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1159/000530124
Received: September 12, 2022
Accepted: March 6, 2023
Published online: March 20, 2023
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Nermina Rizvanovića*, Višnja Nesek Adamc, Merlina Kalajdžijaa, Senada Čauševića, Senad Derviševićb, Jasmina
Smajićd
a
Department of Anaesthesiology, Resuscitation and Intensive Care, Cantonal Hospital Zenica, University of Zenica,
Faculty of Medicine, Zenica, Bosnia and Herzegovina
b
Department of Surgery, Cantonal Hospital Zenica, University of Zenica, Faculty of Medicine, Zenica, Bosnia and
Herzegovina
c
University Department for Anaesthesiology, Resuscitation and Intensive Care, Clinical Hospital Sveti Duh, Zagreb,
Faculty of Medicine J.J. Strossmayer, Osijek, Croatia
d
Clinic of Anaesthesiology, Resuscitation and Intensive Care, University Clinical Center Tuzla, University of Tuzla,
Faculty of Medicine, Tuzla, Bosnia and Herzegovina
Corresponding Author:
Nermina Rizvanović
Department of Anaesthesiology and Intensive Care Unit, Cantonal Hospital Zenica
The University of Zenica, Faculty of Medicine, Zenica, Bosnia and Herzegovina
67 Crkvice St, 72 000 Zenica, Bosnia and Herzegovina
Tel: 0038761806282
E-mail: rizvanovic.nermina@gmail.com
Number of Tables: 4
Number of Figures: 1
Word count: Abstract 249; Body text 2881
Abstract
Introductionː Preoperative carbohydrate oral (CHO) drinks attenuate the surgical stress response; however, the
effects of CHO supplementation on the neutrophil-to-lymphocyte ratio (NLR) as an inflammatory and
immunology-based predictor remain unclear. This study evaluated the effects of preoperative CHO loading on
NLR values and complications following open colorectal surgery compared with a conventional fasting protocol.
Methodsː Sixty eligible participants having planned for routine and open colorectal cancer surgery from May 2020
to January 2022 were prospectively and randomly allocated to either the control (fasting) group, whose members
discontinued oral intake beginning the midnight before surgery, or the intervention (CHO), group, whose
members consumed a CHO solution the night before surgery and 2 h prior to anaesthesia. NLR was assessed at
06:00 h before surgery (baseline) and at 06:00 h on postoperative days 1, 3 and 5. The incidence and severity of
postoperative complications were assessed by Clavien-Dindo Classification up to postoperative day 30. All data
were analysed using descriptive statistics. Resultsː Postoperative NLR and delta NLR values were significantly
higher in controls (p < 0.001; p < 0.001). Control group participants also demonstrated grade IV (n = 5; 16.7%, p <
0.01) and grade V (n = 1; 3.3%, p < 0.313) postoperative complications. There were no major postoperative
complications in the CHO group. Discussion/Conclusion: Preoperative CHO consumption reduced postoperative
NLR values and the incidence and severity of postoperative complications following open colorectal surgery,
compared with a preoperative fasting protocol. Preoperative carbohydrate loading may improve recovery
following colorectal cancer surgery.
Introduction
Colorectal cancer (CRC) is the third most frequent cancer worldwide and the second leading cause of cancer
related deaths. CRC is usually diagnosed between the ages of 65 and 74 [1]. Surgery is the main treatment for
patients with CRC; however, the risk of postoperative complications increases with age. Cancer often worsens a
patient’s preoperative nutritional status, which can predict unfavourable postoperative outcomes. Long-term
preoperative fasting further affects patient’s catabolic state and activates a network of inflammatory pathways
even before surgical tissue damage [2]. Perioperative interventions established in the Enhanced Recovery After
Surgery (ERAS) protocol aim to optimise nutritional status and reduce postoperative complications. As part of the
ERAS programme, a preoperative carbohydrate oral (CHO) drink consumed the evening before surgery and 2 h
before anaesthesia is recommended to alleviate harmful metabolic and inflammatory stress responses to fasting
and surgery [3]. Despite strong evidence, preoperative CHO solutions are not routinely administered, even in
modern healthcare systems [4]. In Bosnia and Herzegovina, preoperative fasting remains the rule rather than the
exception.
The neutrophil-to-lymphocyte Ratio (NLR), calculated as the neutrophil count divided by the lymphocyte count,
represents the balance between the non-specific inflammatory response and adaptive immunity to various
stimuli [5]. Neutrophils release cytokines and chemokines and recruit effector cells during the systemic
inflammatory response (SIRS). Lymphocytes participate in antigen-specific host response. NLR can accurately
predict early-stage sepsis and metabolic syndrome [5, 6]. Postoperative neutrophilia and lymphopenia denote
immunosuppression and favour the development of postoperative complications [7]. Delta NLR (Δ NLR), the
dynamic change between pre- and postoperative NLR values, reflects the intensity of the immune-inflammatory
response elicited by surgery [8] and is negatively associated with overall survival in patients who undergo CRC
resection [9].
The magnitude of the postoperative stress response increases with surgical invasiveness. Open CRC surgery as a
model of major abdominal procedures amplifies SIRS, metabolic and immunological changes, potentially
increasing the likelihood of postoperative adverse events. The detrimental effects of prolonged fasting are
expected to be greater for patients undergoing CRC surgery compared to less-invasive (i.e. “minor”) procedures.
Preoperative CHO loading was more beneficial in CRC surgery than prolonged fasting or placebo. These benefits
encompassed postoperative insulin resistance, glucose, cortisol and triglyceride levels [10], length of hospital
stay, hand grip strength [11] and postoperative well-being [12]. However, there is a lack of evidence on the
impact of preoperative CHO on NLR as an inflammation and immune-status predictor after CRC surgery.
This study focused exclusively on one element of the ERAS pathway: the effects of preoperative CHO loading,
hopefully to increase awareness of the benefits of shortened preoperative fasting. We hypothesised that
preoperative CHO loading would reduce inflammation and improve immune function in patients, as assessed by
NLR after open CRC surgery. We compared changes in NLR values between patients randomly assigned to either
preoperative CHO loading or a conventional preoperative fasting protocol. We then compared the incidence and
severity of postoperative complications between the two groups.
Results
All 60 patients completed the study, and data were analysed on an intent-to-treat basis (Fig. 1). The groups were
homogeneous and comparable at baseline with no significant between-group differences in demographic and
surgical data. The length of postoperative hospital stay was 9.86 ± 3.47 in the control group versus 7.61 ± 2.34 in
the CHO group (p < 0.01) (Table 1).
Preoperative mean WBC, neutrophil, lymphocyte and NLR values did not significantly differ between the groups.
Significantly higher mean WBC (p < 0.001), neutrophil (p < 0.001) and NLR (p < 0.001) values, and significantly
lower mean lymphocytes values (p < 0.001) were noted in the control group during the postoperative period.
Postoperatively, mean WBC and neutrophil values increased in both groups, peaking on POD1 then declining.
Neutrophils peaked at 12.39 ± 1.40 in the control group versus 9.50 ± 1.16 in the CHO group. Leukocytosis and
neutrophilia receded on POD3 in the CHO group; meanwhile, the control group never returned to baseline.
Postoperative lymphopenia was documented on POD1 in the control group. The lowest lymphocyte value in the
CHO group was registered on POD1; however, there was no lymphopenia. The CHO group returned to baseline on
POD3; the control group never returned to baseline.
Postoperative NLR values increased in both groups, peaking on POD1; 9.47 ± 1.06 in the control group versus 5.34
± 0.69 in the CHO group. Although NLR values eventually declined in both groups, there was no return to baseline.
The ΔNRL value was 7.97 ± 0.28 in the control group versus 3.15 ± 0.11 in the CHO group (p < 0.001) (Table 2).
Thirty-seven postoperative complications were registered in the control group versus five in the CHO group (p <
0.01). Significantly higher incidence of Clavien-Dindo grade I (p < 0.015), II (p < 0.002), III (p < 0.01) and IV (p <
0.01) complications were seen in the control group. Minor postoperative complications (grades I–II) were
registered in the CHO group. Minor and major complications (grades I–V) were recorded in the control group.
Two patients in the control group required reoperation: one due to ileus and the other due to anastomosis
leakage. Both patients were admitted to the intensive care unit and mechanically ventilated. One patient with an
anastomosis leakage suffered multi-organ failure and died (Table 3).
There were 43.3% of patients with complications in the control group and 16.7% in the CHO group (p < 0.01).
Group characteristics for postoperative complications are summarised in Table 4.
Discussion
CRC surgery interrupts complete enteral intake postoperatively and activates demanding endocrine and immune
changes. The ongoing metabolic response results in insulin resistance (IR), hyperglycaemia, glycogenolysis, and
gluconeogenesis [14]. Surgical trauma stimulates WBC and endothelial cells to release proinflammatory cytokines
that disrupt insulin signalling pathways, potentiating SIRS and predisposing postoperative complications [15].
Conventional preoperative fasting aims to minimise the risk of pulmonary aspiration but increases catabolic shift
and acute-phase inflammatory markers [16]. Evidence suggests the beneficial effects of preoperative CHO loading
on reducing IR [10] and cytokine levels [17] and improving bowel function [18]; however, the impact of
preoperative CHO loading on postoperative NLR as an inflammatory and immunology-based predictor remains
unclear.
Consumption of a preoperative CHO drink resulted in significantly lower postoperative NLR values compared to
controls. NLR is a simple, inexpensive parameter accessible from the WBC differential count. Postoperative
changes in WBC, leucocytosis, neutrophilia and lymphopenia are expected on POD1, caused by the activities of
endogenous cortisol, catecholamines and cytokines in response to surgery, anaesthesia and bleeding [19]. In the
control group, leucocytosis and neutrophilia persisted at all observed time points. Lymphopenia lasted until POD3
with resultant increases in postoperative NLR. In the CHO group, leucocytosis and neutrophilia receded until
POD3, while lymphopenia was not registered, so the postoperative NLR was significantly lower in the CHO group
compared to controls. These findings indicate an attenuated inflammatory response and preserved cell-mediated
immune function after CHO treatment. Increased NLR is significantly associated with IR [20] and can predict
postoperative complications from CRC surgery [21].
ΔNRL reflects the intensity of the immune-inflammatory response elicited by surgery [8]. In this study,
preoperative CHO treatment decreased ΔNLR by more than half compared to the control group. Cytokines
released during surgery activate multiple inflammatory cells. IL-6 has been identified as a B-cell differentiation
factor. TNF-α and IL-8 activate neutrophils, monocytes, macrophages and CD4 T lymphocytes resulting in cell
recruitment, chemotaxis, proliferation, adhesion and microvascular disturbances [22]. Hu et al. found that
administration of a preoperative CHO drink decreased IL-6, IL-8 and TNF levels suggesting an immune-
inflammatory effect [17]. The researchers reported that preoperative CHO loading preserved preoperative levels
of human leukocyte antigen (HLA)-DR expression on monocytes after surgery. Meanwhile, preoperative fasting
reduced HLA-DR expression [23].
Consumption of a preoperative CHO drink significantly reduced the incidence and severity of postoperative
complications after open CRC surgery compared to controls. The reported rate of postoperative complications in
CRC surgery is 10–37% [24]. In this study, the rate was 43.3% in the control group and 16.7% in the CHO group.
Many factors associated with the incidence of postoperative complications were controlled by sampling criteria.
Our patients’ demographic and surgical data were very similar at baseline, with preoperative fasting being the
main between-group difference. The deleterious consequences of prolonged preoperative fasting are well
recognised. Bicudo-Salomão et al. reported that a shortened preoperative fasting period of <4 h reduced the risk
of postoperative complications [25]. Another study showed that preoperative CHO administration reduced the
incidence of wound infections and paralytic ileus after CRC surgery [10]. In contrast, a meta-analysis by Awad et
al. found that preoperative CHO loading had no effect on postoperative complications [26]. Importantly, the
subgroup analysis revealed the studies to be heterogeneous in terms of the type and magnitude of surgical
procedures, type and timing of CHO intervention, anaesthesia technique, definition of postoperative
complications and follow-up duration.
Preoperative fasting and surgery trigger postoperative IR and hyperglycaemia and expose insulin-independent
cells (e.g. neurons, immunocytes, renal, endothelial and blood cells) to glucotoxicity, mitochondrial dysfunction,
oxygen free radicals and cytokines, causing complications [27]. Preoperative CHO loading is an effective method
to maintain postoperative normoglycaemia [28] stimulating the phosphatidylinositol-3 kinase/protein kinase B
(PI3K/PKB) pathways that improve entry of pyruvate into the Krebs citrate cycle and govern the interplay
between metabolic and anti-inflammatory insulin pathways [29]. In addition, preoperative CHO supplementation
alleviates the metabolic and inflammatory stress response to fasting and surgery, thus accelerating clinical
recovery.
The present study reinforces prior evidence as to the benefits of shortened preoperative fasting. Our
homogeneous study sample, simple intervention and limited focus on patients undergoing open CRC surgery are
study strengths, we would like to highlight.
There are some limitations to our research. This single-centre study had a relatively small sample size, and further
multi-centre investigations are needed to validate our findings. Study participants were not blinded due to the
nature of the evaluated intervention. Although patients with recurrent CRC, metastatic disease, preoperative
radiotherapy or chemotherapy were not included in the sample, we did not assess tumour stages.
In conclusion, a shortening preoperative fasting time and consuming a CHO drink the evening before elective
open CRC surgery and 2 h before anaesthesia reduced postoperative NLR values, ΔNLR value and the incidence
and severity of postoperative complications. Preoperative CHO loading may improve outcomes following CRC
surgery.
Statement of Ethic
This a prospective, randomized, controlled trial was approwed by the Ethics Committee of the Cantonal Hospital
Zenica (aproval number: 00-03-35-1487-11/20) and registered in ClinicalTrials.gov (number: NCT05301985). All
study procedures were in accordance with the ethical standards of the Declaration of Helsinki. The study report
adheres to the applicable CONSORT guidelines. A voluntary written informed consent was obtained from each
patient before enrollment in the study.
Funding Sources
No funding was received for this study.
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