Sepsis, one of the major conditions handled in the emergency department (ED), causes hemodynamic instability through several processes, resulting in tissue hypoperfusion (1, 2). If sepsis progresses either to severe sepsis or septic shock, it has a mortality rate in the range of 30% to 50% (3, 4). The recent development of early-goal directed therapy (EGDT), which is now widely used as a standard therapy for sepsis patients, has been clinically contributing to the survival of sepsis patients (5, 6). The main purpose of EGDT is to perform immediate treatment of severe sepsis and septic shock patients using aggressive fluid therapy. According to the Surviving Sepsis Campaign Guideline released in 2008, initial resuscitation is recommended for the severe sepsis patient whose serum lactate level is higher than 4 mmol/L or septic patients with hypotension (7).
However, the mortality rate in patients with an intermediate level of serum lactate (<4 mmol/L) is higher than that in patients with a normal lactate level, and this factor is well known to be associated with mortality in sepsis patients (8–13). In addition, approximately 20% of sepsis patients with a lactate level lower than 4 mmol/L and normal blood pressure also experience a reduction in blood pressure during treatment, which is known to be associated with increased mortality (14). Therefore, early diagnosis and treatment are critical for sepsis patients with an intermediate lactate level as well as those who are already affected by sepsis.
In particular, specific treatment guidelines have not been provided for sepsis patients with an intermediate lactate level, and the predicting factors that require aggressive treatment have not yet been clearly defined. The authors of this report have, accordingly, attempted to investigate the occurrence rate of clinical deterioration and the associated risk factors in patients with an intermediate serum lactate level presenting to the ED.
This was a retrospective observational study of patients presenting to the ED with sepsis from August 2008 to July 2010 at Samsung Medical Center (a 1960-bed, university-affiliated, tertiary referral hospital in Seoul, South Korea). The study was approved by the institutional review board. Informed consent was waived because of the retrospective, observational, and anonymous nature of the study.
Sepsis was defined as a suspected infection in the presence of two or more systemic inflammatory response syndrome criteria (15). Severe sepsis was defined as sepsis associated with acute organ dysfunction (16). Septic shock was defined as sepsis with acute circulatory failure characterized by persistent arterial hypotension (systolic arterial pressure <90 mmHg, mean arterial pressure <60 mmHg, or a reduction in systolic blood pressure >40 mmHg from baseline) despite adequate volume resuscitation (16).
Initial serum lactate levels were categorized as low (<2 mmol/L), intermediate (>2.0 and <4.0 mmol/L), or high (>4 mmol/L) (17). They were measured before the first intravenous line access, followed by an infusion of crystalloid fluids. Initiation of EGDT was defined as central line insertion followed by measurement of central venous oxygen saturation (18). Early-goal directed therapy was performed according to the protocol by Rivers et al. (1), which was included in our previous study (19).
Sepsis-induced tissue hypoperfusion was defined as persisting hypotension despite initial fluid challenge or a blood lactate concentration of 4 mmol/L or greater, within 72 hours of ED arrival (7). Initial fluid challenge was defined as delivering a minimum of 20 mL/kg of crystalloid (or colloid equivalent) (6).
Patient enrollment criteria
We included sepsis patients without hypotension (systolic blood pressure >90 mmHg, mean arterial pressure >65 mmHg), aged more than 18 years, who had a lactate level 2.0 or greater and less than 4.0 mmol/L. Exclusion criteria were as follows: (1) diagnosis of sepsis-induced tissue hypoperfusion on ED arrival, (2) patients who required mechanical ventilation or vasopressors on ED arrival, (3) transfer from another hospital after initial treatment for sepsis such as vasopressors and fluid administration, (4) previous signing of “do not resuscitate” orders, and (5) presence of definite causes resulting in lactic acidosis such as seizure, acute pulmonary edema, and severe bleeding.
The primary end point was to identify patients who progressed to sepsis-induced tissue hypoperfusion. Secondary end points were in-hospital mortality, admission to the intensive care unit (ICU), and application of mechanical ventilation within 72 hours of ED arrival.
The following variables were considered as potential confounders: demographics, comorbidities, previous medical history (onset of symptoms, organ transplantation, previous hospitalization, chemotherapy, nursing home residence), suspected infection focus, initial vital signs, laboratory data, time variables (ED arrival to first antibiotic use, ED arrival to progression), and treatment variables (total fluids, red blood cell transfusion, and use of vasopressors). Data on each of these factors were collected from our sepsis registry and electronic medical records. Neutropenia was defined as an absolute neutrophil count less than 500/μL. To evaluate organ failure, Sequential Organ Failure Assessment (SOFA) scores were calculated at the time of diagnosis of sepsis (20, 21).
Continuous variables were expressed as the mean (SD) or median with interquartile ranges. Continuous variables were compared using the Wilcoxon rank sum test. Categorical variables were compared with a χ2 test. The Cochran-Armitage test was used to compare the organ failure grades by SOFA score. Multivariate logistic regression models were used to identify independent factors associated with progression to sepsis-induced tissue hypoperfusion. Variables were selected by a backward stepwise method with significance (P < 0.10). Predicted probability was calculated from the multivariate models. Kaplan-Meier curves were plotted to show the cumulative incidence of sepsis-induced tissue hypoperfusion, and a log-rank test was used to compare the progression and nonprogression groups. Stata 11.0 was used for statistical analysis, and a two-tailed P < 0.05 was considered significant.
During the study period, the number of sepsis patients visiting the ED was 1,382. Of these, a total of 474 sepsis patients who were hemodynamically stable and had an intermediate level of lactate in the initial stage were enrolled in the study (Fig. 1). Among the total patients, there were 108 cases of sepsis-induced tissue hypoperfusion (22.7%) and 48 deaths (10.1%). Early-goal directed therapy was initiated before clinical deterioration in only 22 patients (4.6%), although it was performed later in 71 patients (14.9%).
A comparison between the progression group and nonprogression group showed that there were significant differences in initial mean arterial pressure, heart rate, neutropenia, band-form neutrophil appearance, hemoglobin level, platelet count, serum lactate level, blood urea nitrogen, creatinine, and aspartate aminotransferase level (Table 1). Regarding organ failure, the SOFA score and respective organ failure were significantly more severe in the progression group (Table 2). In patients with a SOFA score of 5 or greater, the observed rate of progression was 42.4%. In contrast, in patients with a SOFA score of less than 5, the progression rate was 17.1%.
Patients in the progression group received significantly more fluid than those in the nonprogression group (P < 0.001) and more frequently received red blood cell transfusion (P < 0.001) and vasopressor support (P < 0.001) (Table 2). The need for mechanical ventilation was higher in the progression group (23.2% vs. 3.8%, P < 0.001). With regard to in-hospital mortality and ICU admission rate within 72 hours, the rates of the progression group were also significantly higher by 24.0% (vs. 6.0%, P < 0.001) and 46.3% (vs. 8.4%, P < 0.001), respectively.
Predicting factors for progression
The multivariate regression analysis showed that potential risk factors for progression to sepsis-induced hypoperfusion were hyperthermia, neutropenia, band neutrophils appearance, hyponatremia, blood urea nitrogen level, serum lactate level, and organ failure including respiratory, cardiovascular, and central nervous systems.
Initial SOFA score was also associated with progression in an additional multivariate model (odds ratio, 1.23; 95% confidence interval, 1.11–1.36; P < 0.001). Predicted probabilities for sepsis-induced hypoperfusion within 72 hours, according to the initial SOFA score, are shown in Figure 2. In patients with a SOFA score of 5 or greater, the predicted rate of progression was 38.9% (Table 3).
Kaplan-Meier curves demonstrating cumulative incidences are shown in Figures 3 and 4. Approximately 20% of the patients progressed to hypoperfusion within 72 hours after visiting the ED. In particular, it was found that progression occurred at a significantly higher rate in patients with initial SOFA scores of 5 or greater (P < 0.001 by log-rank test).
Because mortality increases as hemodynamically stable sepsis patients progress to severe sepsis or septic shock, early detection and immediate treatment of sepsis patients are critical to successful management (7, 14, 22, 23). The present study examined the rate of progression to sepsis-induced tissue hypoperfusion and its associated risk factors in patients who were hemodynamically stable and had an intermediate level of serum lactate when presenting to the ED. We also determined that EGDT was initiated in a very small number of patients, although a significant number of patients underwent progression to sepsis-induced tissue hypoperfusion. This is considered to be useful information for the aggressive treatment of sepsis patients in the early stage.
The SOFA score, which represents the degree of organ failure in a patient, has been known to be a useful indicator for the prediction of mortality in sepsis patients and can be measured in a relatively easy and fast way (20, 21). The findings of this study showed that the initial SOFA score had a significant correlation with the clinical deterioration of sepsis, and a SOFA score of 5 or greater was associated with a 40% rate of progression to sepsis-induced hypoperfusion. We also found that organ failure of the respiratory, cardiovascular (low blood pressure, not shock), and central nervous systems had an independent relationship with progression. This finding indicates that there are many severe sepsis patients who need more aggressive early resuscitation depending on the degree of organ failure, despite not being in septic shock or having a severely elevated lactate level. Because there are no detailed resuscitation guidelines available for those patients, other than the general guideline for sepsis treatment, further studies are needed to develop more specific recommendations.
Serum lactate level is known to be an indicator of tissue hypoperfusion and hypoxia in patients with severe sepsis and septic shock, and it is highly associated with the prognosis of sepsis patients (8–13, 17, 24, 25). In particular, the findings of the current study showed that the mortality or ICU admission rate of sepsis patients with an intermediate lactate level was not low. It also showed that, even in the intermediate lactate level range, there was a positive correlation between sepsis deterioration and lactate level, indicating that the measurement of initial lactate level is critical for the early diagnosis and risk assessment of sepsis.
In addition to the SOFA score and lactate level, a few scoring systems have been used for the prediction of death of sepsis patients in the ED, including the Mortality in Emergency Department Sepsis score (26–29). However, a better diagnostic tool is needed to identify high-risk sepsis patients who can deteriorate in the early stage. Furthermore, a study of the relationship between the existing scoring systems and early deterioration is also needed.
A recent study reported that 17.8% of uncomplicated sepsis patients who did not present with any organ failure and who had a lactate level less than 4 mmol/L progressed to septic shock (14). It also reported that older age, female sex, hyperthermia, anemia, comorbid lung disease, and vascular access device infection had significant relationships as early deterioration factors. This previous study was different from our study in that it was conducted on patients with no organ failure and with a different lactate range in a different hospital environment.
In sepsis patients without any complications, various and complex factors are involved in the progression to severe sepsis or septic shock. For example, the responses or symptoms of the patients can vary depending on age, immune condition, underlying diseases, circulating blood volume, the type of bacteria involved, and the infection location. Therefore, the pathophysiologic causality of the risk factors presented in the present study could not be perfectly explained.
Our study has several limitations as a single-center, retrospective, observational study. There is the possibility that selection bias might have influenced the results. We also were unable to fully adjust for the effects of unobserved bias. There might be some interpretation pitfalls that might influence the lactate metabolism such as drugs and comorbidities. The results of this study should be cautiously interpreted for application to other institutions or patient populations. In addition, the small sample size might have resulted in a failure to detect other potential risk factors.
Among sepsis patients who had an intermediate level of serum lactate, a substantial number of patients progressed to sepsis-induced tissue hypoperfusion and required a more aggressive resuscitation strategy. In particular, several potential risk factors, including organ failure, were significantly associated with clinical deterioration to a hypoperfusion state. We suggest that an early aggressive treatment strategy is needed in patients who have these risk factors.
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