Changes in plasma albumin levels in early detection of infectious complications after laparoscopic colorectal cancer surgery with ERAS protocol

Changes in plasma albumin levels in early detection of infectious complications after... Background Combination of laparoscopic approach with ERAS protocol in colorectal surgery allows for an early discharge. However there is a risk that some of the discharged patients are developing, asymptomatic at the time, infectious complica- tions. This may lead to a delay in diagnostics and proper treatment introduction. We aimed to assess the usefulness of pre- operative plasma albumin concentration and their changes as indicators of infectious complications in patients undergoing colorectal cancer surgery. Methods Prospective analysis included 105 consecutive patients who underwent laparoscopic colorectal cancer resection between August 2014 and September 2016. In all cases standardised 16-item perioperative care ERAS protocol was used (mean compliance > 85%). Patients with IBD, distant metastases, undergoing emergency or multivisceral resection were excluded. Blood samples were collected preoperatively and on POD 1, 2, 3. Plasma albumin concentration was measured. Patients were divided into two groups depending on the presence of infectious complications. We analysed the differences in the levels of albumin and the dynamics of changes. Results Group 1—82 not complicated patients, Group 2—23 patients with at least one infectious complication. Preopera- tively, there were no significant differences in the levels of serum albumin between those groups (Group 1—38.7 ± 4.9 g/l; Group 2—37.7 ± 5.0  g/l). In postoperative period, decrease was observed in both (POD 1: Group 1—36.5 ± 4.2  g/l, Group 2—34.7 ± 4.2  g/l, p = 0.07; POD 2: Group 1—36.2 ± 4.1  g/l, Group 2—32.6 ± 5.6  g/l, p = 0.01; POD 3: Group 1—36.0 ± 4.4 g/l, Group 2—30.9 ± 3.5 g/l, p = 0.01). The decrease was significantly greater in Group 2 on POD 2 and 3. Conclusions We showed that a regular measurement of albumin in the early postoperative days may be beneficial in the detection of postoperative infectious complications. Although changes in albumins are observed early after surgery, this parameter is relatively unspecific. Keywords Colorectal cancer · Laparoscopy · Infectious complications · Markers · Albumins Colorectal cancer surgery is associated with a relatively This study has been awarded the Best Poster Presentation at the high morbidity rate, which depends on multiple factors and EAES Congress 2017 in Frankfurt. can occur in 30–40% of patients [1, 2]. One of the signifi- * Michał Pędziwiatr cant components affecting those parameters is the surgical michal.pedziwiatr@uj.edu.pl technique. It has been shown that the laparoscopic approach 1 is correlated with reduced morbidity [3, 4]. Moreover, the 2nd Department of General Surgery, Jagiellonian University implementation of multimodal perioperative care protocols Medical College, Kopernika 21, 31-501 Kraków, Poland 2 enhanced recovery after surgery (ERAS) further decreases Centre for Research, Training and Innovation in Surgery postoperative complications by approximately 20–40% and (CERTAIN Surgery), Kraków, Poland 3 leads to early hospital discharge after 2–5 days [5–8]. These Department of Diagnostics, Chair of Clinical Biochemistry, factors markedly shortened length of stay (LOS). Some Jagiellonian University Medical College, Kraków, Poland 4 complications (i.e. anastomotic leakage) can occur late Department of Physiology, Jagiellonian University Medical after surgery, even on postoperative day (POD) 8–12. This College, Kraków, Poland Vol.:(0123456789) 1 3 3226 Surgical Endoscopy (2018) 32:3225–3233 means that in most cases they are diagnosed after discharge Materials and methods [9]. For these reasons, markers that allow early detection of complications and prediction of their severity, ideally before The study was conducted in a tertiary referral centre (uni- patients become symptomatic, are the area of interest for versity hospital). Consecutive patients undergoing laparo- many surgeons. scopic resection for colorectal cancer were prospectively Albumin, which is mostly used as a nutritional marker analysed. Inclusion criteria were age over 18  years old, and a predictor for outcomes, is a protein which imme- elective laparoscopic surgery for verified colorectal adeno- diately responds to surgical stress. An albumin drop is carcinoma and ERAS protocol in perioperative care. We observed in most major abdominal surgeries within the excluded patients who underwent open or emergency sur- first postoperative hours [10–12]. Although pathophysi- gery and those in which resection exceeding the large bowel ological basics of albumin kinetics are well-established, (T4) was required. Patients with inflammatory bowel disease this parameter is rarely used as a marker of complica- were excluded from the study as well as cases where it was tions in the early postoperative period. Also, the albumin not possible to implement ERAS protocol (i.e. due to hospi- level correlates with the surgical trauma and postopera- talisation in ICU). Other exclusion criteria included distant tive stress response [13]. It is important in the context of metastases (M1), rectal cancer treated with transanal endo- laparoscopy and ERAS protocol, since they both signifi- scopic microsurgery, conversion to open resection, patients cantly reduce the degree of surgical stress [14, 15]. That with an active infection or autoimmune systemic disease. is why it seems reasonable to establish whether regular Moreover, we excluded patients in whom infectious compli- assessments of albumin level in the early postoperative cations were diagnosed within the first 48 h postoperatively. phase are clinically relevant. A laparoscopic approach with five or six trocars and medial to lateral technique was used [16]. All patients had the exact same perioperative care ERAS protocol (Table 1), which has been used in our department for 5 years. Mean Aim compliance with the protocol is over 80% [17]. Blood samples for albumin measurements were drawn The aim of this study was to evaluate the usefulness of from the patients four times: on the day of surgery and on albumin level measurements as an early predictor of the three following PODs. Albumin measurements were infectious complications in patients with colorectal can- included in the routine biochemistry panel; they were per- cer undergoing laparoscopic surgery with ERAS protocol. formed in serum on the day of blood collection using the automated analyser Cobas 6000 (Roche Diagnostics, Basel, Switzerland). Table 1 ERAS protocol used in our unit 1 Preoperative counselling and patient’s education 2 No bowel preparation (oral lavage in the case of low rectal resection with TME and defunctioning loop ileostomy) 3 Preoperative carbohydrate loading (400 ml of Nutricia preOp® 2 h prior surgery) 4 Antithrombotic prophylaxis (Clexane® 40 mg sc. starting in the evening prior surgery) 5 Antibiotic prophylaxis (preoperative cefuroxime 1.5 g + metronidazole 0.5 g iv. 30–60 min prior surgery) 6 Laparoscopic surgery 7 Balanced intravenous fluid therapy (< 2500 ml intravenous fluids during the day of surgery, less than 150 mmol sodium) 8 No nasogastric tubes postoperatively 9 No drains left routinely for colonic resections, one drain placed for < 24 h in case of TME 10 Transversus abdominis plane (TAP) block, epidural anaesthesia in cases with high risk of conversion 11 Avoiding opioids, multimodal 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 postoperative nausea and vomiting (PONV) (dexamethasone 8 mg iv., ondansetron 8 mg iv., metoclopramide 10 mg iv.) 13 Postoperative oxygenation therapy (4–6 l/min) 14 Early oral feeding (oral nutritional supplement 4 h postoperatively, light hospital diet and oral nutritional supplements on the first postopera- tive day, full hospital diet on the second postoperative day) 15 Urinary catheter removal on the first postoperative day 16 Full mobilisation on the first postoperative day (getting out of bed, going to toilet, walking along the corridor, at least 4 h out of bed) 1 3 Surgical Endoscopy (2018) 32:3225–3233 3227 Serum samples were obtained by centrifuging blood, col- the postoperative period. Patients’ flow through the study lected without anticoagulant, for 10 min at 4000 rpm on a and reasons for exclusion are shown in Fig. 1. MPW 351e centrifuge (MPW Med. Instruments, Warsaw, Groups 1 and 2 consisted of 82 (78.1%) and 23 (21.9%) Poland; Rotor No. 12,436). The reference interval for albu- patients, respectively. Table 2 shows a demographic analysis min was 35–50 g/l. of groups. No significant differences were noticed regarding Patients were divided into Groups 1 and 2 that included their demography, ASA scale, type of performed surgery, patients without and with infectious complications, respec- operative time, intraoperative blood loss and cancer stage. tively. The diagnosis of these complications and assessment However, there were significant differences between the of their severity was performed according to ECDC guide- groups in median LOS (4 vs. 9 days, p < 0.001) and read- lines [18]. mission rate (4.9 vs. 17.4%, p = 0.046). In addition, we did Groups were compared for age, sex, body mass index not notice differences in mean intravenous fluids transfused (BMI), American Society of Anaesthesiologists (ASA) during the surgical procedure and first 24 h postoperatively score, type of surgery, tumour staging, operative time and (2134 ± 665 vs. 2333 ± 901  ml, p = 0.42). The compliance intraoperative blood loss. Differences in albumin level with restrictive intravenous fluid therapy according to ERAS between groups were analysed on consecutive PODs. protocol was 91.4 vs. 87.1% in Group 1 and 2, respectively Due to the high variability in preoperative measurements, (p = 0.51). Δ-increments were calculated each day (i.e. ΔPOD1: differ - The overall infectious complication rate was 21.9%. An ence of concentration on POD1 and POD0; ΔPOD2: differ - analysis of infectious complications is presented in Table 3. ence of concentration on POD2 and POD0 etc). Addition- Laboratory measurements are presented in Table  4. ally, albumin level ratios were calculated (i.e. POD1/0, POD Before surgery (POD 0 measurement), albumin levels were 3/0, POD 3/1 etc.). comparable between groups (p = 0.58). On POD 1, the albumin levels decreased in both groups, but the difference between Groups was not statistically significant ( p = 0.07). Statistical analysis On POD 2 and 3, the albumin levels in Group 1 were lower than in Group 2 (p = 0.001, p = 0.00001) (Fig.  2). Fried- All data were analysed with Statsoft STATISTICA v.12. man’s ANOVA showed differences in consecutive albumin The results are presented as mean ± standard deviation (SD), measurements in both groups (p = 0.00012 in Group 1 and median and interquartile range (IQR). The study of categori- p < 0.00001 in Group 2). When Δ-albumin increments were cal variables used the Chi-square test of independence. The analysed, the differences were significant only in Group 2 Shapiro–Wilk test was used to check for a normal distribu- (p = 0.38 in Group 1 and p = 0.00006 in Group 2). Similarly, tion of data and the Student t test was used for normally differences in albumin ratios were statistically significant distributed quantitative data. For non-normally distributed only in Group 2 (p = 0.38 in Group 1 and p = 0.00006 in quantitative variables, the Mann–Whitney U test was used. Group 2) (Figs.3, 4). For dependent variables the Friedman test was used. A A ROC curve was used to determine the optimal cut- receiver operating characteristic (ROC) curve was applied off of albumin levels, Δ-albumin increments and albumin to obtain the area under the curve (AUC) and determine the ratios in consecutive days. This analysis showed that meas- best cut-offs. Results were considered statistically significant urements on POD3 were characterised by highest specificity when p value was less than 0.05. and sensitivity. Figures 5, 6, 7 and 8 show ROC curves and The study was approved by the local Ethics Review Com- their characteristics. mittee (Approval Number KBET/211/B/2014). All proce- dures were performed in accordance with the ethical stand- ards laid down in the 1964 Declaration of Helsinki and its Discussion later amendments. This study showed that regardless of the occurrence of complications, there was a reduction in the albumin level Results in the early PODs after laparoscopic colorectal resection with perioperative ERAS protocol. In addition, it was more 192 patients in our department underwent colorectal resec- pronounced in patients with complications. Moreover, we tion between August 2014 and September 2016. 41 of them observed that among uncomplicated cases the level of albu- did not fulfil inclusion criteria and were initially excluded. mins after initial rapid drop in the first POD remained stable 44 were excluded during surgery. Two patients were over the next days. In patients who developed complications, excluded because ERAS protocol was not implemented in albumins decreased further in the consecutive days. That 1 3 3228 Surgical Endoscopy (2018) 32:3225–3233 Fig. 1 Patients flow through the study also reflected on the analysis of albumin level derivatives complications [12, 13, 19, 20]. However, albumin, which such as Δ-albumin increments and ratios. is considered a negative acute phase protein with a half- Most studies focus on the preoperative level of hypoalbu- life of 20 days, seems to have perfect characteristics for a minemia and its influence on outcomes. Relatively few pub- useful biomarker [19]. It is easy to measure, widely avail- lications analysed it as a potential marker of early adverse able and inexpensive. In addition, its kinetics allows for events, and therefore it is seldom used as a biomarker of measurements within first postoperative hours [13, 21]. 1 3 Surgical Endoscopy (2018) 32:3225–3233 3229 Table 2 Demographic analysis Parameter Group 1 Group 2 p value of patient groups (uncomplicated) (complicated) Number of patients [n (%)] 82 (78.1%) 23 (21.9%) – Females [n (%)] 39 (47.6%) 12 (52.2%) 0.69572 Males [n (%)] 43 (52.4%) 11 (47.8%) Mean age (years ± SD) 63.2 ± 13.4 65.3 ± 13.5 0.62947 BMI (kg/m ± SD) 26.7 ± 5.0 26.8 ± 5.0 0.75312 ASA 1 [n (%)] 1 (1.2%) 1 (4.3%) 0.6609 ASA 2 [n (%)] 53 (64.6%) 14 (60.9%) ASA 3 [n (%)] 27 (33%) 7 (30.4%) ASA 4 [n (%)] 1 (1.2%) 1 (4.3%) Any comorbidity [n (%)] 64 (78%) 17 (73.9%) 0.67663 Cardiovascular [n (%)] 30 (36.6%) 8 (34.8%) 0.87442 Hypertension [n (%)] 42 (51.2%) 12 (52.2%) 0.93331 Diabetes [n (%)] 15 (18.3%) 5 (21.7%) 0.71028 Pulmonary disease [n (%)] 6 (7.3%) 3 (13%) 0.38584 Renal disease [n (%)] 6 (7.3%) 2 (8.7%) 0.82658 Liver disease [n (%)] 4 (4.9%) 1 (4.3%) 0.91647 AJCC Stage I [n (%)] 37 (45.1%) 10 (43.5%) 0.63179 AJCC Stage II [n (%)] 24 (29.3%) 5 (21.7%) AJCC Stage III [n (%)] 21 (25.6%) 8 (34.8%) Colonic resection [n (%)] 53 (64.6%) 16 (69.6%) 0.65748 Rectal resection [n (%)] 29 (35.4%) 7 (30.4%) Mean operative time (min ± SD) 194.4 ± 56.7 215.3 ± 73.3 0.44429 Median operative time [min (IQR)] 190 (160–230) 180 (170–275) Mean intraoperative blood loss (ml ± SD) 113.0 ± 118.4 128.4 ± 107.6 0.55006 Median intraoperative blood loss [ml (IQR)] 100 (50–150) 100 (50–200) Mean length of hospital stay (days, range) 4.8 ± 4.0 10.8 ± 6.7 0.00003 Median length of hospital stay (days, IQR) 4 (3–6) 9 (6–18) Readmission [n (%)] 4 (4.9%) 4 (17.4%) 0.04561 our knowledge they were never investigated as useful mark- Table 3 Types of complications ers of inflammatory complications after surgical procedures. Anastomotic leakage 9 (8.6%) This still needs to be investigated whether other negative Surgical site infection—deep or superficial 6 (5.7%) acute phase proteins may in the future be used for early Intraperitoneal abscess 2 (1.9%) detection of complications. Urinary tract infection 3 (2.8%) According to previous studies, early postoperative albu- Pneumonia 2 (1.9%) min drop is associated with altered metabolism, blood loss, Infectious diarrhoea (C. difficile) 1 (1.0%) dilution or redistribution into the third space [10, 12, 13, 23]. Albumin production is inhibited in an acute condition, which enables increased production of acute phase proteins such as CRP or fibrinogen. It has been shown in experimental stud- Unfortunately, albumin is rather unspecific, and therefore it cannot exactly predict the underlying cause of its changes. ies that 77% of the postoperative albumin decrease was due to redistribution, while 18 and 6% were attributed to blood We focused on albumin, since it is an easy to assess bio- chemical marker, familiar to most clinicians, and routinely loss and catabolism, respectively [10]. Interestingly, redis- tribution is strongly correlated with systemic inflammatory measured in every laboratory. However, apart from albumin, there are other negative acute phase proteins such as trans- response observed in major abdominal surgeries and practi- cally non-existent in minor procedures [10, 23]. ferrin, transthyretin, retinol-binding protein, antithrombin, transcortin, cortisol-binding globulin, transthyretin [22]. In contrast to previously published data, rapid postop- erative albumin drop in our study was relatively low, 2 g/l Although their decrease is observed in inflammation and they were extensively studied some time ago, according to (5.1%) in Group 1 and 5 g/l (12.5%) in Group 2. This is 1 3 3230 Surgical Endoscopy (2018) 32:3225–3233 Table 4 Analysis of biochemical parameters Parameter Group 1 Group 2 p value (uncomplicated) (complicated) Mean albumin ± SD (median, IQR) (g/l) POD 0 38.7 ± 4.9 (39, 36–42) 37.7 ± 5.0 (40, 35–41) 0.58702 POD 1 36.5 ± 4.2 (37, 34–39) 34.7 ± 4.2 (35, 30–37) 0.07131 POD 2 36.2 ± 4.1 (37, 34–39) 32.6 ± 5.6 (33, 30–36) 0.00996 POD 3 36.0 ± 4.4 (36, 34–39) 30.9 ± 3.5 (31, 28–32) 0.00004 Δ-albumin ± SD (median) (g/l) POD 1 − 2.6 ± 4.1 (− 2, − 5 to 1) − 3.0 ± 4.6 (− 4, − 6 to 0) 0.68309 POD 2 − 2.9 ± 4.5 (− 3, − 6 to 0) − 5.2 ± 5.3 (− 6, − 8 to − 1) 0.04953 POD 3 − 3.2 ± 4.4 (− 3, − 6 to 0) − 7.2 ± 4.7 (− 7, − 10 to − 5) 0.00306 Albumin POD 1/POD 0, mean ± SD (median, IQR) 0.94 ± 0.09 (0.94, 0.88–1.02) 0.93 ± 0.13 (0.9, 0.85–1) 0.27379 Albumin POD 2/POD 0, mean ± SD (median, IQR) 0.93 ± 0.11 (0.93, 0.84–1.0) 0.83 ± 0.24 (0.86, 0.79–0.94) 0.02905 Albumin POD 3/POD 0, mean ± SD (median, IQR) 0.92 ± 0.11 (0.91, 0.83–1.0) 0.82 ± 0.11 (0.82, 0.76–0.89) 0.00481 Albumin POD 2/POD 1, mean ± SD (median, IQR) 0.99 ± 0.1 (1, 0.94–1.05) 0.92 ± 0.1 (0.9, 0.86–1.03) 0.01294 Albumin POD 3/POD 1, mean ± SD (median, IQR) 1.0 ± 0.12 (0.97, 0.86–1.03) 0.87 ± 0.08 (0.86, 0.83–0.91) 0.00002 Fig. 4 Albumin ratios in Group 1 and Group 2 in consecutive days Fig. 2 Mean albumin levels in Group 1 and Group 2 in consecutive days Fig. 3 Mean Δ-albumin increments in Group 1 and Group 2 in con- secutive days different from previously published data, where a 20–35% drop was observed [12, 13]. In these studies, however, the greatest decrease in albumin level was observed in patients Fig. 5 Receiver operating characteristic (ROC) curve to determine the optimal cut-off of albumin measurements undergoing liver surgery [19]. There are two potential 1 3 Surgical Endoscopy (2018) 32:3225–3233 3231 Fig. 6 Receiver operating characteristic (ROC) curve to determine the optimal cut-off of Δ-albumin measurements Fig. 8 Receiver operating characteristic (ROC) curve to determine the optimal cut-off of albumin ratio measurements (POD1) high level of adherence. ERAS has been shown to decrease stress response in the postoperative period [14]. Moreover, one of the key elements of ERAS is balanced/restrictive fluid therapy [25– 27]. In our opinion, this might have also prevented excessive hemodilution in the early hours after surgery. All these factors may have an impact on postopera- tive albumin levels. The fundamental question is whether the use of albu- mins in the early postoperative period is clinically relevant. It seems that there is no clear answer to this problem. On the one hand, the kinetics of albumins makes them perfectly suitable as early markers. On the other hand, it drops in any increased stress reaction, making albumins less specific. In addition, their relationship with the extent of surgery, blood loss and fluid resuscitation in the postoperative period can introduce many confounding variables which may bias the interpretation of results. However, we observed that it is not the first drop in the albumin level that differs between complicated and uncomplicated patients but rather the trend over the next days. If the level continues to decrease, it may Fig. 7 Receiver operating characteristic (ROC) curve to determine seem that it is due to an underlying complication, which the optimal cut-off of albumin ratio measurements (POD0) may require further diagnostics or prolonged observation in hospital. The ROC curve analysis showed that measurements on factors that might contribute to the diminished albumin drop in our patients. Firstly, all our patients underwent laparo- POD3 are characterised by the best sensitivity and speci- ficity. Because albumin measurements are rather unspecific scopic colorectal surgery. It is known that laparoscopy has a positive impact on postoperative stress response, and so in determining the development of complications, we tried to increase the specificity using their derivatives. When may contribute to a decreased albumin drop [24]. In addi- tion, in all our patients ERAS protocol has been used, with a Δ-albumin increments were analysed, thus including the 1 3 3232 Surgical Endoscopy (2018) 32:3225–3233 baseline levels of albumins in measurements, we observed Compliance with ethical standards that the sensitivity and specificity on POD 3 were at the Disclosures Mateusz Wierdak, Magdalena Pisarska, Beata Kuśnierz- highest level. Similar observations were made when ratios Cabala, Jan Witowski, Jadwiga Dworak, Piotr Major, Piotr Małczak, were calculated. Unfortunately, none of these derivatives Piotr Ceranowicz, Andrzej Budzyński, Michał Pędziwiatr declare that provided better parameters. In our opinion, it is best to meas- they have no conflicts of interest or financial ties to disclose. ure albumin levels on consecutive PODs in order to monitor their level when searching for postoperative complications. Open Access This article is distributed under the terms of the Creative Other calculations, with the use of albumin levels, do not Commons Attribution 4.0 International License (http://creativecom- improve the results. mons.org/licenses/by/4.0/), which permits unrestricted use, distribu- tion, and reproduction in any medium, provided you give appropriate Our study has certain limitations which are typical for credit to the original author(s) and the source, provide a link to the a single centre study. We did not assess food charts and Creative Commons license, and indicate if changes were made. dietetic preferences of patients. They may have introduced confounding factor to the analysis. The study sample is rela- tively low, especially in the group including patients with complications. Besides, we focused only on infectious com- References plications, since albumin, being the negative acute phase protein, is strongly correlated with inflammatory response. 1. 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Changes in plasma albumin levels in early detection of infectious complications after laparoscopic colorectal cancer surgery with ERAS protocol

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Copyright © 2018 by The Author(s)
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Medicine & Public Health; Surgery; Gynecology; Gastroenterology; Hepatology; Proctology; Abdominal Surgery
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0930-2794
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10.1007/s00464-018-6040-4
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Abstract

Background Combination of laparoscopic approach with ERAS protocol in colorectal surgery allows for an early discharge. However there is a risk that some of the discharged patients are developing, asymptomatic at the time, infectious complica- tions. This may lead to a delay in diagnostics and proper treatment introduction. We aimed to assess the usefulness of pre- operative plasma albumin concentration and their changes as indicators of infectious complications in patients undergoing colorectal cancer surgery. Methods Prospective analysis included 105 consecutive patients who underwent laparoscopic colorectal cancer resection between August 2014 and September 2016. In all cases standardised 16-item perioperative care ERAS protocol was used (mean compliance > 85%). Patients with IBD, distant metastases, undergoing emergency or multivisceral resection were excluded. Blood samples were collected preoperatively and on POD 1, 2, 3. Plasma albumin concentration was measured. Patients were divided into two groups depending on the presence of infectious complications. We analysed the differences in the levels of albumin and the dynamics of changes. Results Group 1—82 not complicated patients, Group 2—23 patients with at least one infectious complication. Preopera- tively, there were no significant differences in the levels of serum albumin between those groups (Group 1—38.7 ± 4.9 g/l; Group 2—37.7 ± 5.0  g/l). In postoperative period, decrease was observed in both (POD 1: Group 1—36.5 ± 4.2  g/l, Group 2—34.7 ± 4.2  g/l, p = 0.07; POD 2: Group 1—36.2 ± 4.1  g/l, Group 2—32.6 ± 5.6  g/l, p = 0.01; POD 3: Group 1—36.0 ± 4.4 g/l, Group 2—30.9 ± 3.5 g/l, p = 0.01). The decrease was significantly greater in Group 2 on POD 2 and 3. Conclusions We showed that a regular measurement of albumin in the early postoperative days may be beneficial in the detection of postoperative infectious complications. Although changes in albumins are observed early after surgery, this parameter is relatively unspecific. Keywords Colorectal cancer · Laparoscopy · Infectious complications · Markers · Albumins Colorectal cancer surgery is associated with a relatively This study has been awarded the Best Poster Presentation at the high morbidity rate, which depends on multiple factors and EAES Congress 2017 in Frankfurt. can occur in 30–40% of patients [1, 2]. One of the signifi- * Michał Pędziwiatr cant components affecting those parameters is the surgical michal.pedziwiatr@uj.edu.pl technique. It has been shown that the laparoscopic approach 1 is correlated with reduced morbidity [3, 4]. Moreover, the 2nd Department of General Surgery, Jagiellonian University implementation of multimodal perioperative care protocols Medical College, Kopernika 21, 31-501 Kraków, Poland 2 enhanced recovery after surgery (ERAS) further decreases Centre for Research, Training and Innovation in Surgery postoperative complications by approximately 20–40% and (CERTAIN Surgery), Kraków, Poland 3 leads to early hospital discharge after 2–5 days [5–8]. These Department of Diagnostics, Chair of Clinical Biochemistry, factors markedly shortened length of stay (LOS). Some Jagiellonian University Medical College, Kraków, Poland 4 complications (i.e. anastomotic leakage) can occur late Department of Physiology, Jagiellonian University Medical after surgery, even on postoperative day (POD) 8–12. This College, Kraków, Poland Vol.:(0123456789) 1 3 3226 Surgical Endoscopy (2018) 32:3225–3233 means that in most cases they are diagnosed after discharge Materials and methods [9]. For these reasons, markers that allow early detection of complications and prediction of their severity, ideally before The study was conducted in a tertiary referral centre (uni- patients become symptomatic, are the area of interest for versity hospital). Consecutive patients undergoing laparo- many surgeons. scopic resection for colorectal cancer were prospectively Albumin, which is mostly used as a nutritional marker analysed. Inclusion criteria were age over 18  years old, and a predictor for outcomes, is a protein which imme- elective laparoscopic surgery for verified colorectal adeno- diately responds to surgical stress. An albumin drop is carcinoma and ERAS protocol in perioperative care. We observed in most major abdominal surgeries within the excluded patients who underwent open or emergency sur- first postoperative hours [10–12]. Although pathophysi- gery and those in which resection exceeding the large bowel ological basics of albumin kinetics are well-established, (T4) was required. Patients with inflammatory bowel disease this parameter is rarely used as a marker of complica- were excluded from the study as well as cases where it was tions in the early postoperative period. Also, the albumin not possible to implement ERAS protocol (i.e. due to hospi- level correlates with the surgical trauma and postopera- talisation in ICU). Other exclusion criteria included distant tive stress response [13]. It is important in the context of metastases (M1), rectal cancer treated with transanal endo- laparoscopy and ERAS protocol, since they both signifi- scopic microsurgery, conversion to open resection, patients cantly reduce the degree of surgical stress [14, 15]. That with an active infection or autoimmune systemic disease. is why it seems reasonable to establish whether regular Moreover, we excluded patients in whom infectious compli- assessments of albumin level in the early postoperative cations were diagnosed within the first 48 h postoperatively. phase are clinically relevant. A laparoscopic approach with five or six trocars and medial to lateral technique was used [16]. All patients had the exact same perioperative care ERAS protocol (Table 1), which has been used in our department for 5 years. Mean Aim compliance with the protocol is over 80% [17]. Blood samples for albumin measurements were drawn The aim of this study was to evaluate the usefulness of from the patients four times: on the day of surgery and on albumin level measurements as an early predictor of the three following PODs. Albumin measurements were infectious complications in patients with colorectal can- included in the routine biochemistry panel; they were per- cer undergoing laparoscopic surgery with ERAS protocol. formed in serum on the day of blood collection using the automated analyser Cobas 6000 (Roche Diagnostics, Basel, Switzerland). Table 1 ERAS protocol used in our unit 1 Preoperative counselling and patient’s education 2 No bowel preparation (oral lavage in the case of low rectal resection with TME and defunctioning loop ileostomy) 3 Preoperative carbohydrate loading (400 ml of Nutricia preOp® 2 h prior surgery) 4 Antithrombotic prophylaxis (Clexane® 40 mg sc. starting in the evening prior surgery) 5 Antibiotic prophylaxis (preoperative cefuroxime 1.5 g + metronidazole 0.5 g iv. 30–60 min prior surgery) 6 Laparoscopic surgery 7 Balanced intravenous fluid therapy (< 2500 ml intravenous fluids during the day of surgery, less than 150 mmol sodium) 8 No nasogastric tubes postoperatively 9 No drains left routinely for colonic resections, one drain placed for < 24 h in case of TME 10 Transversus abdominis plane (TAP) block, epidural anaesthesia in cases with high risk of conversion 11 Avoiding opioids, multimodal 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 postoperative nausea and vomiting (PONV) (dexamethasone 8 mg iv., ondansetron 8 mg iv., metoclopramide 10 mg iv.) 13 Postoperative oxygenation therapy (4–6 l/min) 14 Early oral feeding (oral nutritional supplement 4 h postoperatively, light hospital diet and oral nutritional supplements on the first postopera- tive day, full hospital diet on the second postoperative day) 15 Urinary catheter removal on the first postoperative day 16 Full mobilisation on the first postoperative day (getting out of bed, going to toilet, walking along the corridor, at least 4 h out of bed) 1 3 Surgical Endoscopy (2018) 32:3225–3233 3227 Serum samples were obtained by centrifuging blood, col- the postoperative period. Patients’ flow through the study lected without anticoagulant, for 10 min at 4000 rpm on a and reasons for exclusion are shown in Fig. 1. MPW 351e centrifuge (MPW Med. Instruments, Warsaw, Groups 1 and 2 consisted of 82 (78.1%) and 23 (21.9%) Poland; Rotor No. 12,436). The reference interval for albu- patients, respectively. Table 2 shows a demographic analysis min was 35–50 g/l. of groups. No significant differences were noticed regarding Patients were divided into Groups 1 and 2 that included their demography, ASA scale, type of performed surgery, patients without and with infectious complications, respec- operative time, intraoperative blood loss and cancer stage. tively. The diagnosis of these complications and assessment However, there were significant differences between the of their severity was performed according to ECDC guide- groups in median LOS (4 vs. 9 days, p < 0.001) and read- lines [18]. mission rate (4.9 vs. 17.4%, p = 0.046). In addition, we did Groups were compared for age, sex, body mass index not notice differences in mean intravenous fluids transfused (BMI), American Society of Anaesthesiologists (ASA) during the surgical procedure and first 24 h postoperatively score, type of surgery, tumour staging, operative time and (2134 ± 665 vs. 2333 ± 901  ml, p = 0.42). The compliance intraoperative blood loss. Differences in albumin level with restrictive intravenous fluid therapy according to ERAS between groups were analysed on consecutive PODs. protocol was 91.4 vs. 87.1% in Group 1 and 2, respectively Due to the high variability in preoperative measurements, (p = 0.51). Δ-increments were calculated each day (i.e. ΔPOD1: differ - The overall infectious complication rate was 21.9%. An ence of concentration on POD1 and POD0; ΔPOD2: differ - analysis of infectious complications is presented in Table 3. ence of concentration on POD2 and POD0 etc). Addition- Laboratory measurements are presented in Table  4. ally, albumin level ratios were calculated (i.e. POD1/0, POD Before surgery (POD 0 measurement), albumin levels were 3/0, POD 3/1 etc.). comparable between groups (p = 0.58). On POD 1, the albumin levels decreased in both groups, but the difference between Groups was not statistically significant ( p = 0.07). Statistical analysis On POD 2 and 3, the albumin levels in Group 1 were lower than in Group 2 (p = 0.001, p = 0.00001) (Fig.  2). Fried- All data were analysed with Statsoft STATISTICA v.12. man’s ANOVA showed differences in consecutive albumin The results are presented as mean ± standard deviation (SD), measurements in both groups (p = 0.00012 in Group 1 and median and interquartile range (IQR). The study of categori- p < 0.00001 in Group 2). When Δ-albumin increments were cal variables used the Chi-square test of independence. The analysed, the differences were significant only in Group 2 Shapiro–Wilk test was used to check for a normal distribu- (p = 0.38 in Group 1 and p = 0.00006 in Group 2). Similarly, tion of data and the Student t test was used for normally differences in albumin ratios were statistically significant distributed quantitative data. For non-normally distributed only in Group 2 (p = 0.38 in Group 1 and p = 0.00006 in quantitative variables, the Mann–Whitney U test was used. Group 2) (Figs.3, 4). For dependent variables the Friedman test was used. A A ROC curve was used to determine the optimal cut- receiver operating characteristic (ROC) curve was applied off of albumin levels, Δ-albumin increments and albumin to obtain the area under the curve (AUC) and determine the ratios in consecutive days. This analysis showed that meas- best cut-offs. Results were considered statistically significant urements on POD3 were characterised by highest specificity when p value was less than 0.05. and sensitivity. Figures 5, 6, 7 and 8 show ROC curves and The study was approved by the local Ethics Review Com- their characteristics. mittee (Approval Number KBET/211/B/2014). All proce- dures were performed in accordance with the ethical stand- ards laid down in the 1964 Declaration of Helsinki and its Discussion later amendments. This study showed that regardless of the occurrence of complications, there was a reduction in the albumin level Results in the early PODs after laparoscopic colorectal resection with perioperative ERAS protocol. In addition, it was more 192 patients in our department underwent colorectal resec- pronounced in patients with complications. Moreover, we tion between August 2014 and September 2016. 41 of them observed that among uncomplicated cases the level of albu- did not fulfil inclusion criteria and were initially excluded. mins after initial rapid drop in the first POD remained stable 44 were excluded during surgery. Two patients were over the next days. In patients who developed complications, excluded because ERAS protocol was not implemented in albumins decreased further in the consecutive days. That 1 3 3228 Surgical Endoscopy (2018) 32:3225–3233 Fig. 1 Patients flow through the study also reflected on the analysis of albumin level derivatives complications [12, 13, 19, 20]. However, albumin, which such as Δ-albumin increments and ratios. is considered a negative acute phase protein with a half- Most studies focus on the preoperative level of hypoalbu- life of 20 days, seems to have perfect characteristics for a minemia and its influence on outcomes. Relatively few pub- useful biomarker [19]. It is easy to measure, widely avail- lications analysed it as a potential marker of early adverse able and inexpensive. In addition, its kinetics allows for events, and therefore it is seldom used as a biomarker of measurements within first postoperative hours [13, 21]. 1 3 Surgical Endoscopy (2018) 32:3225–3233 3229 Table 2 Demographic analysis Parameter Group 1 Group 2 p value of patient groups (uncomplicated) (complicated) Number of patients [n (%)] 82 (78.1%) 23 (21.9%) – Females [n (%)] 39 (47.6%) 12 (52.2%) 0.69572 Males [n (%)] 43 (52.4%) 11 (47.8%) Mean age (years ± SD) 63.2 ± 13.4 65.3 ± 13.5 0.62947 BMI (kg/m ± SD) 26.7 ± 5.0 26.8 ± 5.0 0.75312 ASA 1 [n (%)] 1 (1.2%) 1 (4.3%) 0.6609 ASA 2 [n (%)] 53 (64.6%) 14 (60.9%) ASA 3 [n (%)] 27 (33%) 7 (30.4%) ASA 4 [n (%)] 1 (1.2%) 1 (4.3%) Any comorbidity [n (%)] 64 (78%) 17 (73.9%) 0.67663 Cardiovascular [n (%)] 30 (36.6%) 8 (34.8%) 0.87442 Hypertension [n (%)] 42 (51.2%) 12 (52.2%) 0.93331 Diabetes [n (%)] 15 (18.3%) 5 (21.7%) 0.71028 Pulmonary disease [n (%)] 6 (7.3%) 3 (13%) 0.38584 Renal disease [n (%)] 6 (7.3%) 2 (8.7%) 0.82658 Liver disease [n (%)] 4 (4.9%) 1 (4.3%) 0.91647 AJCC Stage I [n (%)] 37 (45.1%) 10 (43.5%) 0.63179 AJCC Stage II [n (%)] 24 (29.3%) 5 (21.7%) AJCC Stage III [n (%)] 21 (25.6%) 8 (34.8%) Colonic resection [n (%)] 53 (64.6%) 16 (69.6%) 0.65748 Rectal resection [n (%)] 29 (35.4%) 7 (30.4%) Mean operative time (min ± SD) 194.4 ± 56.7 215.3 ± 73.3 0.44429 Median operative time [min (IQR)] 190 (160–230) 180 (170–275) Mean intraoperative blood loss (ml ± SD) 113.0 ± 118.4 128.4 ± 107.6 0.55006 Median intraoperative blood loss [ml (IQR)] 100 (50–150) 100 (50–200) Mean length of hospital stay (days, range) 4.8 ± 4.0 10.8 ± 6.7 0.00003 Median length of hospital stay (days, IQR) 4 (3–6) 9 (6–18) Readmission [n (%)] 4 (4.9%) 4 (17.4%) 0.04561 our knowledge they were never investigated as useful mark- Table 3 Types of complications ers of inflammatory complications after surgical procedures. Anastomotic leakage 9 (8.6%) This still needs to be investigated whether other negative Surgical site infection—deep or superficial 6 (5.7%) acute phase proteins may in the future be used for early Intraperitoneal abscess 2 (1.9%) detection of complications. Urinary tract infection 3 (2.8%) According to previous studies, early postoperative albu- Pneumonia 2 (1.9%) min drop is associated with altered metabolism, blood loss, Infectious diarrhoea (C. difficile) 1 (1.0%) dilution or redistribution into the third space [10, 12, 13, 23]. Albumin production is inhibited in an acute condition, which enables increased production of acute phase proteins such as CRP or fibrinogen. It has been shown in experimental stud- Unfortunately, albumin is rather unspecific, and therefore it cannot exactly predict the underlying cause of its changes. ies that 77% of the postoperative albumin decrease was due to redistribution, while 18 and 6% were attributed to blood We focused on albumin, since it is an easy to assess bio- chemical marker, familiar to most clinicians, and routinely loss and catabolism, respectively [10]. Interestingly, redis- tribution is strongly correlated with systemic inflammatory measured in every laboratory. However, apart from albumin, there are other negative acute phase proteins such as trans- response observed in major abdominal surgeries and practi- cally non-existent in minor procedures [10, 23]. ferrin, transthyretin, retinol-binding protein, antithrombin, transcortin, cortisol-binding globulin, transthyretin [22]. In contrast to previously published data, rapid postop- erative albumin drop in our study was relatively low, 2 g/l Although their decrease is observed in inflammation and they were extensively studied some time ago, according to (5.1%) in Group 1 and 5 g/l (12.5%) in Group 2. This is 1 3 3230 Surgical Endoscopy (2018) 32:3225–3233 Table 4 Analysis of biochemical parameters Parameter Group 1 Group 2 p value (uncomplicated) (complicated) Mean albumin ± SD (median, IQR) (g/l) POD 0 38.7 ± 4.9 (39, 36–42) 37.7 ± 5.0 (40, 35–41) 0.58702 POD 1 36.5 ± 4.2 (37, 34–39) 34.7 ± 4.2 (35, 30–37) 0.07131 POD 2 36.2 ± 4.1 (37, 34–39) 32.6 ± 5.6 (33, 30–36) 0.00996 POD 3 36.0 ± 4.4 (36, 34–39) 30.9 ± 3.5 (31, 28–32) 0.00004 Δ-albumin ± SD (median) (g/l) POD 1 − 2.6 ± 4.1 (− 2, − 5 to 1) − 3.0 ± 4.6 (− 4, − 6 to 0) 0.68309 POD 2 − 2.9 ± 4.5 (− 3, − 6 to 0) − 5.2 ± 5.3 (− 6, − 8 to − 1) 0.04953 POD 3 − 3.2 ± 4.4 (− 3, − 6 to 0) − 7.2 ± 4.7 (− 7, − 10 to − 5) 0.00306 Albumin POD 1/POD 0, mean ± SD (median, IQR) 0.94 ± 0.09 (0.94, 0.88–1.02) 0.93 ± 0.13 (0.9, 0.85–1) 0.27379 Albumin POD 2/POD 0, mean ± SD (median, IQR) 0.93 ± 0.11 (0.93, 0.84–1.0) 0.83 ± 0.24 (0.86, 0.79–0.94) 0.02905 Albumin POD 3/POD 0, mean ± SD (median, IQR) 0.92 ± 0.11 (0.91, 0.83–1.0) 0.82 ± 0.11 (0.82, 0.76–0.89) 0.00481 Albumin POD 2/POD 1, mean ± SD (median, IQR) 0.99 ± 0.1 (1, 0.94–1.05) 0.92 ± 0.1 (0.9, 0.86–1.03) 0.01294 Albumin POD 3/POD 1, mean ± SD (median, IQR) 1.0 ± 0.12 (0.97, 0.86–1.03) 0.87 ± 0.08 (0.86, 0.83–0.91) 0.00002 Fig. 4 Albumin ratios in Group 1 and Group 2 in consecutive days Fig. 2 Mean albumin levels in Group 1 and Group 2 in consecutive days Fig. 3 Mean Δ-albumin increments in Group 1 and Group 2 in con- secutive days different from previously published data, where a 20–35% drop was observed [12, 13]. In these studies, however, the greatest decrease in albumin level was observed in patients Fig. 5 Receiver operating characteristic (ROC) curve to determine the optimal cut-off of albumin measurements undergoing liver surgery [19]. There are two potential 1 3 Surgical Endoscopy (2018) 32:3225–3233 3231 Fig. 6 Receiver operating characteristic (ROC) curve to determine the optimal cut-off of Δ-albumin measurements Fig. 8 Receiver operating characteristic (ROC) curve to determine the optimal cut-off of albumin ratio measurements (POD1) high level of adherence. ERAS has been shown to decrease stress response in the postoperative period [14]. Moreover, one of the key elements of ERAS is balanced/restrictive fluid therapy [25– 27]. In our opinion, this might have also prevented excessive hemodilution in the early hours after surgery. All these factors may have an impact on postopera- tive albumin levels. The fundamental question is whether the use of albu- mins in the early postoperative period is clinically relevant. It seems that there is no clear answer to this problem. On the one hand, the kinetics of albumins makes them perfectly suitable as early markers. On the other hand, it drops in any increased stress reaction, making albumins less specific. In addition, their relationship with the extent of surgery, blood loss and fluid resuscitation in the postoperative period can introduce many confounding variables which may bias the interpretation of results. However, we observed that it is not the first drop in the albumin level that differs between complicated and uncomplicated patients but rather the trend over the next days. If the level continues to decrease, it may Fig. 7 Receiver operating characteristic (ROC) curve to determine seem that it is due to an underlying complication, which the optimal cut-off of albumin ratio measurements (POD0) may require further diagnostics or prolonged observation in hospital. The ROC curve analysis showed that measurements on factors that might contribute to the diminished albumin drop in our patients. Firstly, all our patients underwent laparo- POD3 are characterised by the best sensitivity and speci- ficity. Because albumin measurements are rather unspecific scopic colorectal surgery. It is known that laparoscopy has a positive impact on postoperative stress response, and so in determining the development of complications, we tried to increase the specificity using their derivatives. When may contribute to a decreased albumin drop [24]. In addi- tion, in all our patients ERAS protocol has been used, with a Δ-albumin increments were analysed, thus including the 1 3 3232 Surgical Endoscopy (2018) 32:3225–3233 baseline levels of albumins in measurements, we observed Compliance with ethical standards that the sensitivity and specificity on POD 3 were at the Disclosures Mateusz Wierdak, Magdalena Pisarska, Beata Kuśnierz- highest level. Similar observations were made when ratios Cabala, Jan Witowski, Jadwiga Dworak, Piotr Major, Piotr Małczak, were calculated. Unfortunately, none of these derivatives Piotr Ceranowicz, Andrzej Budzyński, Michał Pędziwiatr declare that provided better parameters. In our opinion, it is best to meas- they have no conflicts of interest or financial ties to disclose. ure albumin levels on consecutive PODs in order to monitor their level when searching for postoperative complications. Open Access This article is distributed under the terms of the Creative Other calculations, with the use of albumin levels, do not Commons Attribution 4.0 International License (http://creativecom- improve the results. mons.org/licenses/by/4.0/), which permits unrestricted use, distribu- tion, and reproduction in any medium, provided you give appropriate Our study has certain limitations which are typical for credit to the original author(s) and the source, provide a link to the a single centre study. We did not assess food charts and Creative Commons license, and indicate if changes were made. dietetic preferences of patients. They may have introduced confounding factor to the analysis. The study sample is rela- tively low, especially in the group including patients with complications. Besides, we focused only on infectious com- References plications, since albumin, being the negative acute phase protein, is strongly correlated with inflammatory response. 1. 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Journal

Surgical EndoscopySpringer Journals

Published: Jan 16, 2018

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