A Possible Role of Interleukin-18 Binding Protein in Immune Regulation of Postoperative Pain: A Prospective Randomized Clinical Trial.

BACKGROUND/AIM: A possible role of interleukin-18 binding protein (IL-18BP) in immune regulation of pain and analgesics following surgery is rarely studied. The aim of this study was to investigate serum IL-18BP values in a cohort of laparoscopic cholecystectomy (LC) and minilaparotomy cholecystectomy (MC) patients and to establish their relationship with other cytokines and number of analgesic doses (NAD) of LC and MC patients postoperatively. PATIENTS AND METHODS: Blood levels of IL-18BP, six other interleukins (IL-18, IL-1ra, IL-6, IL-10, IL-1ß, and IL-8) and high-sensitivity C-reactive protein were measured before operation (PRE), immediately after operation (POP1), and six hours after operation (POP2) in 114 patients with cholelithiasis. RESULTS: Following surgery, the mean serum IL-18BP values correlated significantly to numeric rating scale (NRS) pain scores at 24 hours (r=0.194, p=0.009). In addition, the mean serum IL-18BP values correlated significantly to NAD (r=0.254, p<0.001). CONCLUSION: IL-18BP, a soluble antagonist of IL-18, correlates to NRS and NAD in LC and MC patients, which may support a possible role of IL-18BP in immune regulation of postoperative pain.

Interleukin-18 (IL-18) Cytokine Serum Concentrations Correlate With Pain Scores and the Number of Analgesic Doses Following Surgery.

BACKGROUND/AIM: Anti- and proinflammatory cytokines and plasma high-sensitivity C-reactive protein (hs-CRP) are used to assess inflammatory stress response (ISR) following surgery. However, the serum IL-18 (interleukin-18) cytokine values versus numeric rating scale (NRS) pain score and number of analgesic doses (NAD) postoperatively are unknown. PATIENTS AND METHODS: Blood levels of six interleukins (IL-18, IL-1ra, IL-6, IL-10, IL-1ß, and IL-8) and hs-CRP were measured at three time points; before operation (PRE), immediately after operation (POP1), and six hours after operation (POP2) in 114 patients with cholelithiasis. RESULTS: Following surgery, the blood levels of hs-CRP and IL-1ra, IL-6, IL-10, and IL-1ß cytokines had a trend for increase (p<0.001 and p=0.014, respectively). The serum IL-18 concentrations inversely correlated to NRS and NAD during the first 24 h postoperatively. CONCLUSION: The correlation of IL-18 levels to NRS and NAD values supports the hypothesis that ISR and pain are related.

Plasma Concentration of the Lipid Peroxidation (LP) Biomarker 4-Ηydroxynonenal (4-HNE) in Benign and Cancer Patients.

BACKGROUND/AIM: The present study investigated the plasma concentration of the lipid peroxidation (LP) biomarker 4-hydroxynonenal (4-HNE) in benign and cancer patients having the rectus sheath block (RSB) analgesia after midline laparotomy. Plasma concentrations of catalase (CAT) and malondialdehyde (MDA) were used as a reference. PATIENTS AND METHODS: This study assessed three LP biomarkers; CAT, MDA and 4-HNE and compared the plasma levels to the patient satisfaction 24 h postoperatively (SFS24; 0=fully unsatisfied; 10=fully satisfied); the overall pain at rest (NRSr) and when pressing the wound at 20 Newton force (NRSp) were surveyed and filed on a 11-point numeric rating scale at 24 h following surgery (NRS; 0=no pain; 10=worst pain). There were 56 patients in the study, of whom 12 were excluded due to missing plasma samples. The final study cohort consisted of 15 patients with benign disease and 29 patients with cancer. RESULTS: The RSB analgesia enhanced significantly the SFS24 scores in the study groups (p=0.001). The plasma 4-HNE decreased immediately after operation (POP1) and the postoperative decrease between the preoperative and the POP1 values in the 4-HNE marker were statistically significant (p<0.001). The individual plasma 4-HNE and MDA concentration correlated significantly in benign and cancer patients (r=0.413, p<0.001). CONCLUSION: The present study confirms the applicability of the plasma biomarker 4-HNE to cast further light on the postoperative pain in midline laparotomy patients.

The Rectus Sheath Block (RSB) Analgesia Following Laparotomy Could Affect Malonidialdehyde (MDA) Concentrations in Benign Disease and Cancer.

BACKGROUND/AIM: The aim of the study was to compare the MDA (malonidialdehyde) plasma concentrations versus CAT (catalase)/NT (nitrotyrosine) plasma concentrations, patient satisfaction and pain score at rest/pressure to the wound area in laparotomy patients with rectus sheath block (RSB) analgesia. PATIENTS AND METHODS: Initially, 56 patients were randomized to four groups; control group (n=12), single-dose (n=16), repeated-dose (n=12) and continuous infusion (n=16) RSB analgesia groups. The plasma concentrations of CAT, NT and MDA markers were measured just before, immediately after and 24 h after operation. RESULTS: The RSB analgesia enhanced significantly patient satisfaction (p=0.001). The plasma MDA decreased immediately after operation (POP1) and the postoperative decrease between the preoperative and the POP1 values in the MDA marker were statistically significant (p<0.001). In linear mixed model, the time effect in both the single group and in the benign group in plasma NT biomarker was statistically significant (p=0.001, p=0.013, respectively). The median plasma MDA concentrations (ng/ml) following surgery were significantly lower in patients with cancer versus patients with benign disease (589 vs. 852, p=0.021). Jitterplots of the individual plasma NT versus plasma MDA showed that there was significant correlation in benign and cancer patients (r=0.347, p<0.001). CONCLUSION: Plasma MDA decreased significantly after operation in all patients and cancer patients had significantly lower MDA concentrations following surgery than patients with benign disease.

Levels of Growth Differentiation Factor 15 and Early Mortality Risk Stratification in Cardiogenic Shock.

BACKGROUND: The aim of this study was to assess the levels, kinetics, and prognostic value of growth differentiation factor 15 (GDF-15) in cardiogenic shock (CS). METHODS AND RESULTS: Levels of GDF-15 were determined in serial plasma samples (0-120 h) from 177 CS patients in the CardShock study. Kinetics of GDF-15, its association with 90-day mortality, and incremental value for risk stratification were assessed. The median GDF-150h level was 9647 ng/L (IQR 4500-19,270 ng/L) and levels above median were significantly associated with acidosis, hyperlactatemia, renal dysfunction, and higher 90-day mortality (56% vs 28%, P < .001). Serial sampling showed that non-survivors had significantly higher GDF-15 levels at all time points (P < .001 for all). Furthermore, non-survivors displayed increasing and survivors declining GDF-15 levels during the first days in CS. Higher levels of GDF-15 were independently associated with mortality. A GDF-1512h cutoff >7000 ng/L was identified as a strong predictor of death (OR 5.0; 95% CI 1.9-3.8, P = .002). Adding GDF-1512h >7000 ng/L to the CardShock risk score improved discrimination and risk stratification for 90-day mortality. CONCLUSIONS: GDF-15 levels are highly elevated in CS and associated with markers of systemic hypoperfusion and end-organ dysfunction. GDF-15 helps to discriminate survivors from non-survivors very early in CS.

Nitrotyrosine (NT), a Nitrosative Stress Biomarker, Plasma Concentrations in Gallstone Disease and Cancer Patients.

BACKGROUND/AIM: The aim of this study was to assess the plasma concentration of the nitrosative stress biomarker nitrotyrosine (NT) in gallstone disease and cancer patients. MATERIALS AND METHODS: Initially, 114 patients with symptomatic gallstone disease were randomized into the laparoscopic cholecystectomy (LC) (n=54) and the minicholecystectomy (MC) (n=60) groups. The plasma concentrations of NT were measured just before, immediately after (POP1) and 6 h after operation (POP2). The cancer patients of this study included ten patients with gastrointestinal cancer and 19 patients with gynecological cancer. RESULTS: There was a statistically significant correlation in the median plasma NT concentrations versus plasma catalase (CAT) concentrations in cholecystectomy patients (r=0.169, p=0.001). Interestingly, there was a statistically significant inverse correlation between the individual values of the pain assessed and filed using a 11-point numeric rating scale 8 h postoperatively (NAD8) and plasma NT median values in cholecystectomy patients (r=-0.337, p=0.004). CONCLUSION: Patients with high plasma concentrations of NT appeared to have significantly lower pain scores 8 h postoperatively.

Novel renal markers for the assessment of renal integrity in patients undergoing knee arthroplasty - a pilot study.

BACKGROUND: The feasibility of novel kidney injury biomarkers in consecutive patients having total knee arthroplasty with local infiltration analgesia was evaluated. METHODS: We enrolled 30 patients scheduled for elective unilateral total knee arthroplasty. Paired plasma and urine samples were taken before surgery and at 4 h, 24 h and 48 h after surgery to measure creatinine, cystatin C, neutrophil gelatinase associated lipocalin, kidney injury molecule-1, interleukin-18 and liver-type fatty acid-binding protein. RESULTS: At baseline, 13 subjects had normal kidney function, 15 had mild and two had moderate kidney failure evaluated by calculated glomerular filtration rate. None of the subjects had all measured novel renal markers below proposed cut-off concentrations. Altogether 28/30 subjects had one (n = 3), two (n = 7) or three (n = 18) plasma neutrophil gelatinase associated lipocalin values above normal. In seven of these 28 subjects plasma creatinine, calculated glomerular filtration rate and plasma cystatin C were within the reference values. Five subjects had a low urine output, < 0.5 mL/h, indicating transient acute kidney injury, four of these had high plasma neutrophil gelatinase associated lipocalin and one high plasma cystatin C. CONCLUSIONS: In the present study plasma neutrophil gelatinase associated lipocalin was elevated in most subjects with total knee arthroplasty and local infiltration analgesia as a marker of possible renal proximal tubular injury. Five subjects had transient low urine output, but none developed renal deterioration requiring treatment.

Cholecystectomy Patients with High Plasma Level of Catalase Have Significantly Lower Analgesia Requirement: A Prospective Study of Two Different Cholecystectomy Techniques with Special Reference to Patients with Cancer.

BACKGROUND/AIM: The plasma level of the oxidative stress biomarker catalase in patients with gallstone disease has not been previously compared with that of patients with cancer. Moreover, the number of analgesic doses required during the first 24 h postoperatively (NAD24) after laparoscopic cholecystectomy (LC) or mini-cholecystectomy (MC) in patients with gallstones is unreported. The aim of the present study was to determine the correlation between the plasma catalase level in patients with gallstones according to cholecystectomy technique versus patients with cancer. PATIENTS AND METHODS: Initially, 114 patients with symptomatic gallstone disease were randomized into LC (n=54) or MC (n=60) groups. The plasma level of catalase was measured immediately before, immediately after and 6 hours after operation. RESULTS: The median plasma catalase levels preoperatively and following surgery in the LC and MC patients versus those with cancer did not differ statistically significantly. The median plasma level of catalase increased immediately after operation, but the alteration was statistically insignificant (p=0.132). Interestingly, there was a statistically significant weak inverse correlation between the individual NAD24 and median plasma catalase values postoperatively in patients with gallstone disease (r=-0.283, p=0.042). CONCLUSION: The plasma catalase levels preoperatively and following surgery in the LC and MC patients versus those with cancer were quite similar. Cholecystectomy patients with high plasma levels of catalase appeared to require significantly fewer analgesic doses during the first 24 hours postoperatively (NAD24), suggesting that better oxidative balance following surgery could have a protective role against postoperative pain.

Inflammatory response to surgical trauma in patients with minilaparotomy cholecystectomy versus laparoscopic cholecystectomy: a randomised multicentre study.

OBJECTIVE: The aim of the study was to evaluate the inflammatory response to surgical trauma in minilaparotomy cholecystectomy (MC) compared to laparoscopic cholecystectomy (LC). Assessment of inflammatory response to surgical trauma in MC has not been addressed properly. Therefore, we investigated five interleukins (IL) and C-reactive protein (CRP) in MC versus LC group in a prospective randomised trial. METHODS: Initially, 106 patients with non-complicated symptomatic gallstone disease were randomised into MC (n = 56) or LC (n = 50) groups. Plasma levels of five interleukins (IL-1ß, IL-1ra, IL-6, IL-8, IL-10) and hs-CRP were measured at three time points; before operation (PRE), immediately after operation (POP1) and six hours after operation (POP2). The primary end-point of the study was to compare the plasma levels of five interleukins and CRP in LC versus MC group. RESULTS: The demographic variables and the surgical data were similar in the study groups. The patients in the MC group had higher elevation of the CRP mean values post-operatively (p = 0.01). However, the patients in the MC group had higher elevation of the IL-1ra mean values post-operatively, the mean pre-/post-operative IL-1ra values being 299/614 pg/ml in the MC group versus 379/439 pg/ml in the LC group (p = 0.003). There was no statistical significance in IL-6 mean values between the MC and LC groups pre- and post-operatively (POP1). However, the patients in the MC group had higher IL-6 mean values six hours post-operatively (POP2), the mean IL-6 values being 27.6 pg/ml in the MC group versus 14.8 pg/ml in the LC group (p = 0.037). In addition, the patients in the MC group had higher elevation of the IL-6 mean values post-operatively, the mean pre-/post-operative IL-6 values being 4.1/27.6 pg/ml in the MC group versus 3.8/14.8 pg/ml in the LC group (p = 0.04). There was no statistical significance in IL-8, IL-10, and IL-1ß mean values between the MC and LC groups pre- and post-operatively. CONCLUSION: Our results suggest that the inflammatory response in MC versus LC groups was similar based on the IL-8, IL-10, and IL-1ß values. A new finding with possible clinical relevance in the present work is higher relative elevation of the IL-1ra and IL-6 mean values post-operatively in the MC group.