INTRODUCTION

Sepsis remains a substantial source of mortality and health care costs worldwide. In the US, the incidence of sepsis has steadily risen at a rate of 13% annually over the past decade and is estimated to carry a significant burden of healthcare in the future.[1-4] Sepsis-related mortality is reported to be as high as 29.9%.[3,5] From a cost perspective, sepsis is associated with over $24 billion annually in the United States alone.[1-3] Worldwide, the incidence and mortality associated with sepsis continues to climb.[2,6]

高校辅导员素质建设的好坏,影响着学生的未来成长,所以要高度认识自身所承担的崇高责任和伟大使命,充分认识所肩负的重要职责和为适应工作而必备的素质和能力,为高校学生教育的开展奠定良好的基础,这样会增强学生走入社会的综合竞争力,满足21世纪社会的需求。

The focus of sepsis management has been on early recognition and timely initiation of therapies.Historically, severity of illness was evaluated as a continuum composed of systemic inflammatory response syndrome (SIRS), severe sepsis, and septic shock.Beginning with SIRS, sepsis was defined based on meeting SIRS criteria and having a suspected source of infection. This stage of sepsis carried a 28-day mortality rate of 10%. Severe sepsis suggested a more grave illness and was characterized by organ dysfunction. Septic shock identified the highest risk patients who experience hypotension after adequate volume resuscitation.Mortality associated with severe sepsis and septic shock was 35% and 50%, respectively.[5,6] In 2016, the third international consensus definitions for sepsis and septic shock redefined these terms.[4] Our study was conducted prior to the release and adoption of the new Definitions of sepsis. Therefore, all analysis was performed using the previously accepted definitions of sepsis, severe sepsis,and septic shock.

多少对夫妻，不都是这样过来的。娶的或者嫁的，并不是原先想要的。心心念念想圆一场关于初恋的梦，可等到那个梦里的人出现时，才发现那真的只是一场梦。而身边这个和你吵了一辈子的人，才是真真实实抓得住的幸福，她陪着你走过无数个春夏秋冬，她实实在在地站在你的身边，一起面对生活的耗磨和人生的起伏，一直走到暮年。

Early investigations into sepsis revealed that a serum lactate level ≥ 4 mmol/L correlated with poor prognosis in critically ill patients.[5-7] This eventually led to a 4 mmol/L lactate threshold as inclusion criteria for patients in many randomized controlled trials evaluating sepsis.[7-10]However, some studies have revealed that lactate values of ≥ 2 mmol/L are associated with increased mortality.[11-14]At present, the risk of mortality associated with lactate values between 2 and 4 mmol/L is not well understood.Further investigation into this group of patients may improve our ability to stratify risk in the setting of sepsis.This study’s aim was to evaluate outcomes in patients with severe sepsis and septic shock categorized into three cohorts based on presenting serum lactate levels of ＜ 2 mmol/L, 2-4 mmol/L, and ≥ 4 mmol/L.

METHODS

Once identified, septic patients were divided into three tiers based on initial lactate level. Group 1 presented with serum lactate levels ＜ 2 mmol/L; group 2 had initial levels 2-4 mmol/L; and group 3 had levels≥ 4 mmol/L. Data were collected on age, gender, race,comorbidities, infection source, SIRS criteria, organ dysfunction, Acute Physiology and Chronic Health Evaluation (APACHE) II score, serum lactate levels,ICU length of stay (ICU LOS), hospital length of stay(HLOS), and in-hospital mortality.

Severe sepsis was defined as acute organ dysfunction secondary to infection. Septic shock was defined as severe sepsis plus hypotension (systolic blood pressure ＜ 90) that was not reversed by adequate fluid resuscitation.[9,15,16] The criteria for organ dysfunction were as follows: (1) acute respiratory failure: (PaO2/FiO2) ＜ 300; (2) acute renal failure: urine output less than 0.5 mL/(kg·hour) or a creatinine increase ＞ 0.5 mg/dL; (3) acute liver injury:INR ＞ 1.5; alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than three times the normal value (120 IU/L); or (4) thrombocytopenia with platelets ＜ 100,000/microL.

以晋江为例，晋江原创网DAU（日活跃用户）和MAU（月活跃用户）较为稳定。根据晋江文学城百度贴吧2017年的数据显示，作者总数190万，读者号2000万，这数据不包括日访问量，网站海外流量占全站流量的35%，如此庞大又稳定的流量，招信息流广告商位，是网络文学网站的变现方式之一。

The study was limited to patients with severe sepsis or septic shock so that the study population would match the populations found in many large sepsis trials. In addition, restricting the focus to the infected patients with the highest expected mortality rates was an advantage during data analysis when comparing mortality as an outcome of interest.

This retrospective cohort study was approved for waiver of consent by the McGovern Medical School,UTHealth institutional review board. The study was conducted in an urban, academic tertiary care center with 60,000 annual ED visits.

An electronic query of the medical records of all patients hospitalized between October 1, 2010 and December 31, 2013 was performed to identify patients with a discharge diagnosis consistent with an infectionor sepsis-related ICD-9 billing code. The charts of the 1,004 patients identified by the query were reviewed for study eligibility. Patients ≥ 18 years old with an infection,two SIRS criteria and evidence of organ dysfunction were included if they had a serum lactate level obtained within 24 hours of admission. Pediatric patients and those admitted for trauma, out-of-hospital cardiac arrest,or cardiogenic shock were excluded from the study. The primary outcome of interest was in-hospital mortality.Length of stay in the ICU and hospital were evaluated as secondary outcomes.

Since there were differences in baseline characteristics between the groups, multivariable logistic regression was performed to adjust for these variations. No statistically significant association between mortality and tiered lactate group was identified after the false discovery rate (FDR) correction, P=0.087. However, there was a statistically significant increased odds of death in group 3 when compared to group 1 (OR=2.05, 95% CI=1.08 to 3.89). Similarly, group 2 demonstrated a trend toward significance for increased mortality compared to group 1 (OR=1.68, 95% CI=0.87 to 3.28, P=0.087). The APACHE II score remained independently associated with mortality (OR=1.10, 95% CI=1.16 to 1.13, P＜0.001) as shown in Table 2.

This study has several limitations. First and foremost,it was a retrospective review of medical records. As such,septic patients who did not have an infection-related discharge diagnosis might not have been included. Also,patient management was not standardized. Therefore,practice variation among providers may have contributed to mortality differences. Information regarding the timing of antibiotic administration, volume of fluid resuscitation,and other interventions were not easily extractable from the charts. As a result, variability in care and possible delays in therapy may have contributed to morbidity and mortality. To minimize mistakes in assessing eligibility and data collection, two study investigators independently reviewed each medical record.

RESULTS

不必倚遍阑干，亦无须抬头相望。有关人海的始末，都在新旧的轮回中，一眼便可望见尽头。人们扬着各种旗号，身着各色彩衣，不计其数，来来往往。在这莫名的躁动之中，又确确实实微妙地平衡了无休无止的人来人往，一边忙乱而喧嚣，一边又恪守着某种井然的秩序。白日异常短暂，不一会儿就到了暮里。当洋红色的落霞掉入人海里，背影渐渐孤寂，成了迟滞的淡橙色。

An important finding of our study is that the mortality rates within each of these groups of patients with severe sepsis and septic shock was high. The overall mortality for this cohort of patients with severe sepsis and septic shock was 37%, with mortality increasingfrom 21.6% in group 1 to 51.9% in group 3. This represents the mortality of sepsis in the real world setting of a high acuity center, which is different than what has been reported in recent clinical trials where the mortality for the entire group was approximately 20% in the ProCESS trial and 15% in the ARISE trial.[17,18] This can partially be explained by the differences in the severity of illness between the groups in our study versus the severity of illness scores in the aforementioned clinical trials. In addition, as a tertiary care center, we have high risk patient populations, including transplant patients,patients with end-stage liver and renal disease, advanced heart failure, and malignancies. Many of them have relatively or iatrogenically suppressed immune systems.

Demographic continuous variables were summarized by their median and interquartile range (IQR).Categorical variables were described as counts and percentages. Differences in continuous variables,stratified by lactate group, were assessed using the Wilcoxon Rank Sum test, while Chi-square tests were used to analyze the categorical variables. The association between in-hospital mortality and lactate group was assessed using a multivariable logistic regression adjusting for gender, age, white race, pneumonia infection, comorbid End-Stage-Renal-Disease (ESRD),and Apache II score. Similarly for log-transformed hospital LOS and ICU LOS, multivariable regression models were generated and included the same covariate adjustments used for in-hospital mortality. A False Discovery Rate (FDR) multiple testing correction was applied using a 5% significance level. Statistical analyses were carried out in SAS 9.4 (SAS Institute, Inc., Cary, NC).

Figure 1. Enrollment and stratification of all patients.

Additionally, we generated other multivariable regression models of log-transformed hospital LOS and ICU LOS. Lactate tier group was not found to have a statistically significant correlation with hospital or ICU LOS. The APACHE II score, however, remained statistically significant in the model for HLOS, but not ICU LOS, after the FDR correction (P-value=0.001 and P-value=0.762 respectively).

DISCUSSION

In this study, an intermediate elevation in lactate level, 2-4 mmol/L, was not independently associated with increased mortality as compared to those with lactate ＜ 2 mmol/L. Group 2 did have increased severity of illness and increased mortality as compared to septic patients in group 1. This adds further to the conflicting findings previously reported in septic patients with lactate levels ＜ 4 mmol/L.[11-14]

Patients were divided into groups based on lactate level. Group 1 was composed of 111 (32.8%) patients with a serum lactate concentration of ＜ 2 mmol/L. Group 2 had 96 (28.4%) patients with serum lactate values 2-4 mmol/L. Group 3 consisted of 131 (38.8%) patients with an initial lactate ≥ 4 mmol/L. Baseline characteristics,APACHE II Score, pneumonia infection, ESRD,and outcomes for the groups are shown in Table 1.Statistically significant differences between the cohorts were noted in relation to APACHE II score, ESRD, and mortality. The APACHE II score was highest in the third group. ESRD prevalence was highest in the first tier group. The in-hospital mortality rose from group 1 to group 3, with rates of 21.6% for the first group, 35.4% for the second, and 51.9% for the third. These differences were statistically significant on univariate analysis.

Table 2. Mortality by gender, age, white race, pneumonia infection,comorbid ESRD, APACHE II score, and tier groups

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Table 1. Summary statistics of demographic and outcome variables by lactate tier groups

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The fact that patients who meet the criteria for severe sepsis or septic shock have a substantial mortality risk despite normal or intermediate range lactate values is of consequence. This finding draws focus to the need for early identification and aggressive therapy in patients with severe sepsis or septic shock who have lactate values of ＜ 4 mmol/L. This study is not alone in this finding. Emerging evidence suggests that patients who meet criteria for severe sepsis and have lactate values ＜ 4 mmol/L still carry a significant mortality burden and may benefit from vasopressors and aggressive support.[19,20]

Risk-stratifying patients in regard to sepsis is an evolving process. Traditionally when lactate is used as a surrogate marker for end-organ perfusion, it is a binary stratification in which values ≥ 4 mmol/L are considered to require early and aggressive resuscitation whereas values ＜4 mmol/L are associated with patients who do not require the typical interventions in the early management of sepsis. Our study suggests this is not the case. It is more apparent that just as the systemic response to infection varies by individual, so does lactate expression in sepsis. Rising lactate levels correlate with increasing severity of illness and the associated mortality. Ultimately, patients with normal to mildly elevated lactate in the setting of severe sepsis are still at substantial risk. Lactate values are useful tools in sepsis but should not be used in isolation for risk stratification.As described in our study and previous trials, it is possible to have a grave response to infection in the absence of lactate elevation.[19,20]

Of the 1,004 patients screened for this study, 360 adult patients met criteria for severe sepsis or septic shock that was not caused by another primary process. Of these, 22 patients did not have an initial lactate measured and were excluded from the study. As a result, a total of 338 patients were included in the analysis. Figure 1 shows the enrollment distribution and stratification of all patients evaluated in this study.

不用套我的笼子，我不说具体，只跟你说个大概，你自己默算。我的田打算养龙虾，一亩水面只算赚一万，三年算算。

Limitations

1.3 观察指标 脑脊液阳性患者中无症状神经梅毒患者154例，有明显的麻痹性痴呆和视神经萎缩神经梅毒患者46例，其中记忆力下降22例，有暴力行为22例，四肢感觉障碍4例，视力模糊的24例，癫痫1例，耳聋1例，其中有精神病家属史1例。

In addition, patients were not followed after discharge. Hence, the study may have underestimated the overall sepsis-related mortality. A recent review article reported that severe sepsis patients who survived to hospital discharge had a 51.4% mortality rate at 1 year and 74.2% at 5 years.[3] Our study was not designed to follow mortality trends after discharge. Lastly, this study was conducted at an academic tertiary care center, and the results may not be widely generalizable to patients presenting to other medical facilities.

CONCLUSIONS

This study demonstrated that patients with severe sepsis and septic shock who had higher initial lactate levels were likely to have a worse prognosis. Although, an intermediate elevation in lactate was not independently associated with mortality, this study found that normal and intermediate lactate tier groups had a high mortality burden. Further study is needed to determine optimal therapeutic strategies to improve the outcomes of these groups of patients.

Funding: The study was funded by Dean’s Summer Research Program Grant and Department of Emergency Medicine at McGovern Medical School.

Ethical approval: This retrospective cohort study was approved for waiver of consent by the institutional review board.

Conflicts of interest: None of the authors have any conflicts of interest as it pertains to this work. PD receives grant funding,which goes to his institution, from Vapotherm Inc.

Contributors: AP and PD conceived the project and supervised the data collection and analysis. AP, KC, BA, BD, AM, MT, and PD participated in the acquisition and interpretation of the data.RB performed the statistical analysis. AP, RB, KC, BA, BD, AM,MT and PD were all involved substantially in the manuscript preparation and revision. All authors approve the submitted version of the manuscript. KC takes responsibility for the paper as a whole.

处理开发商与城市居民之间的关系，据激励相容理论，要做到在保障开发商和企业对利益追逐的基础上同时实现其对于城市更新中公共利益的贡献。城市政府在规划方案中需对开发商进行激励与约束。主要目的是防止出现开发商的成本社会化，避免公众成为承担开发商在城市更新中经济、社会成本的替罪羊。以此而论，对于城市公众，利益保障与补偿机制是关键。

REFERENCES

1 Kumar G, Kumar N, Taneja A, Kaleekal T, Tarima S, McGinley E, et al. Nationwide Trends of Severe Sepsis in the 21st Century (2000-2007). Chest. 2011;140(5):1223-31.

2 Gaieski DF, Edwards JM, Kallan MJ, Carr BG. Benchmarking the Incidence and Mortality of Severe Sepsis in the United States. Crit Care Med. 2013;41(5):1167-74.

3 Tiru B, DiNino EK, Orenstein A, Mailloux PT, Pesaturo A,Gupta A, et al. The economic and humanistic burden of severe sepsis. Pharmacoeconomics. 2015;33(9):925-37.

4 Singer M, Deutschman CS, Seymour CW, Shankar-Hari M,Annane D, Bauer M, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (SEPSIS-3). JAMA.2016;315(8):801-10.

5 Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G,Carcillo J, Pinsky MR. Epidemiology of severe sepsis in the United States: Analysis of incidence, outcome, and associated costs of care. Crit Care Med. 2001;29(7):1303-10.

6 Brun-Buisson C. The Epidemiology of the systemic inflammatory response. Intensive Care Med. 2000;26 Suppl 1:S64-74.

7 Rangel-Fausto MS, Pittet D, Costigan M. The natural history of the systemic inflammatory response syndrome (SIRS). A prospective study. JAMA. 1995;273(2):117-23.

8 Broder G, Weil MH. Excess lactate: an index of reversibility of shock in human patients. Science. 1964;143(3613):1457-9.

9 Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001;345(19):1368-77.

10 Rivers EP, Coba V, Whitmill M. Early goal-directed therapy in severe sepsis and septic shock: a contemporary review of the literature. Curr Opin Anaesthesiol. 2008;21(2):128-40.

11 Mikkelsen ME, Miltiades AN, Gaieski DF, Goyal M, Fuchs BD, Shah CV, et al. Serum lactate is associated with mortality in severe sepsis independent of organ failure and shock. Crit Care Med. 2009;37(5):1670-7.

12 Trzeciak S, Dellinger RP, Chansky ME, Arnold RC, Schorr C,Milcarek B, et al. Serum lactate as a predictor of mortality in patients with infection. Intensive Care Med. 2007;33(6):970-7.

13 Shapiro NI, Howell MD, Talmor D, Nathanson LA, Lisbon A, Wolfe RE, et al. Serum lactate as a predictor of mortality in emergency department patients with infection. Ann Emerg Med. 2005;45(5):524-8.

14 Kjelland CB, Djogovi D. The role of serum lacate in the acute care setting. J Intensive Care Med. 2010;25(5):286-300.

15 Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, et al. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med.2003;31(4):1250-6.

16 Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock:2012. Crit Care Med. 2013;41(2):580-637.

17 ARISE Investigators and the ANZICS Clinical Trials Group.Goal-directed resuscitation for patients with early septic shock.N Engl J Med. 2014; 371(16):1496-506.

18 ProCESS Investigators, Yealy DM, Kellum JA, Huang DT,Barnato AE, Weissfeld LA, et al. A randomized trial of protocol-based care for early septic shock. N Engl J Med.2014;370(18):1683-93.

19 Wacharasint P, Nakada TA, Boyd JH, Russell JA, Walley KR.Normal-range blood lactate concentration in septic shock is prognostic and predictive. Shock. 2012;38(1):4-10.

20 Dugas AF, Mackenhauer J, Salciccioli J, Cocchi MN,Gautam S, Donnino MW. Prevalence and characteristics of nonlactate and lactate expressors in septic shock. J Crit Care.2012;27(4):244-350.