CRP in Drain Fluid as a Predictive Marker of Anastomotic Leak in Colorectal Surgery: A Systematic Review of the Literature

Abstract

Background/Aim: Anastomotic leak (AL) remains one of the most troublesome complications in general surgery. The current review aimed to assess the level of C-reactive protein (CRP) in drainage fluid after entero-enteric, colonic, or colorectal anastomosis as a predictive biomarker for AL.

Materials and Methods: Four medical databases (PUBMED-MEDLINE, Google Scholar, UpToDate, and Cochrane Library) were searched in January 2023 for prospective or retrospective studies on the role of acute-phase proteins in drainage fluid as a predictive biomarker of AL. Two independent researchers gathered and processed the data using MedCalc. The data were pooled and Student’s t-test was used to compare the data between the AL and non-AL groups.

Results: Overall, four studies were included in the current review, containing 753 patients in total, for whom various types of enteric and colonic anastomoses were constructed. Overall 79 (10.49%) of patients demonstrated AL and the mean CRP level (±standard deviation) on postoperative day 3 was 167.7±77.13 mg/l. On the contrary, the non-AL group (674/753) had a statistically significantly lower mean CRP level at 83.76±20.32 mg/l. CRP values were not related to mortality. It was not possible to propose a CRP cut-off indicating an increased risk for AL as the data were insufficient.

Conclusion: The CRP level in drainage fluid might be a valuable biomarker for predicting the possibility of AL in general surgery. However, further and larger-scale studies are needed to establish a CRP cut-off value and this variable would possibly be different for patients with different pathologies.

Anastomotic leak (AL) remains one of the most dreadful complications in general surgery, with an incidence ranging from 2% to 14% when performed by an experienced general surgeon. Most often it takes place around the seventh postoperative day (1). Non-specific plasma biomarkers such as increased white blood cells, C-reactive protein (CRP), and procalcitonin (PCT) indicate an ongoing inflammatory process, which increases the possibility of an AL (2).

A CRP level >12.4 mg/dl on postoperative day (POD) 4 and an elevated PCT level have negative predictability peaking at 99.3% in one study (3). White blood cell (WBC) count and cytokines such as interleukin 6 (IL6) have also been studied and proven to be associated with increased septic complications and therefore affect the AL rate among patients directly or indirectly, through a subclinical, emerging inflammation. However, all the above biomarkers demonstrate poor positive predictability and are influenced by various other complications, mainly postoperative infections (2).

As clinicians are searching for a more sensitive and specific indicator of AL, they have focused on acute-phase proteins in drainage fluid, especially CRP in peritoneal fluid. Such a marker would be vital in Enhanced Recovery After Surgery protocols, permitting the safe and early discharge of patients, and reducing re-admission rates. The current systematic review, through gathering and combining of all available data, aimed to compare CRP in drainage fluid of patients having AL after colectomy or enterectomy to those who did not.

Materials and Methods

PubMed, Cochrane Library, UpToDate, and Google Scholar databases were searched for all prospective and retrospective studies that compared CRP in drainage fluid in groups of patients who had a colectomy or enterectomy for malignant and non-malignant diseases and either demonstrated AL or not. The search took place in January 2023. The PubMed algorithm was “acute phase proteins in drain fluid AND anastomotic leakage” and its results are shown in Figure 1, while the Patient/Population, Intervention, Comparison, Outcomes (PICO) model is shown in Table I. The same algorithm was used to search the Google Scholar database. Cochrane Library and UpToDate had no articles related to our topic. Finally, studies were included in the qualitative synthesis having met all of the following inclusion criteria: (i) Patients underwent colectomy or enterectomy and primary anastomosis, (ii) patients underwent surgery for malignant and non-malignant diseases, (ii) patients underwent elective surgery only.

Figure 1. PubMed search algorithm results.

Table I. PICO model of our review.

CRP: C-Reactive protein.

Two independent researchers reviewed the search results and double-proofed their data. After gathering all data, MedCalc was used to group and process them, and to compare the mean CRP values of the AL and non-AL groups using Student’s t-test.

The current review was conducted in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) (4) and A Measurement Tool to Assess Systematic Reviews (AMSTAR) (5) guidelines.

Results

Cochrane Library and UpToDate had no articles related to our topic. The PubMed algorithm resulted in seven articles. One was excluded as being irrelevant based on its title. Three more articles were excluded after screening of their abstracts, as two referred to acute-phase proteins in serum and one was a letter to the editor. One more of the remaining articles was in Chinese and was also not included.

Two more studies were found from Google Scholar, while through the snowball method, only one article was identified but was a duplicate with a Google Scholar result. In total, four studies met the criteria mentioned above and were included in the current systematic review (6-9). Table II presents the studies included.

Table II. Studies included in the qualitative synthesis.

All in all 753 patients were included in the synthesis 449 (59.6%) men and 274 (36.4%) women. Their ages ranged from 33 to 87 years old. The range was calculated using three studies’ data, as Jaju et al. (6) did not provide specific age data about their patients and divided them into age groups. All studies provided inclusion criteria, while three of them also mentioned the exclusion criteria: Pregnant women and patients undergoing emergency procedures, patients in whom no drain fluid was obtained, infection or other inflammatory condition, tumor recurrence surgery, and reversals of colostomy. We present all the inclusion and exclusion criteria, along with patient demographics in Table III.

Table III. Patient demographics.

*Patients were divided into age groups: 41-50, 51-60 and above 60 years.

All researchers grouped their patients into two categories, those who demonstrated AL and those who did not, and calculated the mean CRP in the drainage fluid from patients of these groups on different POD. The mean [±standard deviation (SD)] CRP of the AL group in our pooled data was 167.7±77.125 mg/l on POD 3, and 164.6±105.34 mg/l on POD 5. These values were significantly higher than those of the non-AL group, where the mean CRP was 83.76±20.316 mg/l (SD) and 68.62±23.26 mg/l on POD 3 and 5, respectively.

The overall sensitivity of CRP as a biomarker for AL was calculated to be a mean of 54.93% on POD 3, but specificity was much higher for that day, reaching almost 80%. It was not possible to calculate the predictive value of the marker as only one study provided the necessary data.

Mortality across the studies ranged from two to nine patients out of 79 patients with AL overall (a total of 19 patients died), although only Komen et al (9). commented on the reason for death and its relation to AL. No information about the duration of the drainage was given.

We used Student’s t-test to compare the CRP values of the AL and non-AL groups on POD 3, demonstrating a statistically significant difference between the two groups. More specifically, on POD 3 the mean CRP±SD for the AL group was 167.7±77.125 mg/l, in contrast to the much lower CRP of the non-AL group: 83.76±20.316 mg/l (p<0.001).

This indicates that CRP in drainage fluid on POD 3 might be used as a biomarker to predict AL. Of course, further research is needed to establish this due to the small number of studies and the heterogeneity of the diseases and types of anastomosis. All described data are presented in Table IV and Table V.

Table IV. Uni-and multi-variate analyses to identify clinicopathological characteristics related to relapse-free survival (n=52).

Table V. Outcomes of patients in the anastomotic leakage group.

Discussion

AL remains a troublesome complication in general surgery, often requiring reoperation and increasing patient morbidity and hospital stay (10). Traditionally, leaks are diagnosed either through postoperative computed tomography scans where one can see a leakage of gastrografin outside the bowel’s lumen, or because they are clinically evident in the drainage fluid of the patient. Various blood biomarkers have been proposed such as CRP, WBC, PCT, neutrophil-to-lymphocyte ratio, amylase, and others (11,12).

According to the Italian Colorectal Anastomotic Leakage Study Group, the most reliable indicator of all, regarding AL after elective colorectal surgery, was the Dutch Leakage Score (13,14). The purpose of this clinical score was to diagnose AL and related mortality earlier. Originally based on 11 easily acquired and measurable clinical parameters and on two laboratory tests (a 5% increase in WBC or CRP, and a 5% increase in blood urea or creatinine), with scores ranging from 0 to 20 (cut-off=4), it was then simplified and revalidated using three clinical parameters and one laboratory test (CRP level above 250 mg/l), with scores ranging from 0 to 4 (cut-off=1), and maintained the same diagnostic accuracy (15).

A recent metanalysis by Su’a et al. (16), reported that blood PCT is a reliable negative predictor of AL after colorectal surgery, with the highest diagnostic accuracy on POD 5 and using a cut-off value of 0.86 (95% confidence interval=0.79-0.94) mg/l. Other investigators tried to establish a correlation between PCT after colorectal surgery and IL6 levels, but the regression analysis failed to demonstrate a statistically significant association (17).

Other laboratory biomarkers such as the neutrophil-to-lymphocyte ratio and drain fluid amylase have been investigated and proven to be indicators of worse outcomes after colorectal surgery, having a close correlation to patients’ morbidity and AL. These markers demonstrated their highest sensitivity and specificity on POD 4 and 5 (18,19).

Despite the encouraging existing data, which tend to establish all these markers as predictors of AL with satisfactory sensitivity, they all lack specificity, especially in patients who demonstrate other postoperative complications such as respiratory or urinary tract infections (2,16,17).

Therefore, researchers have tried to identify new, more specific biomarkers for AL in peritoneal fluid. Acute-phase proteins are the first candidates, as they are easy to measure in everyday practice. CRP in drainage fluid in patients undergoing colectomy or enterectomy is increased during the first PODs. However, as this review indicates, in patients with AL, CRP values are much higher than in those that without AL. On top of this observation, Jaju et al. (6) proposed that a steady increase of the CRP in the peritoneal fluid better predicted an AL. However, this assumption was not verified by Kostić et al. (8).

All the included studies showed that when AL is present, CRP values in the drainage fluid are higher, but due to the small number of studies, an estimation of a potential cut-off is not feasible. Furthermore, as it is known that inflammation is closely related to cancer, patients with advanced disease are more likely to have higher CRP values without ever manifesting AL. An interesting proposal was made by Sparreboom et al. (7) – they created a parallel scale nomogram, which matched the CRP and metalloproteinase levels with the risk of AL.

Mortality and morbidity were not associated with CRP in the current review, while we should not forget that such parameters are influenced by various other factors such as the type of anastomosis (colorectal or coloanal anastomosis have a much worse prognosis than enteroenteric or ileocolonic ones) and the patient’s comorbidities.

Conclusion

CRP in drainage fluid seems a promising predictive biomarker for AL after colorectal surgery. A larger number of patients is needed to calculate a sensitive and specific cut-off, with a better stratification regarding the initial reason for surgery.

Conflicts of Interest

There were no competing interests and no sources of funding for the current review.

Authors’ Contributions

IK and ES performed the literature search and drafted the article; GA screened the retrieved articles and performed data extraction; GT, DD and NN critically revised the final version of the article.