Ryan C. Arnold

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.

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.

Multicenter Study of Central Venous Oxygen Saturation (ScvO2) 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.

Biomarkers of endothelial cell activation in early sepsis.

Purpose The objective of this study was to investigate the association of endothelial-related markers with organ dysfunction and in-hospital mortality to validate our earlier findings in a multicenter study. We hypothesize that (i) endothelial biomarkers will be associated with organ dysfunction and mortality in sepsis and that (ii) soluble fms-like tyrosine kinase 1 (sFlt-1) holds promise as a novel prognostic marker in sepsis. Methods This was a prospective, multicenter, observational study of a convenience sample of emergency department (ED) patients with a suspected infection presenting to one of four urban, academic medical center EDs between January 2009 and January 2010. We collected plasma while the patients were in the ED and subsequently assayed endothelial-related biomarkers, namely, sFlt-1, soluble E-selectin, soluble intercellular adhesion molecule 1, soluble vascular cell adhesion molecule 1, and plasminogen activator inhibitor 1 (PAI-1). Outcomes were organ dysfunction and in-hospital mortality. Results We enrolled a total of 166 patients: 63 with sepsis (38%), 61 with severe sepsis (37%), and 42 with septic shock (25%). All endothelial biomarkers were significantly associated with sepsis severity, P < 0.002. We found a significant intercorrelation between all biomarkers, strongest between sFlt-1 and PAI-1 (r = 0.61, P < 0.001) and PAI-1 and soluble E-selectin and soluble intercellular adhesion molecule 1 (r = 0.49, P < 0.001). Among the endothelial biomarkers, sFlt-1 had the strongest association with Sequential Organ Failure Assessment score (r = 0.58, P < 0.001). Soluble fms-like tyrosine kinase 1 and PAI-1 had the highest area under the operating receiver characteristic curve for mortality of 0.87. Conclusions This multicenter validation study confirms that markers of endothelial activation are associated with sepsis severity, organ dysfunction, and mortality in sepsis. This supports the hypothesis that the endothelium plays a central role in the pathophysiology of sepsis and may serve as a more accurate prediction tool and a target for therapies aimed at ameliorating endothelial cell dysfunction. In addition, sFLT-1 holds promise as a novel sepsis severity biomarker.

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.

Heparin-Binding Protein Measurement Improves the Prediction of Severe Infection With Organ Dysfunction in the Emergency Department.

Objectives: Early identification of patients with infection and at risk of developing severe disease with organ dysfunction remains a difficult challenge. We aimed to evaluate and validate the heparin-binding protein, a neutrophil-derived mediator of vascular leakage, as a prognostic biomarker for risk of progression to severe sepsis with circulatory failure in a multicenter setting. Design: A prospective international multicenter cohort study. Setting: Seven different emergency departments in Sweden, Canada, and the United States. Patients: Adult patients with a suspected infection and at least one of three clinical systemic inflammatory response syndrome criteria (excluding leukocyte count). Intervention: None. Measurements and Main Results: Plasma levels of heparin-binding protein, procalcitonin, C-reactive protein, lactate, and leukocyte count were determined at admission and 12–24 hours after admission in 759 emergency department patients with suspected infection. Patients were defined depending on the presence of infection and organ dysfunction. Plasma samples from 104 emergency department patients with suspected sepsis collected at an independent center were used to validate the results. Of the 674 patients diagnosed with an infection, 487 did not have organ dysfunction at enrollment. Of these 487 patients, 141 (29%) developed organ dysfunction within the 72-hour study period; 78.0% of the latter patients had an elevated plasma heparin-binding protein level (> 30 ng/mL) prior to development of organ dysfunction (median, 10.5 hr). Compared with other biomarkers, heparin-binding protein was the best predictor of progression to organ dysfunction (area under the receiver operating characteristic curve = 0.80). The performance of heparin-binding protein was confirmed in the validation cohort. Conclusion: In patients presenting at the emergency department, heparin-binding protein is an early indicator of infection-related organ dysfunction and a strong predictor of disease progression to severe sepsis within 72 hours.

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.

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.

Proceedings from the Montebello Round Table Discussion. Second annual conference on Complexity and Variability discusses research that brings innovation to the bedside.

Abstract : September 28 October 1 2010. Montebello, Quebec: Scientists, mathematicians, and physicians from across Canada, United States, and France were invited to participate in the second round table discussion on Complexity and Vari ability at the Bedside to present research, discuss, methodology, and promote applications of variability analysis a novel method for continuous monitoring of variations in physiological systems at the bedside of patients. Recent advancements in research and technology of variability analysis may significantly improve the care provided to patients afflicted with acute and critical illness. Using mathematical models to analyze data harvested from heart, respiratory, and brain monitors at the bedside of adults and children, preliminary findings show that doctors in intensive care units (ICUs) and acute ambulatory clinics can better determine severity of certain diseases, such as trauma and asthma, and may even predict the onset of illness, such as septic shock. It has been reported that sepsis, a systemic inflammatory response to an infection, strikes an estimated 750 000 adults in the United States annually, with 215 000 deaths per year. It costs the US health care system an average of

Prospective multicenter study of the effect of early fluid resuscitation on trends in IL-6 and TNFα levels in severe sepsis

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