Notice to comply: A systematic review of clinician compliance with guidelines surrounding acute hospital-based infection management.

PURPOSE: To identify and characterize studies evaluating clinician compliance with infection-related guidelines, and to explore trends in guideline design and implementation strategies. DATA SOURCES: PubMed database, April 2017. Followed the PRISMA Statement for systematic reviews. STUDY SELECTION: Scope was limited to studies reporting compliance with guidelines pertaining to the prevention, detection, and/or treatment of acute hospital-based infections. Initial search (1,499 titles) was reduced to 49 selected articles. DATA EXTRACTION: Extracted publication and guideline characteristics, outcome measures reported, and any results related to clinician compliance. Primary summary measures were frequencies and distributions of characteristics. Interventions that led to improved compliance results were analyzed to identify trends in guideline design and implementation. RESULTS OF DATA SYNTHESIS: Of the 49 selected studies, 18 (37%), 13 (27%), and 10 (20%) focused on sepsis, pneumonia, and general infection, respectively. Six (12%), 17 (35%), and 26 (53%) studies assessed local, national, and international guidelines, respectively. Twenty studies (41%) reported 1-instance compliance results, 28 studies (57%) reported 2-instance compliance results (either before-and-after studies or control group studies), and 1 study (2%) described compliance qualitatively. Average absolute change in compliance for minimal, decision support, and multimodal interventions was 10%, 14%, and 25%, respectively. Twelve studies (24%) reported no patient outcome alongside compliance. CONCLUSIONS: Multimodal interventions and quality improvement initiatives seem to produce the greatest improvement in compliance, but trends in other factors were inconsistent. Additional research is required to investigate these relationships and understand the implications behind various approaches to guideline design, communication, and implementation, in addition to effectiveness of protocol impact on relevant patient outcomes.

Data-driven approach to Early Warning Score-based alert management.

BACKGROUND: Increasing adoption of electronic health records (EHRs) with integrated alerting systems is a key initiative for improving patient safety. Considering the variety of dynamically changing clinical information, it remains a challenge to design EHR-driven alerting systems that notify the right providers for the right patient at the right time while managing alert burden. The objective of this study is to proactively develop and evaluate a systematic alert-generating approach as part of the implementation of an Early Warning Score (EWS) at the study hospitals. METHODS: We quantified the impact of an EWS-based clinical alert system on quantity and frequency of alerts using three different alert algorithms consisting of a set of criteria for triggering and muting alerts when certain criteria are satisfied. We used retrospectively collected EHRs data from December 2015 to July 2016 in three units at the study hospitals including general medical, acute care for the elderly and patients with heart failure. RESULTS: We compared the alert-generating algorithms by opportunity of early recognition of clinical deterioration while proactively estimating alert burden at a unit and patient level. Results highlighted the dependency of the number and frequency of alerts generated on the care location severity and patient characteristics. CONCLUSION: EWS-based alert algorithms have the potential to facilitate appropriate alert management prior to integration into clinical practice. By comparing different algorithms with regard to the alert frequency and potential early detection of physiological deterioration as key patient safety opportunities, findings from this study highlight the need for alert systems tailored to patient and care location needs, and inform alternative EWS-based alert deployment strategies to enhance patient safety.

Multicenter observational study of the development of progressive organ dysfunction and therapeutic interventions in normotensive sepsis patients in the emergency department.

OBJECTIVES: Progressive organ dysfunction is the leading cause of sepsis-associated mortality; however, its incidence and management are incompletely understood. Sepsis patients with moderately impaired perfusion (serum lactate 2.0 to 3.9 mmol/L) who are not in hemodynamic shock ("preshock" sepsis patients) may be at increased risk for progressive organ dysfunction and increased mortality. The objectives of this study were to: 1) quantify the occurrence of progressive organ dysfunction among preshock sepsis patients, 2) examine if there were baseline differences in demographic and physiologic parameters between preshock sepsis patients who experienced progressive organ dysfunction and those who did not, and 3) examine if intravenous (IV) fluid administered in the emergency department (ED) differed between these two groups of patients. METHODS: This was a prospective, observational study in four urban EDs targeting the preshock sepsis population, defined as adults (18 years or older) with suspected infection, serum lactate between 2.0 and 3.9 mmol/L, and without hypotension (systolic blood pressure [sBP] < 90 mm Hg or mean arterial pressure [MAP] < 70 mm Hg) or requiring mechanical ventilation at ED presentation. The primary composite outcome was progressive organ dysfunction, defined as a rise in the Sequential Organ Failure Assessment (SOFA) score of ≥1, vasopressor use, mechanical ventilation use within 72 hours after ED presentation, or in-hospital death. The secondary outcomes were any intensive care unit (ICU) admission, and total ICU and hospital lengths of stay (LOS). RESULTS: Among 94 preshock sepsis patients, the primary composite outcome occurred in 24 of 94 (26%). In patients with the primary outcome, 22 of 24 (92%) experienced a rise in SOFA score of ≥1, five of 24 (21%) received vasopressor agents, and seven of 24 (30%) required mechanical ventilation. There were no baseline demographic or physiologic parameter differences between patients who met the primary outcome versus those who did not, while patients with the primary outcome had a higher average SOFA score at admission (2.4 vs. 1.3, p = 0.011) and at all subsequent time points. Median IV fluid volume administered to all preshock sepsis patients during their ED stay was 1,225 mL (interquartile range [IQR] = 712 to 2,000 mL) and did not differ significantly between patients with (1,150 mL, IQR = 469 to 2,000 mL) or without (1,250 mL, IQR = 750 to 2,000 mL) the primary outcome (p = 0.73). Patients with progressive organ dysfunction or death were more likely to be admitted to an ICU (50% vs. 20%, p < 0.01) and have an increased median hospital LOS (6 days vs. 3 days, p = 0.005), compared to those without progressive organ dysfunction. CONCLUSIONS: Over one-quarter of preshock sepsis patients developed progressive organ dysfunction with associated increased resource use. Demographic and physiologic parameters were unable to differentiate patients with progressive organ dysfunction, while the initial SOFA score was increased in patients meeting the outcome. Overall, these patients received relatively little IV fluid therapy during their ED stays. Further research to determine if more aggressive therapy can prevent progressive organ dysfunction in this population is warranted.

Discordance between microcirculatory alterations and arterial pressure in patients with hemodynamic instability.

PURPOSE: Recent studies reported that microcirculatory blood flow alterations occur in patients with circulatory shock independent of arterial pressure but typically lack baseline microcirculatory data before the insult and after recovery. We selected cardiopulmonary bypass (CPB) patients with expected and rapidly reversible hemodynamic instability to test the hypothesis that microcirculatory alterations can occur independent of mean arterial pressure (MAP). METHODS: Prospective observational study using sidestream darkfield videomicroscopy to measure sublingual microcirculatory flow preoperative (PRE), postoperatively after CPB (POST), and after recovery (REC). We determined the microcirculatory flow index (MFI) at each time point, blinded to all clinical data and compared change in MFI and MAP across time points using analysis of variance adjusted for multiple comparisons. RESULTS: We enrolled 20 subjects, 17 of 20 required inotrope/vasopressor agents at CPB discontinuation, 7 of 20 were on inotrope/vasopressor agents at the time of imaging, 20 of 20 were receiving continuous nitroglycerin. We observed an increase in post-CPB MFI (PRE, 2.16 ± 0.29; POST, 2.45 ± 0.62; REC, 2.26 ± 0.25; P < .01) without a concomitant increase in MAP. CONCLUSION: In this cohort of patients with hemodynamic instability, we observed discordance between microcirculatory blood flow and arterial pressure. These data support the concept that microcirculatory blood flow indices can yield physiologic information distinct from macrocirculatory hemodynamic parameters.

Prognostic value and agreement of achieving lactate clearance or central venous oxygen saturation goals during early sepsis resuscitation.

OBJECTIVES: Lactate clearance (LC) and central venous oxygen saturation (ScvO(2)) have been proposed as goals of early sepsis resuscitation. The authors sought to determine the agreement and prognostic value of achieving ScvO(2) or LC goals in septic shock patients undergoing emergency department (ED)-based early resuscitation. METHODS: This was a preplanned analysis of a multicenter ED randomized controlled trial of early sepsis resuscitation targeting three variables: central venous pressure, mean arterial pressure, and either ScvO(2) or LC. Inclusion criteria included suspected infection, two or more systemic inflammation criteria, and either systolic blood pressure of <90 mm Hg after intravenous fluid bolus or lactate level of >4 mmol/L. Both ScvO(2) and LC were measured simultaneously. The ScvO(2) goal was defined as ≥70%. Lactate was measured at enrollment and every 2 hours until the goal was reached or up to 6 hours. LC goal was defined as a decrease of ≥10% from initial measurement. The primary outcome was in-hospital mortality. RESULTS: A total of 203 subjects were included, with an overall mortality of 19.7%. Achievement of the ScvO(2) goal only was associated with a mortality rate of 41% (9/22), while achievement of the LC goal only was associated with a mortality rate of 8% (2/25; proportion difference = 33%; 95% confidence interval [CI] = 9% to 55%). No agreement was found between goal achievement (κ = -0.02), and exact test for matched pairs demonstrated no significant difference between discordant pairs (p = 0.78). CONCLUSIONS: No agreement was found between LC and ScvO(2) goal achievement in early sepsis resuscitation. Achievement of a ScvO(2) ≥ 70% without LC ≥ 10% was more strongly associated with mortality than achievement of LC ≥ 10% with failure to achieve ScvO(2) ≥ 70%.

Association between timing of antibiotic administration and mortality from septic shock in patients treated with a quantitative resuscitation protocol.

OBJECTIVE: We sought to determine the association between time to initial antibiotics and mortality of patients with septic shock treated with an emergency department-based early resuscitation protocol. DESIGN: Preplanned analysis of a multicenter randomized controlled trial of early sepsis resuscitation. SETTING: Three urban U.S. emergency departments. PATIENTS: Adult patients with septic shock. INTERVENTIONS: A quantitative resuscitation protocol in the emergency department targeting three physiological variables: central venous pressure, mean arterial pressure, and either central venous oxygen saturation or lactate clearance. The study protocol was continued until all end points were achieved or a maximum of 6 hrs. MEASUREMENTS AND MAIN RESULTS: Data on patients who received an initial dose of antibiotics after presentation to the emergency department were categorized based on both time from triage and time from shock recognition to initiation of antibiotics. The primary outcome was inhospital mortality. Of 291 included patients, mortality did not change with hourly delays in antibiotic administration up to 6 hrs after triage: 1 hr (odds ratio [OR], 1.2; 0.6-2.5), 2 hrs (OR, 0.71; 0.4-1.3), 3 hrs (OR, 0.59; 0.3-1.3). Mortality was significantly increased in patients who received initial antibiotics after shock recognition (n = 172 [59%]) compared with before shock recognition (OR, 2.4; 1.1-4.5); however, among patients who received antibiotics after shock recognition, mortality did not change with hourly delays in antibiotic administration. CONCLUSION: In this large, prospective study of emergency department patients with septic shock, we found no increase in mortality with each hour delay to administration of antibiotics after triage. However, delay in antibiotics until after shock recognition was associated with increased mortality.

A prospective multicenter cohort study of the association between global tissue hypoxia and coagulation abnormalities during early sepsis resuscitation.

OBJECTIVE: Coagulation activation is an integral part of sepsis pathogenesis. Experimental data suggest that endothelial exposure to hypoxia activates coagulation. We aimed to test the hypothesis that the quantity of exposure to global tissue hypoxia is associated with the degree of coagulation activation during early sepsis resuscitation. DESIGN: Prospective, multicenter cohort study. SETTING: Emergency department and intensive care unit of three academic hospitals. PATIENTS: Inclusion criteria were age older than 17, acute infection with two or more signs of systemic inflammation, hypotension despite fluid challenge (or lactate >4 mM), and continuous central venous oxygen saturation (Scvo2) monitoring for quantitative resuscitation. Exclusion criteria were anticoagulant or blood product administration. MEASUREMENTS AND MAIN RESULTS: We recorded central venous oxygen saturation continuously for 0 to 6 hrs of resuscitation and calculated the area under the curve for central venous oxygen saturation <70%. We defined hypoxia exposure as exceeding the median area under the curve for the entire cohort. At 0, 6, and 24 hrs, we measured conventional coagulation biomarkers plus thrombin-antithrombin complex, plasmin-antiplasmin complex, tissue plasminogen activator, plasminogen activator inhibitor-1, protein C, antithrombin, and endothelial markers (E-selectin, intracellular adhesion molecule-1, thrombomodulin). We compared changes during 0 to 6 hrs and 0 to 24 hrs in biomarkers between hypoxia exposure and nonexposure groups. We enrolled 40 patients (60% requiring vasopressors; 30% mortality). We found that exposure to hypoxia alone was not associated with a significant degree of coagulation activation. However, in secondary analyses we found that exposure to arterial hypotension induced E-selectin and thrombin-antithrombin complex, whereas concomitant exposure to both hypotension and hypoxia was associated with amplification of E-selectin and thrombomodulin, and a reduction in protein C. CONCLUSION: In this sample of patients undergoing quantitative resuscitation for sepsis, we found that exposure to global tissue hypoxia (as quantified by low central venous oxygen saturation) was not associated with major coagulation activation. Further investigation to elucidate the clinical factors that trigger or intensify the procoagulant response to sepsis is warranted.

Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial.

CONTEXT: Goal-directed resuscitation for severe sepsis and septic shock has been reported to reduce mortality when applied in the emergency department. OBJECTIVE: To test the hypothesis of noninferiority between lactate clearance and central venous oxygen saturation (ScvO2) as goals of early sepsis resuscitation. DESIGN, SETTING, AND PATIENTS: Multicenter randomized, noninferiority trial involving patients with severe sepsis and evidence of hypoperfusion or septic shock who were admitted to the emergency department from January 2007 to January 2009 at 1 of 3 participating US urban hospitals. INTERVENTIONS: We randomly assigned patients to 1 of 2 resuscitation protocols. The ScvO2 group was resuscitated to normalize central venous pressure, mean arterial pressure, and ScvO2 of at least 70%; and the lactate clearance group was resuscitated to normalize central venous pressure, mean arterial pressure, and lactate clearance of at least 10%. The study protocol was continued until all goals were achieved or for up to 6 hours. Clinicians who subsequently assumed the care of the patients were blinded to the treatment assignment. MAIN OUTCOME MEASURE: The primary outcome was absolute in-hospital mortality rate; the noninferiority threshold was set at Delta equal to -10%. RESULTS: Of the 300 patients enrolled, 150 were assigned to each group and patients were well matched by demographic, comorbidities, and physiological features. There were no differences in treatments administered during the initial 72 hours of hospitalization. Thirty-four patients (23%) in the ScvO2 group died while in the hospital (95% confidence interval [CI], 17%-30%) compared with 25 (17%; 95% CI, 11%-24%) in the lactate clearance group. This observed difference between mortality rates did not reach the predefined -10% threshold (intent-to-treat analysis: 95% CI for the 6% difference, -3% to 15%). There were no differences in treatment-related adverse events between the groups. CONCLUSION: Among patients with septic shock who were treated to normalize central venous and mean arterial pressure, additional management to normalize lactate clearance compared with management to normalize ScvO2 did not result in significantly different in-hospital mortality. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00372502.

Multicenter study of central venous oxygen saturation (ScvO(2)) as a predictor of mortality in patients with sepsis.

STUDY OBJECTIVE: Abnormal (both low and high) central venous saturation (ScvO(2)) is associated with increased mortality in emergency department (ED) patients with suspected sepsis. METHODS: This was a secondary analysis of 4 prospectively collected registries of ED patients treated with early goal-directed therapy-based sepsis resuscitation protocols from 4 urban tertiary care hospitals. Inclusion criteria were sepsis, hypoperfusion defined by systolic blood pressure less than 90 mm Hg or lactate level greater than or equal to 4 mmol/L, and early goal-directed therapy treatment. ScvO(2) levels were stratified into 3 groups: hypoxia (ScvO(2) <70%); normoxia (ScvO(2) 71% to 89%); and hyperoxia (ScvO(2) 90% to 100%). The primary exposures were initial ScvO(2) and maximum ScvO(2) achieved, with the primary outcome as inhospital mortality. Multivariate analysis was performed. RESULTS: There were 619 patients who met criteria and were included. For the maximum ScvO(2), compared with the mortality rate in the normoxia group of 96 of 465 (21%; 95% confidence interval [CI] 17% to 25%), both the hypoxia mortality rate, 25 of 62 (40%; 95% CI 29% to 53%) and hyperoxia mortality rate, 31 of 92 (34%; 95% CI 25% to 44%) were significantly higher, which remained significant in a multivariate modeling. When the initial ScvO(2) measurement was analyzed in a multivariate model, only hyperoxia was significantly higher. CONCLUSION: The maximum ScvO(2) value achieved in the ED (both abnormally low and high) was associated with increased mortality. In multivariate analysis for initial ScvO(2), the hyperoxia group was associated with increased mortality, but not the hypoxia group. This study suggests that future research aimed at targeting methods to normalize high ScvO(2) values by therapies that improve microcirculatory flow or mitochondrial dysfunction may be warranted.

Continuous cardiac index monitoring: A prospective observational study of agreement between a pulmonary artery catheter and a calibrated minimally invasive technique.

INTRODUCTION: Continuous cardiac index (CCI) monitoring can provide information to assist in hemodynamic support. However, pulmonary artery catheters (PAC) pose logistic challenges in acute care settings. We hypothesized that CCI measured with a calibrated minimally invasive technique (LiDCO/PulseCO, UK) would have good agreement with the PAC. METHODS: We performed a prospective observational study in post-operative cardiac surgery patients. All patients had a PAC with CCI monitoring capability. We connected the LiDCO apparatus to a radial artery line and performed a one-time calibration with a lithium dilution indicator. In order to test the least invasive method possible, we used a peripheral intravenous (IV) line for indicator delivery rather than the conventional central line technique. We recorded paired PAC/LiDCO-PulseCO CCI measurements every minute for 3h. We blinded investigators and clinicians to minimally invasive data with an opaque shield over the monitor. We assessed agreement with Bland-Altman analysis. RESULTS: We obtained 1485 paired measurements in 8 subjects. The mean CI was 2.9L/min/m(2). By Bland-Altman plot, PAC and LiDCO measurements showed minimal bias (-0.01), but the 95% limits of agreement (+/-2SD) of+/-1.3L/min/m(2) were relatively wide with respect to the mean. CONCLUSIONS: This calibrated minimally invasive (i.e. radial arterial line and peripheral IV) technique demonstrated low bias compared with CCI measured by PAC. However, the relatively wide confidence limits indicate that differences in the two measurements could still be clinically significant.

Point-of-care assessment of microvascular blood flow in critically ill patients.

OBJECTIVE: Sublingual microvascular videomicroscopy can assess tissue perfusion in critically ill patients; however, data analysis is currently limited to delayed off-line evaluation. We hypothesized that a real-time point-of-care (POC) determination of the microcirculatory flow index (MFI), an established metric for assessing microcirculatory perfusion, agrees well with the conventional off-line analysis. DESIGN: Prospective observational study. SETTING: Urban academic intensive care unit. PARTICIPANTS: A heterogeneous population of critically ill patients. MEASUREMENTS AND RESULTS: A single operator performed side stream darkfield videomicroscopy of the sublingual microcirculation and made a POC determination of MFI in real-time on a portable bedside monitor by assigning a score (0 = no flow to 3 = normal) to each quadrant of the image and averaging the four values. After image processing, de-identification and randomization, the same operator, blinded to the previous interpretation, repeated the MFI assessment by viewing an AVI-formatted image sequence on a 94 cm 1,080 pixel LCD monitor (reference standard). There were 205 paired measurements in 18 subjects. The POC and reference standard MFI had good agreement by Bland-Altman analysis [mean difference of -0.031, SD = 0.198 (95% CI, -0.43 to 0.37)]. The POC assessment was 94% sensitive and 92% specific for detecting impaired microvascular flow (defined a priori as an MFI < 2.5 based on previously published data). CONCLUSIONS: A POC determination of MFI had good agreement with conventional off-line analysis, and was highly sensitive and specific for detecting impaired microvascular flow. This real-time technique may be useful in future clinical trials targeting impaired microcirculatory perfusion in critically ill patients.

Multicenter study of early lactate clearance as a determinant of survival in patients with presumed sepsis.

We sought to determine (a) if early lactate clearance is associated with improved survival in emergency department patients with severe sepsis and (b) the concordance between central venous oxygen saturation (ScvO2) optimization and lactate clearance during early sepsis resuscitation. Within a multicenter shock research network that uses quantitative resuscitation for severe sepsis, we analyzed prospectively collected registries of consecutive emergency department patients diagnosed with severe sepsis at three urban hospitals. Inclusion criteria are as follows: (a) age older than 17 years, (b) two or more systemic inflammation criteria, (c) systolic blood pressure 90 mmHg or less after fluid challenge or initial lactate of 4 mmol/L or greater, and (d ) initial and repeat lactate measurement within 6 h of resuscitation initiation. We stratified patients into two groups defined a priori based on previously published data: (a) lactate clearance--repeat lactate decrease by 10% or greater from initial (or both initial and repeat levels < or = 2.0 mmol/L), and (b) lactate non-clearance--repeat lactate decrease by less than 10% from initial. The primary outcome was in-hospital mortality. Among 166 patients, lactate non-clearance occurred in 15 (9%) of 166. Mortality was 60% for lactate nonclearance versus 19% for lactate clearance, P < 0.001. On multivariate analysis, lactate non-clearance was an independent predictor of death (odds ratio, 4.9 [confidence interval, 1.5-15.9]). We found discordance between ScvO2 optimization and lactate clearance; 79% of lactate non-clearance had concomitant ScvO2 of 70% or greater. In this multicenter cohort of sepsis patients, failing to clear lactate during resuscitation carried a high risk of death, and ScvO2 optimization did not reliably exclude lactate non-clearance. These data provide rationale for a clinical trial of lactate clearance as a distinct end point of early sepsis resuscitation.

Early increases in microcirculatory perfusion during protocol-directed resuscitation are associated with reduced multi-organ failure at 24 h in patients with sepsis.

OBJECTIVE: Sepsis mortality is closely linked to multi-organ failure, and impaired microcirculatory blood flow is thought to be pivotal in the pathogenesis of sepsis-induced organ failure. We hypothesized that changes in microcirculatory flow during resuscitation are associated with changes in organ failure over the first 24 h of sepsis therapy. DESIGN: Prospective observational study. SETTING: Emergency Department and Intensive Care Unit. PARTICIPANTS: Septic patients with systolic blood pressure <90 mmHg despite intravenous fluids or lactate >or=4.0 mM/L treated with early goal-directed therapy (EGDT). MEASUREMENTS AND RESULTS: We performed Sidestream Dark Field (SDF) videomicroscopy of the sublingual microcirculation <3 h from EGDT initiation and again within a 3-6 h time window after initial. We imaged five sites and determined the mean microcirculatory flow index (MFI) (0 no flow to 3 normal) blinded to all clinical data. We calculated the Sequential Organ Failure Assessment (SOFA) score at 0 and 24 h, and defined improved SOFA a priori as a decrease >or=2 points. Of 33 subjects; 48% improved SOFA over 0-24 h. Age, APACHE II, and global hemodynamics did not differ significantly between organ failure groups. Among SOFA improvers, 88% increased MFI during EGDT, compared to 47% for non-improvers (P = 0.03). Median change in MFI was 0.23 for SOFA improvers versus -0.05 for non-improvers (P = 0.04). CONCLUSIONS: Increased microcirculatory flow during resuscitation was associated with reduced organ failure at 24 h without substantial differences in global hemodynamics. These data support the hypothesis that targeting the microcirculation distinct from the macrocirculation could potentially improve organ failure in sepsis.

Resuscitating the microcirculation in sepsis: the central role of nitric oxide, emerging concepts for novel therapies, and challenges for clinical trials.

Microcirculatory dysfunction is a critical element of the pathogenesis of severe sepsis and septic shock. In this Bench-to-Bedside review, we present: 1) the central role of the microcirculation in the pathophysiology of sepsis; 2) new translational research techniques of in vivo video microscopy for assessment of microcirculatory flow in human subjects; 3) clinical investigations that reported associations between microcirculatory dysfunction and outcome in septic patients; 4) the potential role of novel agents to "rescue" the microcirculation in sepsis; 5) current challenges facing this emerging field of clinical investigation; and 6) a framework for the design of future clinical trials aimed to determine the impact of novel agents on microcirculatory flow and organ failure in patients with sepsis. We specifically focus this review on the central role and vital importance of the nitric oxide (NO) molecule in maintaining microcirculatory homeostasis and patency, especially when the microcirculation sustains an insult (as with sepsis). We also present the scientific rationale for clinical trials of exogenous NO administration to treat microcirculatory dysfunction and augment microcirculatory blood flow in early sepsis therapy.

Serum lactate as a predictor of mortality in patients with infection.

OBJECTIVE: To determine the utility of an initial serum lactate measurement for identifying high risk of death in patients with infection. DESIGN AND SETTING: Post-hoc analysis of a prospectively compiled registry in an urban academic hospital. PARTICIPANTS: Patients with (a) a primary or secondary diagnosis of infection and (b) lactate measurement who were admitted over the 18 months following hospital-wide implementation of the Surviving Sepsis Campaign guideline for lactate measurement in patients with infection and possible severe sepsis. There were 1,177 unique patients, with an in-hospital mortality of 19%. MEASUREMENTS AND RESULTS: Outcome measures included acute-phase (or=4.0 mmol/l and performed a Bayesian analysis to determine its impact on a full range (0.01-0.99) of hypothetical pretest probability estimates for death. In-hospital mortality was 15%, 25%, and 38% in low, intermediate, and high lactate groups, respectively. Acute-phase deaths and in-hospital deaths increased linearly with lactate. An initial lactate >or=4.0 mmol/l was associated with sixfold higher odds of acute-phase death; however, a lactate level less than 4 mmol/l had little impact on probability of death. CONCLUSIONS: When broadly implemented in routine practice, measurement of lactate in patients with infection and possible sepsis can affect assessment of mortality risk. Specifically, an initial lactate >or=4.0 mmol/l substantially increases the probability of acute-phase death.

Early microcirculatory perfusion derangements in patients with severe sepsis and septic shock: relationship to hemodynamics, oxygen transport, and survival.

STUDY OBJECTIVE: To study early microcirculatory perfusion indices in patients with severe sepsis/septic shock, compare early microcirculatory indices in sepsis survivors versus nonsurvivors, and identify systemic hemodynamic/oxygen transport variables that correlate with early microcirculatory perfusion indices. METHODS: This prospective observational study used orthogonal polarization spectral imaging to directly visualize the sublingual microcirculation in patients with severe sepsis/septic shock treated with early goal-directed therapy. We performed initial imaging within 6 hours of early goal-directed therapy initiation and late follow-up studies at 24-hour intervals until death or resolution of organ dysfunction. We imaged 5 sublingual sites and analyzed the data offline in a blinded fashion. We calculated 3 microcirculatory perfusion indices: flow velocity score, flow heterogeneity index, and capillary density. We analyzed early data to compare survivors versus nonsurvivors and examine correlations with systemic hemodynamic measurements. We used a linear mixed-effects model for longitudinal analyses. RESULTS: We performed 66 orthogonal polarization spectral studies in 26 sepsis patients. Early microcirculatory indices were more markedly impaired (lower flow velocity and more heterogeneous perfusion) in nonsurvivors compared with survivors. These same early indices, flow velocity and heterogeneity, were also more markedly impaired with increasing severity of systemic cardiovascular dysfunction (lower arterial pressure or increasing vasopressor requirement). CONCLUSION: Early microcirculatory perfusion indices in severe sepsis and septic shock are more markedly impaired in nonsurvivors compared with survivors and with increasing severity of global cardiovascular dysfunction.