Emanuel P. Rivers

Early lactate clearance is associated with improved outcome in severe sepsis and septic shock

Objective:Serial lactate concentrations can be used to examine disease severity in the intensive care unit. This study examines the clinical utility of the lactate clearance before intensive care unit admission (during the most proximal period of disease presentation) as an indicator of outcome in severe sepsis and septic shock. We hypothesize that a high lactate clearance in 6 hrs is associated with decreased mortality rate. Design:Prospective observational study. Setting:An urban emergency department and intensive care unit over a 1-yr period. Patients:A convenience cohort of patients with severe sepsis or septic shock. Interventions:Therapy was initiated in the emergency department and continued in the intensive care unit, including central venous and arterial catheterization, antibiotics, fluid resuscitation, mechanical ventilation, vasopressors, and inotropes when appropriate. Measurements and Main Results:Vital signs, laboratory values, and Acute Physiology and Chronic Health Evaluation (APACHE) II score were obtained at hour 0 (emergency department presentation), hour 6, and over the first 72 hrs of hospitalization. Therapy given in the emergency department and intensive care unit was recorded. Lactate clearance was defined as the percent decrease in lactate from emergency department presentation to hour 6. Logistic regression analysis was performed to determine independent variables associated with mortality. One hundred and eleven patients were enrolled with mean age 64.9 ± 16.7 yrs, emergency department length of stay 6.3 ± 3.2 hrs, and overall in-hospital mortality rate 42.3%. Baseline APACHE II score was 20.2 ± 6.8 and lactate 6.9 ± 4.6 mmol/L. Survivors compared with nonsurvivors had a lactate clearance of 38.1 ± 34.6 vs. 12.0 ± 51.6%, respectively (p = .005). Multivariate logistic regression analysis of statistically significant univariate variables showed lactate clearance to have a significant inverse relationship with mortality (p = .04). There was an approximately 11% decrease likelihood of mortality for each 10% increase in lactate clearance. Patients with a lactate clearance ≥10%, relative to patients with a lactate clearance <10%, had a greater decrease in APACHE II score over the 72-hr study period and a lower 60-day mortality rate (p = .007). Conclusions:Lactate clearance early in the hospital course may indicate a resolution of global tissue hypoxia and is associated with decreased mortality rate. Patients with higher lactate clearance after 6 hrs of emergency department intervention have improved outcome compared with those with lower lactate clearance.

Early Goal-Directed Therapy in Severe Sepsis and Septic Shock Revisited: Concepts, Controversies, and Contemporary Findings

Studies of acute myocardial infarction, trauma, and stroke have been translated into improved outcomes by earlier diagnosis and application of therapy at the most proximal stage of hospital presentation. Most therapies for these diseases are instituted prior to admission to an ICU; this approach to the sepsis patient has been lacking. In response, a trial comparing early goal-directed therapy (EGDT) vs standard care was performed using specific criteria for the early identification of high-risk sepsis patients, verified definitions, and a consensus-derived protocol to reverse the hemodynamic perturbations of hypovolemia, vasoregulation, myocardial suppression, and increased metabolic demands. Five years after the EGDT publication, there has been much discussion generated with regard to the concepts of EGDT, as well as debate fueled regarding diagnostic and therapeutic interventions. However, during this time period further investigations by the primary investigators and others have brought additional contemporary findings. EGDT modulates some of the components of inflammation, as reflected by improved organ function. The end points used in the EGDT protocol, the outcome results, and the cost-effectiveness have subsequently been externally validated, revealing similar or even better findings than those from the original trial. Although EGDT is faced with challenges, a coordinated approach to sepsis management is necessary to duplicate the progress in outcomes seen in patients with conditions such as acute myocardial infarction, stroke, and trauma.

Resuscitation of the critically III in the ED: Responses of blood pressure, heart rate, shock index, central venous oxygen saturation, and lactate☆

To describe the simultaneous responses of systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial blood pressure (MAP), heart rate (HR), shock index (SI = HR/SBP), central venous oxyhemoglobin saturation (ScvO2), and arterial blood lactate concentration (Lact) to resuscitation of critically ill patients in the emergency department (ED), an observational descriptive study was conducted in the ED of an urban teaching hospital. Thirty- six patients admitted from the ED to the medical intensive care unit were studied. Vital signs were measured immediately on arrival to the ED (phase 1). After initial resuscitation and stabilization, ie, HR between 50 and 120 beats/min and MAP between 70 and 110 mm Hg (phase 2), ScvO2 and Lact were measured and additional therapy was given in the ED to increase ScvO2 to > 65% and decrease Lact to < 2 mmol/L, if needed (phase 3). SBP, DBP, MAP, HR. SI, ScvO2, and Lact were measured. Initial resuscitation increased SBP from 103 +/- 39 to 118 +/- 29 mm Hg (P < .05) and MAP from 67 +/- 35 to 82 +/- 22 mm Hg (P < .05) but did not affect DBP (53 +/- 35 to 63 +/- 22 mm Hg, P = NS), HR (110 +/- 26 to 110 +/- 22 beats/min, P = NS) or SI (from 1.3 +/- 0.7 to 1.0 +/- 0.3, P =NS) from phase 1 to phase 2. ScvO2 remained < 65% and/or Lact > 2.0 mmol/L in 31 of 36 patients at phase 2, and additional therapy was required. Lact was decreased (from 4.6 +/- 3.8 to 2.6 +/- 2.5 mmol/L, P < .05) and ScvO2 was increased (from 52 +/- 18 to 65 +/- 13%, P < .05) without significant additional changes in SBP, DBP, MAP, HR, or SI at phase 3. The in-hospital mortality was 14% for this group of patients. It was concluded that additional therapy is required in the majority of critically ill patients to restore adequate systemic oxygenation after initial resuscitation and hemodynamic stabilization in the ED. Additional therapy to increase ScvO2 and decrease Lact may not produce substantial responses in SBP, DBP, MAP, HR, and SI. The measurement of ScvO2 and Lact can be utilized to guide this phase of additional therapy in the ED.

Central venous oxygen saturation monitoring in the critically ill patient

In the initial treatment of a critically ill patient, blood pressure, heart rate, urine output, and central venous pressure guide resuscitative efforts. Despite normalization of these variables, global tissue hypoxia may still persist and has been implicated in the development of multiorgan failure and increased mortality. Definitive management includes intensive care unit admission, pulmonary artery catheterization using mixed venous oxygen saturation (SvO2), and hemodynamic optimization. In the absence of or before definitive management, hemodynamic optimization can be performed using central venous oxygen saturation (ScvO2) as a surrogate. The physiology, technology, clinical uses, and rationale for ScvO2 monitoring are reviewed, including issues regarding physiologic equivalence to SvO2. The clinical use of ScvO2 monitoring, evidence-based outcome implications, and limitations of ScvO2 monitoring will also be examined.

A comparison of the shock index and conventional vital signs to identify acute, critical illness in the emergency department.

STUDY OBJECTIVE Shock index (SI) (heart rate/systolic blood pressure; normal range, 0.5 to 0.7) and conventional vital signs were compared to identify acute critical illness in the emergency department. DESIGN Quasi-prospective study. PATIENTS Two hundred seventy-five consecutive adults who presented for urgent medical care. INTERVENTIONS Patients had vital signs, SI, and triage priority recorded on arrival in the ED and then their final disposition. RESULTS Two groups were identified retrospectively by the SI; group 1 (41) had an SI of more than 0.9, and group 2 (234) had an SI of less than 0.9 on arrival in the ED. Although both groups had apparently stable vital signs on arrival, group 1 had a significantly higher proportion of patients who were triaged to a priority requiring immediate treatment (23 versus 45; P < .01) and required admission to the hospital (35 versus 105; P < .01) and continued therapy in an ICU (10 versus 13; P < .01). CONCLUSION With apparently stable vital signs, an abnormal elevation of the SI to more than 0.9 was associated with an illness that was treated immediately, admission to the hospital, and intensive therapy on admission. The SI may be useful to evaluate acute critical illness in the ED.

Postgraduate Education CornerEarly Goal-Directed Therapy in Severe Sepsis and Septic Shock Revisited: Concepts, Controversies, and Contemporary Findings

Studies of acute myocardial infarction, trauma, and stroke have been translated into improved outcomes by earlier diagnosis and application of therapy at the most proximal stage of hospital presentation. Most therapies for these diseases are instituted prior to admission to an ICU; this approach to the sepsis patient has been lacking. In response, a trial comparing early goal-directed therapy (EGDT) vs standard care was performed using specific criteria for the early identification of high-risk sepsis patients, verified definitions, and a consensus-derived protocol to reverse the hemodynamic perturbations of hypovolemia, vasoregulation, myocardial suppression, and increased metabolic demands. Five years after the EGDT publication, there has been much discussion generated with regard to the concepts of EGDT, as well as debate fueled regarding diagnostic and therapeutic interventions. However, during this time period further investigations by the primary investigators and others have brought additional contemporary findings. EGDT modulates some of the components of inflammation, as reflected by improved organ function. The end points used in the EGDT protocol, the outcome results, and the cost-effectiveness have subsequently been externally validated, revealing similar or even better findings than those from the original trial. Although EGDT is faced with challenges, a coordinated approach to sepsis management is necessary to duplicate the progress in outcomes seen in patients with conditions such as acute myocardial infarction, stroke, and trauma.

The influence of early hemodynamic optimization on biomarker patterns of severe sepsis and septic shock.

Background:Despite abundant experimental studies of biomarker patterns in early severe sepsis and septic shock, human data are few. Further, the impact of the severity of global tissue hypoxia resulting from resuscitative strategies on these early biomarker patterns remains unknown. Methods:The temporal patterns of interleukin-1 receptor antagonist, intercellular adhesion molecule-1, tumor necrosis factor-&agr;, caspase-3, and interleukin-8 were serially examined over the first 72 hrs of hospitalization after early hemodynamic optimization strategies of early goal-directed vs. standard therapy for severe sepsis and septic shock patients. The relationship of these biomarker patterns to each hemodynamic optimization strategy, severity of global tissue hypoxia (reflected by lactate and central venous oxygen saturation), organ dysfunction, and mortality were examined. Results:Abnormal biomarker levels were present upon hospital presentation and modulated to distinct patterns within 3 hrs based on the hemodynamic optimization strategy. The temporal expression of these patterns over 72 hrs was significantly associated with the severity of global tissue hypoxia, organ dysfunction, and mortality. Conclusion:In early severe sepsis and septic shock, within the first 3 hrs of hospital presentation, distinct biomarker patterns emerge in response to hemodynamic optimization strategies. A significant association exists between temporal biomarker patterns in the first 72 hrs, severity of global tissue hypoxia, organ dysfunction, and mortality. These findings identify global tissue hypoxia as an important contributor to the early inflammatory response and support the role of hemodynamic optimization in supplementing other established therapies during this diagnostic and therapeutic “window of opportunity.”

Sepsis: An integrated clinico-metabolomic model improves prediction of death in sepsis

A molecular signature, derived from integrated analysis of clinical data, the metabolome, and the proteome in prospective human studies, improved the prediction of death in patients with sepsis, potentially identifying a subset of patients who merit intensive treatment. Understanding Survival of the Fittest in Sepsis Differentiating mild infections from life-threatening ones is a complex decision that is made millions of times a year in U.S. emergency rooms. Should a patient be sent home with antibiotics and chicken soup? Or should he or she be hospitalized for intensive treatment? Sepsis—a serious infection that is associated with a generalized inflammatory response—is one of the leading causes of death. In two prospective clinical studies reported by Langley et al., patients arriving at four urban emergency departments with symptoms of sepsis were evaluated clinically and by analysis of their plasma proteome and metabolome. Survivors and nonsurvivors at 28 days were compared, and a molecular signature was detected that appeared to differentiate these outcomes—even as early as the time of hospital arrival. The signature was part of a large set of differences between these groups, showing that better energy-producing fatty acid catabolism was associated with survival of the fittest in sepsis. A test developed from the signature was able to predict sepsis survival and nonsurvival reproducibly and better than current methods. This test could help to make all important decisions in the emergency room more accurate. Sepsis is a common cause of death, but outcomes in individual patients are difficult to predict. Elucidating the molecular processes that differ between sepsis patients who survive and those who die may permit more appropriate treatments to be deployed. We examined the clinical features and the plasma metabolome and proteome of patients with and without community-acquired sepsis, upon their arrival at hospital emergency departments and 24 hours later. The metabolomes and proteomes of patients at hospital admittance who would ultimately die differed markedly from those of patients who would survive. The different profiles of proteins and metabolites clustered into the following groups: fatty acid transport and β-oxidation, gluconeogenesis, and the citric acid cycle. They differed consistently among several sets of patients, and diverged more as death approached. In contrast, the metabolomes and proteomes of surviving patients with mild sepsis did not differ from survivors with severe sepsis or septic shock. An algorithm derived from clinical features together with measurements of five metabolites predicted patient survival. This algorithm may help to guide the treatment of individual patients with sepsis.

A prospective, multicenter derivation of a biomarker panel to assess risk of organ dysfunction, shock, and death in emergency department patients with suspected sepsis

Objective:To define a biomarker panel to predict organ dysfunction, shock, and in-hospital mortality in emergency department (ED) patients with suspected sepsis. Design:Prospective observational study. Setting:EDs of ten academic medical centers. Patients:There were 971 patients enrolled. Inclusion criteria: 1) ED patients age > 18; 2) suspected infection or a serum lactate level > 2.5 mmol/L; and 3) two or more systemic inflammatory response syndrome criteria. Exclusion criteria: pregnancy, do-not-resuscitate status, or cardiac arrest. Measurements and Main Results:Nine biomarkers were assayed from blood draws obtained on ED presentation. Multivariable logistic regression was used to identify an optimal combination of biomarkers to create a panel. The derived formula for weighting biomarker values was used to calculate a “sepsis score,” which was the predicted probability of the primary outcome of severe sepsis (sepsis plus organ dysfunction) within 72 hrs. We also assessed the ability of the sepsis score to predict secondary outcome measures of septic shock within 72 hrs and in-hospital mortality. The overall rates of each outcome were severe sepsis, 52%; septic shock, 39%; and in-hospital mortality 7%. Among the nine biomarkers tested, the optimal 3-marker panel was neutrophil gelatinase-associated lipocalin, protein C, and interleukin−1 receptor antagonist. The area under the curve for the accuracy of the sepsis score derived from these three biomarkers was 0.80 for severe sepsis, 0.77 for septic shock, and 0.79 for death. When included in multivariate models with clinical variables, the sepsis score remained highly significant (p < 0.001) for all the three outcomes. Conclusions:A biomarker panel of neutrophil gelatinase-associated lipocalin, interleukin-1ra, and Protein C was predictive of severe sepsis, septic shock, and death in ED patients with suspected sepsis. Further study is warranted to prospectively validate the clinical utility of these biomarkers and the sepsis score in risk-stratifying patients with suspected sepsis.

Continuous central venous oximetry and shock index in the emergency department: Use in the evaluation of clinical shock

Initial therapy of shock in the emergency department (ED) emphasizes the normalization of physiologic variables such as heart rate (HR), mean arterial pressure (MAP), and central venous pressure (CVP) rather than restoration of adequate tissue oxygenation. After hemodynamic stabilization of MAP, CVP, and HR, the authors examined tissue oxygenation as indicated by continuous central venous oximetry (SCVO2), lactic acid concentration, and shock index (SI). Sixteen consecutive nonrandomized patients presenting to the ED of a large urban hospital in shock (MAP < 60 mm Hg, HR > 120 beats/min, and altered sensorium) were initially resuscitated with fluid, blood, inotropes, and/or vasoactive drug therapy to normalize MAP, CVP, and HR. In addition, SCVO2, arterial lactate concentration, and SI were measured after completion of resuscitation in the ED. Eight patients (group no. 1) had inadequate tissue oxygenation reflected by low SCVO2 (less than 65%). Four patients in group no. 1 had elevated arterial lactic acid concentration. All group no. 1 patients had an elevated SI (> 0.7) suggesting persistent impairment of left ventricular stroke work. Eight patients (group no. 2) had normal or elevated SCVO2 (> 65%). In group no. 2, arterial lactic acid concentration was elevated in six and SI in seven patients. Normalization of hemodynamic variables does not adequately reflect the optimal endpoint of initial therapy in shock in the ED. Most (94%) of these patients continue to have significant global ischemia and cardiac dysfunction as indicated by reduced SCVO2 and elevated lactic acid concentration and SI. Systemic tissue oxygenation should be monitored and optimized in the ED in these critically ill patients.(ABSTRACT TRUNCATED AT 250 WORDS)