MULTICENTER STUDY OF EARLY LACTATE CLEARANCE AS A DETERMINANT OF SURVIVAL IN PATIENTS WITH PRESUMED SEPSIS

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1 SHOCK, Vol. 32, No. 1, pp. 35Y39, 2009 MULTICENTER STUDY OF EARLY LACTATE CLEARANCE AS A DETERMINANT OF SURVIVAL IN PATIENTS WITH PRESUMED SEPSIS Ryan C. Arnold,* Nathan I. Shapiro, Alan E. Jones, Christa Schorr, Jennifer Pope, Elisabeth Casner, Joseph E. Parrillo, R. Phillip Dellinger, Stephen Trzeciak,* and on behalf of the Emergency Medicine Shock Research Network (EMShockNet) Investigators *Department of Emergency Medicine, UMDNJ-Robert Wood Johnson Medical School at Camden, Cooper University Hospital, Camden, New Jersey; Department of Emergency Medicine, Beth Israel Deaconess Medical Center Boston, Massachusetts; Department of Emergency Medicine, Carolinas Medical Center, Charlotte, North Carolina; and Department of Medicine, Divisions of Cardiovascular Disease and Critical Care Medicine, UMDNJ-Robert Wood Johnson Medical School at Camden, Cooper University Hospital, Camden, New Jersey Received 31 Oct 2008; first review completed 05 Nov 2008; accepted in final form 19 Nov 2008 ABSTRACT 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 (ScvO 2 ) 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 4mmol/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 clearancevrepeat lactate decrease by 10% or greater from initial (or both initial and repeat levels e2.0 mmol/l), and (b) lactate non-clearancevrepeat 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 G On multivariate analysis, lactate non-clearance was an independent predictor of death (odds ratio, 4.9 [confidence interval, 1.5Y15.9]). We found discordance between ScvO 2 optimization and lactate clearance; 79% of lactate non-clearance had concomitant ScvO 2 of 70% or greater. In this multicenter cohort of sepsis patients, failing to clear lactate during resuscitation carried a high risk of death, and ScvO 2 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. KEYWORDS Shock, severe sepsis, resuscitation, lactic acid, emergency medicine INTRODUCTION Severe sepsis is the most common cause of death in critically ill patients (1). The effectiveness of early resuscitation is an important determinant of sepsis survival (2). Specifically, early quantitative resuscitation, the use of a structured set of cardiovascular interventions targeting predefined hemodynamic end points, can have a profound effect on hospital mortality (3). Currently, international consensus treatment guidelines recommend a quantitative resuscitation strategy that includes targeting central venous oxygen saturation (ScvO 2 ) of 70% or greater in the first 6 h of severe sepsis therapy (4). However, the optimal end points of sepsis resuscitation remain controversial (5, 6). Serum lactate elevation is an important marker of impaired tissue perfusion in patients with sepsis and is often elevated even Address reprint requests to Ryan C. Arnold, MD, Department of Emergency Medicine UMDNJ-Robert Wood Johnson Medical School at Camden Cooper University Hospital, One Cooper Plaza, Camden, NJ arnold-ryan@ cooperhealth.edu. Funding: Dr Trzeciak s effort to this project was supported by a grant from the National Institutes of Health/National Institutes of General Medical Sciences (K23GM83211). Dr Jones effort to this project was supported by a grant from the National Institutes of Health/National Institutes of General Medical Sciences (K23GM76652). DOI: /SHK.0b013e d47 Copyright Ó 2009 by the Shock Society in the absence of arterial hypotension (7). Numerous studies show that a single early lactate measurement has important prognostic significance and predicts mortality in populations of patients with infection (8, 9). A small number of studies have previously reported that serial measurements of lactate have potential prognostic value during conventional sepsis management (10Y12); however, it is not known if lactate clearance is associated with survival in the context of medical centers that have adopted and routinely perform aggressive quantitative resuscitation for severe sepsis. In addition, it is not known if lactate clearance is important independent of other recommended quantitative resuscitation end points, specifically ScvO 2. The objectives of this study were to determine (a) if early lactate clearance is associated with improved survival in emergency department (ED) patients with severe sepsis and (b) the concordance between ScvO 2 optimization and lactate clearance during early sepsis resuscitation. METHODS Setting and study design We analyzed prospectively collected registries of consecutive ED patients diagnosed with severe sepsis at three urban hospitals. The three hospitals are part of a multicenter research collaborative (Emergency Medicine Shock Research Network) (13), where each institution uses ED-based protocoly directed quantitative resuscitation for patients with severe sepsis (14Y16). The registries were compiled between 2004 and 2007 and were approved 35

2 36 SHOCK VOL. 32, NO. 1 ARNOLD ET AL. FIG. 1. Quantitative resuscitation protocol. Common elements of the resuscitation protocols in the ED of each participating center (14Y16) (based on international consensus guidelines from the Surviving Sepsis Campaign [2004]). by the institutional review board at each institution. Of the 166 subjects in this report, the subjects from one center (n = 110) were a subset of a total of 1,352 patients in two prior publications (8, 15), and the remainder were previously unpublished. Neither of the previous reports was focused on serial lactate measurement in sepsis. Participants The inclusion criteria were based on consensus definitions for severe sepsis (17) and included (a) age older than 17 years, (b) suspected infection, (c) two or more criteria of the systemic inflammatory response syndrome, (d) either a systolic blood pressure (SBP) less than 90 mmhg after 20 ml/kg or greater i.v. fluid or an initial serum lactate 4 mmol/l or greater, (e) initial and repeat lactate measurement within 6 h of resuscitation initiation, and (e) intensive care unit admission. Interventions Consistent with international treatment guidelines for patients with severe sepsis and evidence of tissue hypoperfusion (hypotension after i.v. fluids or initial lactate Q4 mmol/l) (4), each participating center uses a similar quantitative resuscitation algorithm targeting normalization of ScvO 2 (Q70%) in the ED (14Y16). Figure 1 displays elements of the resuscitation protocol common to each center. The registry used in this study was designed to measure the achievement of each goal within the protocol as a dichotomous variable (yes/no) at specified time intervals (i.e., 6 h). We did not accrue specific data on the use of red blood cell transfusion, dobutamine use, or time of antibiotic administration. ScvO 2 was measured using a central venous catheter inserted into the superior vena cava via internal jugular or subclavian venous access that provides continuous measurement of ScvO 2 via reflection spectrophotometry (Edwards Lifesciences, Irvine, Calif). Treatment algorithms at each center mandate the measurement of an initial serum lactate in the ED. Obtaining a repeat lactate level is not a mandated practice at any of the centers and is obtained at the discretion of the treating clinician. All lactate assessments were obtained from venous blood samples and were measured according to local institutional standard methods using a central laboratory at two centers and a point-of-care analyzer (Abbott Point of Care, Abbott Park, Ill) at the third center. Data collection Using a standardized data abstraction template, we queried each of the three registries and collected the following data: demographics, suspected source of infection, vital signs, initial and repeat serum lactate concentrations, laboratory values for organ failure assessment, and outcome information. Illness severity was defined using the presence of individual organ system failures as assessed by the worst recorded values for each organ system while in the ED: cardiovascular = initial SBP less than 90 mmhg; pulmonary = new oxygen requirement or PaO 2 /FIO 2 less than 300 or SpO 2 /FIO 2 less than 221; renal = serum creatinine more than 2.0 mg/dl; hepatic = serum bilirubin greater than 2.0 mg/dl; hematologic = platelets less than 100,000/2L or international normalized ratio more than 1.5 sec (18); and calculation of the Sequential Organ Failure Assessment (SOFA) score (19) as modified by Vincent et al. (20). Data analysis To determine the association between lactate clearance and mortality, we stratified patients into two groups defined a priori based on previously published data (12): (a) lactate clearancevrepeat lactate decrease by 10% or greater from initial (or both initial and repeat levels e2.0 mmol/l), and (b) lactate non-clearancevrepeat lactate decrease by less than 10% from initial. The primary outcome was in-hospital mortality. We wanted to determine if ScvO 2 optimization during resuscitation could reliably exclude lactate non-clearance; therefore, we evaluated the concordance between achievement of ScvO 2 optimization (Q70%) and lactate clearance goals (Q10%) over the first 6 h of resuscitation using a 2 2 table. Statistical analysis We analyzed the difference in proportions of death between lactate clearance and non-clearance groups using the binomial test and the associated 95% confidence intervals (CIs) and P values. All other variables between lactate clearance versus lactate non-clearance groups and between survivors versus nonsurvivors were compared using the binomial test or Student t test when appropriate. We performed multivariate logistic regression analysis using candidate variables that were significantly different (P G 0.05) between survivors and nonsurvivors on bivariate analysis, with in-hospital mortality as the dependent variable. We used SigmaStat (v. 3.5; Systat, Chicago, Ill) for all analyses. Sample size estimate We estimated the necessary sample size based on the following assumptions: (a) a predicted mortality rate of 25% overall (based on previously published experience with quantitative resuscitation for severe sepsis at the three centers) (14Y16); (b) an event (death) per variable ratio of

3 SHOCK JULY 2009 EARLY LACTATE CLEARANCE IN SEPSIS RESUSCITATION 37 TABLE 1. Characteristics of the study cohort (n = 166) Age, mean (SD), y 66 (15) Sex, % female, n (%) 83 (50) Suspected source of infection in ED, n (%) Urinary tract 46 (28) Pneumonia 22 (13) Skin/soft tissue 23 (14) Intra-abdominal 14 (8) Line/device 10 (6) Other 7 (4) Unknown primary source 44 (27) Signs of systemic inflammation, n (%) Body temperature 938-C org36-c 131 (79) Heart rate 990 beats/min 140 (84) Respiratory rate 920 breaths/min 137 (83) White blood cell count, 912,000 or G4,000/2L 121 (73) SBP G90 mmhg despite i.v. fluids, n (%) 91 (55) Initial serum lactate 94 mmol/l, n (%) 90 (54) Vasopressor use in ED, n (%) 39 (23) Individual organ failures, n (%) Cardiovascular 63 (44) Pulmonary 28 (17) Renal 54 (33) Hepatic 14 (8) Coagulopathy 23 (14) Acidosis 140 (84) Total SOFA score, mean (SD) 3.6 (2.6) Mortality, n (%) 38 (23) SOFA, Sequential Organ Failure Assessment; ED, Emergency Department. TABLE 2. Lactate clearance versus lactate non-clearance Lactate clearance (n = 151) Lactate non-clearance (n = 15) P Age, mean (SD), y 67 (15) 62 (16) 0.22 SBP G90 mmhg despite i.v. 50 (33) 13 (87) 0.02 fluids, n (%) Initial serum lactate, mean (SD) 4.5 (2.7) 3.9 (1.7) 0.08 Serial serum lactate, mean (SD) 2.3 (1.8) 5.1 (2.9) G0.001 Vasopressor usage, n (%) 87 (58) 11 (73) 0.39 Individual organ failure, n (%) Cardiovascular 50 (33) 13 (87) G0.001 Pulmonary 25 (17) 3 (20) 0.94 Renal 48 (32) 6 (40) 0.73 Hepatic 12 (8) 2 (13) 0.86 Coagulopathy 18 (12) 5 (33) 0.06 Total SOFA score, mean (SD) 3.6 (2.6) 4.1 (2.3) 0.47 Continuous ScvO 2 monitoring, 134 (81) 14 (93) 0.42 n (%) ScvO 2 Q70% achieved 114 (85) 11 (79) 0.84 Mortality, n (%) 29 (19) 9 (60) G0.001 Characteristics of study subjects with lactate clearance (910%) and nonclearance (G10%) over the first 6 h (n = 166). SOFA, Sequential Organ Failure Assessment; ED, Emergency Department. FIG. 2. Kaplan-Meier survival curves. This graph depicts survival curves over time for lactate clearance (lactate decrease by Q10%) and lactate nonclearance (lactate decrease G10%) groups. The curves diverge significantly by log-rank test (P = 0.003). 10:1 necessary for multivariate modeling (21, 22); and (c) the multivariate model would need to, at a minimum, include the following covariates that have previously been shown to differentiate sepsis survivors from nonsurvivors: arterial hypotension (23), failure to achieve ScvO 2 70% or greater (2), and lactate non-clearance (12). To accrue the necessary 30 cases of mortality to test these three covariates in a multivariate model, we estimated that a minimum of 120 total cases would be necessary. RESULTS Characteristics of study cohort There were 166 subjects who met inclusion criteria. The overall mortality rate was 23% (38/166). Table 1 shows characteristics of the entire cohort. Of the 166 subjects, 110 came from center 1, 22 came from center 2, and 34 came from center 3. Using multivariate analysis, there was no apparent center effect on in-hospital mortality. The quantitative resuscitation algorithm targeting ScvO 2 70% or greater was successfully initiated in the ED in 148 (89%) of 166 study subjects. Study patients received an average of 4.4 L (95% CI, 4.1Y4.7 L) of i.v. crystalloid fluid during their ED resuscitation. Lactate non-clearance occurred in 15 (9%) of 166, and the remainder (151/166, 91%) cleared lactate. Lactate clearance versus lactate non-clearance Table 2 displays data for comparison between lactate clearance and lactate non-clearance groups. Mortality was 60% in the lactate non-clearance group versus 19% in the lactate clearance group (proportion difference, 41% [95% CI, 19%Y63%; P G 0.001]). Vasopressor use was not significantly dissimilar between the groups (lactate non-clearance: 11/15 or 73%, and lactate clearance: 87/151 or 58%; P = 0.39). Figure 2 displays the Kaplan-Meier curves for survival fractions over time. The curves diverge significantly by log-rank test (P = 0.003). There was no significant difference in achievement of TABLE 3. Lactate clearance and ScvO 2 goals Lactate non-clearance Lactate clearance Total ScvO 2 G70% ScvO 2 Q70% Among 148 subjects in whom ScvO 2 was targeted as an end point of resuscitation, this table depicts the lack of concordance between lactate clearance and ScvO 2. There was no evidence of a relationship between lactate clearance and ScvO 2 (Fisher exact test, P = 0.457).

4 38 SHOCK VOL. 32, NO. 1 ARNOLD ET AL. TABLE 4. Survivors versus nonsurvivors (n = 166) Survivors (n = 128) Nonsurvivors (n = 38) P Age, mean (SD), y 66 (15) 66 (16) 1.00 SBP G90 mmhg despite i.v. 42 (33) 21 (55) 0.02 fluids, n (%) Initial serum lactate, mean (SD) 4.3 (2.6) 4.7 (2.8) 0.41 Serial serum lactate, mean (SD) 2.2 (1.6) 3.6 (2.8) G0.001 Individual organ failure, n (%) Cardiovascular 42 (33) 21 (55) 0.02 Pulmonary 20 (16) 8 (21) 0.64 Renal 43 (34) 11 (29) 0.70 Hepatic 9 (7) 5 (13) 0.40 Coagulopathy 15 (12) 8 (21) 0.26 Total SOFA score, mean (SD) 3.6 (2.6) 3.7 (2.7) 0.84 Continuous ScvO 2 monitoring, n (%) 112 (87) 36 (95) 0.28 ScvO 2 Q70% achieved, n (%) 99 (88) 26 (72) 0.03 Lactate clearance Q10%, n (%) 122 (95) 29 (76) the ScvO 2 goal between the two groups (85% lactate clearance vs. 79% lactate non-clearance; proportional difference, 6% [95% CI, j14% to 26%]; P = 0.84). Table 3 is a 2 2 table comparing the concordance of ScvO 2 measurement with lactate clearance. There was no evidence of a relationship between lactate clearance and ScvO 2 (Fisher exact test, P = 0.457). We found discordance between the two measurements. Specifically, 79% of lactate non-clearance had concomitant ScvO 2 70% or greater. Survivors versus nonsurvivors Table 4 compares survivors with nonsurvivors. On bivariate analysis, there were four factors that were significantly different (P G 0.05) between survivors and nonsurvivors: (a) initial cardiovascular organ failure (initial SBP G90 mmhg), (b) persistent hypotension (SBP G90 mmhg) despite intravenous fluids, (c) maximum ScvO 2 less than 70%, and (d ) lactate non-clearance. Table 5 shows the results for the multivariate logistic regression model. Because ScvO 2 had a significant association with mortality in the bivariate analysis, we limited the regression model to include only subjects in whom ScvO 2 was measured continuously (n = 148). We omitted one of the two hypotension-related covariates (initial SBP G90 mmhg) from inclusion in the model on the grounds that it could be collinear with the persistent hypotension covariate. Lactate nonclearance was found to be a strong independent predictor of inhospital mortality (odds ratio, 4.9; 95% CI, 1.5Y15.9). DISCUSSION In this multicenter sample of ED patients with severe sepsis, we found that early lactate clearance was a strong independent predictor of in-hospital death. In addition, optimization of ScvO 2 during resuscitation was not sufficient to exclude lactate non-clearance. This is the first study to evaluate the impact of lactate clearance on survival in the presence of a protocol-directed quantitative resuscitation algorithm for the treatment of patients with severe sepsis, and to date, this is the largest study evaluating lactate clearance in patients with sepsis (10Y12). The cause of an elevated serum lactate in patients with sepsis can be multifactorial. Although lactate elevation may result from acute tissue hypoperfusion and anaerobic metabolism (24), other possible causes may include (a) sepsisinduced impairment of pyruvate-dehydrogenase enzyme activity (25), (b) increased lactate production via catecholamine-driven pathways (26Y28), and (c) decreased lactate clearance due to hepatic dysfunction (29, 30). However, regardless of etiology of an elevated serum lactate, lactate elevation in sepsis has been consistently linked to increased mortality (7Y12). Although initial reports of lactate clearance in sepsis were published more than 15 years ago (10), evaluating lactate trends during resuscitation is not yet part of the current consensus recommendations for sepsis management (4) and is not routinely performed in practice. While optimizing ScvO 2 could in theory be a single comprehensive monitor of the systemic balance between global oxygen delivery and consumption in sepsis patients with circulatory shock (2, 4), our data show that assessment of lactate clearance is important as a predictor of mortality independent of achievement of ScvO 2 goals and that tracking ScvO 2 does not reliably reflect the effectiveness of lactate clearance during resuscitation. Therefore, these data suggest that serial lactate measurement may provide unique and important information on resuscitation effectiveness. We acknowledge important limitations in interpreting these results. First, this is a nonexperimental observational study and as such can detect only the association between lactate clearance and mortality but cannot establish cause and effect. Second, because performing serial lactate measurement in patients with sepsis is not a mandatory practice in our centers and measurements are performed at the discretion of the clinician, this could potentially represent a source of selection bias. Third, there was a relatively low incidence (9%) of lactate non-clearance in this cohort. This may be attributable to highly aggressive resuscitation practices in the EDs of the participating centers (14Y16). In the only other ED-based study of lactate clearance in severe sepsis, Nguyen et al. (12) reported a lactate non-clearance rate of 29% using the same cutoffs for clearance and non-clearance used in this study. One potential explanation for this disparity is the aggressiveness of crystalloid resuscitation administered in the first 6 h, 4.4 L TABLE 5. Multivariate logistic regression analysis Variable Coefficient Odds ratio 95% CIs for odds ratio Lactate non-clearance Y15.9 Maximum ScvO 2 G70% Y7.6 Hypotension despite fluid challenge Y2.5 Factors associated with increased mortality on bivariate analysis were evaluated with in-hospital mortality as the dependent variable (n = 148) Logistic regression model was limited to subjects for which ScvO 2 was measured continuously (148/166). lactate non-clearance = less than 10% decrease in repeat lactate value; hypotension = SBP G90 mmhg after a 20-mL/kg i.v. fluid bolus.

5 SHOCK JULY 2009 EARLY LACTATE CLEARANCE IN SEPSIS RESUSCITATION 39 compared with 3.3 L in the Nguyen et al. study. Therefore, an additional limitation is that the results of the current study may be applicable only to centers that have implemented quantitative resuscitation for sepsis in the ED setting. It is possible that there were deviations from the quantitative resuscitation protocols; however, this study was implemented as an effectiveness trial, so we did not specifically catalogue potential deviations. We identified and enrolled our patients prospectively in the ED, and it is possible that some of the patients diagnosed with sepsis in the ED may have been misclassified and had other etiologies accounting for their presentation. Fourth, our registry did not account for underlying comorbidities that may have had an association with outcome and should be addressed in future studies. Finally, we used all-cause in-hospital mortality as our outcome; it is possible that patients may have died from nonysepsis-related causes. As severe sepsis carries a persistently high mortality rate and the adequacy of resuscitation is a critical determinant of survival (2, 3), the identification of the optimal markers for restoration of effective tissue perfusion and the ideal end points for a resuscitation algorithm are a high priority for sepsis research. Although ScvO 2 optimization has been shown to be important in one clinical trial (2) and was an independent predictor of mortality in the current study, lactate clearance may prove to be an equivalent resuscitation end point for patients with severe sepsis. This hypothesis warrants further investigation in future clinical trials (31). CONCLUSION Early lactate clearance seems to be an important determinant of survival in patients with severe sepsis. 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