Clinical and Laboratory Predictive Factors for Mortality in Acute Mesenteric Ischemia: A Single-Center Experience

Introduction

Acute mesenteric ischemia (AMI) is a life-threatening emergency. Based on the occlusion mechanism, AMI is classified as either occlusive or non-occlusive mesenteric ischemia, both of which lead to cellular hypoxia due to impaired perfusion. Therefore, prognosis largely depends on prompt diagnosis and treatment to prevent intestinal infarction. In-hospital mortality rates range from 50% to 55%, and the reported incidence of mesenteric ischemia has been increasing in recent years [1]. Bowel ischemia remains a diagnostic challenge for clinicians due to its frequently nonspecific clinical presentation and difficulty in recognizing the condition before bowel necrosis occurs. Another disadvantage is that although numerous guidelines are based on randomized controlled trials, they are often regional treatment guidelines with a low level of evidence [1,2].

For laboratory assessment of AMI, conventional recommendations include evaluation of white blood cell (WBC) count, acid-base status, aspartate aminotransferase (AST), blood urea nitrogen (BUN), creatinine, C-reactive protein (CRP), alanine aminotransferase (ALT), alkaline phosphatase (ALP), and amylase levels [1]. Although laboratory findings are not definitive, they play a supportive role in clinical suspicion. In more than 90% of cases, leukocytosis and metabolic acidosis with elevated lactate levels are the 2 most common pathological findings. The primary goal of AMI treatment is to restore blood flow to the ischemic intestine, resect all non-viable segments, and preserve as much viable bowel as possible [3].

The patient population affected by acute mesenteric ischemia (AMI) generally consists of elderly individuals with severe comorbidities, and the associated mortality rates are high. In this context, numerous laboratory parameters have been investigated to reduce mortality and facilitate early diagnosis in AMI; however, the results have been inconsistent [1–3]. The aim of this study was to evaluate the effectiveness of clinical characteristics and laboratory parameters in predicting mortality among patients who underwent surgery for mesenteric ischemia.

Material and Methods

Patients who underwent surgery for mesenteric ischemia at the Department of General Surgery, Tokat Gaziosmanpaşa University Faculty of Medicine, between January 1, 2011, and December 31, 2019, were retrospectively analyzed as part of a cohort study. To identify patients with mesenteric ischemia, the hospital information management system database was searched for computed tomography (CT) reports containing the terms “mesenteric artery embolism”, “mesenteric artery thrombosis”, “portal vein thrombosis”, and “mesenteric vein thrombosis”. Additionally, histopathological examination reports from the pathology department were reviewed for the presence of the term “intestinal ischemia”. Patients with intestinal ischemia secondary to strangulated hernia, adhesions, malignancy, or other major surgical procedures were excluded.

For the identified mesenteric ischemia cases, data on age, sex, comorbidities, clinical characteristics, American Society of Anesthesiologists (ASA) classification, laboratory and radiological findings, symptoms, time from the initial symptom to laparotomy, surgical procedures, ischemia etiology, and operative mortality (in-hospital mortality following surgery) were collected from the database.

Comorbid conditions such as cardiac disease (heart failure, ischemic heart disease), atrial fibrillation, diabetes mellitus, arterial hypertension, chronic obstructive pulmonary disease, and chronic renal failure were recorded. Coronary artery disease was diagnosed based on ECG findings, angiography, or a history of previous myocardial infarction. Atrial Fibrillation was diagnosed based on ECG findings and a previous cardiologic diagnosis. Diabetes mellitus was defined as HbA1c >6.5 or fasting blood glucose levels exceeding 126 mg/dL. Hypertension was defined as blood pressure readings above 140 mmHg. Cerebrovascular disease was diagnosed based on a history of stroke or transient ischemic attack (TIA). Heart failure was diagnosed in a cardiology outpatient clinic with heart failure and an ejection fraction (EF) below 50%. Chronic kidney disease was diagnosed after evaluation in a nephrology outpatient clinic. Chronic obstructive pulmonary disease (COPD) was diagnosed after assessment in a pulmonology outpatient clinic. Malignancy was defined by a history and diagnosis of malignancy.

Laboratory parameters included complete blood count parameters, plasma glucose, blood urea nitrogen (BUN), creatinine, amylase, lipase, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and albumin levels. Additionally, based on complete blood count parameters and albumin levels, the Systemic Immune-Inflammation Index (SII), Systemic Inflammation Response Index (SIRI), hemoglobin-albumin-lymphocyte-platelet (HALP) score, lymphocyte-to-monocyte ratio (LMR), platelet-to-lymphocyte ratio (PLR), and neutrophil-to-lymphocyte ratio (NLR) were calculated. Abdominal CT findings were also recorded.

The surgical procedures performed included bowel resection (segmental, ileum, jejunum, or colon), type of ostomy, type of anastomosis, and second-look surgery, all of which were retrieved from the system and documented. None of the patients who were indicated for surgery and underwent laparotomy had evidence of intestinal perforation at the initial evaluation. Based on clinical, surgical, radiological, and histological findings, patients were classified into 4 categories: arterial embolism, arterial thrombosis, venous thrombosis, and non-occlusive mesenteric ischemia. Patients were further categorized into 2 groups: survivors and non-survivors, and the collected data were compared between these groups.

The study was conducted in accordance with the Declaration of Helsinki and approved by the Local Research Ethics Committee registered under the number 20-KAEK-112. All methods were performed in accordance with the relevant guidelines and regulations of the institution. All patients provided written informed consent prior to surgery.

Statistical analyses of the data were conducted using SPSS software (Versiyon 22.0 SPSS Inc., Chicago, IL, USA). Categorical variables are presented as frequency and percentage (%). Normally distributed continuous variables were presented as mean±standard deviation (SD), and non-normally distributed variables as median±interquartile range (IQR). The normality of the distribution was assessed with the Shapiro-Wilk test. The 2 independent groups were compared using the t test for normally distributed continuous variables data and Mann-Whitney U test for non-normally distributed continuous variables. The comparisons between categorical variables were conducted using chi-square test or Fisher’s exact test, depending on the size of the data in the crosstab cells. Receiver operating characteristic (ROC) analysis was used to determine whether whole-blood parameters and some index scores such as HALP, SII, LMR, NLR, and PLR could be used as prognostic markers for the mortality or survival status. The area under the ROC curve (AUC) was calculated with 95% confidence intervals. AUC evaluation was as follows: Excellent 0.9–1, Good 0.8–0.9, Fair 0.7–0.8, Poor 0.6–0.7, and Fail 0.5–0.6. After the ROC analysis, the Youden index (maximum sensitivity and specificity) was used to determine the optimum cut-off point for the parameters that were significant in ROC analysis. The success of cut-off points was assessed with sensitivity, specificity, positive-negative predictive values, and likelihood ratio (+) values. The statistical significance level set at P<0.05. Since our study was exploratory in nature and aimed to investigate the predictive value of clinical and laboratory parameters, the Benjamini-Hochberg false discovery rate (FDR) correction was applied.

Results

The mean age of the patients was 66.96±13.44 years: 29 (63%) were male and 17 (37%) were female. The mean hospital stay duration was 18.98±21.18 days, and the mean time from symptom onset to surgery was 2.71±2.55 days. The distribution of etiology, ASA classification, discharge/exitus status, second-look surgery, resected intestinal segment, surgical procedures, comorbidities, and symptoms are presented in Table 1.

When comparing sex, etiology, ASA classification, resected intestinal area, comorbidities, symptoms, age, and time to surgery according to mortality status, significant differences were observed in mortality rates based on etiology, ASA classification, and resected intestinal area (P<0.001, P=0.031, and P=0.024, respectively). Among comorbidities, patients with diabetes mellitus (P=0.012), cerebrovascular disease (P=0.05), and chronic renal failure (P=0.05) had significantly higher mortality rates, whereas no significant differences were observed in mortality rates among patients with other comorbidities or symptoms (P>0.05). There were no statistically significant differences among in terms of age or time delay to surgery (P >0.05) (Table 2).

When laboratory parameters were compared according to mortality status, creatinine and urea levels were significantly higher in the mortality group, whereas HALP and LMR values were significantly lower in the mortality group (P<0.001, P<0.001, P=0.011, and P=0.029, respectively). No significant differences were observed in other laboratory parameters (Table 3).

In the ROC analysis conducted for the statistically significant HALP, LMR, creatinine, and urea values, all 4 parameters were found to be significant predictors of survival versus mortality (P=0.029, P=0.011, P<0.001, and P<0.001, respectively) (Figure 1, Table 4). Based on AUC values, LMR demonstrated a significantly better discriminatory power compared to HALP, whereas creatinine showed superior discrimination compared to urea (Figure 2).

Discussion

Acute mesenteric ischemia (AMI) is a rare cause of abdominal pain, accounting for less than 0.2% of emergency department visits. Despite advancements in diagnosis and treatment, mortality rates remain above 50%. The incidence of AMI increases with age, typically affecting individuals over 65 years without significant sex differences [4,5]. Prognosis worsens in advanced age, with an approximately 10-fold increase in incidence among patients in the eighth decade of life compared to those in the sixth decade [6]. A previous study demonstrated a significant association between age, sex, and mortality [7]. However, in our study, the mean age of patients diagnosed with AMI was above 60 years, and no significant relationship was found between age, sex, and mortality.

Arterial embolism is the most common etiology in mesenteric ischemia, accounting for nearly half of all cases and, together with arterial thrombosis, is responsible for approximately 75% of cases [8]. Generally, patients with arterial involvement have higher mortality rates than those with venous involvement, while non-occlusive mesenteric ischemia (NOMI) cases are also associated with high mortality rates [3,9]. One study found that mesenteric venous thrombosis had a better prognosis than arterial involvement [10]. In our study, no mortality was observed in venous thrombosis cases, and arterial embolism was the most common etiology. Further analysis demonstrated that arterial embolism was significantly associated with higher mortality rates. In a study by Gupta et al, a higher ASA score was identified as a significant risk factor for mortality [11]. Similarly, in our study, ASA 4 patients had significantly higher mortality rates.

Acosta et al [12] analyzed data from 132 patients and found that the affected intestinal segment was associated with mortality. Mortality was significantly higher in cases where both the small intestine and colon were involved, which was attributed to the colonic microbiota and proximal mesenteric vascular occlusion. Although they noted a protective effect of intestinal resection, they reported that they did not perform resection in patients with extensive involvement. In our study, intestinal resection was performed even in patients with extensive involvement. Approximately half of the patients underwent intestinal resection with stoma creation, and 7 patients required second-look surgery. Mortality was significantly higher in patients who underwent colon resection or those with both small intestine and colon resection. Thus, as the extent of intestinal involvement increased, the risk of mortality also increased.

Several studies have identified peripheral vascular diseases, atrial fibrillation, diabetes mellitus, chronic kidney disease, and heart failure as risk factors for mesenteric ischemia, although their direct association with mortality remains unclear [3,13,14]. In our study, the most common comorbidity was hypertension. Further analysis revealed that diabetes mellitus, cerebrovascular disease, and chronic kidney failure were significantly associated with mortality. Atherosclerotic changes in diabetes mellitus, genetic predisposition and immobility in cerebrovascular disease, and renal dysfunction may be the primary underlying mechanisms.

Various biochemical markers have been investigated for the diagnosis of AMI, with conflicting results regarding their ability to identify ischemic or necrotic bowel. A study demonstrated a significant relationship between early AMI detection and platelet volume, neutrophil-to-lymphocyte ratio (NLR), elevated serum lactate, D-dimer levels, C-reactive protein, acidosis, and leukocyte count [15]. Several other parameters, including lactate, pH, hemoglobin, platelet count, urea, creatinine, AST, bicarbonate, and potassium levels, have been found useful in AMI diagnosis and mortality prediction [16]. Bala et al [3] identified increased creatinine and urea levels as independent prognostic mortality factors. Similarly, our study confirmed that elevated urea and creatinine levels were significantly associated with high mortality rates. ROC analysis demonstrated that a creatinine level >1.11 mg/dL and a urea level >27.2 mg/dL were statistically significant for mortality prediction.

In recent years, several predictive parameters, such as NLR, LMR, PLR, SII, and SIRI, have been introduced using laboratory ratios. These parameters have been demonstrated to be valuable prognostic factors in various malignancies, including renal, gynecological, and colorectal cancers [17]. However, a study concluded that among these parameters, NLR and PLR were not independent prognostic factors in pancreatic cancer [18]. These parameters are easily obtainable from complete blood count and other standard laboratory values. Several studies have identified low LMR as a poor prognostic factor in ischemia [19,20]. Our study also found that LMR values were significantly lower in patients who died.

A novel biomarker, the HALP (hemoglobin, albumin, lymphocyte, platelet) score, has been introduced to assess both systemic inflammation and nutritional status. The role of the HALP score has been investigated in inflammatory emergency surgical conditions such as acute diverticulitis, and low HALP scores have been shown to be associated with a more severe clinical course [21]. In a study investigating ischemia due to bowel obstruction, low HALP scores were associated with high mortality rates [22]. Another study evaluating the relationship between neutrophils, albumin, lymphocytes, and HALP scores with surgical modality found no significant association with neutrophil or albumin levels, while low lymphocyte and HALP scores were significantly correlated with mortality [23]. A study found that, although the difference was not statistically significant, patients who developed strangulation and required resection were observed to have lower median HALP scores [24]. In a study on acute ischemic stroke, higher HALP scores were associated with a reduced risk of poor clinical outcomes at 90 days and 1 year after stroke onset [25]. Similarly, our study found no significant relationship between lymphocyte or albumin levels and mortality; however, low LMR and HALP scores were significantly associated with increased mortality. While HALP had lower sensitivity than LMR, its specificity was higher. Nevertheless, LMR demonstrated superior discriminative power in identifying fatal mesenteric ischemia cases compared to HALP.

The main limitations of our study are its single-center design, the relatively small sample size, and its retrospective design. Nevertheless, it is among the limited number of investigations evaluating the prognostic value of certain laboratory parameters and the HALP score in mesenteric ischemia.

Conclusions

In acute mesenteric ischemia (AMI), etiological factors, ASA classification, extensive resection, and certain comorbid conditions have been identified as risk factors for mortality. Elevated urea and creatinine levels, as well as low LMR and HALP scores, significantly increase the risk of mortality in patients with mesenteric ischemia. Further prospective, multicenter, and large-population studies are needed to validate these findings.