Relationship between inflammatory factors, lactic acid levels, acute skin failure, bad mood, and sleep quality

Abstract

BACKGROUND

The central link between septic shock and acute skin failure (ASF) is the inflammatory response, which occurs throughout disease progression and can lead to systemic inflammatory response syndrome. Patients often experience bad moods, sleep disorders, and other health issues. Despite recognizing these factors, no studies have examined the correlation between inflammatory factors, lactic acid levels, ASF, mood disturbances, and sleep quality in critically ill patients. We hypothesize that higher levels of inflammatory factors and lactic acid are associated with more severe ASF and poorer mood and sleep quality, which may inform clinical treatment for septic shock and ASF.

AIM

To explore the relationship between inflammatory factors, lactic acid levels, the severity of ASF, bad mood, and sleep quality.

METHODS

The retrospective study included 150 patients with septic shock from the Second Hospital of Dalian Medical University, categorized into ASF (n = 35) or non-ASF groups (n = 115). We compared the peripheral blood inflammatory factors, including tumor necrosis factor-α (TNF-α), C-reactive protein (CRP), interleukin-6 (IL-6), lactic acid levels, skin mottling score (SMS), modified early warning score (MEWS), self-rating depression scale (SDS), self-rating anxiety scale (SAS), and Pittsburgh sleep quality index (PSQI) scores. Pearson correlation analysis assessed relationships among these variables.

RESULTS

The ASF group had significantly higher levels of CRP (19.60 ± 4.10 vs 15.30 ± 2.96 mg/mL), IL-6 (298.65 ± 48.65 vs 268.66 ± 33.66 pg/L), procalcitonin, lactic acid (8.42 ± 2.32 vs 5.70 ± 1.27 mmol/L), SMS [0 (0, 1) vs 3 (2, 3)], MEWS (9.34 ± 1.92 vs 6.48 ± 1.96), SAS (61.63 ± 12.03 vs 53.71 ± 12.48), SDS (60.17 ± 12.64 vs 52.27 ± 12.64), and PSQI scores (14.23 ± 3.94 vs 8.69 ± 2.46) compared with the non-ASF group (all P < 0.001). Pearson correlation analysis revealed that IL-6, CRP, TNF-α, and lactic acid were positively correlated with SMS, MEWS, SAS, SDS, and PSQI scores (P < 0.05).

CONCLUSION

Peripheral blood levels of IL-6, CRP, TNF-α, and lactic acid correlate positively with SMS, MEWS, SAS, SDS, and PSQI in critically ill patients with ASF.

Key Words: Septic shock; Acute skin failure; Inflammatory factors; Lactic acid level; Degree of acute skin failure; Bad mood

Core Tip: The pathological changes in acute skin failure (ASF) include acute skin hypoperfusion caused by hemodynamic instability in critically ill patients. Systemic inflammatory response syndrome permeates the entire pathological mechanism of septic shock complicated by ASF, and the relevant blood indices can reflect changes in ASF. Bad mood and sleep disturbances are common accompanying symptoms in patients with sepsis, which significantly impact their overall health. Through this project, we found that the levels of peripheral blood-related inflammatory factors and lactic acid were positively correlated with skin mottling score, self-rating anxiety scale, self-rating depression scale, and Pittsburgh sleep quality index scores in critically ill patients with ASF.

INTRODUCTION

Critically ill patients are prone to systemic inflammatory response syndrome, which induces septic shock and multiple organ dysfunction and is the main cause of death[1]. When a patient experiences septic shock, the effective circulating blood volume is reduced, skin vasoconstriction and diastolic function are abnormal, and skin tissue hypoperfusion can easily occur. Clinical manifestations include cold, clammy skin, mottling, hypoelasticity, prolonged capillary refill time, and decreased fingertip percutaneous oxygen saturation. Acute skin failure (ASF) refers to necrosis of the skin and/or subcutaneous tissue caused by skin hypoperfusion in critically ill patients owing to myocardial infarction, stroke, sepsis, trauma, or postoperative complications[2].

It is well known that systemic inflammatory response syndrome occurs throughout the development and progression of sepsis. In the early stage of sepsis, pathogenic microorganisms infect the host, triggering an excessive immune response and the secretion of numerous inflammatory factors, leading to a “cytokine storm”. This causes human tissues and organs to be infiltrated by inflammatory mediators, eventually resulting in simultaneous functional failure and shock of multiple organs, leading to death[3,4]. In recent years, scholars in the field of acute and critical care have conducted many studies on the early treatment of septic shock[4,5], suggesting that inflammatory factors such as serum C-reactive protein (CRP), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in the early stage of septic shock are proportional to its severity and prognosis, which can effectively reflect the changes in ASF following septic shock.

With the worsening of infection, the condition of patients with sepsis deteriorates. When the patient’s systemic circulatory blood volume decreases, and tissue perfusion becomes insufficient to maintain adequate blood flow to vital organs such as the heart, brain, and kidneys, the skin - being the largest organ of the body - is the first to show signs of insufficient tissue perfusion. Compared with the increase in lactic acid levels during the decompensated phase, the clinical symptoms of compensatory ASF are important early warning indicators for the early detection of shock in patients with sepsis[6,7]. Studies have pointed out that skin failure is closely associated with hypoperfusion, hemodynamic instability, and skin changes at the end of life[8]. Increased lactic acid levels and infection due to epidermal rupture caused by ASF are risk factors for poor prognosis and increased mortality in critically ill emergency patients. Predicting ASF in patients is the key to improving the prognosis of critically ill patients and reducing medical disputes related to skin care problems[9,10]. Most patients with sepsis often have a bad mood, sleep disorders, and other issues, which typically manifest as anxiety, depression, dizziness, headaches, decreased sleep quality, and nighttime sleep disturbances, affecting their overall health[11-13].

Current studies of other diseases, such as peripheral vascular disease, organ failure, and sepsis, have confirmed that inflammatory factors are closely related to the severity and prognosis of the disease[8,14]. At the same time, studies report that inflammatory factors also play an important role in patients with depression or sleep disorders[15,16]. To date, no studies have examined the correlation between levels of inflammatory factors, lactic acid, and the severity of ASF, bad mood, and sleep quality in patients with critical ASF. This study explored the relationship between blood inflammatory factors, lactic acid levels, ASF, bad mood, and sleep quality in patients with critical ASF. The findings may provide ideas for the clinical treatment of critically ill patients with ASF.

MATERIALS AND METHODS

Patient selection

We selected 150 patients with septic shock from the Second Hospital of Dalian Medical University between March 2022 and March 2024. Patients were divided into ASF (n = 35) and non-ASF (n = 115) groups based on the occurrence of ASF. Inclusion criteria were: (1) Met the diagnostic criteria of septic shock[17]; (2) Age ≥ 18 years; and (3) Intensive care units (ICU) stay ≥ 24 hours. Exclusion criteria included: (1) Patients with serious skin diseases resulting in darker skin or skin collapse; (2) Patients with conditions such as vasculitis obliterans, lower extremity thrombosis, or diabetic foot that cause blood circulation obstruction or gangrene in the extremities; (3) Patients with severe limb trauma leading to skin loss; (4) Patients with lymphoma, cancer, severe acute liver failure, and long-term hormone therapy; (5) Patients with chronic diseases causing systemic chronic skin failure; (6) Patients with skin failure at the end of life; and (7) Patients with incomplete medical records. This study was reviewed and approved by the Institutional Review Board of the Second Hospital of Dalian Medical University. The diagnostic criteria for ASF are based on its pathophysiology and clinical manifestations[1,9]. Specifically, the arterial end-perfusion pressure of skin capillaries is < 25 mmHg (1 mmHg = 0.133 kPa)[18,19] and red, purple, or yellow-black flaky plaques with irregular edges - resembling shapes such as pears, butterflies, or horseshoes - appear on any part of the skin in a short period.

Methods

General information questionnaire: General demographic data and disease-related clinical monitoring indicators, including age, sex, and body mass index, were collected using a self-administered questionnaire. The disease-related clinical monitoring indicators at admission: Included peripheral blood inflammatory factors (TNF-α, IL-6, CRP), arterial lactic acid value, and the level of ASF [measured by the skin mottling score (SMS)]. Additionally, the modified early warning score (MEWS) was assessed within 2 hours of entry, along with bad mood [(measured by the self-rating anxiety scale (SAS), and self-rating depression scale (SDS)], and sleep quality [Pittsburgh sleep quality index (PSQI)].

Arterial blood lactic acid value: After ICU admission, arterial blood gas analysis was routinely performed using a Roche Cobasb 123 blood gas analyzer. Each measurement ensured accurate sampling, proper machine operation, and reliable results. Arterial blood measurements were taken within 24 hours as per the doctor’s advice, once every 8 hours, and the mean lactic acid value in 24 hours was calculated.

SMS score: The SMS total score ranges from 0 to 5 points: 0 indicates no spots; 1 indicates a small area (coin-sized) spot located at the center of the knee; 2 indicates that the markings do not exceed the edge of the kneecap; 3 indicates that the markings do not exceed the middle of the thigh; 4 indicates that the mottled area does not extend beyond the groin; and 5 indicates that spots extend beyond the groin. Points 0 to 2 are considered early spots, mainly confined to the knee[20,21].

MEWS: MEWS uses five physiological indices: Respiratory rate, systolic blood pressure, body temperature (axillary temperature), consciousness, and heart rate. The total score ranges from 0 to 15 points, and each parameter was assigned a score of 0 to 3 points based on different ranges. The score value of each individual parameter of the patient’s MEWS was determined using the comparative scoring standard for the patient’s clinical physiological indicators. This scoring system evaluates the potential risk of the patient’s condition, with the MEWS score being directly proportional to the severity of the disease[22].

Bad mood: Adverse emotions of the enrolled patients were evaluated using the SAS[23] and SDS[24]. There are 20 items on the two scales, and each item is divided into four grades; the scores are proportional to the degree of anxiety and depression. For the SAS, the scoring is as follows: Normal mean score < 50, mild anxiety = 50-60, moderate anxiety = 61-70, and severe anxiety ≥ 70. For the SDS, the scores were categorized as normal, < 53; mild depression, 53-62; moderate depression, 63-72; and severe depression, > 73.

PSQI score: The PSQI[25] was used to evaluate sleep quality in the patient group. There were nine items on the scale (with a total of 21 points), and the score was inversely proportional to sleep quality. A score ≤ 7 points indicates good sleep quality, while a score > 7 points indicates poor sleep quality.

Statistical analysis

Data were analyzed using IBM SPSS (version 29.0). Quantitative data with a normal distribution were described as mean ± SD. Quantitative data with non-normal distribution were described using the median and quartiles (P25 and P75). Qualitative data were presented as n (%). The t-test, rank sum test, and χ² test were performed sequentially. Statistical significance was set at P < 0.05.

RESULTS

General information

There were no significant differences in age, sex, and body mass index between the ASF and the non-ASF groups (P > 0.05; Table 1).

Table 1 General data comparison of patients.

Group	Age (years)	Sex		BMI (kg/m2)
		Male	Female
ASF group (n = 35)	56.60 ± 11.03	18	17	22.34 ± 2.36
Non-ASF group (n = 115)	56.35 ± 10.68	64	51	22.17 ± 2.40
t/χ2	-0.121	0.193		-0.362
P value	0.904	0.660		0.718

ASF: Acute skin failure; BMI: Body mass index.

Levels of inflammatory factors and lactic acid

Compared with the non-ASF group, the levels of IL-6, CRP, procalcitonin, and lactic acid were significantly higher in the ASF group (P < 0.05; Table 2).

Table 2 Comparison of inflammatory factors and blood lactic acid levels between the acute skin failure and non-acute skin failure groups.

Group	IL-6 (pg/L)	CRP (mg/mL)	TNF-α (ng/mL)	Lactic acid (mmol/L)
ASF group (n = 35)	298.65 ± 48.65	19.60 ± 4.10	382.11 ± 43.56	8.42 ± 2.32
Non-ASF group (n = 115)	268.66 ± 33.66	15.30 ± 2.96	339.66 ± 34.56	5.70 ± 1.27
t	-17.923	-5.828	-5.971	-8.989
P value	< 0.001	< 0.001	< 0.001	< 0.001

ASF: Acute skin failure; IL-6: Interleukin-6; CRP: C-reactive protein; TNF-α: Tumor necrosis factor α.

SMS, MEWS score

Compared with the non-ASF group, the SMS and MEWS scores were significantly higher in the ASF group (P < 0.05; Table 3).

Table 3 Comparison of skin mottling score and modified early warning scores between the acute skin failure and non-acute skin failure groups.

Group	SMS (points)	MEWS (points)
ASF group (n = 35)	0 (0, 1)	9.34 ± 1.92
Non-ASF group (n = 115)	3 (2, 3)	6.48 ± 1.96
t/U	-7.982	-7.597
P value	< 0.001	< 0.001

ASF: Acute skin failure; MEWS: Modified early warning score; SMS: Skin mottling score.

SAS, SDS, and PSQI scores

Compared with the non-ASF group, the SAS, SDS, and PSQI scores were significantly higher in the ASF group (P < 0.05; Table 4).

Table 4 Comparison of self-rating anxiety scale, self-rating depression scale, and Pittsburgh sleep quality index scores between the acute skin failure group and non-acute skin failure group.

Group	SAS (points)	SDS (points)	PSQI (points)
ASF group (n = 35)	61.63 ± 12.03	60.17 ± 12.64	14.23 ± 3.94
Non-ASF group (n = 115)	53.71 ± 12.48	52.27 ± 12.64	8.69 ± 2.46
t	-3.314	-3.339	-10.003
P value	< 0.001	< 0.001	< 0.001

ASF: Acute skin failure; SAS: Self-rating anxiety scale; SDS: Self-rating depression scale; PSQI: Pittsburgh sleep quality index.

Correlation of IL-6, CRP, TNF-α, and lactic acid levels with SMS MEWS, SAS, SDS, and PSQI scores

Pearson correlation analysis showed that IL-6, CRP, TNF-α, and lactic acid levels were positively correlated with SMS, MEWS, SAS, SDS, and PSQI scores (P < 0.05; Figures 1-4).

Figure 1 Correlation of interleukin-6, C-reactive protein, tumor necrosis factor-α, and lactic acid levels with skin mottling score. A: Interleukin-6 levels are positively correlated with the skin mottling score (SMS); B: C-reactive protein levels are positively correlated with the SMS score; C: Tumor necrosis factor-α levels are positively correlated with the SMS score; D: Lactic acid levels are positively correlated with the SMS score. SMS: Skin mottling score; IL-6: Interleukin-6; CRP: C-reactive protein; TNF-α: Tumor necrosis factor-α.

Figure 2 Correlation of interleukin-6, C-reactive protein, tumor necrosis factor-α, and lactic acid levels with modified early warning score. A: Interleukin-6 levels are positively correlated with the modified early warning score (MEWS); B: C-reactive protein levels are positively correlated with the MEWS score; C: Tumor necrosis factor-α levels are positively correlated with the MEWS score; D: Lactic acid levels are positively correlated with the MEWS score. MEWS: Modified early warning score; IL-6: Interleukin-6; CRP: C-reactive protein; TNF-α: Tumor necrosis factor-α.

Figure 3 Correlation of interleukin-6, C-reactive protein, tumor necrosis factor-α, and lactic acid levels with self-rating anxiety scale score and self-rating depression scale. A: Interleukin-6 levels are positively correlated with the self-rating anxiety scale (SAS) score; B: C-reactive protein levels are positively correlated with the SAS score; C: Tumor necrosis factor-α levels are positively correlated with the SAS score; D: Lactic acid levels are positively correlated with the SAS score; E: Interleukin-6 levels are positively correlated with the self-rating depression scale (SDS) score; F: C-reactive protein levels are positively correlated with the SDS score; G: Tumor necrosis factor-α levels are positively correlated with the SDS score; H: Lactic acid levels are positively correlated with the SDS score. SAS: Self-rating anxiety scale; IL-6: Interleukin-6; CRP: C-reactive protein; TNF-α: Tumor necrosis factor-α; SDS: Self-rating depression scale.

Figure 4 Correlation of interleukin-6, C-reactive protein, tumor necrosis factor-α, and lactic acid levels with Pittsburgh sleep quality index score. A: Interleukin-6 levels are positively correlated with the Pittsburgh sleep quality index (PSQI) score; B: C-reactive protein levels are positively correlated with the PSQI score; C: Tumor necrosis factor-α levels are positively correlated with the PSQI score; D: Lactic acid levels are positively correlated with the PSQI score. PSQI: Pittsburgh sleep quality index; IL-6: Interleukin-6; CRP: C-reactive protein; TNF-α: Tumor necrosis factor-α.

DISCUSSION

Septic shock is characterized by a high incidence, complex pathogenesis, and high mortality and has become a leading cause of death in the ICU due to the lack of early characteristic manifestations and clear indicators[26]. An epidemiological survey of patients with sepsis in the ICUs of 44 hospitals across the country[27] showed that sepsis was more prevalent in the ICU (20.6%), with septic shock accounting for 53.3% of cases and a 90-day fatality rate of 51.94%. The skin, the body’s largest and most complex organ, consists of the epidermis, dermis, and subcutaneous tissue. The surface of the skin covers approximately 1.8 m² and serves important functions such as resisting pathogenic microorganisms, acting as a protective barrier, and regulating temperature[28,29]. Patients with septic shock often have critical conditions, multiple complications, hypoperfusion, poor tissue oxygenation, malnutrition, and limited activity, making them a high-risk group for ASF[30]. Hemodynamic abnormalities, including impaired heart function, changes in peripheral vascular resistance, and a sharp decrease in circulating blood volume, are common in patients with ASF and can lead to skin microcirculation dysfunction or ischemic necrosis of the skin and subcutaneous tissue. In addition, increased peripheral vascular resistance due to the body’s compensatory response exacerbates skin tissue hypoperfusion, making the development of ASF more likely. The occurrence of ASF can prolong ICU stay and increase mortality rates. Cohen et al[31] reported that the mortality rate of patients with ASF can reach 42%. In this study, 35 out of 150 patients with septic shock (23.33%) developed ASF. These findings suggest that ASF is associated with disease progression in patients with severe septic shock and has a higher incidence in these cases.

Currently, the pathogenesis of ASF in septic shock remains unclear; however, it is believed to involve various factors, including systemic inflammatory network effects, tissue damage, and elevated lactic acid levels. The inflammatory response triggered by sepsis produces numerous inflammatory mediators through cascading effects, leading to infiltration of tissues and organs, which eventually results in simultaneous functional failure and shock in multiple organs, potentially leading to death. In patients with sepsis, a long-term imbalance between anti-inflammatory factors and inflammatory can occur, contributing to the dysregulation of inflammation. The most typical inflammatory mediators, such as TNF-α, CRP, and IL-6, participate in various biological reactions, exacerbating the inflammatory response and promoting organ failure. These indicators can be used for diagnosing and assessing infectious diseases[32,33]. CRP is an acute-phase protein that can increase, on average, due to viral infections, inflammation, trauma, and other factors. IL-6 plays a pivotal role in the acute inflammatory cascade, and its increased expression can induce chemotactic infiltration of inflammatory cells, aggravating local inflammation. TNF-α is a mononuclear factor that can cause tissue damage, induce the continuous progression of sepsis, and complicate clinical treatment. Koskela et al[34] created blisters on the skin of patients with severe sepsis through artificial negative pressure induction. The extracted blisters were examined in the laboratory, revealing that the levels of inflammatory factors in the skin were higher than those in the serum.

In patients with septic shock, tissue hypoperfusion leads to abnormal metabolism in organs and produces excessive lactic acid, exceeding the liver’s clearance capacity. Therefore, lactic acid levels can reflect tissue hypoxia and hypoperfusion in patients with septic shock[35]. The occurrence of ASF indicates that the patient’s effective circulating blood volume is insufficient to meet the skin’s blood perfusion needs, causing tissue cells to produce lactic acid under hypoxic conditions, which represents the early stage of sepsis. It has been reported that the MEWS can predict the progression and prognosis of patients with septic shock[18,36]. However, there are few reports on the occurrence and prognosis of ASF in relation to MEWS.

The levels of IL-6, CRP, procalcitonin, lactic acid, SMS, and MEWS scores were significantly higher in the ASF group than in the non-ASF group. Further analysis showed that IL-6, CRP, TNF-α, and lactic acid levels were positively correlated with SMS and MEWS scores (P < 0.05). These findings suggest that inflammatory factors are expressed at higher levels in patients with ASF and septic shock, indicating that the disease is more severe. As inflammatory factors increase, both the disease and degree of skin failure are continuously aggravated. Anxiety and depressive, negative emotions are common in regular patients in ICU and can adversely affect health-related quality of life[37]. According to survey data, 57%-81% of patients in ICU have varying degrees of sleep disorders, with some continuing to have these issues after discharge[38]. The condition of patients with ASF is critical, and they often suffer from psychological disorders, such as anxiety and depression, which form a vicious circle that exacerbates sleep disorders. It was found that compared with the non-ASF group, the SAS, SDS, and PSQI scores were significantly higher in the ASF group (P < 0.05). This suggests that patients with ASF and septic shock have worse mood and sleep quality.

A study on survivors of severe sepsis and their relatives showed that two-thirds of the patients reported clinically relevant post-traumatic stress disorder and approximately one-third exhibited abnormal levels of anxiety and depression[39]. Statistical data from animal experiments[40] showed that the mortality rate of 8-week-old mice after sepsis modeling was 31%, while that of 8-week-old mice after 48 hours of sleep deprivation increased to 67%. Clinical studies have shown that the expression of IL-6 and TNF-α secreted by monocytes, mediated by lipopolysaccharids-Toll-like receptor 4 signaling pathway, is increased after sleep deprivation in young people aged 25-39 years. This suggests that sleep deprivation can be considered a risk factor for infectious diseases and is associated with the severity of inflammatory response, promoting poor prognosis in sepsis[41]. The results of this study showed that levels of IL-6, CRP, TNF-α and lactic acid were positively correlated with SAS, SDS, and PSQI scores (P < 0.05), suggesting that an increase in the levels of inflammatory factors worsens patients’ mood and sleep quality. The limitations of this study include its small sample size and limited sources. In the future, the sample size will be expanded, and a multicenter clinical study will be conducted to obtain more objective and scientific conclusions.

CONCLUSION

In summary, patients with septic shock and ASF exhibit abnormal levels of peripheral blood inflammatory factors, lactic acid, bad mood, and sleep disorders. Additionally, the levels of related inflammatory factors and lactic acid are positively correlated with the severity of ASF, bad mood, and sleep quality.