At present, the main controversial topics regarding the early management of sepsis are the lack of a robust definition and reliable markers that can assist in the early identification of sepsis and the development of a therapeutic strategy. In this retrospective analysis, we found that the arterial blood lactate level, MAP, albumin level, SOFA score, and APACHE II score were risk factors for mortality in the univariate analysis, of which the MAP, albumin level, and APACHE II score had high prognostic value. Therefore, the above clinical parameters were analyzed in detail.
Blood lactate levels indicate organ dysfunction. Septic patients have decreased tissue perfusion and cellular hypoxia, in this context, the energy supply depends on anaerobic glycolysis, and the production of lactate gradually increases. Normally, the liver can further convert this lactic acids, but impaired liver function reduces lactate clearance.[11, 12] In critically ill patients, lactate can be used as an indicator of the cumulative oxygen load and as a prognostic indicator. Mikkelsen et al reported that the initial lactate level was independently associated with mortality in patients with severe sepsis (OR 1.34, 95% CI 1.30–1.40, P = 0.001). Our study showed that the lactate level was a risk factor for mortality in patients with sepsis (OR 1.482, 95% CI 1.105–1.988), but it was not an independent factor. The difference between the two studies may be due to the larger sample size and fewer confounders in the former study. To date, the efficacy of lactate for the guidance of resuscitation has been reported because of its prognostic value, but multicenter randomized trials have shown that fluid resuscitation is not beneficial in septic shock patients with or without hyperlactatemia.[15, 16] In addition, when hyperlactatemia is not caused by hypoperfusion, fluid resuscitation and lactate removal may be harmful. Therefore, high lactate levels should be interpreted on a patient-by-patient basis.
The main physiological functions of serum albumin are the regulation of the plasma colloid osmotic pressure and capillary membrane permeability, as well as the binding and transport of ligands. As a reservoir and carrier of many endogenous and exogenous compounds with antioxidant and circulatory protective properties, albumin is involved in free radical scavenging. Current studies have shown that protein metabolism can indicate not only liver function but also prognosis in patients with critical illness. In a comprehensive meta-analysis of 90 cohort studies including 291,433 patients with critical illness, the efficacy of hypoalbuminemia as a predictor of the outcome was evaluated by multivariate analysis, which showed that a 10g/L decrease in the serum albumin concentration was associated with a significant 137% increase in mortality. Similarly, our study showed that the serum albumin level was an independent risk factor for sepsis-related mortality (adjusted OR 0.755, 95% CI 0.583–0.979), and the AUC was 0.641. All of the above findings indicate that albumin, as a nutritional indicator, can predict the later outcome of the disease. To ameliorate hypoalbuminemia, several albumin replacement studies have been conducted, such as the SAFE, CRISTAL, and ALBIOS projects, but these interventions have not reduced mortality of septic patients. One thing can be sure is that nutritional therapy is recommended in patients with sepsis as early as possible, as it may help improve hypoalbuminemia, maintain normal vascular permeability, and reduce mortality to some extent.[19–21]
The international guidelines define severe sepsis as a subset of sepsis cases wherein, despite adequate fluid resuscitation, patients have hypotension requiring vasopressors to maintain an MAP above 65 mmHg. This hemodynamic indicator is a simple, convenient, and more accurate reflection of the perfusion level. Decreased tissue perfusion worsens clinical outcomes by affecting organ function. In a similarly designed study involving 274 patients with sepsis and septic shock, the results were adjusted for disease severity. Patients with one or more hypotensive episodes during which the MAP was below 60 mmHg for at least 2 min had higher mortality at day 28 than those without hypotension.  However, the SEPSISPAM trial, a large prospective randomized controlled study that compared septic shock patients with high and low MAP, showed no difference in mortality between the two groups. Our study showed that MAP was an independent risk factor for mortality in patients with sepsis (adjusted OR 0.889, 95% CI 0.822–0.961), and the area under the ROC curve was 0.747, (95% CI 0.654–0.839), indicating that it could be used as a prognostic indicator and resuscitation goal for patients with sepsis. It has been shown that sepsis is associated with altered microcirculation.[24, 25] The relationship between systemic hemodynamics and microcirculatory blood flow is complex. An increase in MAP levels above 65 mmHg may not alter microvascular perfusion per se, and conditions in which MAP has been corrected while microcirculatory abnormalities still persist often occur. However, it is important to note that the timely initiation of interventions may play a major role. DeBacker et al reported that microcirculation could be improved by fluid resuscitation in the early stage of sepsis. Fluid resuscitation is the preferred method of MAP enhancement, and the SSC advocates for the use of crystalloids. In fact, fluid overload can lead to the worsening of myocardial contractility, acute pulmonary edema, and possibly death. Hence, patients with septic shock and left-sided ventricular-arterial uncoupling may require more rigorous fluid management. In addition, vasoactive agents are required when fluid resuscitation is ineffective in patients with septic shock. Norepinephrine is recommended by the SSC as the most commonly used vasopressor in patients with sepsis. However, to date, no precise MAP target has been identified for septic shock, and more research is needed. In conclusion, MAP affects the prognosis of patients, and the targeted treatment goal needs to be individualized. More attention should be given to the appropriate use of vasoactive drugs for sepsis.
Multiple organ dysfunction is associated with a high risk of mortality. The SOFA and APACHE II scores are two comparatively comprehensive scores used to assess organ function, both of which correlate well with the outcome of sepsis.
The APACHE II score is widely used for the evaluation of the systemic functioning in critically ill patients to predict the severity of the disease and to facilitate risk stratification. In 1985, the University of Washington Medical Center proposed the APACHE II scoring system in a study of 5030 cases in 13 ICUs across the United States performed by Knaus et al. This score provides an initial picture of the patient's general condition in the ICU and helps predict the clinical outcome. One study showed that APACHE II score could be used to identify disease severity, and there were significant differences in mortality among patient groups stratified by the APACHE II score. Regression analysis showed that an APACHE II score ≥ 15 and soluble urokinase-type plasminogen activator receptor (suPAR) ≥ 10.82 ng/mL were independently associated with adverse outcomes. Our study also showed that this score was an independent risk factor for mortality in patients with sepsis, (adjusted OR 1.356, 95% CI 1.119–1.643), and it possessed some prognostic value, with an AUC of 0.839. Thus, the APACHE II score should be calculated daily for patients with sepsis in the ICU to accurately monitor the overall condition of these patients in a timely manner. This study also indicated that the predictive value of the combination of the APACHE II score, MAP, and albumin level was significantly better than those of the individual indicators, with an AUC of 0.890. We recommend the use of these indicators in clinical practice.
The SOFA score can be used as one of the key indicator for the diagnosis of sepsis and is also included by the European Medicines Agency (EMA) as a treatment efficacy indicator and clinical endpoint in phase II clinical trials on new treatment options. It can reflect the severity of the disease to a certain extent and has some suggestive value with regard to prognosis. In the past, the improvement in 28-day mortality has been used as a primary endpoint in sepsis trials, which may result in the underestimation of some of the potential beneficial effects of the initial intervention. Pocock et al proposed that the SOFA score could be selected as a surrogate endpoint when the primary outcome of the study failed. The usefulness of serial evaluation of the SOFA score for the prediction of the outcome in critically ill patients has been previously reported many times. However, those studies only provided a fixed SOFA score, which is not able to comprehensively reflect the condition of patients with sepsis. Then, DeGrooth et al put forward the idea of using the change in the SOFA score (i.e., the score at a fixed date after randomization minus the baseline score, or the maximum score during the ICU stay minus the baseline score) as an endpoint in studies evaluating the treatment effect in critically ill patients. Based on the 87 randomized controlled studies included in the analysis, the change in the SOFA score appeared to be reliably and consistently associated with mortality. Additionally, a series of observational studies have shown a significant effect on mortality of a small changes in the SOFA scores. Studies have shown that changes in the SOFA scores within 48 hours in patients with sepsis are associated with DIC, sudden cardiac arrest, and other serious illnesses in the ICU and emergency room.[33, 34] In our study, univariate regression results showed that the SOFA score was a risk factor for sepsis-related mortality, although the relationship was nonsignificant after accounting for confounders, probably because we used a fixed SOFA score. Therefore, the change in the SOFA score is suggested is suggested as a useful predictor, in agreement with the above studies.
There are some limitations in this study. First, it was a retrospective study including 123 patients. Prospective randomized trials with larger sample sizes are needed to more accurately analyze the factors predictive of mortality in patients with sepsis. Second, the influential factors included in this study are not exhaustive. Finally, some patients were in critical condition, died within 24 hours or were discharged automatically, leading to insufficient clinical data and possibly affecting the final results.