Author Affiliations: Department of Pancreatic and Biliary Surgery, First Affiliated Hospital of Harbin Medical University, Harbin 150001, China (Ji L, Lv JC, Song ZF, Jiang MT, Li L and Sun B)

Corresponding Author: Bei Sun, MD, PhD, Department of Pancreatic and Biliary Surgery, First Affiliated Hospital of Harbin Medical University, Harbin 150001, China (Tel: +86-451-85555734; Fax: +86-451-85555493; Email: sunbei70@tom.com)

 

© 2016, Hepatobiliary Pancreat Dis Int. All rights reserved.

doi: 10.1016/S1499-3872(15)60043-1

Published online December 31, 2015.

 

 

Contributors: SB proposed the study. JL performed the research and wrote the first draft. LJC, SZF and JMT collected the relevant data. LL performed statistical analyses. All authors contributed to the design and interpretation of the study and to further drafts. SB is the guarantor.

Funding: This study was supported by grants from the National Natural Science Foundation of China (81372613 and 81170431), Doctoral Fund of Ministry of Education of China (21022307110012) and Special Fund of Ministry of Public Health of China (210202007).

Ethical approval: The study was approved by the Ethics Committee of First Affiliated Hospital of Harbin Medical University.

Competing interest: No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

 

 

BACKGROUND: Severe acute pancreatitis (SAP) remains a clinical challenge with considerable morbidity and mortality. An early identification of infected pancreatic necrosis (IPN), a life-threatening evolution secondary to SAP, is obliged for a more preferable prognosis. Thus, the present study was conducted to identify the risk factors of IPN secondary to SAP.

 

METHODS: The clinical data of patients with SAP were retrospectively analyzed. Univariate and multivariate logistic regression analyses were sequentially performed to assess the associations between the variables and the development of IPN secondary to SAP. A receiver operating characteristic (ROC) curve was created for each of the qualified independent risk factors.

 

RESULTS: Of the 115 eligible patients, 39 (33.9%) progressed to IPN, and the overall in-hospital mortality was 11.3% (13/115). The early enteral nutrition (EEN) (P=0.0092, OR=0.264), maximum intra-abdominal pressure (IAP) (P=0.0398, OR=1.131) and maximum D-dimer level (P=0.0001, OR=1.006) in the first three consecutive days were independent risk factors associated with IPN secondary to SAP. The area under ROC curve (AUC) was 0.774 for the maximum D-dimer level in the first three consecutive days and the sensitivity was 90% and the specificity was 58% at a cut-off value of 933.5 µg/L; the AUC was 0.831 for the maximum IAP in the first three consecutive days and the sensitivity was 95% and specificity was 58% at a cut-off value of 13.5 mmHg.

 

CONCLUSIONS: The present study suggested that the maximum D-dimer level and/or maximum IAP in the first three consecutive days after admission were risk factors of IPN secondary to SAP; an EEN might be helpful to prevent the progression of IPN secondary to SAP.

 

(Hepatobiliary Pancreat Dis Int 2016;15:428-433)

 

KEY WORDS: D-dimer; enteral nutrition; infected pancreatic necrosis; intra-abdominal pressure; risk factor; severe acute pancreatitis

Acute pancreatitis (AP) is an inflammation of the pancreas and can generate severe local and/or systemic complications. Approximately 20% of patients with AP eventually progress to severe AP (SAP), which is characterized by persistent (>48 hours) organ failure.^[1] Pancreatic necrosis is a severe evolution during the natural course of SAP. The mortality rate is 43% for the patients who have infected pancreatic necrosis (IPN) and organ failure.^[2]

 

Few publications provide precise and adequate early predictions of the outcomes of SAP, including the development of IPN.^[3-5] Therefore, the present study was to identify the early-phase baseline parameters that were associated with the development of IPN secondary to SAP.

 

 

Consecutive adult patients with SAP (age ≥18 years old) admitted to the Department of Pancreatic and Biliary Surgery, First Affiliated Hospital of Harbin Medical University between January 2009 and December 2013 were enrolled. The exclusion criteria for patients are shown in a flow chart (Fig. 1), and the included patients were followed up for 90 days after discharge. The study was approved by the Ethics Committee of our hospital.

 

According to the modified Atlanta Criteria,^[1] AP was diagnosed based on the presence of at least two of the following three criteria: (1) an initial serum amylase and/or lipase level at least three-fold above the normal upper limit; (2) typical abdominal pain consistent with AP; and (3) suggestive imaging evidence compatible with AP. SAP was defined as AP accompanied by the persistent organ failure. To exclude any iatrogenic factors that might incur infections, the IPN investigated in the present study was defined as any infection of the necrotic pancreatic parenchyma or peripancreatic collections that developed prior to any invasive intervention. The presence of IPN was suspected if the patient had a continuous fever and/or general deterioration despite the appropriate management, and IPN was confirmed by computed tomography (CT). Microbiological confirmations were established with positive cultures of samples obtained by fine needle aspirations under CT/ultrasound guidance and/or samples obtained during invasive therapeutic procedures.

 

Immediately after admission, all patients received individualized conservative therapy for SAP that included intensive monitoring, fluid resuscitation, oxygen administration, fasting, analgesia and suppression of pancreatic exocrine function. Additionally, antibiotics were prescribed in the presence of other infections (e.g., biliary tract, urinary tract, pulmonary, etc.) in the setting of SAP. Contrast-enhanced CT was routinely performed on the third day after admission or earlier when warranted by diagnostic dilemmas.

 

Intra-abdominal pressure (IAP) was measured with the following technique. All patients were told to remain in a complete supine position after bladder empting; then, 25 mL of sterile saline was instilled through a Foley catheter into the bladder. The indices were scaled at the end-expiration without any abdominal muscle contraction and calculated (1 mmHg=1.36 cmH₂O) using the mid-axillary line as the zero reference point. The IAP was measured at admission and every 12 hours thereafter for initial consecutive five to seven days. The time interval was shortened to 6 hours or 3 hours if intra-abdominal hypertension (IAH, defined as a persistent increase of IAP >12 mmHg) or acute compartment syndrome (ACS, defined as sustained IAP >20 mmHg combined with new onset organ failure) was detected.^[6]

 

Endoscopic nasojejunal tubes were selectively inserted beyond the ligament of Treitz within the first 24-48 hours after admission, and the position of the tip was confirmed by fluoroscopy. During the next 24 hours, enteral nutrition (EN) using a small peptide medium-chain triglyceride semi-elemental formula was commenced and gradually increased. The total calories required were calculated as 25-30 kcal/kg per day, and the protein needs were calculated as 1.25-1.50 g/kg per day. Early EN (EEN) was defined as the patient tolerated at least 70% of his or her daily required calories at the third day after admission. Total parenteral nutrition was only initiated in response to EN contradictions, intolerance or insufficient delivery (failure to provide >60% of the daily required calories after 7 days). Once IPN was confirmed, a minimally invasive procedure or a laparotomy was performed as soon as possible. Additionally, antibiotic therapies were guided by the results of culture and sensitivity.

 

The following data were collected from all eligible patients: (1) demographic data, including age, gender, etiology and body mass index (BMI); and (2) the maximum value for the following clinical data within the first 3 days: white blood cell count, hematocrit, platelet count, C-reactive protein, blood urea nitrogen, creatinine, D-dimer, IAP, sequential organ failure assessment score, modified Marshall score and acute physiology and chronic health evaluation II score. The CT severity index (CTSI) at the third day, the Imrie score at the end of second day and an indicator of whether each patient could successfully undergo EEN were also documented.

 

The data were analyzed using SAS 9.1 for Windows (SAS Institute, Cary, NC, USA). Quantitative variables were presented as the median (interquartile range, IQR) in cases of non-normal distributions or as mean±standard deviation for normal distributions. Categorical variables were presented as absolute numbers and percentages. The variables found to be statistically significant in the univariate logistic regression analysis were introduced into a multivariate logistic analytic model (stepwise regression) to identify the independent risk factors with the odds ratios (ORs) and 95% confidence intervals. Furthermore, utilizing receiver operating characteristic (ROC) curves, the areas under the curves (AUCs) and the cut-off values with the associated sensitivities and specificities of the qualified independent risk factors were calculated. A P value less than 0.05 was taken to indicate the statistical significance.

 

 

Of the 115 eligible patients, 39 (33.9%) progressed to IPN with a median (IQR) interval of 13 (11.5) days after admission. The demographic data and clinical characteristics of both IPN and non-IPN groups are shown in Table 1. The range of time from admission to discharge or death among these 115 patients was 9-141 days, and the overall in-hospital mortality was 11.3% (13/115). Of the 13 mortalities, 10 were IPN deaths due to the progression of pancreatic fistula, intra-abdominal hemorrhage, sepsis, multiple organ dysfunction syndrome, etc. at 15-33 days after admission. Among the IPN patients, mixed infections (24, 61.5%) were dominant, followed by infections with Gram-positive bacteria alone (11, 28.2%) and Gram-negative bacteria alone (4, 10.3%). Additionally, concomitant fungal infections were identified in 7 patients (17.9%). Among the infectious microbes, Escherichia coli (26, 66.7%) and Staphylococcus (21, 53.8%) were the most commonly isolated.

 

The results of univariate logistic regression analysis are shown in Table 2. The EEN (P=0.0136), maximum IAP (P=0.0003), maximum D-dimer level (P<0.0001) and BMI (P=0.0354) were statistically significant. Table 3 illustrates the results of multivariate analysis by stepwise regression. The EEN (P=0.0092, OR=0.264), maximum IAP (P=0.0398, OR=1.131) and maximum D-dimer level (P=0.0001, OR=1.006) remained statistically significant, whereas the BMI was not. Furthermore, ROC curves (Fig. 2, Table 4) indicated that the cut-off value of 13.5 mmHg for the maximum IAP and 933.5 µg/L for the maximum D-dimer level were most suitable for sensitivities and specificities.

 

 

Although IPN typically occurs in the late phase of SAP, it accounts for up to 50%-80% of mortalities.^{[7, 8]} Therefore, the early prediction of IPN and specific targeted interventions are imperative to reduce IPN-related mortalities.^{[9, 10]}

 

Coagulopathy and disrupted microcirculation are commonly detected during the course of SAP.^{[11, 12]} Salomone et al^[13] reported that increases in the D-dimer (a marker of fibrinolysis activation that is routinely tested) levels are due to the occurrence of pancreatitis, and the degree of this increase is related to the progression of the illness. Our data suggested that maximum D-dimer level was correlated with the severity of SAP and the presence or absence of IPN (P<0.0001). Furthermore, the maximum D-dimer level was an independent risk factor of IPN secondary to SAP (P=0.0001, OR=1.006). Although the OR value for the maximum D-dimer level was very close to 1, suggesting only a humble greater chance of progressing to IPN when the maximum D-dimer level was elevated, it is still of importance to alert physicians the possibility of development of IPN and the prompt treatment. The specificity of the cut-off value for the maximum D-dimer level was relatively lower (58%), and we sacrificed the specificity to obtain a high sensitivity of 90%.^[14]

 

The incidence of IAH in patients with SAP is approximately 60%-80%.^[15] A series of pathological alternations followed by IAH might finally result in sepsis-related complications.^{[8, 16, 17]} Our data suggested that the maximum IAP is an independent risk factor of IPN secondary to SAP (P=0.0398, OR=1.131). Previously, a significant discrepancy related to the IAP was observed between patients with and without IPN.^{[18, 19]} We considered a relatively lower cut-off value with a higher sensitivity to be more instructive, although the relatively lower specificity might result in certain overestimated assessments. Given the adverse outcomes that follow IAH/ACS, it is imperative to identify the subgroups of patients with relatively higher risks of IPN development timely so that proper surveillance and interventions can be implemented. The results of studies suggested that it is necessary to initiate careful and frequent surveillance of IAP when its level approaches the upper limit of grade 1 IAH.^{[6, 20]}

 

For patients with SAP, nutritional support is warranted due to the hypercatabolic and negative nitrogen-balanced status that might impede disease recovery.^[21-23] Compared to total parental nutrition or no nutrition, EEN reduces mortality, septic complications and hospital stay.^{[22, 24-27]} Our data suggested that EEN, in contrast to the maximum IAP and maximum D-dimer level, acted as a protective factor of IPN secondary to SAP (P=0.0092, OR=0.264). Recently, the results of a well-designed multicentric randomized clinical trial did not show positive effects of EEN (within 24 hours after admission) against on-demand nutrition (72 hours later since admission) with the incidence of IPN as an endpoint.^[28] Except for the possible explanations listed by the authors, there might be one more attribution: the timing of feeding. There is no doubt that a nasoenteric tube should be placed as soon as possible when patients with SAP were admitted, but it is worthy to be discussed if it is rational to initiate feeding within first 24 hours.^{[29, 30]} From the pathophysiological prospective, the gut is hypoperfused as the result of fluid sequestration followed by the attack of SAP. It seems more rational to restore blood volume and overcome reflex splanchnic vasoconstriction by appropriate fluid resuscitation before enteral feeding.^[30] So, instead of an active endeavor to maintain the gut integrity anatomically and functionally, feeding within first 24 hours might act as a burden which might be of no benefit to prevent gut-derived infectious complications. Additionally, some data showed that feeding was more beneficial when initiated in 24-48 hours of admission than that within first 24 hours.^{[29, 31]} Nevertheless, the results of this randomized clinical trial could not simply be undermined by the theoretical derivations above and its subsequent controversies need to be further investigated.

 

There were two primary advantages of the present study. First, by introducing the updated definition of SAP,^[1] we were able to minimize selection bias by ruling out patients who were overestimated due to their seemingly severe signs and symptoms. Second, we attempted to identify specific, routinely tested and reproducible baseline clinical parameters that were associated with IPN secondary to SAP in the timeframe of the first 3 days after admission. However, the relatively small and asymmetric sample of the present study represents a major drawback that might have reduced the statistical power.

 

In conclusion, the present study suggested that the maximum D-dimer level and/or maximum IAP in the first three consecutive days after admission might be indicative of the likelihood of IPN secondary to SAP; EEN in 24-48 hours after admission might have protective effect on IPN secondary to SAP.

 

 

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