (HR 11.2; 95% CI 5.6-24.4; p < 0.001), CT inflammation grade ≥ 4 (HR 4.8; 95% CI 1.9-12.3; p = 0.001), and attending surgeon inexperience (HR 7.4; 95% CI 2.6-20.8; p < 0.001) were independent predictors of conversion. CONCLUSION The conversion rate during laparoscopic appendectomy has not changed significantly over the past seven years and remains ~4%. Independent pre-operative predictors of conversion are advanced age, ASA score >2 points, attending surgeon inexperience, and extensive inflammation observed on pre-operative CT scan. Proceeding directly with open appendectomy under these circumstances may reduce operative time, expense, and morbidity.

Implementation of tight glucose control for critically ill surgical patients: a process improvement analysis.

BACKGROUND Tight glucose control has been advocated as a method to improve outcomes of surgical critical care. However, continuous infusion of insulin has potential morbidity (e.g., neurologic consequences of hypoglycemia), and it remains unclear to what degree the glucose concentration must be controlled. We examined our performance in instituting a protocol for tight glucose control in our surgical intensive care unit (ICU). METHODS Prospective study of 220 consecutive patients (February, 2003-March, 2006) who received an infusion of insulin for glucose control for >24 h by protocol. Data collected included age, acuity (Acute Physiology and Chronic Health Evaluation [APACHE] III) score, sex, history of diabetes mellitus, organ dysfunction (Marshall), and death or survival. Infusion-related data included initial glucose concentration, time to glucose <120 mg/dL, h/day of glucose <110 mg/dL and <140 mg/dL, duration of infusion (days), insulin units/day, year of therapy, and complications. Analysis was performed by chi(2), analysis of variance, and logistic regression, with p < 0.05 considered significant. RESULTS Insulin drips were required by 10.2% of patients (287/2,804); 29 of these (10.1%) had diabetes mellitus. The mean APACHE III score for the treated patients was 77 +/- 2 (standard deviation), and the mortality rate was 24%. Hypoglycemia (<60 mg/dL) occurred in 4.2% of patients. The trigger insulin concentration decreased over time (2003 vs. 2005) from 249 +/- 14 to 160 +/- 5 mg/dL, and the h/day of glucose <140 increased from 11 +/- 1 to 16 +/- 1. However, age, acuity, APACHE III, days of insulin, time to achieve glucose <120, h/day of glucose <110, and mortality rate were unchanged. By logistic regression, only the year of treatment (odds ratio [OR] 1.871; 95% confidence interval [CI] 1.177, 2.972; p = 0.008] predicted success in controlling the blood glucose concentration to <140 mg/dL; age, illness severity, diabetes history, and trigger glucose concentration [OR 0.996; 95% CI 0.992, 1.001; p = 0.11] did not. CONCLUSIONS Success in implementing tight glucose control was modest, albeit improving, despite a specific protocol for administration. No medical reason could be identified for inability to achieve tight glucose control; therefore, successful implementation must be volitional. Education, particularly regarding hypoglycemia, and possible refinement of our protocol may improve our ability to control blood glucose in our ICU.