Serum Amyloid A as an Early Marker of Infectious Complications after Laparoscopic Surgery for Colorectal Cancer

Abstract

Background:

Our aim was to evaluate the usefulness of serum amyloid A (SAA) measurements in comparison with C-reactive protein (CRP) in the early prediction of infectious complications among patients undergoing laparoscopic surgery for colorectal cancer

Methods:

Consecutive patients undergoing laparoscopic resection for colorectal cancer were analyzed prospectively. All subjects had the Enhanced Recovery After Surgery protocol implemented. Blood samples were taken from all patients and SAA and CRP were measured on the day of surgery and on the three consecutive post-operative days (PODs). Patients were divided into two groups (Group 1 without complications, Group 2 with complications), and these groups were compared.

Results:

The study included 81 patients (61 in Group 1 and 20 in Group 2). Starting from POD2, significant differences between the groups were observed for both SAA and CRP. On POD2, the median CRP values were 116.7 mg/L and 256.9 mg/L in Groups 1 and 2, respectively (p = 0.00002). On POD3, the median SAA concentration was 445 mg/L in Group 1 and 1,412 mg/L in Group 2 (p = 0.00003). The CRP concentrations were 80.2 mg/L and 247.1 mg/L in Groups 1 and 2, respectively (p = 0.00001). A receiver operating characteristic (ROC) curve analysis showed that measurements of POD3 had the highest specificity and sensitivity with no significant differences between CRP and SAA (on POD3 for SAA sensitivity 83.3% and specificity 94%; for CRP: sensitivity 88% and specificity 86%).

Conclusion:

Measurements of SAA are useful in predicting infectious complications even on the early post-operative days. It has characteristics similar to CRP, and its best values are reached on POD3.

Colorectal cancer surgery is associated with a relatively high morbidity rate. Post-operative complications occur in 30%–40% of patients, even with the laparoscopic approach and implementation of novel multimodal perioperative care protocols based on Enhanced Recovery after Surgery (ERAS) principles. These measures can lower post-operative complications and accelerate the healing process, leading to hospital discharge as early as after 2–5 days [1 –6]. On the one hand, shorter length of stay (LOS) is considered beneficial. On the other, some complications, especially infectious (e.g., anastomotic leakage) can occur relatively late, even on post-operative days (PODs) 6–12 [7 –10]. This poses a risk that patients may be discharged before they become symptomatic from those late complications. This can result in delayed diagnosis and create a need for additional treatment. For these reasons, it seems reasonable to search for new early objective markers of infectious complications in this specific group of patients.

Well-known markers, such as white blood-cell count, C-reactive protein (CRP), or procalcitonin, have been described as auxiliary tools in the diagnosis of post-operative infection [11 –15]. However, their biochemical characteristics in the early detection of complications (POD 1–3) are not entirely satisfying because of their relatively late rise after surgery) [16]. Although the use of serum amyloid A (SAA)—an acute-phase protein produced by the liver in response to systemic inflammation—has been described in the assessment of systemic inflammatory reaction and in a few specific surgical disorders [17,18], no study has examined its use as a marker of complications in general surgery in the post-operative setting.

The aim of this study was to evaluate the usefulness of SAA measurements in the early prediction of infectious complications in comparison with CRP among patients undergoing laparoscopic surgery for colorectal cancer.

Patients and Methods

The study was approved by the local Ethics Review Committee (approval number KBET/211/B/2014). All procedures were performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.

The study was conducted in a tertiary referral center (university hospital). Consecutive patients undergoing laparoscopic resection for colorectal cancer were analyzed prospectively. Inclusion criteria were age more than 18 years, elective laparoscopic surgery for colorectal adenocarcinoma, and ERAS protocol for peri-operative care. We excluded patients submitted to open or emergency surgery and multi-visceral resections (stage T4 cancer). Patients with inflammatory bowel disease also were excluded from the study. Other exclusion criteria were distant metastases (stage M1), rectal cancer treated with transanal endoscopic microsurgery (TEM), conversion to open resection, active infection, or autoimmune systemic disease. Moreover, we excluded patients with infectious or other complications diagnosed within the first 48 hours post-operatively.

A laparoscopic approach with five or six trocars and medial to lateral technique was used [19]. All patients had the same peri-operative care by the ERAS protocol (Table 1), which has been used in our department for five years. Mean compliance with the protocol exceeded 85% [20,21].

Table 1.

ERAS Protocol Used in Our Unit

1. Preoperative counselling and patient education

2. No bowel preparation (oral lavage in the case of low rectal resection with total mesorectal excision (TME) and defunctioning loop ileostomy)

3. Pre-operative carbohydrate loading (400 mL of Nutricia preOp^® 2 h prior to surgery)

4. Antithrombotic prophylaxis (Clexane^® 40 mg subcutaneously starting on the evening prior to surgery)

5. Antibiotic prophylaxis (pre-operative cefuroxime 1.5 g + metronidazole 0.5 g intravenously (IV) 30–60 min prior to surgery)

6. Laparoscopic surgery

7. Balanced IV fluid therapy (<2500 mL of IV liquids during the day of surgery with <150 mmol sodium)

8. No nasogastric tubes post-operatively

9. No drains left routinely for colonic resections; one drain placed for <24 h in case of TME

10. Transversus abdominis plane (TAP) bloc; epidural anesthesia in cases at high risk of open conversion

11. Avoid opioids, multi-modal analgesia (oral when possible: paracetamol 4 × 1 g, ibuprofen 2 × 200 mg, metamizole 2 × 2.5 g, or ketoprofen 2 × 100 mg)

12. Prevention of post-operative nausea and vomiting (dexamethasone 8 mg IV, ondansetron 8 mg IV, metoclopramide 10 mg IV)

13. Post-operative oxygenation therapy (4–6 L/min.)

14. Early oral feeding (oral nutritional supplement 4 h post-operatively, light hospital diet and oral nutritional supplements on the first post-operative day (POD), full hospital diet on the second POD)

15. Urinary catheter removal on the first POD

16. Full mobilization on the first POD (getting out of bed, going to the toilet, walking along the corridor; at least 4 h out of bed)

Blood samples for SAA and CRP measurements were taken from all patients on the day of surgery (pre-operatively) and every morning before the first meal for three consecutive PODs.

Serum from a blood sample (1 vial of 4.9 mL) was centrifuged for 10 minutes at 4,000 rpm and then frozen at −80°C until a full set of specimens was collected. Patients were divided into two groups: Group 1 was patients without and Group 2 patients with infectious complications. Diagnosis of these complications and assessment of their severity was performed according to European Center for Disease Prevention and Control guidelines [22].

Groups were compared by age, sex, body mass index (BMI), American Society of Anesthesiologists (ASA) score, type of surgery, tumor stage, operative time, and intra-operative blood loss. Differences in SAA and CRP concentrations between groups were analyzed on consecutive PODs. The optimal time for obtaining the markers (POD) and the cut-off values for each marker were analyzed from the data collected using ROC analysis.

All data were analyzed with Statsoft STATISTICA v. 12.5 (Statsoft Inc., Tulsa, OK, USA). The results are presented as mean ± standard deviation (SD) or median and interquartile range (IQR). The study of categorical variables used the χ² test of independence. The Shapiro-Wilk test was employed to check for normal distribution of data, and the Student t-test was applied for normally distributed quantitative data. For non-normally distributed quantitative variables, the U Mann-Whitney test was used. For dependent variables, the Friedman test was applied. A receiver operating characteristic (ROC) curve was constructed to obtain the area under the curve (AUC) and determine the best cut-off values. Values were considered statistically significant when p was <0.05.

Results

A series of 171 patients in our department underwent colorectal resection between August 2014 and May 2016. Of these, 57 did not fulfil the inclusion criteria and were excluded. A total of 33 were excluded in the peri-operative period. Patient flow through the study and the reasons for exclusion are shown in Fig. 1.

FIG. 1.

Patient flow through study.

Groups 1 and 2 consisted of 61 (75.3%) and 20 (24.7%) patients, respectively. Table 2 shows the demographics of the groups. No significant differences were noted regarding their sex, age, BMI, ASA score, type of surgery, operative time, intra-operative blood loss, or cancer stage. However, there was a significant difference between the groups in median LOS (4 vs 10 days; p < 0.001). The overall infectious complication rate was 21.9%. The analysis of infectious complications is presented in Table 3.

Table 2.

Demographic Features of Patient Groups

	Group 1	Group 2	p
Number of patients	61	20	–
Females (%)	28 (45.9)	10 (50)	0.74994
Males (%)	33 (54.1)	10 (50)	0.74994
Mean age, years ± SD	64.6 ± 12.8	65.9 ± 13.6	0.80249
Body mass index, kg/m² ± SD	26.5 ± 5.8	26.5 ± 5.0	0.936155
American Society of Anesthesiologists score (%)
1	1 (1.6)	1 (5)	0.69767
2	37 (60.7)	12 (60)
3	23 (37.7)	7 (35)
American Joint Committee on Cancer stage (%)
I	28 (45.9)	10 (50)	0.47902
II	17 (27.9)	3 (15)
III	16 (26.2)	7 (35)
Median operative time, min (IQR)	192 (155–240)	180 (170–275)	0.52486
Median intraoperative blood loss, mL (IQR)	70 (50–150)	100 (5–225)	0.30387
Median length of hospital stay, days (IQR)	4 (2–5)	10 (4–18)	0.00047
Readmission (%)	4 (6.5)	4 (20)	0.37209

IQR = interquartile range.

Table 3.

Numbers of Complications

Anastomotic leakage	8
Surgical site infection: deep or superficial	5
Intraperitoneal abscess	3
Urinary tract infection	2
Pneumonia	1
Infectious diarrhea (Clostridium difficile)	1

Laboratory measurements are available in Table 4. Before surgery (POD 0), SAA and CRP concentrations were similar in the two groups. On POD 1, the SAA concentration increased in both groups, and the difference between groups was not statistically significant. On PODs 2 and 3, the SAA and CRP concentrations in Group 1 were lower than in Group 2 (Figs. 2 and 3). Friedman's analysis of variance showed differences in consecutive SAA and CRP measurements in both groups (POD 2: SAA [median, IQR; mg/l]: Group 1 [736; 426–1,010] vs Group 2 [1,223; 860–1,460] p = 0.00036; CRP [median, IQR; mg/L] Group 1 [116.7; 60.3–192.9] vs Group 2 [256.9; 173.1–281.6] p = 0.00002; POD 3: SAA: Group 1 [445, 236–863] vs Group 2 [1412, 1210–1760] p = 0.00003; CRP: Group 1 [80.2, 42.8-147.1], Group 2 [247.1, 212.7–356] p = 0.00001).

FIG. 2.

Mean serum amyloid A concentrations in Groups 1 and 2 on consecutive days.

FIG. 3.

Mean C-reactive protein concentrations in Groups 1 and 2 on consecutive days.

Table 4.

Analysis of Biochemical Data

		Group 1 (no complications)	Group 2 (complications)	p
Mean SAA ± SD (median, IQR) [mg/L]	POD 0	20.2 ± 42.1 (8, 4.6–14.7)	63.8 ± 143.8 (9.5, 4.3–11.9)	0.80882
	POD 1	372.2 ± 253.2 (352, 186–498)	459.1 ± 250.7 (423.5, 265–610)	0.12616
	POD 2	716.4 ± 383.5 (736, 426–1,010)	1202.8 ± 351.7 (1223, 860–1,460)	0.00036
	POD 3	561 ± 456.1 (445, 236–863)	1419.3 ± 453.4 (1412, 1,210–1,760)	0.00003
Mean CRP ± SD (median, IQR) [mg/L]	POD 0	13.7 ± 34.8 ( 3.3, 1.8–6)	14.0 ± 21.7 ( 3.4, 2–11.8)	0.56823
	POD 1	77.8 ± 38.4 ( 76.2, 45.7–109)	107.5 ± 62.4 ( 89.2, 68.4–145.4)	0.08161
	POD 2	125.8 ± 75.4 (116.7, 60.3–192.9)	238.2 ± 74.9 (256.9, 173.1–281.6)	0.00002
	POD 3	96.2 ± 75.7 ( 80.2, 42.8–147.1)	272.8 ± 108 ( 247.1, 212.7–356)	0.00001

CRP = C-reactive protein; IQR = interquartile range; POD = post-operative day; SAA = serum amyloid A protein.

A ROC curve was used to determine the optimal cut-off value for SAA and CRP concentrations on consecutive days. This analysis showed that measurements on POD3 were characterized by the highest specificity and sensitivity. Figures 4 –6 show ROC curves and their characteristics. We established the cut-off point for SAA on POD 3 at 1,190 mg/L (sensitivity 83%; specificity 94%). For CRP on POD 3, the cut-off point was set at 186 mg/L (sensitivity 88%; specificity 86%). As shown in Figure 6, there was no statistically significant difference in AUC for SAA and CRP. We performed a similar analysis for POD 2 (not presented); there were no differences in AUCs.

FIG. 4.

Receiver operating characteristic (ROC) curve to determine the optimal cut-off of serum amyloid A measurement.

FIG. 5.

Receiver operating characteristic (ROC) curve to determine the optimal cut-off of C-reactive protein measurement.

FIG. 6.

Receiver operating characteristic (ROC) curve for serum amyloid A and C-reactive protein concentrations on post-operative day 3.

Discussion

Our study showed that measurement of SAA in the early post-operative days is useful in the detection of infectious complications. Compared with CRP, SAA has similar characteristics (specificity and sensitivity), reaching the most useful values on POD 3.

The clinical benefits of laparoscopy in colorectal surgery are well known [23,24]. The minimally invasive approach has shown its advantages also on a biochemical level by diminishing the inflammatory response to surgical trauma in comparison with open surgery [25]. Enhanced Recovery After Surgery protocols are a combination of multi-modal peri-operative items that aim to further reduce surgical stress and accelerate patients' recovery by diminishing insulin resistance, a key factor leading to homeostasis imbalance early after surgery [26]. The ERAS positively impacts post-operative morbidity, and for this reason, its use is gaining popularity [10,27 –30].

Although many previous studies have investigated the use of acute-phase proteins in the monitoring of post-operative outcomes, most of them were based on patients undergoing open surgery without peri-operative ERAS protocols [31,32]. It may be expected that the combination of laparoscopy and ERAS would influence the systemic inflammatory response and concentrations of inflammatory markers. Several studies unequivocally confirmed this theory [25,33,34]. This combination also leads to a shorter post-operative recovery period and LOS. Therefore, in the case of ultra-short post-operative stays, early detection of infectious complications is crucial, and our study showed that both inflammatory markers analyzed can be used as a surrogate for determining the high-risk group for infectious complications.

We used CRP, which is a well-studied plasma marker (for many considered a gold standard) for anastomotic leakage and other infectious complications after colorectal surgery. However, most of the studies indicate its usefulness and define cut-off values at four or five post-operative days, which is of little relevance for ultra-short post-operative stays thanks to ERAS [31,32].

So far, only a few published studies analyzed the concentration of this marker in the first three PODs in laparoscopic surgery, usually without the implementation of an ERAS protocol. All of them showed that CRP measurements can be justified clinically to some extent [12,16]. We agree that CRP is a reliable marker when screening for infection development, but because of its limitations (quite long half-life, insufficient sensitivity and specificity in the early post-operative period), there is a need to find other faster and more specific biochemical markers of post-operative infections. For instance, procalcitonin has been proposed as an auxiliary tool in the prediction of complications. However, it has characteristics similar to those of CRP and thus the same drawbacks [35,36]. Change in albumin concentration also has been observed early after surgery, but this feature is relatively unspecific [37]. Therefore, in order to overcome the limitations, we tried to use SAA, which is considered an excellent marker of the systemic inflammatory response, comparing it with CRP. So far, we have not found any published studies that compare these markers in the post-operative period in patients undergoing colorectal surgery.

The SAA protein is produced by hepatocytes and constitutes another major positive acute-phase reactant. It can act as a chemoattractant for immune cells such as monocytes, polymorphonuclear leukocytes, mast cells, and T lymphocytes to the site of inflammation [38,39]. The induction of SAA is regulated primarily by inflammatory cytokines, such as interleukin (IL)-1, IL-6, and tumor necrosis factor-α. Thus, SAA plays a key role in a wide range of inflammatory processes. The literature indicates its significance in surgical disciplines; e.g. assessment of post-operative trauma, detecting organ failure in patients with septic shock, and monitoring allograft rejection of a kidney or liver [40 –43]. Some research shows that it could also be a prognostic marker in breast cancer [44]. Owens et al. found that it is a good predictor of peripheral arterial disease severity before vascular surgery [45]. Other research shows that SAA can be a good predictive marker of post-operative infectious complications in orthopedic surgery [46]. The SAA half-time of 18 hours is shorter than that of CRP (30 hours) and therefore could be more useful in early post-operative monitoring of patients after laparoscopic colorectal resection.

Our study showed that regardless of the occurrence of complications, there was an increase in the SAA concentration in the early PODs in all cases, but it was more pronounced in patients with complications. Moreover, we observed that among uncomplicated cases, the concentration of SAA in the first POD remained stable or even decreased over the following days after initial rapid increase. On the other hand, in patients who developed complications, SAA increased further in the following days. Both CRP and SAA are similar in the prediction of infectious morbidity. The ROC curve analysis showed that measurements of both proteins on POD3 are characterized by the best sensitivity and specificity. The tests have similar values of AUC.

Our study has certain limitations, which are typical for a single-center study. The study sample is rather small, and therefore to establish the cut-off values for SAA reliably, a larger sample is needed. On the other hand, all patients were selected cases undergoing a similar type of minimally invasive colorectal procedure. The baseline characteristics of groups of patients with and without complications, as well as the adherence to the protocol, were similar, which allows the conclusion to be drawn that the differences are closely related to the occurrence of complications. The other limitation is that the types of complications are heterogeneous (e.g., surgical site infection vs. anastomotic leakage). It has to be further investigated whether the benefit of SAA measurements in determining post-operative complications can be found in all patients, regardless of the severity of the complication.

Conclusion

We conclude that SAA may be useful in early detection of post-operative complications. It has predictive characteristics similar to those of CRP. However, to increase sensitivity and specificity, monitoring of both SAA and CRP (especially on POD 3) may be particularly beneficial in an early post-operative course after radical laparoscopic colorectal resection with ERAS protocol.

Author Disclosure Statement

Some of the data in this paper were presented at the 68th Congress of the Society of Polish Surgeons in September 2017.

The authors declare that there is no conflict of interest regarding the publication of this article.

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