Towards personalized medicine in sepsis: Quest for Shangri-La?

Background: Severe sepsis is typically characterized by initial cytokine-mediated hyper-inflammation. Whether this hyper-inflammatory phase is followed by immunosuppression is a subject of controversy. Animal studies suggest that multiple immune defects occur in sepsis, but data from humans remain conflicting.Methods: Results: The mean ages (standard deviations) of patients with sepsis and controls were 71.7 (15.9) and 52.7 (15.0) years, respectively. Patients with sepsis were in the ICU for a median of 8 days (range of 1 to 195 days), whereas control patients were in the ICU for not more than 4 days. The median duration of sepsis was 4 days (range of 1 to 40 days). Anti-CD3/anti-CD28-stimulated splenocytes from patients with sepsis, compared with those from controls, had significant reductions in cytokine secretion at 5 hours: tumor necrosis factor, 5,361 (95% confidence interval (CI) 3,327 to 7,485) pg/mL versus 418 (95% CI 98 to 738) pg/mL; interferon-gamma, 1,374 (95% CI 550 to 2,197) pg/mL versus 37.5 (95% CI -5 to 80) pg/mL; interleukin-6, 3,691 (95% CI 2,313 to 5,070) versus 365 (95% CI 87 to 642) pg/mL; and interleukin-10, 633 (95% CI -269 to 1,534) versus 58 (95% CI -39 to 156) pg/mL (P < 0.001 for all). There were similar reductions in 5-hour lipopolysaccharidestimulated cytokine secretion. Cytokine secretion in patients with sepsis was generally less than 10% of that in controls, independently of age, duration of sepsis, corticosteroid use, and nutritional status. Despite differences between spleen and lung, flow cytometric analysis showed increased expression of selected inhibitory receptors and ligands and expansion of suppressor cell populations in both organs. Unique differences in cellular inhibitory molecule expression existed in immune cells isolated from lungs of patients with sepsis versus patients with cancer and versus transplant donors. Immunohistochemical staining showed extensive depletion of splenic CD4, CD8, and HLA-DR cells and expression of ligands for inhibitory receptors on lung epithelial cells.Conclusions: Patients who die in the ICU following sepsis compared with patients who die of non-sepsis etiologies have bio-chemical, flow cytometric, and immunohistochemical findings consistent with those of immunosuppression. Targeted immune-enhancing therapy may be a valid approach in selected patients with sepsis. © 2013 BioMed Central Ltd

Benefits of lung-protective ventilation: Looking beyond the ICU

Background\ud Lung-protective ventilation with the use of low tidal volumes and positive end-expiratory pressure is considered best practice in the care of many critically ill patients. However, its role in anesthetized patients undergoing major surgery is not known.\ud \ud Methods\ud Objective: The aim of the study was to determine whether lung-protective ventilation improves outcomes in anesthetized patients undergoing major abdominal surgery.\ud \ud Design: The Intraoperative Protective Ventilation (IMPROVE) trial is a multicenter, open-label double-blind, parallel-group randomized control trial in seven French university hospitals.\ud \ud Setting: The IMPROVE study enrolled 400 adults at intermediate to high risk of pulmonary complications undergoing major abdominal surgeries between 31 January 2011 and 10 August 2012.\ud \ud Intervention: Patients were randomly assigned to receive volume-controlled ventilation in one of two strategies: nonprotective ventilation with a tidal volume of 10 to 12 ml/kg predicted body weight with no positive end-expiratory pressure and no scheduled recruitment maneuver, or lung-protective ventilation with a tidal volume of 6 to 8 ml/kg predicted body weight, a positive end-expiratory pressure of 6 to 8 cmH2O, and recruitment maneuvers every 30 minutes after intubation. Recruitment maneuvers were also standardized and applied as continuous positive airway pressure of 30 cmH2O for 30 seconds.\ud \ud Outcomes: The primary outcome was a composite of major pulmonary and extrapulmonary complications within the first 7 days after surgery. Major pulmonary complications were defined as pneumonia or the need for invasive or noninvasive ventilation for acute respiratory failure. Major extrapulmonary complications were defined as sepsis, severe sepsis, septic shock, and death. Secondary outcomes included components of primary outcome, surgical complications, and healthcare utilization endpoints such as the duration of stay in the ICU and hospital at the end of a 30-day follow-up period.\ud \ud Results\ud The two intervention groups had similar characteristics at baseline. In the intention-to-treat analysis, the primary outcome occurred in 21 of 200 patients (10.5%) assigned to lung-protective ventilation, as compared with 55 of 200 patients (27.5%) assigned to nonprotective ventilation (relative risk, 0.40; 95% confidence interval, 0.24 to 0.68; P = 0.001). Over the 7-day postoperative period, 10 patients (5.0%) assigned to lung-protective ventilation required noninvasive ventilation or intubation for acute respiratory failure, as compared with 34 patients (17.0%) assigned to nonprotective ventilation (relative risk, 0.29; 95% confidence interval, 0.14 to 0.61; P = 0.001). The length of the hospital stay was shorter among patients receiving lung-protective ventilation than among those receiving nonprotective ventilation (mean difference, −2.45 days; 95% confidence interval, 4.17 to −0.72; P = 0.006).\ud \ud Conclusions\ud As compared with a practice of nonprotective mechanical ventilation, the use of a lung-protective ventilation strategy in intermediate-risk and high-risk patients undergoing major abdominal surgery was associated with improved clinical outcomes and reduced healthcare utilization

Understanding skeletal muscle wasting in critically ill patients

Background\ud Survivors of critical illness demonstrate skeletal muscle wasting with associated functional impairment.\ud \ud Methods\ud Objective: The objective was to perform a comprehensive prospective characterization of skeletal muscle wasting, defining the pathogenic roles of altered protein synthesis and breakdown.\ud \ud Design: Prospective observational study.\ud \ud Setting: Patients were recruited from a university and community hospital in England.\ud \ud Subjects: The study involved 63 critically ill patients >18 years old who were anticipated to be intubated >48 hours and to spend >7 days in the ICU and to survive their ICU stay. Subjects were enrolled within 24 hours of admission.\ud \ud Outcomes: Muscle loss was determined through serial ultrasound measurement of the rectus femoris cross-sectional area (CSA) on days 1, 3, 7, and 10. In a subset of patients, the fiber CSA area was quantified along with the ratio of protein to DNA on days 1 and 7. Histopathological analysis was performed. In addition, muscle protein synthesis, breakdown rates, and respective signaling pathways were characterized.\ud \ud Results\ud There were significant reductions in the rectus femoris CSA observed at day 10 (−17.7%; 95% confidence interval (CI), −25.9 to 8.1%; P <0.001). In the 28 patients assessed by all three measurement methods on days 1 and 7, the rectus femoris CSA decreased by 10.3% (95% CI, 6.1 to 14.5%), the fiber CSA by 17.5% (95% CI, 5.8 to 29.3%), and the ratio of protein to DNA by 29.5% (95% CI, 13.4 to 45.6%). Decrease in the rectus femoris CSA was greater in patients who experienced multiorgan failure by day 7 (−15.7%; 95% CI, −27.7 to 11.4%) compared with single organ failure (−3.0%; 95% CI, −5.3 to 2.1%; P <0.001), even by day 3 (−8.7%; 95% CI, −59.3 to 50.6% versus −1.8%; 95% CI, −12.3 to 10.5%, respectively; P =0.03). Myofiber necrosis occurred in 20 of 37 patients (54.1%). Protein synthesis measured by the muscle protein fractional synthetic rate was depressed in patients on day 1 (0.035%/hour; 95% CI, 0.023 to 0.047%/hour) compared with rates observed in fasted healthy controls (0.039%/hour; 95% CI, 0.029 to 0.048%/hour; P =0.57) and increased by day 7 (0.076%; 95% CI, 0.032 to 0.120%/hour; P =0.03) to rates associated with fed controls (0.065%/hour; 95% CI, 0.049 to 0.080%/hour; P =0.30), independent of nutritional load. Leg protein breakdown remained elevated throughout the study (8.5; 95% CI, 4.7 to 12.3 μmol phenylalanine/minute/ideal body weight × 100 to 10.6; 95% CI, 6.8 to 14.4 μmol phenylalanine/minute/ideal body weight × 100; P =0.40). The pattern of intracellular signaling supported increased breakdown (n =9, r = −0.83, P =0.005) and decreased synthesis (n =9, r = −0.69, P =0.04).\ud \ud Conclusions\ud Among these critically ill patients, muscle wasting occurred early and rapidly during the first week of critical illness and was more severe among those with multiorgan failure compared with single organ failure. These findings may provide insights into skeletal muscle wasting and critical illness

Weighing risks and benefits of stress ulcer prophylaxis in critically ill patients

Citation: Marik PE, Tajender Vasu T, Hirani A, Pachinburavan M: Stress ulcer prophylaxis in the new millennium: a systematic review and meta-analysis. Critical Care Med 2010, 38:11.Background: Recent observational studies suggest that bleeding from stress ulceration is extremely uncommon in intensive care unit patients. Furthermore, the risk of bleeding may not be altered by the use of acid suppressive therapy. Early enteral tube feeding (initiated within 48 h of intensive care unit admission) may account for this observation. Stress ulcer prophylaxis may, however, increase the risk of hospital-acquired pneumonia and Clostridia difficile infection.Methods: Results: Seventeen studies (which enrolled 1836 patients) met the inclusion criteria. Patients received adequate enteral nutrition in three of the studies. Overall, stress ulcer prophylaxis with a histamine-2 receptor blocker reduced the risk of gastrointestinal bleeding (odds ratio 0.47; 95% confidence interval, 0.29-0.76; P < 0.002; Heterogeneity [I 2] = 44%); however, the treatment effect was noted only in the subgroup of patients who did not receive enteral nutrition. In those patients who were fed enterally, stress ulcer prophylaxis did not alter the risk of gastrointestinal bleeding (odds ratio 1.26; 95% confidence interval, 0.43-3.7). Overall histamine-2 receptor blockers did not increase the risk of hospital-acquired pneumonia (odds ratio 1.53; 95% confidence interval, 0.89-2.61; P = 0.12; I 2 = 41%); however, this complication was increased in the subgroup of patients who were fed enterally (odds ratio 2.81; 95% confidence interval, 1.20-6.56; P = 0.02; I 2 = 0%). Overall, stress ulcer prophylaxis had no effect on hospital mortality (odds ratio 1.03; 95% confidence interval, 0.78-1.37; P = 0.82). The hospital mortality was, however, higher in those studies (n = 2) in which patients were fed enterally and received a histamine-2 receptor blocker (odds ratio 1.89; 95% confidence interval, 1.04-3.44; P = 0.04, I 2 = 0%). Sensitivity analysis and metaregression demonstrated no relationship between the treatment effect (risk of gastrointestinal bleeding) and the classification used to define gastrointestinal bleeding, the Jadad quality score or the year the study was reported.Conclusions: The results of this meta-analysis suggest that, in those patients receiving enteral nutrition, stress ulcer prophylaxis may not be required and, indeed, such therapy may increase the risk of pneumonia and death. However, because no clinical study has prospectively tested the influence of enteral nutrition on the risk of stress ulcer prophylaxis, those findings should be considered exploratory and interpreted with some caution. © 2012 BioMed Central Ltd

Protocol-directed care in the ICU: Making a future generation of intensivists less knowledgeable?

Background: Clinical protocols are associated with improved patient outcomes; however, they may negatively affect medical education by removing trainees from clinical decision making.Methods: Objective: To study the relationship between critical care training with mechanical ventilation protocols and subsequent knowledge about ventilator management.Design: A retrospective cohort equivalence study linking a national survey of mechanical ventilation protocol availability with knowledge about mechanical ventilation. Exposure to protocols was defined as high intensity if an intensive care unit had 2 or more protocols for at least 3 years and as low intensity if 0 or 1 protocol.Setting: Accredited US pulmonary and critical care fellowship programs.Subjects: First-time examinees of the American Board of Internal Medicine (ABIM) Critical Care Medicine Certification Examination in 2008 and 2009.Intervention: N/A. Outcomes: Knowledge, measured by performance on examination questions specific to mechanical ventilation management, calculated as a mechanical ventilation score using item response theory. The score is standardized to a mean (SD) of 500 (100), and a clinically important difference is defined as 25. Variables included in adjusted analyses were birth country, residency training country, and overall first-attempt score on the ABIM Internal Medicine Certification Examination.Results: The 90 of 129 programs (70%) responded to the survey. Seventy seven programs (86%) had protocols for ventilation liberation, 66 (73%) for sedation management, and 54 (60%) for lung-protective ventilation at the time of the survey. Eighty eight (98%) of these programs had trainees who completed the ABIM Critical Care Medicine Certification Examination, totaling 553 examinees. Of these 88 programs, 27 (31%) had 0 protocols, 19 (22%) had 1 protocol, 24 (27%) had 2 protocols, and 18 (20%) had 3 protocols for at least 3 years. 42 programs (48%) were classified as high intensity and 46 (52%) as low intensity, with 304 trainees (55%) and 249 trainees (45%), respectively. In bi-variable analysis, no difference in mean scores was observed in high-intensity (497; 95% CI, 486-507) vs low-intensity programs (497; 95% CI, 485-509). Mean difference was 0 (95% CI, -16 to 16), with a positive value indicating a higher score in the high-intensity group. In multivariable analyses, no association of training was observed in a high-intensity program with mechanical ventilation score (adjusted mean difference, -5.36; 95% CI, -20.7 to 10.0).Conclusions: Among first-time ABIM Critical Care Medicine Certification Examination examinees, training in a high-intensity ventilator protocol environment compared with a low-intensity environment was not associated with worse performance on examination questions about mechanical ventilation management. © 2012 BioMed Central Ltd

A touch of cooling may help

Background: Fever control may improve vascular tone and decrease oxygen consumption; however, fever may help combat infection.Methods: Results: There were 200 patients randomized, 101 to the cooling group and 99 to the no-cooling group. The percentage of patients with a 50% vasopressor dose decrease versus baseline was not significantly different at 48 hours of treatment (72% vs. 61%; absolute difference, 11%; 95% confidence interval (CI), -23 to 2; P = 0.4), although it was at 12 hours (54% vs. 20%; absolute difference, 34%; 95% CI, -46 to -21; P < 0.001). External cooling significantly reduced the number of patients needing a vasopressor dose increase (34% vs. 52%; absolute difference, -18%; 95% CI, -4 to -31%; P = 0.011) and significantly increased the shock reversal during the study period (86% vs. 73%; absolute difference, 13%; 95% CI, 2 to 25%; P = 0.021). Day 14 mortality was significantly lower in the cooling group (19% vs. 34%; absolute difference, -16%; 95% CI, -28 to -4; P = 0.013), but mortality was not different at ICU and hospital discharge.Conclusions: Fever control using external cooling was safe, and decreased vasopressor requirements and early mortality in septic shock. © 2013 BioMed Central Ltd

Additions to the Human Plasma Proteome via a Tandem MARS Depletion iTRAQ-Based Workflow

Robust platforms for determining differentially expressed proteins in biomarker and discovery studies using human plasma are of great interest. While increased depth in proteome coverage is desirable, it is associated with costs of experimental time due to necessary sample fractionation. We evaluated a robust quantitative proteomics workflow for its ability (1) to provide increased depth in plasma proteome coverage and (2) to give statistical insight useful for establishing differentially expressed plasma proteins. The workflow involves dual-stage immunodepletion on a multiple affinity removal system (MARS) column, iTRAQ tagging, offline strong-cation exchange chromatography, and liquid chromatography tandem mass spectrometry (LC-MS/MS). Independent workflow experiments were performed in triplicate on four plasma samples tagged with iTRAQ 4-plex reagents. After stringent criteria were applied to database searched results, 689 proteins with at least two spectral counts (SC) were identified. Depth in proteome coverage was assessed by comparison to the 2010 Human Plasma Proteome Reference Database in which our studies reveal 399 additional proteins which have not been previously reported. Additionally, we report on the technical variation of this quantitative workflow which ranges from ±11 to 30%

Blood transfusion for upper gastrointestinal bleeding: Is less more again?

Background: The hemoglobin threshold for transfusion of red blood cells in patients with acute gastrointestinal (GI) bleeding is controversial. We compared the efficacy and safety of a restrictive transfusion strategy with those of a liberal transfusion strategy. Methods: Objective: The objective was to prove that the restrictive threshold for red blood cell transfusion in patients with acute upper GI bleeding (UGIB) was safer and more effective than a liberal transfusion strategy. Design: A single-center, randomized controlled trial was conducted. Setting: Patients with GI bleeding were admitted to the de la Santa Creu i Sant Pau hospital in Barcelona, Spain. Subjects: The subjects were adult intensive care unit patients admitted with high clinical suspicion of UGIB (hematomemesis, melena, or both). Patients were excluded if they had massive exsanguinating bleeding, acute coronary syndrome, symptomatic peripheral vascular disease, stroke/transient ischemic attack, transfusion within the previous 90 days, recent trauma or surgery, lower GI bleeding, or a clinical Rockall score of 0 with hemoglobin higher than 12 g/dL. Intervention: A total of 921 patients with severe acute UGIB were enrolled. Of these, 461 were randomly assigned to a restrictive strategy (transfusion when the hemoglobin level fell to below 7 g/dL) and 460 to a liberal strategy (transfusion when the hemoglobin fell to below 9 g/dL). Random assignment was stratified according to the presence or absence of liver cirrhosis. Outcomes: The primary outcome was rate of death from any cause within the first 45 days. Secondary outcomes were further bleeding, defined as hematemesis or melena with hemodynamic instability or hemoglobin decrease of 2 g/dL or more, and in-hospital complications. Results: In total, 225 patients assigned to the restrictive strategy (51%) and 65 assigned to the liberal strategy (15%) did not receive transfusions (P <0.001). The probability of survival at 6 weeks was higher in the restrictive-strategy group than in the liberal-strategy group (95% versus 91%; hazard ratio (HR) for death with restrictive strategy, 0.55; 95% confidence interval (CI) 0.33 to 0.92; P = 0.02). Further bleeding occurred in 10% of the patients in the restrictive-strategy group and in 16% of the patients in the liberal-strategy group (P = 0.01), and adverse events occurred in 40% and 48%, respectively (P = 0.02). The probability of survival was slightly higher with the restrictive strategy than with the liberal strategy in the subgroup of patients who had bleeding associated with a peptic ulcer (HR 0.70, 95% CI 0.26 to 1.25) and was significantly higher in the subgroup of patients with cirrhosis and Child-Pugh class A or B disease (HR 0.30, 95% CI 0.11 to 0.85) but not in those with cirrhosis and Child-Pugh class C disease (HR 1.04, 95% CI 0.45 to 2.37). Within the first 5 days, the portal-pressure gradient increased significantly in patients assigned to the liberal strategy (P = 0.03) but not in those assigned to the restrictive strategy. Conclusions: Compared with a liberal transfusion strategy, a restrictive strategy significantly improved outcomes in patients with acute UGIB. © 2013 licensee BioMed Central Ltd

Glucocorticoid therapy for trauma--ready for prime time?

Methods\ud Objective\ud To test the efficacy of hydrocortisone therapy in trauma patients.\ud \ud Design\ud Multicenter randomized, double blind, placebocontrolled study.\ud \ud Setting\ud Seven intensive care units (ICUs) in France during November 2006 to August 2009.\ud \ud Subjects\ud 150 patients with severe trauma who required ICU stay for at least 48 hours were included in the study.\ud \ud Intervention\ud Patients were randomly assigned to a continuous intravenous infusion of either hydrocortisone (200 mg/day for 5 days, followed by 100 mg on day 6 and 50 mg on day 7) or placebo. The treatment was stopped if patients had an appropriate adrenal response.\ud \ud Outcomes\ud Hospital-acquired pneumonia within 28 days. Secondary outcomes included the duration of mechanical ventilation, ICU length of stay, hyponatremia, and death.\ud \ud Results\ud An intention-to-treat (ITT) analysis included 149 patients and the modified ITT analysis included 113 patients with corticosteroid insufficiency. In the ITT analysis, 26 of 73 patients (35.6%) treated with hydrocortisone and 39 of 76 patients (51.3%) receiving placebo developed hospital -acquired pneumonia by day 28 (hazard ratio (HR), 0.51; 95% confidence interval (CI), 0.30-0.83; P = 0.007). In the modified ITT analysis, 20 of 56 patients (35.7%) in the hydrocortisone group and 31 of 57 patients (54.4%) in the placebo group developed hospital-acquired pneumonia by day 28 (HR, 0.47; 95% CI, 0.25-0.86; P = 0.01). Mechanical ventilation-free days increased with hydrocortisone use by 4 days (95% CI, 2-7; P = 0.001) in the ITT analysis and 6 days (95% CI, 2-11; P < 0.001) in the modified ITT analysis. Hyponatremia was observed in 7 of 76 (9.2%) in the placebo group vs. none in the hydrocortisone group (absolute difference, −9%; 95% CI, −16% to −3%; P = 0.01). Four of 76 patients (5.3%) in the placebo group and 6 of 73 (8.2%) in the hydrocortisone group died (absolute difference, 3%; 95% CI, −5% to 11%; P = 0.44).\ud \ud Conclusions\ud In intubated trauma patients, the use of an intravenous stress-dose of hydrocortisone, compared with placebo, resulted in a decreased risk of hospital-acquired pneumonia