Effect of melatonin in patients with low anterior resection syndrome (MELLARS): a study protocol for a randomised, placebo-controlled, crossover trial.

INTRODUCTION: After rectal cancer surgery, a majority of patients suffer from sequelae known as low anterior resection syndrome (LARS). It is a collection of symptoms consisting of flatus and/or stool incontinence, evacuation frequency, re-evacuation and urgency. The circadian hormone, melatonin, has shown to possess anti-inflammatory properties, and in high doses, it reduces bowel movements. The aim of the study is to investigate if locally administered melatonin has an alleviating effect on LARS. Secondarily, the effect of melatonin on bowel movements, other patient-reported symptoms, quality of life, depression, anxiety, sleep disturbances, motilin levels and rectal mucosa histology will be examined. METHODS AND ANALYSIS: This is a randomised, placebo-controlled, double-blinded, two-period crossover trial. The participants are randomised to 28 days of 25 mg melatonin administered rectally via an enema daily (or placebo) followed by a 28-day washout and then 28 days of placebo (or melatonin). Three participants will be included in an internal feasibility test. They will receive 25 mg of melatonin daily for 28 days. Data from these participants will be used to assess the feasibility of the rectally administered melatonin and to analyse the course of recruitment and outcome measurements. Afterwards, 18 participants will be included in the crossover trial. The severity of the LARS symptoms will be evaluated using the LARS Score on the first and last day of each treatment period. ETHICS AND DISSEMINATION: The Regional Ethics Committee, the Danish Medicines Agency and the Data and Development Support in Region Zealand approved this study. The study will be performed according to the Helsinki II declaration. Written informed consent will be obtained from all participants. The results of the study will be submitted to peer-reviewed journals for publication and presented at congresses. TRIAL REGISTRATION NUMBERS: EudraCT Registry (2020-004442-11) and ClinicalTrial.gov Registry (NCT05042700).

Effect of modifying high-risk factors and prehabilitation on the outcomes of colorectal cancer surgery: controlled before and after study.

BACKGROUND: Low functional capacity, malnutrition, and anaemia are associated with an increased risk of complications after surgery. These high-risk indicators can be improved through preoperative interventions. The aim of the study was to examine the effect of screening for modifiable high-risk factors combined with targeted interventions on postoperative complications in patients undergoing colorectal cancer surgery. METHODS: A controlled before-and-after study was conducted including patients with colorectal cancer undergoing elective curative surgery between August 2015 and October 2018, in two institutions (intervention and control hospital). The intervention consisted of a screening for anaemia, low functional capacity, and nutritional status and their implementation (iron supplementation, prehabilitation, nutritional supplements, and consultation with a dietician), for a minimum of 4 weeks before surgery. The primary outcome was a composite measure consisting of unplanned admission to the intensive care unit, complications with Clavien-Dindo score of 3a or above, length of hospital stay less than 10 days, readmission, or death within 30 days during the postoperative course. RESULTS: A total of 1591 patients were included for analysis with 839 at the intervention hospital and 752 at the control hospital. In a difference-in-difference analysis, adjusted for age, sex, smoking, stage of disease, ASA score, surgical approach, and surgical procedure, the intervention was associated with a 10.9 per cent (95 per cent c.i. 2.1 to 19.7 per cent) absolute risk reduction of a complicated postoperative course, primarily due to a reduction in severe complications. CONCLUSION: The combined intervention of screening and prehabilitation was associated with a decreased risk of a complicated course, primarily in a reduction of severe complications.

The Effect of Perioperative Iron Therapy in Acute Major Non-cardiac Surgery on Allogenic Blood Transfusion and Postoperative Haemoglobin Levels: A Systematic Review and Meta-analysis.

BACKGROUND: Perioperative anaemia in relation to surgery is associated with adverse clinical outcomes. In an elective surgical setting, it is possible to optimize patients prior to surgery, often by iron supplementation with correction of anaemia. Possibilities for optimization prior to and during acute surgical procedures are limited. This review investigates whether iron treatment initiated perioperatively improves outcomes in patients undergoing major acute non-cardiac surgery. METHOD: This systematic review was performed using PubMed, EMBASE (Ovid) and Scopus to identify current evidence on iron supplementation in acute surgery. Primary outcomes were allogenic blood transfusion (ABT) rate and changes in haemoglobin. Secondary outcomes were postoperative mortality, length of stay (LOS), and postoperative complications. Iron was administered at latest within 24 h after end of surgery. RESULTS: Of the 5413 studies screened, four randomized controlled trials and nine observational cohort studies were included. Ten studies included patients with hip fractures. A meta-analysis of seven studies showed a risk reduction of transfusion (OR = 0.35 CI 95% (0.20-0.63), p = 0.0004, I2 = 66%). No influence on plasma haemoglobin was found. Postoperative mortality was reduced in the iron therapy group in a meta-analysis of four observational studies (OR 0.50 (CI 95% 0.26-0.96) p = 0.04). No effect was found on LOS, but a reduction in postoperative infection was seen in four studies. CONCLUSIONS: This review examined perioperative iron therapy in acute major non-cardiac surgery. IV iron showed a lower 30-day mortality, a reduction in postoperative infections and a reduction in ABT largely due to the observational studies. The review primarily consisted of small observational studies and does not have the power to formally recommend this practice.

[Hyperthermic intraperitoneal chemotherapy at the primary gastrointestinal cancer operation].

Up to 20% of the patients who undergo radical surgery for colorectal cancer experience recurrence. Hyperthermic intraperitoneal chemotherapy (HIPEC) and cytoreductive surgery have shown to be effective treatment of peritoneal carcinomatosis. HIPEC administered at the primary operation in high-risk patients may also be effective in preventing peritoneal carcinomatosis and improve survival in patients with advanced gastrointestinal cancer.

Effect of topical application of melatonin cream 12.5% on cognitive parameters: A randomized, placebo-controlled, double-blind crossover study in healthy volunteers.

BACKGROUND: Skin cancer is an increasing problem in modern dermatology. Earlier studies have shown protective effects against ultraviolet radiation (UVR)-induced skin damage by topical treatment with melatonin. However, the potential sedative effects of full body topical application of melatonin have never been investigated. Objectives The aim of this study was to assess the degree of cognitive dysfunction when using melatonin cream as full body topical application. METHODS: In a randomized, placebo-controlled, double-blind crossover study in healthy volunteers, the degree of cognitive dysfunction when using cream containing 12.5% melatonin as full body application was assessed. A group of ten volunteers had melatonin cream 12.5% applied on 80% of their body surface area, and degree of cognitive dysfunction was assessed using a test battery consisting of Karolinska sleepiness scale (KSS), Finger tapping test (FTT) and Continuous Reaction time (CRT). RESULTS: No significant effects on cognitive parameters were found. However, great inter-individual variations on cognitive parameters were observed. CONCLUSION: This study was the first to assess degree of cognitive dysfunction resulting from application of melatonin cream on a full body surface area. The results support that melatonin is a safe drug for dermal application even in a high dosage.

Pharmacokinetics of high-dose intravenous melatonin in humans.

This crossover study investigated the pharmacokinetics and adverse effects of high-dose intravenous melatonin. Volunteers participated in 3 identical study sessions, receiving an intravenous bolus of 10 mg melatonin, 100 mg melatonin, and placebo. Blood samples were collected at baseline and 0, 60, 120, 180, 240, 300, 360, and 420 minutes after the bolus. Quantitative determination of plasma melatonin concentrations was performed using a radioimmunoassay technique. Pharmacokinetic parameters were estimated by a compartmental pharmacokinetic analysis. Adverse effects included assessments of sedation and registration of other symptoms. Sedation, evaluated as simple reaction times, was measured at baseline and 120, 180, 300, and 420 minutes after the bolus. Twelve male volunteers completed the study. Median (IQR) Cmax after the bolus injections of 10 mg and 100 mg of melatonin were 221,500.0 (185,637.5-326,175.0) pg/mL and 1,251,500.0 (864,375.0-1,770,500.0) pg/mL, respectively; mean (SD) t1/2 was 42.3 (5.6) minutes and 46.2 (6.2) minutes; mean (SD) Vd was 1.6 (0.9) L/kg and 2.0 (0.8) L/kg; mean (SD) CL was 0.0253 (0.0096) L/min · kg and 0.0300 (0.0120) L/min · kg; and median (IQR) AUC0- ∞ , 8,997,633.0 (6,071,696.2-11,602,811.9) pg · min/mL and 54,685,979.4 (36,028,638.6-105,779,612.0) pg · min/mL. High-dose intravenous melatonin did not induce sedation, evaluated as simple reaction times. No adverse effects were reported in the study.

Effect of melatonin on human nighttime endotoxaemia: randomized, double-blinded, cross-over study.

BACKGROUND: Endotoxaemia is widely used as an experimental model to study sepsis under controlled conditions. Nighttime endotoxaemia induces a more pronounced inflammatory stress response compared to daytime. Previously, we have shown that melatonin has antioxidative and anti-inflammatory effects in inflammatory response to daytime endotoxaemia. Herein, we examined the effect of melatonin in response to human nighttime endotoxaemia. PATIENTS AND METHODS: Twelve healthy male volunteers were enrolled in a randomized, placebo-controlled, double-blinded cross-over trial. Subjects were induced by lipopolysaccharide (LPS) endotoxin 0.3 ng/kg body weight intravenously at 24:00. One hour prior to induction of endotoxaemia, an 8-h infusion of melatonin 100 mg or placebo was initiated. Blood samples were drawn before and 2, 4, 6 and 8 h after induction of endotoxaemia and plasma was tested for pro-inflammatory markers (tumor necrosis factor alpha, TNF-α, interleukin-1ß, IL-1ß, interleukin-1, IL-6, and YKL-40), anti-inflammatory markers (interleukin-1 receptor antagonist, IL-1Ra, interleukin-10, IL-10, soluble tumor necrosis factor receptors I and II, sTNF-RI and sTNF-RII), marker for oxidative damage (malondialdehyde (MDA)) and antioxidative enzyme (ascorbic acid (AA) and dehydroascorbic acid (DHA)). RESULTS: Compared to placebo, melatonin did not reduce plasma levels of any of pro- and anti-inflammatory markers and it also failed to influence levels of AA, DHA and MDA. CONCLUSION: Melatonin has no beneficial effect on inflammation and oxidative damage induced by nighttime endotoxaemia in contrast to daytime endotoxaemia.

Melatonin does not affect oxidative/inflammatory biomarkers in a closed-chest porcine model of acute myocardial infarction.

AIM: To test whether melatonin reduces oxidative and inflammatory biomarkers in a closed-chest porcine model of acute myocardial infarction. MATERIALS AND METHODS: Twenty pigs were randomized to receive a total dosage of 200 mg (0.4 mg/ml) of melatonin, or placebo immediately prior to reperfusion of a coronary artery balloon occlusion in a randomized, observer-blinded, placebo-controlled trial. We assessed high-sensitivity troponin T (hs-TnT), malondialdehyde and interleukin-1b, -6 and -10 at baseline, 30 min and 1, 2, 3 and 4 h after the start of reperfusion. RESULTS: Seventeen pigs completed the trial. There was an increase in hs-TnT, but no significant difference between the melatonin-treated and placebo-treated groups. There were no significant differences in development of any of the circulating plasma markers between the two groups. CONCLUSION: Melatonin treatment did not result in reduction of inflammatory or oxidative stress markers after experimental myocardial infarction compared to placebo.

Reduced oxidative stress in STEMI patients treated by primary percutaneous coronary intervention and with antioxidant therapy: a systematic review.

PURPOSE: Coronary reperfusion by primary percutaneous coronary intervention (PCI) has been established as an essential therapy of ST-elevation myocardial infarction (STEMI). Although the coronary intervention is undoubtedly beneficial, reperfusion itself can induce processes resulting in additional myocardial damage-a phenomenon known as ischemia-reperfusion injury (IRI). Oxidative stress is one of the major factors contributing to IRI. This systematic review focuses on the effect of antioxidant therapy on reperfusion triggered oxidative stress and myocardial IRI in patients with STEMI. METHODS: We performed a systematic search in EMBASE and Pubmed and included eight randomised clinical trials evaluating edaravone, allopurinol, vitamin c, nicorandil, N-acetylcysteine, glucose-insulin-potassium, atorvastatin and deferoxamine. RESULTS: Administration of edaravone, allopurinol, atorvastatin and nicorandil as a supplement to primary PCI significantly reduced oxidative stress and myocardial damage as well as improved cardiac function and clinical outcomes. Treatment with deferoxamine and N-acetylcysteine reduced the oxidative stress but an effect on the clinical outcome parameters could not be shown. CONCLUSIONS: Preliminary studies of edaravone, allopurinol, atorvastatin and nicorandil seems promising though larger clinical trials with a wider range of clinical outcome parameters and trials of higher methodological quality should confirm the clinical benefits before a general recommendation can be given. Moreover, the included studies revealed a complex link between oxidative stress and cardiac function and/or cardiac adverse events and in order to further elucidate the detrimental role of oxidative stress in IRI in relation to primary PCI the assessment of oxidative stress and the clinical outcome parameters should be standardized.

Intraperitoneal instillation of saline and local anesthesia for prevention of shoulder pain after laparoscopic cholecystectomy: a systematic review.

BACKGROUND: The laparoscopic technique has many advantages compared with open surgery for symptomatic cholecystolithiasis. Despite these advantages, many patients complain about shoulder pain (SP) after laparoscopic cholecystectomy. The purpose of this review was to evaluate intraperitoneal instillation (IPI) of saline and local anesthesia (LA) to minimize SP. METHODS: A search of the literature was conducted using PubMed and Excerpta Medica Database (EMBASE). Eligibility criteria were: randomized clinical trials (RCT) evaluating IPI of saline and/or LA to minimize incidence or severity of SP after laparoscopic cholecystectomy. Only papers published in English were included. Data extracted were year of publication, number of participants and allocation, timing of IPI, and nonsignificant or significant effect on incidence or severity of SP. RESULTS: A total of 24 RCTs were included in the review. Four RCTs reported results on IPI saline as intervention versus nothing as control. Seven RCTs reported results on IPI LA as intervention versus nothing as control. Sixteen RCTs reported results on IPI LA as intervention versus saline as control. IPI saline resulted in a significant reduction in SP severity compared with nothing. IPI LA was associated with an overall significant reduction of SP severity compared with nothing. Results regarding the effect IPI LA versus saline showed contradictory results in regards to both SP incidence and severity. CONCLUSIONS: Both IPI of saline and LA can be used to reduce SP severity after laparoscopic cholecystectomy. It is not possible to conclude whether the incidence of SP can be reduced with saline or LA, due to contradictive results.