The Utility of Serial Lipid Measurements as a Potential Predictor of Sepsis Outcome: A Prospective Observational Study in a Tertiary Care Hospital

Sepsis is one of the most common causes of hospital admission worldwide and often requires an aggressive management protocol. Despite the advanced approach in management, sepsis accounts for the major cause of morbidity and mortality for patients admitted to an intensive care unit [1]. A prospective study conducted in a tertiary care hospital in India observed an ICU mortality of 56% and 28-day mortality of 62.8% [2].

Sepsis can be defined as life-threatening organ dysfunction caused by a dysregulated host response to infection [3]. Organ dysfunction can be identified clinically by an acute change in two or more SOFA (Sequential Organ Failure Assessment) points, along with either suspicion or evidence of infection [4]. Management protocol for sepsis patients comprises antibiotic therapy, adequate volume repletion and good glycaemic control. Despite aggressive treatment, the mortality rate due to sepsis is still high.

An early prognostic marker is essential to identify those at the highest risk for mortality to optimise treatment. Currently, Procalcitonin (PCT) is found to have better accuracy and is a widely used prognostic marker for sepsis [5]. The high cost of estimating Procalcitonin limits its utility in all healthcare facilities. Hence, it is essential to find simple, cost-effective markers to predict the progress of sepsis, which can be used in everyday practice.

The hallmark of sepsis is a dysregulated inflammatory response. Fatty acid-derived lipid mediators play a significant role in the generation and resolution of inflammation. These mediators can provide insight into the patient’s inflammatory status and immune response. Thus, lipid profiling can be used to assess the interaction between metabolic changes and immune response. These metabolic signatures can improve the chances of better prognostic and diagnostic evaluation, paving the path to personalized treatment strategies [6].

There has been evidence that serum cholesterol and lipoprotein levels change over time in septic patients. The inflammatory cascade produced by binding CD14 with lipopolysaccharides present in the outer membrane of gram-negative bacteria initiates the onset of sepsis [7]. HDL binds with the lipopolysaccharide (LPS) of gram-negative bacteria, neutralises it and helps in the clearance of Lipoteichoic Acid (LTA) produced from gram-positive bacteria [8,9].

Sequential Organ Failure Assessment (SOFA) score and Acute Physiology and Chronic Health Evaluation (APACHE) II score are prognostic models that use clinical findings and laboratory parameters to predict the severity of sepsis. APACHE II scoring system was found to be both sensitive as well as specific [10,11].

In this study, we aimed to study the association of serum lipid profile parameters, namely total cholesterol, triglycerides and high-density lipoprotein (HDL) with procalcitonin and clinical outcome by using APACHE II score in patients with sepsis.

We have enrolled 95 volunteered patients from the ICU diagnosed with sepsis with various causes for 4 months. Out of which, 9 patients deceased before the 5th day of admission, and 6 patients with triglycerides more than 400 mg/dl were excluded from the study. A total of 80 patients were included in the study based on the inclusion criteria and follow-up details. Out of 80 patients, 59 (74%) survived, and 21 (26%) were non-survivors. Coronary artery disease, respiratory diseases and trauma are the three leading causes of sepsis in the study participants (Table 1).

Procalcitonin, HDL – C and APACHE II Score were significantly decreased on day 5 compared to day 0, while total cholesterol, LDL – C and non-HDL cholesterol were significantly elevated on day 5 compared to day 0 in both survivors and non-survivors (Table 2 and Figure 1). Meanwhile, TGL values were elevated but not statistically significant (p = 0.13).

Fig. 1.

In survivors, procalcitonin was significantly decreased on day 5 compared to day 0, while total cholesterol, LDL – C and non-HDL cholesterol were significantly elevated on day 5 compared to day 0 (Table-3).

In non - survivors, HDL–C was significantly decreased on day 5 compared to day 0, while the APACHE II score was elevated on day 5 compared to day 0 (Table 4). Serum triglyceride levels were elevated but not statistically significant.

When comparing the lipid profile between survivors & non-survivors, no significant difference was observed on day 0. On day 5, HDL-C showed a significant decrease in non-survivors. APACHE II score was significantly increased in non-survivors on both day 0 & day 5 (Table 5).

A correlation study was done using Spearman correlation between lipid profile and procalcitonin & APACHE II among survivors & non-survivors on day 0 & day 5.

Total cholesterol, LDL – C & non-HDL – C showed a negative correlation with Procalcitonin on day 0. Meanwhile, HDL-C showed a negative correlation with PCT on day 5 (Table 6).

Sepsis is a life-threatening disorder characterized by the systemic inflammatory response to microbial invasion. As per WHO, in 2017, the major contributors to sepsis and its related mortality across all ages were diarrheal diseases and respiratory infections. Since non-communicable diseases are increasing, nearly half of sepsis-related deaths were due to chronic illness [13]. Patients affected with infection, severe injury or serious noncommunicable disease can progress to sepsis. However, older persons, hospitalised patients, and patients in intensive care units are at higher risk of developing sepsis [14]. In our study, sepsis was higher in patients with underlying systemic illness. Causative organisms for healthcare-associated infections are often multi-drug resistant to drugs, and antimicrobial resistance contributes majorly to clinical unresponsiveness to treatment and rapid evolution to sepsis and septic shock [15]. In our study, the Gram-negative bacteria are the most frequent cause of sepsis. The bacteria identified in the blood culture are Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa, Acinetobacter baumannii, Enterococcus and Staphylococcus aureus. Early diagnosis and appropriate antibiotic administration are crucial for saving lives. Despite blood culture being considered as gold standard investigation for septicaemia, delayed diagnosis of sepsis is the main drawback. Early recognition of sepsis prevents the transition into septic shock, which is associated with a 40% mortality rate [16]. PCT is a better biomarker, helpful for early detection of sepsis and can be used to track the disease course and guide in therapeutic intervention [17]. In this study, PCT levels were compared among survivors and non-survivors at two-time points, day 0 and day 5, of ICU admission with sepsis. The results showed that there was a significant reduction in serum PCT levels on day 5 compared to day 0 among survivors. This reduction in PCT levels might be explained by appropriate antibiotic management in those patients with sepsis. However, there is no significant reduction among non-survivors, which can explain the poor prognosis even after antibiotic therapy. According to Dahaba AA et al. [18], procalcitonin levels in early sepsis are significantly lower among survivors than non-survivors. In our study, even though there is a reduction in PCT levels among survivors compared to non-survivors, the difference is not significant. However, the APACHE II score was significantly higher in non-survivors on both day 0 and day 5 compared to survivors. According to Brunkhorst FM et al. [19] and Iram Yunus et al. [20], PCT could be used as a complementary comparator with severity scoring systems for the prediction of survival outcomes. The correlation of PCT with the APACHE II severity scoring system in sepsis patients showed a weakly positive correlation. We have observed in the current study that the change in PCT on admission and at the end of the observation period significantly indicated the disease severity in survivors.

The high cost factor and unavailability in primary care limited the use of PCT in all healthcare systems. Fatty acid-derived lipid mediators play a significant role in the generation and resolution of inflammation. These mediators can provide insight into the patient’s inflammatory status and immune response. Thus, lipid profiling can be used to assess the interaction between metabolic changes and immune response. These metabolic signatures can improve the chances of better prognostic and diagnostic evaluation, paving the path to personalized treatment strategies [6]. Lipid profile, being a frequently done routine investigation, is studied in sepsis patients to predict the prognosis of sepsis. This study was conducted to assess the pattern of lipid profile parameters in patients with sepsis and the usefulness of lipid profile as a severity and mortality indicator in patients with sepsis. We have estimated lipid profiles in patients with sepsis on day 0 and day 5 among survivors and non-survivors. We observed statistically significant higher total cholesterol levels on day 5 of treatment compared to the day of admission, which is consistent with the previous findings by Doaa Rashwan et al. [21]. Our study observed elevated triglyceride levels between survivors and non-survivors, but not statistically significant. Sunanya P et al. and Cetinkaya et al. observed elevated triglyceride levels in patients with septic shock [22,23].

Cholesterol metabolism is related to inflammation by the influence of pro-inflammatory cytokines. HDL plays a significant role in innate and adaptive immunity. Previous studies state that there is a dramatic decrease of HDL in Sepsis due to marked consumption of HDL particles by bacterial endotoxins [24].

Morin EE et al. and Chien JY et al. have observed the association between low HDL levels and the severity of sepsis [25,26]. In our study, HDL – C showed a significant decrease on day 5 compared to day 0 in non-survivors and showed a negative correlation with APACHE II in both survivors and non-survivors. Like HDL, LDL plays a key role in neutralizing endotoxins, such as Lipopolysaccharide (LPS). Maile MD et al. observed in 2020 [27] that higher levels of LDL were associated with low mortality in sepsis patients. In our study, LDL–C was found to be significantly higher on day 5 compared to day 0 in survivors. But LDL – C was lower in non-survivors on day 5 compared to day 0, although it is not statistically significant. In addition to this, Baseline LDL-C values were found to correlate with procalcitonin in non–survivors. In our study, non-HDL-cholesterol showed a negative correlation with Procalcitonin among sepsis patients in accordance with the observation by Chang L et al. [28].

As a standalone value, procalcitonin may not be used to assess prognosis in non-survivors, whereas serial PCT measurements can be used to monitor the prognosis of sepsis in survivors. Serum lipid profile levels, namely Total cholesterol, HDL – C and LDL – C, have possible associations with the severity of sepsis. HDL–C has a negative association with the clinical scoring system in sepsis patients. Overall, the findings from our study suggest that lipid profile parameters have possible implications on the outcome of patients with sepsis.