Evaluation of Inflammatory Infiltration in the Retroperitoneal Space of Acute Pancreatitis Using Computer Tomography and Its Correlation with Clinical Severity

This paper investigates the correlation between the degree and severity of CT inflammatory infiltration in the retroperitoneal space of acute pancreatitis (AP). A total of 113 patients were included based on diagnostic criteria. The general data of the patients and the relationship between the computed tomography severity index (CTSI) and pleural effusion (PE), involvement, degree of inflammatory infiltration of retroperitoneal space (RPS), number of peripancreatic effusion sites, and degree of pancreatic necrosis on contrast-enhanced CT at different times were studied. The results showed that the mean age of onset in females was later than that in males; 62 cases involved RPS to varying degrees, with a positive rate of 54.9% (62/113), and the total involvement rates of only the anterior pararenal space (APS); both APS and perirenal space (PS); and APS, PS, and posterior pararenal space (PPS) were 46.9% (53/113), 53.1% (60/113), and 17.7% (20/113), respectively. The degree of inflammatory infiltration in the RPS worsened with the increase in CTSI score; the incidence of PE was higher in the group greater than 48 hours than in the group less than 48 hours; necrosis >50% grade was predominant (43.2%) 5 to 6 days after onset, with a higher detection rate than other time periods (P < 0.05). Thus, when the PPS was involved, the patient's condition can be treated as severe acute pancreatitis (SAP); the higher the degree of inflammatory infiltration in the retroperitoneum, the higher the severity of AP. Enhanced CT examination 5 to 6 days after onset in patients with AP revealed the greatest extent of pancreatic necrosis.


Introduction
Acute pancreatitis (AP) is caused by the early activation of many lytic enzymes (such as pancreatic lipase and trypsin) in the pancreas under the infuence of various causes of the disease, resulting in diferent "autolytic" destruction of pancreatic acinar cells, pancreatic ductal epithelial cells, and pancreatic cells, and pancreatic edema, massive hemorrhage, and pancreatic/peripancreatic necrosis can be observed [1,2]. In China, AP is a common and frequently occurring disease of the human digestive system, but due to diferent severities, many occurrences, and high mortality rates, AP has become a "challenging" serious acute abdomen disease that seriously afects the health of the Chinese people. AP, as a heterogeneous condition, has numerous causes and is divided into congenital causes and acquired causes [3].
Congenital factors are mainly divided into hereditary genetic causes, changes in pancreaticobiliary development/changes in pancreaticobiliary junction, pancreatic division, and annular pancreas. In addition, because AP is a systemic disease, it often leads to pathophysiological changes in many organ systems of the body, which can produce systemic complications and local complications in both the early and late stages of the disease [4]. After the diagnosis of AP, physicians must evaluate the severity of the patient's disease, but the prognosis of patients with AP of diferent severities is completely diferent. From the historical record of AP, there are various ways and related studies to diagnose the severity of the disease. Usually, clinicians try to determine the patient's condition by obtaining an indicator or some indicator in the patient's plasma sample by means of blood examination, while imaging scientists have to determine the patient's condition through the patient's imaging test data [5,6]. At present, the diagnosis of AP can be roughly judged based on abdominal pain fndings and imaging diagnosis, but the classifcation of its severity and the judgment of pancreatic necrosis are not deep enough.
AP is a systemic disease in which, in addition to a peripancreatic leak, extravasation of infammatory cells can spread through many retroperitoneal spaces (RPS), intermediate levels of fascia, subperitoneal spaces, and the abdominopelvic cavity with extensive involvement [7]. Studies have confrmed that the infltration thickness of left subphrenic fat presents a signifcant positive correlation with both the Ranson score and Balthazar grade, which can refect the severity of clinical research conditions to some extent [8][9][10]. Infammatory efusions resulting from peripancreatic/extrapancreatic exudates may propagate into many spaces in the body, including the APS, omental bursa, and intraperitoneal spaces in the abdominopelvic cavity that are of interest to the radiologists. However, other common anatomical sites are likely to be overlooked in daily work, such as the subperitoneal space and gastric bare area and the left subphrenic extraperitoneal space [11,12]. Te anterior layer of the right anterior renal fascia runs to the left at the front edge of the horizontal descending segment of the duodenum, and the posterior layer at the posterior edge of the descending segment of the duodenum continues to extend to the connective tissue membrane near the inferior vena cava to the left. Terefore, the bilateral anterior renal fascia running inward at the connective tissue membrane segment of the anterior inferior vena cava forms the extension of the same fascial layer, while the infammatory efusion layer extends along the interfascial pathway, resulting in the consistency of both sides. Tis anatomical basis can explain the continuous imaging fndings of CT/ MRI images of bilateral APS efusion in front of the retroperitoneal great vessels (inferior vena cava and abdominal aorta), and it is speculated that this anatomical basis may also be one of the mechanisms of AP patients with bilateral APS efusion often coexisting. Most researchers have proposed that AP continues to spread to the RPS, including pancreatic enzyme infltration rich in AP, which can cause the dissolution of renal fascia and infammatory edema and efusion between renal fascia due to the histolytic efect. When the infammation exceeds the prerenal and retrorenal fascia, the infammation continues to proliferate and infltrate the APS, PS, and PPS, causing transfascial and interspace difusion of retroperitoneal changes [13].
Te diagnosis and classifcation of pathology is a commonly used "gold standard" in clinical practice. For AP, it is difcult to obtain pancreatic and peripancreatic histological samples for medical data analysis because general patients do not undergo postoperative treatment and puncture angiographic sections during hospitalization [14]. Terefore, the current "gold standard" for the treatment of AP is to perform ultrasound imaging examination, generally enhanced CT examination. Te CTSI scoring modality also has an important impact on predicting the severity of pancreatitis [15,16]. CT examination is also helpful for diagnosis, and evaluation of the severity of the disease, such as pancreatic enlargement, decreased pressure, slurred contour, and peripancreatic exudate, can be observed during plain CT, while enhanced CT examination is not only helpful to distinguish the severity of angioedema and progressive necrosis but also helpful for the identifcation of pancreatic necrosis, chronic edema severity, and peripancreatic and extrapancreatic multipore exudate [17]. Te morphological changes of pancreatic necrosis can be observed during contrast-enhanced CT examination, which is of great signifcance for judging the severity during examination; is also helpful for early detection, staging diagnosis of severity, and grading criteria; and can detect the presence of adverse complications. Te qualitative and quantitative data analysis of pancreatic parenchyma and peripancreatic necrosis is also of signifcance for clinical diagnosis [18][19][20]. Te general data of patients and the relationship between CTSI and PE involvement, RPS infammatory infltration, the number of peripancreatic efusion sites, and the degree of pancreatic necrosis examined by enhanced CT at diferent times were studied to explore the correlation between the degree and severity of CT infammatory infltration in RPS of AP and provide a reference for clinical treatment.

Study Subjects.
From January 2021 to March 2022, 113 patients with AP were enrolled in the Department of Emergency Medicine of Anhui No. 2 Provincial People's Hospital. Tey were divided into groups according to CTSI classifcation, including 54 cases of grade I, 31 cases of grade II, and 28 cases of grade III. Clinical examination and laboratory data were obtained from the hospital. After the data were complete, enhanced CT detection was carried out in the hospital. Te inclusion criteria and exclusion criteria are shown in Table 1. When the conclusions are released by using the patient's images and data, the individual privacy information of each patient is managed anonymously, ensuring the personal information security of each patient to the maximum extent. Before CT examination, patients knew the purpose, steps, and precautions of each examination, and in CT examination, the health status of each patient must be closely monitored to ensure the safety of the examination. It was approved by the Medical Ethics Committee of Anhui No. 2 Provincial People's Hospital. Te patients and their families understood the content and methods and agreed to sign the corresponding informed consent form.

Diagnostic Criteria.
Te criteria for AP judgment in the 2012 Atlanta Global Cooperative Consensus are shown in Table 2.
At least two of the above criteria were met to confrm the diagnosis of AP. Criteria for moderate to SAP: transient organ failure (normal organ function within 48 hours) and/ or local disease after onset. Criteria for SAP: persistent organ failure after onset (organ failure for more than 48 hours). Diagnostic criteria for organ failure were assessed using the revised Marshall score. Local complications included evaluation of the modifed Marshall scoring system. Local diseases were mainly divided into acute peripancreatic efusion, acute necrotic aggregation, pseudocyst, capsular injury, pancreatic injury with infection, portal vein and hepatic vein thrombosis, acute gastric outfow obstruction, gastrointestinal fstula, abdominal bleeding, and PE.
"2004 Chinese Guidelines for the Diagnosis and Treatment of Acute Pancreatitis (Draft)": the clinical manifestations of AP are acute persistent abdominal pain (no abdominal pain occasionally), elevated serum amylase activity 3 times above the upper limit of normal, imaging fndings with or without pancreatic morphological changes, excluding other diseases. SAP was defned as one of the following criteria: organ failure (especially shock, pulmonary insufciency, and renal failure); local complications (pancreatic necrosis, pseudocyst, and pancreatic abscess); Ranson score ≥3; APACHEii score ≥8; and grades D and E of CT.

Imaging Grading and Clinical Severity Grading Standard of AP.
According to Balthazar grading, pancreatic Balthazar grading was divided into 5 grades (A ∼ E), with 0∼4 points in turn (Table 3).
Te grading criteria (3 grades) for pancreatic necrosis were degree of necrosis <30%, 30% ∼ 50%, and >50%. Pancreatic necrosis and necrotic area accounted for 30% of the pancreas, Balthazar score plus 2 points; necrotic area accounted for 50% of the pancreas, Balthazar score plus 4 points; necrotic area accounted for more than 50% of the pancreas, Balthazar score plus 6 points.
CTSI � Balthazar AP grade + degree of pancreatic necrosis. CTSI divided AP into three diferent grades: grade I 0∼3 points, grade II 4∼6 points, and grade III 7∼10 points. CTSI >4 was classifed as severe pancreatitis. Te degree of infammatory infltration in the RPS was classifed into four grades: grade A, without RPS involvement; grade B, with APS involvement only; grade C, with both APS and PS involvement; and grade D, with APS, PS, and PPS involvement.

Data Acquisition.
CT examinations were performed using a 16-row (Somatom Sensation 16; Siemens Medical Solutions, Erlangen, Germany) or 64-row (GE Healthcare, Milwaukee, WI, USA) CTscanner with a display feld of view (FOV) of 35 cm, tube voltage of 120 KV, tube current of 140 mA, and scanning range from the diaphragmatic surface of the liver to the pelvis. Te contrast agent was 300 mg I/mL with Ultravist (Schering, Germany) or 300 mg I/mL with Iopamiron (Schering, Germany) or 300 mg I/mL with Omnipaqu (Nycomed, Norway), and the contrast medium was injected intravenously into the forearm with a highpressure syringe at a dose of 80-100 mL. For further enhanced examination, a three-dimensional fat-saturated t1 weighted sequence was used for enhanced scanning. A gadolinium-based contrast agent (0.1 mmoL/kg) was injected with a high-pressure injector at a rate of 3-4 mL/sec, followed by 20 mL of normal saline. Te injection rate was 2 mL/sec. Before the examination, the patients were required to actively cooperate during the examination and complete all sequences as much as possible. If the inspection process could not continue, the inspection was stopped. During the examination, the patients were required to lie fat, breathe as calmly as possible, and wear soundproof earplugs.

Statistical
Processing. All statistical analyses were performed using IBM SPSS Statistics 26 software. Measurement data are expressed as the mean ± standard deviation. Comparisons were performed by t-test or analysis of variance. Statistical data were expressed by absolute logarithm and percentage, χ 2 test was used for comparison, chi-square segmentation was used for pairwise comparison among three groups, rank sum test was used for comparison of rank data, and Spearman analysis was adopted for correlation analysis. Normally distributed quantitative data were evaluated using the Kolmogorov-Smirnov test, and variance alignment was evaluated using Levene's test. Te quantitative data that met a normal distribution are expressed as the mean ± standard deviation (x ±s); the quantitative data that did not meet a normal distribution are expressed as the median and interquartile range. Qualitative data were expressed as percentages. Diferences in quantitative data were compared by adopting Student's T-test or the Mann-Whitney U test. One-way variance (ANOVA) was applied  Acute abdomen such as upper abdominal pain and discomfort 2 Serum lipase or amylase level 3 times or more above the normal upper limit 3 CT imaging of the abdomen suggesting the diagnosis of AP to compare the quantitative data among the three groups, and Tukey's test was adopted for pairwise comparison. Qualitative data were compared using Pearson's χ 2 test or Fisher's exact test. Te measured fuid volume in each anatomical space in two rounds was observed (after the frst round of CT measurement at admission, the same patient was measured again in the same order every other week). Data from both rounds were recorded using intraclass correlation coefcients to determine the reproducibility of the measured data.

General Information.
Of the 113 cases of AP, there were 54 patients with mild acute pancreatitis (MAP) and 59 patients with SAP. Te CT images of MAP and SAP patients were randomly selected ( Figure 1). According to the general data, there were 75 males with a mean age of 47.45 ± 17.05 years and 38 females with a mean age of 53.6 ± 20.04 years. In AP, the number of male patients was more than that of females, approximately twice that of females, and the mean age of onset in females was later than that in males, and the diference was statistically signifcant (P < 0.01). Te causes were biliary in 44 cases (39.0%), alcoholic in 20 cases (17.7%), hypertriglyceridemia (HTG) in 17 cases (15.0%), overeating in 29 cases (25.7%), other causes in 3 cases, accounting for 2.7%, and biliary as the main cause of AP (Figure 2).

Relationship between CTSI and Infammatory Extension in the Retroperitoneum.
To facilitate the statistics and analysis of subsequent data, AP patients were divided into three diferent grades according to CTSI, including 54 patients in grade I group, 31 patients in grade II group, and 28 patients in grade III group (Figure 3).
According to the classifcation of involvement: grade A, no RPS involvement; grade B, only APS involvement; grade C, both APS and PS involvement; and grade D, both APS, PS, and PPS involvement. Of the 113 patients, 62 had diferent degrees of RPS involvement, with a positive rate of 54.9% (62/113), and the overall involvement rates of APS, PS, and PPS were 46.9% (53/113), 53.1% (60/113), and 17.7% (20/ 113), respectively. APS involvement was predominant in grade I group; both APS and PS were predominant in grade II group, while APS, PS, and PPS were predominant in grade III group (Figure 4). PPS involvement in grade III group was greater than that in the grade I and II groups, and the diference was statistically signifcant (P < 0.05); that is, PPS involvement in the SAP group was higher than that in the MAP group.
In grade I group, infammatory infltration of RPS was mild, mainly grade A and B, accounting for 92.3% (49/54) and 7% (4/54), respectively; only 1 case of grade C, accounting for 1.9% (1/54), and no cases of grade D. In grade II group, the degree of infammatory infltration of RPS was mainly grade C in 87.1% (27/31), grade B and grade D in 3.2% (1/31) and 9.7% (3/31) of the cases, respectively. In the grade III group, the degree of infltration was mostly above grade C, mainly grade D, accounting for 67.9% (19/28). Te results of the correlation test showed that the diference was statistically signifcant (P < 0.01) ( Figure 5). Te degree of infammatory infltration in the RPS increased with increasing CTSI score (P < 0.05); that is, the more signifcant the infammatory infltration in the RPS, the more the severity of AP.

Relationship between CTSI and PE.
In grade I group, 11 cases were complicated with PE in 54 cases, with a positive rate of 20.4%; in grade II group, 16 cases were complicated with PE in 31 cases, with a positive rate of 51.6%; in grade III group, 22 cases were complicated with PE in 28 cases, and the positive rate was 78.6%. Chi-square test among the three groups: the diference was statistically signifcant, P < 0.01; chi-square segmentation was used for pairwise comparison; grade I group was compared with grade II group, P < 0.01; grade I group was compared with grade III group, P < 0.05; grade II group was compared with grade III group, P < 0.05; the incidence of PE in grade I, II, and III groups was different, and the incidence of PE increased with the increase of CTSI score. Te incidence of PE in SAP was higher than that in MAP, and the false line in Figure 6(a) indicates the positive and negative predictive curve. Nine cases of PE were found in AP patients with an onset less than 48 h, including four cases, four cases, and one case in the grade I, II, and III groups; PE was found in 40 AP patients with an onset more than 48 h, including 8 cases in grade I group, 11 cases in grade II group, and 21 cases in grade III group. Te incidence of PE in the group greater than 48 h was higher than that in the group less than 48 h (P < 0.05), and the incidence of PE increased with increasing CTSI score. Te above data are shown in Figure 6(b).

Te Relationship between CTSI and the Number of Peripancreatic Efusion Sites.
Tere were 76 cases (67.3%) of peripancreatic efusion, including 28 cases (51.9%) of Having two or more efusions or pneumatosis with unclear boundary in glands or adjacent areas 4 peripancreatic efusion in the grade I group, 23 cases (74.2%) of peripancreatic efusion in the grade II group, and 25 cases (89.3%) of peripancreatic efusion in the grade III group. When there was 1 efusion, the grade I group accounted for the highest proportion (34.7%), while having ≥2 efusions. Te proportion gradually increased with disease aggravation. In conclusion, when the disease severity increased, the number of peripancreatic efusion sites increased, and the diference was statistically signifcant (P < 0.01). Te correlation analysis results with the disease severity showed that there was a positive correlation between the two (P < 0.01). Te distribution of the number of peripancreatic efusion sites in each group is shown in Figure 7. ; the detection rate of necrosis >50% grade found by enhanced CT 5 ∼ 6 days after onset was higher than other time periods (P < 0.05), indicating that pancreatic necrosis was more likely to be found by enhanced CT 5 ∼ 6 days after onset ( Figure 8).

Discussion
AP is a common acute abdomen in clinical treatment, often involving many organs of the body. Its disease complications are very strict, and the mortality rate is high. It is clinically divided into acute MAP and SAP. SAP accounts for about 20% of AP. Te clinical pathological changes during treatment are very complex, with a mortality rate as high as 2/ 10-3/10. Timely and correct evaluation of the severity of AP and reasonable systematic treatment will help to improve the prognosis of patients [21]. Ultrasonography can also be the most important detection modality for AP imaging, but because the results of ultrasonography are susceptible to gastrointestinal air accumulation, while CT examination can reveal signifcant changes in the morphology and pathology of AP, CT examination is also the most accurate imaging modality for the detection of AP, and enhanced CT examination is helpful to identify the severity of necrosis and chronic edema in the pancreas and the status of  Contrast Media & Molecular Imaging peripancreatic and extrapancreatic multiple space exudates [22]. As medical care progresses, multiple assessment systems have been developed. Te RPS is defned as having three spaces: PS, APS, and PPS. Te PS consists of the anterior renal fascia on the front of the kidney and the posterior renal fascia on the back. Bridging septa composed of connective tissue are widespread in the PS fat, between the renal capsule and the renal tendon layer, between the anterior and posterior renal muscle layer, and between the renal capsule and capsule [23,24]. Most researchers proposed to continue to spread AP to the RPS, including the pancreatic enzyme exudate rich in AP, because histolytic efect can cause the melting of the renal muscle layer and cause infammatory edema and effusion between the renal tendon layers. When the infammation exceeds the prerenal and retrorenal muscle layers, the infammation continues to proliferate and infltrate APS, PS, PPS, etc., and cause transmuscular and trans-space spread of retroperitoneal changes. When efusion occurs in PPS, the mortality rate of AP patients is increased, while when examination shows PPS involvement, the risk of SAP is great, so PPS involvement can also be used as an important indicator for the diagnosis of SAP. If PPS involvement is used as a positive criterion for judging SAP, its specifcity (88.2%) and positive predictive value (91.8%) indicate that after PPS involvement, the risk of working for SAP is greater, but it generally does not afect MAP judgment [25][26][27]. APS involvement was more common in MAP, while both APS and PPS involvement were more common in SAP. Te degree of infammatory cell infltration in the retroperitoneum could refect the severity of AP to some extent. Particularly, the involved period of PPS mostly is shown as  Figure 6: Relationship between diferent CTSI groups and PE. (a) Detection rate of PE of diferent CTSI grades (in grade II group, # represents comparison with grade I group, in grade III group, # represents comparison with grade I group and grade II group, respectively); (b) Number of PE cases at diferent time points; * represents the diference has statistical signifcance (P < 0.05), * * represents the diference has statistical signifcance (P < 0.01), # represents comparison among groups (P < 0.05), ## represents the diference has statistical signifcance (P < 0.01). SAP, so the disease can be managed as SAP during the involved period of PPS.
Patients with AP are more likely to have confuent lung disease, including human PE, atelectasis, lung disease, or concurrent ARDS and circulatory depletion. Tere are many studies on PE in China. At present, it mainly holds the view that peripancreatic infammation spreads from the extrapancreatic to the pleural cavity to form PE [28]. It is generally believed that anatomically, the lymphatic plexus around the transverse septum is connected with the mediastinal and subcostal spaces, the giant infammatory cells formed by AP spread into the mediastinum and subcostal space through the lymph plexus around the septum, and the pancreatic enzyme efusion containing soluble tissue gradually entered the chest cavity. PE is important for assessing the severity and prognosis of AP and is the main symptom of extrapancreatic involvement of AP [29]. Although PE can also be detected radiologically early, most of them occur earlier than the date of pancreatic injury, and the incidence of PE increases with increasing CTSI score [30]. Tis revealed that PE can be recommended as a reference technical index for the diagnosis of severe pancreatitis, especially if PE is found within 24 hours after onset, and the mortality rate will be signifcantly improved. It was also found that there was a diference between PE and the incidence in patients with MAP/SAP, and if the incidence of AP patients with PE was more severe in early detection, it could also be used as an early index for AP severity judgment.
Early contrast-enhanced CT examination without signifcant changes is often found in clinical practice in pancreatic necrosis, and a second contrast-enhanced CT examination can detect massive pancreatic necrosis. Patients with early pancreatitis had CTSI scores of grades I and II, and over time, patients developed grade III. Tis is because it takes some time for the infammation of the pancreas to transform into necrosis, and it also takes some time for imaging changes. It should be noted that there is a time diference between the imaging fndings of AP and the clinical presentation. If CT enhancement is performed early in patients with AP, some SAP may be misdiagnosed as MAP. Terefore, the optimal time for AP-enhanced CT examination can be better used for the corresponding treatment [31,32]. Many clinical data have demonstrated that changes in pancreatitis can be found by CT 12 h-24 h after onset, but there is no uniform consensus on the time of contrast-enhanced CT examination. Enhanced CT 2-3 days after admission more easily distinguishes interstitial pancreatitis from necrotizing pancreatitis than enhanced CT on admission [33]. Since pancreatic necrosis does not occur early, some studies suggest that SAP is dynamically enhanced 3-0 days after admission to avoid afecting the early assessment of disease severity by CTSI.
A total of 113 patients with AP were retrospectively analyzed. If pancreatic necrosis occurs 5-6 days after the onset of the disease detected by enhanced CT, it can be found to the maximum extent, but it is not the peak period of AP severity. Te imaging causes of AP: the imaging fndings of AP have a certain time diference compared with the clinical manifestations. It takes a certain time for exudative infammation of the pancreas to develop into pancreatic necrosis, which is a pathological change, and it also takes a certain time for the corresponding changes to be found by imaging monitoring. According to the principle of enhanced CT imaging, when the normal pancreatic tissue progresses to the completion of pancreatic liquefaction necrosis, the enhanced contrast agent cannot be perfused into the necrotic pancreatic tissue through the microcirculation, and the pancreatic parenchymal necrosis shows an unenhanced low-density pancreatic area on imaging.

Conclusion
Te examination of the degree of retroperitoneal infammatory infltration showed that the higher the degree of infammatory infltration was, the higher the severity of AP was. Especially when PPS is involved, SAP is often recommended. Terefore, when PPS is involved, the patient's condition can be treated according to SAP. Analysis of AP patients with early PE found that the condition of AP patients with PE was more serious, and PE can be used as an early indicator of AP severity. According to the analysis of the degree of pancreatic necrosis in AP patients, the maximum range of pancreatic necrosis can be found by enhanced CT examination 5-6 days after the onset of AP.

Data Availability
Te datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Conflicts of Interest
Te authors declare that they have no conficts of interest.