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Context: Perioperative red blood cell transfusion is commonly used to address anemia, an independent risk factor for morbidity and mortality after cardiac operations; however, evidence regarding optimal blood transfusion practice in patients undergoing cardiac surgery is lacking.Objective: To define whether a restrictive perioperative red blood cell transfusion strategy is as safe as a liberal strategy in patients undergoing elective cardiac surgery.Design, Setting, and Patients: The Transfusion Requirements After Cardiac Surgery (TRACS) study, a prospective, randomized, controlled clinical noninferiority trial conducted between February 2009 and February 2010 in an intensive care unit at a university hospital cardiac surgery referral center in Brazil. Consecutive adult patients (n = 502) who underwent cardiac surgery with cardiopulmonary bypass were eligible; analysis was by intention-to-treat.Intervention: Patients were randomly assigned to a liberal strategy of blood transfusion (to maintain a hematocrit ≥30%) or to a restrictive strategy (hematocrit ≥24%).Main Outcome Measure: Composite end point of 30-day all-cause mortality and severe morbidity (cardiogenic shock, acute respiratory distress syndrome, or acute renal injury requiring dialysis or hemofiltration) occurring during the hospital stay. The noninferiority margin was predefined at -8% (ie, 8% minimal clinically important increase in occurrence of the composite end point).Results: Hemoglobin concentrations were maintained at a mean of 10.5 g/dL (95% confidence interval [CI], 10.4-10.6) in the liberal-strategy group and 9.1 g/dL (95% CI, 9.0-9.2) in the restrictive-strategy group (P < .001). A total of 198 of 253 patients (78%) in the liberal-strategy group and 118 of 249 (47%) in the restrictive-strategy group received a blood transfusion (P < .001). Occurrence of the primary end point was similar between groups (10% liberal vs 11% restrictive; between-group difference, 1% [95% CI, -6% to 4%]; P = .85). Independent of transfusion strategy, the number of transfused red blood cell units was an independent risk factor for clinical complications or death at 30 days (hazard ratio for each additional unit transfused, 1.2 [95% CI, 1.1-1.4]; P = .002).Conclusion: Among patients undergoing cardiac surgery, the use of a restrictive perioperative transfusion strategy compared with a more liberal strategy resulted in noninferior rates of the combined outcome of 30-day all-cause mortality and severe morbidity.Trial Registration: clinicaltrials.gov Identifier: NCT01021631. [ABSTRACT FROM AUTHOR]

Background: Differences in outcomes have been demonstrated for critically ill patients with late-onset compared with early-onset renal failure and late-onset compared with early-onset shock, which could cause a lead-time bias in clinical trials assessing potential therapies for these conditions. We used data from a large, multicenter observational study to assess whether late-onset ARDS was similarly associated with worse outcomes compared with early-onset ARDS.Methods: Data were extracted from the Sepsis Occurrence in Acutely Ill Patients (SOAP) study, which involved 198 ICUs from 24 European countries. All adult patients admitted to a participating ICU between May 1, 2002 and May 15, 2002, were eligible, except those admitted for uncomplicated postoperative surveillance. Early/late onset acute lung injury (ALI)/ARDS was defined as ALI/ARDS occurring within/after 48 h of ICU admission.Results: Of the 3,147 patients included in the SOAP study, 393 (12.5%) had a diagnosis of ALI/ARDS; 254 had early-onset ALI/ARDS (64.6%), and 139 (35.5%) late-onset. Patients with early-onset ALI/ARDS had higher Simplified Acute Physiology II scores on admission and higher initial Sequential Organ Failure Assessment scores. Patients with late-onset ALI/ARDS had longer ICU and hospital lengths of stay than patients with early-onset ALI/ARDS. ICU and hospital mortality rates were, if anything, lower in late-onset ALI/ARDS than in early-onset ALI/ARDS, but these differences were not statistically significant.Conclusions: There were no significant differences in mortality rates between early- and late-onset ARDS, but patients with late-onset ALI/ARDS had longer ICU and hospital lengths of stay. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To clarify the role of the pulmonary artery catheter in the intensive care unit. DATA SOURCES: Recent and relevant literature from MEDLINE and authors' personal databases. STUDY SELECTION: Studies on pulmonary artery catheter use and use of other monitoring devices in critically ill patients. DATA EXTRACTION: Based largely on clinical experience and assessment of the relevant published literature and in response to recent articles attacking the pulmonary artery catheter, we propose that the pulmonary artery catheter is still a valuable tool for the hemodynamic monitoring of patients with complex disease processes in whom the information obtained from the pulmonary artery catheter may influence management. We suggest that there is a need to revisit the basics of hemodynamic management and reassess the way in which the pulmonary artery catheter is used, applying three key principles: correct measurement, correct data interpretation, and correct application. CONCLUSION: The pulmonary artery catheter is still a valuable tool for hemodynamic monitoring when used in selected patients and by physicians adequately trained to correctly interpret and apply the data provided. [ABSTRACT FROM AUTHOR]

BACKGROUND: Studies have suggested worse outcomes in transfused patients and improved outcomes in patients managed with restricted blood transfusion strategies. The authors investigated the relation of blood transfusion to mortality in European intensive care units (ICUs). METHODS: The Sepsis Occurrence in Acutely Ill Patients study was a multicenter, observational study that included all adult patients admitted to 198 European ICUs between May 1 and May 15, 2002 and followed them until death, until hospital discharge, or for 60 days. Patients were classified depending on whether they had received a blood transfusion at any time during their ICU stay. RESULTS: Of 3,147 patients, 1,040 (33.0%) received a blood transfusion. These patients were older (mean age, 62 vs. 60 yr; P = 0.035) and were more likely to have liver cirrhosis or hematologic cancer, to be a surgical admission, and to have sepsis. They had a longer duration of ICU stay (5.9 vs. 2.5 days; P < 0.001) and a higher ICU mortality rate (23.0 vs. 16.3%; P < 0.001) but were also more severely ill on admission (Simplified Acute Physiology Score II, 40.2 vs. 34.7; P < 0.001; Sequential Organ Failure Assessment score, 6.5 vs. 4.5; P < 0.001). There was a direct relation between the number of blood transfusions and the mortality rate, but in multivariate analysis, blood transfusion was not significantly associated with a worse mortality rate. Moreover, in 821 pairs matched according to a propensity score, there was a higher 30-day survival rate in the transfusion group than in the other patients (P = 0.004). CONCLUSION: This observational study does not support the view that blood transfusions are associated with increased mortality rates in acutely ill patients. [ABSTRACT FROM AUTHOR]

OBJECTIVES: : To assess the use of antibiotic de-escalation in patients with hospital-acquired severe sepsis in an academic setting. DESIGN: : We reviewed all episodes of severe sepsis treated over a 1-yr period in the department of intensive care. Antimicrobial therapy was considered as appropriate when the antimicrobial had in vitro activity against the causative microorganisms. According to the therapeutic strategy in the 5 days after the start of antimicrobial therapy, we classified patients into four groups: de-escalation (interruption of an antimicrobial agent or change of antibiotic to one with a narrower spectrum); no change in antibiotherapy; escalation (addition of a new antimicrobial agent or change in antibiotic to one with a broader spectrum); and mixed changes. SETTING: : A 35-bed medico-surgical intensive care department in which antibiotic strategies are reviewed by infectious disease specialists three times per week. PATIENTS: : One hundred sixty-nine patients with 216 episodes of severe sepsis attributable to a hospital-acquired infection who required broad-spectrum [beta]-lactam antibiotics alone or in association with other anti-infectious agents. MEASUREMENTS AND MAIN RESULTS: : The major sources of infection were the lungs (44%) and abdomen (38%). Microbiological data were available in 167 of the 216 episodes (77%). Initial antimicrobial therapy was inappropriate in 27 episodes (16% of culture-positive episodes). De-escalation was applied in 93 episodes (43%), escalation was applied in 22 episodes (10%), mixed changes were applied in 24 (11%) episodes, and there was no change in empirical antibiotic therapy in 77 (36%) episodes. In these 77 episodes, the reasons given for maintaining the initial antimicrobial therapy included the sensitivity pattern of the causative organisms and previous antibiotic therapy. The number of episodes when the chance to de-escalate may have been missed was small (4 episodes [5%]). CONCLUSION: : Even in a highly focused environment with close collaboration among intensivists and infectious disease specialists, de-escalation may actually be possible in <50% of cases. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The vasopressor effect of arginine vasopressin, a mixed V1a/V2 receptor (V1aR/V2R) agonist, is mediated through the V1aR. Because V2R stimulation may aggravate sepsis-induced vasodilation, fluid accumulation, and microvascular thrombosis, a higher V1aR vs. V2R selectivity might be advantageous. The objective of this study was to elucidate the effects of a first-line therapy with the selective V1aR agonist Phe2-Orn8-Vasotocin vs. arginine vasopressin or norepinephrine on cardiopulmonary hemodynamics and organ function in ovine septic shock. DESIGN: Randomized controlled laboratory experiment. SETTING: University animal research facility. SUBJECTS: : Twenty-four chronically instrumented sheep. INTERVENTIONS: After the onset of fecal peritonitis-induced septic shock (mean arterial pressure <60 mm Hg), sheep were randomly assigned to receive first-line treatment with Phe2-Orn8-Vasotocin (0.05 [mu]g·kg·h), arginine vasopressin (0.05 [mu]g·kg·h), or normal saline (each n = 8). In all groups, open-label norepinephrine was additionally titrated up to 1 [mu]g·kg·min to maintain mean arterial pressure at 70 ± 5 mm Hg, if necessary. MEASUREMENTS AND MAIN RESULTS: Compared with single norepinephrine therapy, the selective V1aR agonist Phe2-Orn8-Vasotocin reduced norepinephrine requirements (2-6 hrs: p < .05 each) and fluid accumulation (p = .043). In addition, mean arterial pressure (6-10 hrs: p < .05 each), pulmonary gas exchange (8-10 hrs: p < .05 each), and global oxygen transport (10 hrs: p < .05 each) were improved by Phe2-Orn8-Vasotocin vs. both other groups. Despite similar preload left ventricular stroke work index was higher in Phe2-Orn8-Vasotocin- than in arginine vasopressin-treated animals (10 hrs: p = .02). Metabolic dysfunction (base excess, lactate concentrations) and renal dysfunction (urinary output, creatinine clearance) were attenuated by Phe2-Orn8-Vasotocin infusion when compared with arginine vasopressin and single norepinephrine therapy. Immunohistochemical analyses of lung tissue revealed higher hemeoxygenase-1 and lower 3-nitrotyrosine concentrations in Phe2-Orn8-Vasotocin-treated animals vs. both other groups (p < .05 each). In addition, the selective V1aR agonist Phe2-Orn8-Vasotocin slightly prolonged survival when compared with arginine vasopressin (p = .01) and standard treatment with norepinephrine (p = .003). CONCLUSIONS: Selective V1aR agonism appears to be superior to the V1aR/V2R agonist arginine vasopressin and single norepinephrine infusion for hemodynamic support in septic shock. [ABSTRACT FROM AUTHOR]

Objective: Lack of evidence that some monitoring systems can improve outcomes has raised doubts about their use in the intensive care unit (ICU). The objective of this study was to determine which monitoring techniques have been shown to improve outcomes in ICU patients.Design: Comprehensive literature review.Methods: We conducted a highly sensitive search, up to June 2006, in the Cochrane Central Register of Controlled Trials (CENTRAL) and MedLine, for prospective, randomized controlled trials (RCTs) conducted in adult patients in the ICU and the operating room (major surgical procedures) and focusing on the impact of monitoring on outcome.Measurements and Results: Of 4,175 potential articles, 67 evaluated the impact of monitoring in acutely ill adult patients. There were 40 studies related to hemodynamic monitoring, 17 to respiratory monitoring, and 10 to neurological monitoring. Seven studies were classified in two different categories. Positive non-mortality outcomes were observed in 17 of 40 hemodynamic studies, 11 of 17 respiratory, and in all 10 neurological studies. Mortality was evaluated in 31 hemodynamic studies, but a beneficial impact was demonstrated in only 10. For respiratory monitoring, 7 studies evaluated mortality, but only 3 of them showed an improved outcome. We found no neurological monitoring studies that assessed mortality.Conclusion: There is no broad evidence that any form of monitoring improves outcomes in the ICU and most commonly used devices have not been evaluated by RCT. This review puts into perspective the recent negative studies on the use of the pulmonary artery catheter in the acutely ill. [ABSTRACT FROM AUTHOR]

OBJECTIVES: To determine how many multicenter, randomized controlled trials have been published that assess mortality as a primary outcome in the adult intensive care unit population, and to evaluate their methodologic quality. DATA SOURCE: A sensitive search strategy for randomized controlled trials was conducted in the Cochrane Central Register of Controlled Trials and in MedLine using the PubMed interface. STUDY SELECTION: All publications of adult, multicenter randomized controlled trials carried out in the intensive care unit, with mortality as a primary outcome, and including >50 patients were selected. DATA EXTRACTION: Seventy-two randomized controlled trials were retrieved and were classified according to their effect on mortality: beneficial, detrimental, or neutral. DATA SYNTHESIS: Ten of the studies reported a positive impact of the studied intervention on mortality, seven studies reported a detrimental effect of the intervention, and 55 studies showed no effect on mortality. CONCLUSIONS: This literature search demonstrates that relatively few of the randomized controlled trials conducted in intensive care units and using mortality as a primary outcome show a beneficial impact of the intervention on the survival of critically ill patients. Methodological limitations of some of the randomized controlled trials may have prevented positive results. Other forms of evidence and end points other than mortality need to be considered when evaluating interventions in critically ill patients. [ABSTRACT FROM AUTHOR]

OBJECTIVE: : Supplementation with tetrahydrobiopterin, a nitric oxide synthase cofactor, may reduce microvascular endothelial dysfunction in severe sepsis. We studied whether tetrahydrobiopterin administration exerts beneficial effects in an ovine septic shock model. DESIGN: : Randomized animal study. SETTING: : University hospital animal research laboratory. SUBJECTS: : Fourteen adult female sheep. INTERVENTIONS: : Fecal peritonitis was induced, and the sheep were randomized to receive tetrahydrobiopterin (n = 7), given intravenously as 20mg/kg boluses at 4 and 12 hrs after sepsis induction, or placebo (n = 7). All animals were fluid resuscitated. The experiment was continued until death or for a maximum of 30 hrs. MEASUREMENTS AND MAIN RESULTS: : In addition to standard hemodynamic assessment, the sublingual microcirculation was evaluated using sidestream dark-field videomicroscopy. The first bolus of tetrahydrobiopterin blunted the increase in heart rate and cardiac index seen in the control group without affecting mean arterial pressure, and the second bolus of tetrahydrobiopterin prevented the decreases in cardiac index and mean arterial pressure. The reduction in mixed venous blood oxygen saturation and the increase in blood lactate seen in the control group were also delayed. Tetrahydrobiopterin significantly attenuated the deterioration in perfused small vessel proportion and density, microvascular flow index, and the increase in microvascular heterogeneity observed in the control group. Tetrahydrobiopterin was associated with better preserved lung compliance and PaO2/FIO2 ratio, which were associated with a lower lung wet/dry weight ratio at the end of the study. Median survival time was significantly prolonged in the tetrahydrobiopterin group (25.0 vs. 17.8 hrs, p < .01). CONCLUSION: : In this clinically relevant model of sepsis, tetrahydrobiopterin supplementation attenuated the impairment in sublingual microvascular perfusion and permeability, which was accompanied by better preserved gas exchange, renal flow and urine output, and prolonged survival. [ABSTRACT FROM AUTHOR]

OBJECTIVES: : There has long-been controversy about the possible superiority of norepinephrine compared to dopamine in the treatment of shock. The objective was to evaluate the effects of norepinephrine and dopamine on outcome and adverse events in patients with septic shock. DATA SOURCES: : A systematic search of the MEDLINE, Embase, Scopus, and CENTRAL databases, and of Google Scholar, up to June 30, 2011. STUDY SELECTION AND DATA EXTRACTION: : All studies providing information on the outcome of patients with septic shock treated with dopamine compared to norepinephrine were included. Observational and randomized trials were analyzed separately. Because time of outcome assessment varied among trials, we evaluated 28-day mortality or closest estimate. Heterogeneity among trials was assessed using the Cochrane Q homogeneity test. A Forest plot was constructed and the aggregate relative risk of death was computed. Potential publication bias was evaluated using funnel plots. METHODS AND MAIN RESULTS: : We retrieved five observational (1,360 patients) and six randomized (1,408 patients) trials, totaling 2,768 patients (1,474 who received norepinephrine and 1,294 who received dopamine). In observational studies, among which there was significant heterogeneity (p < .001), there was no difference in mortality (relative risk, 1.09; confidence interval, 0.84-1.41; p = .72). A sensitivity analysis identified one trial as being responsible for the heterogeneity; after exclusion of that trial, no heterogeneity was observed and dopamine administration was associated with an increased risk of death (relative risk, 1.23; confidence interval, 1.05-1.43; p < .01). In randomized trials, for which no heterogeneity or publication bias was detected (p = .77), dopamine was associated with an increased risk of death (relative risk, 1.12; confidence interval, 1.01-1.20; p = .035). In the two trials that reported arrhythmias, these were more frequent with dopamine than with norepinephrine (relative risk, 2.34; confidence interval, 1.46-3.77; p = .001). CONCLUSIONS: : In patients with septic shock, dopamine administration is associated with greater mortality and a higher incidence of arrhythmic events compared to norepinephrine administration. [ABSTRACT FROM AUTHOR]

OBJECTIVE: : Hypothermia impairs blood glucose homeostasis and insulin sensitivity. However, the impact of therapeutic hypothermia on blood glucose levels and insulin requirements is unknown. We analyzed blood glucose variability during therapeutic hypothermia in patients with coma after cardiac arrest and examined its impact on outcome. DESIGN: : Prospective observational study. SETTING: : Two university hospital medical/surgical intensive care units. PATIENTS: : Comatose cardiac arrest patients treated with therapeutic hypothermia (33°C, 24 hrs). INTERVENTIONS: : Insulin therapy (blood glucose target 6-8 mmol/L [110-150 mg/dL]), according to a written algorithm, with nurse-driven adjustment of insulin dose. MEASUREMENTS AND MAIN RESULTS: : Two-hundred and twenty patients (median age 61 yrs, median time to return of spontaneous circulation 20 min) were studied. Two time periods, comparable in duration, were categorized: therapeutic hypothermia (stable maintenance phase) and normothermia (after rewarming). Blood glucose variability was defined as the difference between maximum and minimum blood glucose concentration during each time period. Mean blood glucose (8.3 ± 2.3 vs. 7.1 ± 1.3 mmol/L), blood glucose variability (5.7 ± 3.9 vs. 3.7 ± 3.6 mmol/L), and insulin dose (2 ± 2 vs. 1 ± 1 U/h) were higher during therapeutic hypothermia compared to normothermia (all p < .001). Higher mean blood glucose (7.9 ± 1.8 mmol/L in survivors vs. 8.7 ± 2.6 mmol/L in nonsurvivors, p = .02) and increased blood glucose variability (4.9 ± 3.5 vs. 6.5 ± 4.1 mmol/L, p = .003) during therapeutic hypothermia were associated with mortality. After adjusting for time to return of spontaneous circulation, initial arrest rhythm, and cardiac arrest etiology, increased blood glucose variability during therapeutic hypothermia, but not mean blood glucose level, was an independent predictor of inhospital mortality (odds ratio for death 1.10 [confidence interval 1.02-1.19], p = .016). CONCLUSIONS: : Mild therapeutic hypothermia is associated with higher blood glucose levels, increased blood glucose variability, and greater insulin requirements compared to the postrewarming normothermic phase. Increased blood glucose variability during therapeutic hypothermia is a predictor of inhospital mortality after cardiac arrest, independent of injury severity and mean blood glucose levels. [ABSTRACT FROM AUTHOR]

Background: Altered brain perfusion may play an important role in the development of sepsis-associated encephalopathy. However, whether or not cerebral autoregulation (CA) is preserved in such condition has been debated. CA is dependent on cerebral vascular tone, the main determinant of which is the concentration of carbon dioxide (CO2). The purpose of this study was to evaluate the influence of PaCO2 on the cerebral autoregulatory capacity in patients with septic shock.Methods: Using transcranial Doppler sonography recordings from the middle cerebral artery (MCA), we evaluated the static cerebral autoregulatory responses within the first 3 days of septic shock. Changes in cerebrovascular resistance (CVR) were calculated from the changes in the mean velocity in the MCA (VMCA, cm/s), in response to an increase in mean arterial pressure (MAP, mmHg) induced by vasopressors. The cerebral autoregulation index (CAI) was calculated as the ratio of the relative changes in CVR and MAP (CAI = DeltaMAP%/DeltaCVR%), with normal values ranging between 0 and 2.Results: We studied 21 mechanically ventilated patients, with a baseline MAP of 65 +/- 6 mmHg, a mean VMCA of 60 +/- 20 cm/s and a median PaCO(2) of 35 [28-49] mmHg. Fourteen of the 21 patients had impaired CA, including 7 of the 14 patients with a PaCO2 <40 mmHg and all 7 patients with a PaCO2 >40 mmHg (Fisher's exact test, P = 0.046).Conclusions: According to these data, CA is impaired in the majority of patients with septic shock, especially in the presence of hypercapnia. [ABSTRACT FROM AUTHOR]

BACKGROUND: Positive end expiratory pressure (PEEP) is an important component of therapy in patients with acute lung injury or acute respiratory distress syndrome. The independent effect of PEEP on mortality is currently unknown. METHODS: A systematic review and meta-analysis of randomized controlled clinical trials comparing the use of higher and lower levels of PEEP. RESULTS: Six trials with a total of 2,484 patients from 102 intensive care units and 9 countries met the eligibility criteria. In three trials, the effect of different levels of PEEP was compared in groups receiving comparable tidal volumes. Three trials accounted for more than 85% of total weighting in the meta-analyses. The pooled relative risk obtained from these three trials showed a trend towards improved mortality with high PEEP, even though the difference did not reach statistical significance: Pooled cumulative risk of 0.90 (95% CI 0.72-1.02, P = 0.077). The reduction in absolute risk of death was approximately 4%. There was no evidence of a significant increase in baro-trauma in patients receiving high PEEP, with a pooled risk of 0.95 (95% CI 0.62-1.45, P = 0.81). CONCLUSION: High PEEP strategy may have a clinically relevant independent mortality benefit. Despite a possible increase in baro-trauma, the benefits far outweigh potential risks. Current evidence therefore favors the use of high PEEP as the preferred option when ventilating patients with severe acute respiratory distress syndrome. As the reduction in absolute risk of death is less than 5%, a future clinical trial aimed at demonstrating statistical significance is likely to pose considerable financial and ethical burdens. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the effects of hydrocortisone on microcirculatory blood flow alterations in patients with septic shock.Design: Prospective, open-label study.Setting: A 31-bed, medico-surgical intensive care unit of a university hospital.Patients: Twenty patients with septic shock.Interventions: Intravenous hydrocortisone (50 mg/6 hr).Measurements and Main Results: An orthogonal polarization spectral device (Cytoscan ARII, Cytometrics; Philadelphia, PA) was used to investigate the sublingual microcirculation in 20 patients who received so-called "stress doses" of hydrocortisone as part of their management for septic shock. Hemodynamic measurements and orthogonal polarization spectral images were obtained before administration of the first dose (50 mg) of hydrocortisone and 1, 2, 4, and 24 hours later. Measurements were also made before an adrenocorticotropic hormone (ACTH) test, whenever performed. Global hemodynamic variables were similar at all study time points. Microcirculatory variables improved slightly already at 1 hour after the start of hydrocortisone administration. In particular, perfused vessel density increased from 5.7 (4.8-6.4) to 7.2 (6.5-9.0)n/mm, p < 0.01, which was due to combined increases in small vessel density from 5.2 (4.6-6.2) to 6.0 (5.1-7.5)n/mm, p < 0.01, and in the proportion of perfused vessels from 82.1 (68.7-88.0) to 89.2 (83.4-92.6)%, p < 0.01. There were no differences in microcirculatory variables during hydrocortisone administration between ACTH test responders and nonresponders.Conclusions: The administration of moderate doses of hydrocortisone in septic shock results in a modest but consistent improvement in capillary perfusion, independent of the response to the ACTH test. The mechanisms underlying this effect need to be elucidated. [ABSTRACT FROM AUTHOR]