Pharmacokinetics of oral and intravenous melatonin in healthy volunteers

BACKGROUND: The aim was to investigate the pharmacokinetics of oral and iv melatonin in healthy volunteers. METHODS: The study was performed as a cohort crossover study. The volunteers received either 10 mg oral melatonin or 10 mg intravenous melatonin on two separate study days. Blood samples were collected at different time points following oral administration and short iv infusion, respectively. Plasma melatonin concentrations were determined by RIA technique. Pharmacokinetic analyses were performed by “the method of residuals” and compartmental analysis. The pharmacokinetic variables: k(a), t(1/2 absorption), t(max), C(max), t(1/2 elimination,)AUC(0-∞), and bioavailability were determined for oral melatonin. C(max), t(1/2 elimination), V(d), CL and AUC(0-∞) were determined for intravenous melatonin. RESULTS: Twelve male volunteers completed the study. Baseline melatonin plasma levels did not differ significantly between the study days (P = 0.067). Mean (SD) t(1/2 absorption) of oral melatonin was 6.0 (3.1) min. Mean t(max) was 40.8 (17.8) min with a median (IQR) C(max) of 3550.5 (2500.5–8057.5) pg ml(-1). Mean t(1/2 elimination) was 53.7 (7.0) min. Median absolute bioavailability was 2.5 (1.7–4.7) %. Median C(max) after short iv infusion of melatonin was 389,875.0 (174,775.0–440,362.5) pg ml(-1). Mean t(1/2 elimination) was 39.4 (3.6) min, mean V(d) 1.2 (0.6) l kg(-1) and mean CL 0.0218 (0.0102) l min(-1) kg(-1). CONCLUSIONS: This cohort crossover study estimated pharmacokinetics of oral and iv melatonin, respectively in healthy volunteers. Bioavailability of oral melatonin was only 3 %. TRIAL REGISTRATION: Eudra-CT number: 2013-000205-23 (initial registration 27.03.2013). Clinicaltrials.gov Identifier: NCT01923974 (initial registration 08.08.2013)

Long-term recurrence and complication rates after incisional hernia repair with the open onlay technique

<p>Abstract</p> <p>Background</p> <p>Incisional hernia after abdominal surgery is a well-known complication. Controversy still exists with respect to the choice of hernia repair technique. The objective of this study was to evaluate the long-term recurrence rate as well as surgical complications in a consecutive group of patients undergoing open repair using an onlay mesh technique.</p> <p>Methods</p> <p>Consecutive patients undergoing open incisional hernia repair with onlay-technique between 01/05/1995 and 01/09/2007 at a single institution were included in the study. For follow-up patients were contacted by telephone, and answered a questionnaire containing questions related to the primary operation, the hernia and general risk factors. Patients were examined by a consultant surgeon in the outpatient clinic or in the patient's home if there was suspicion of an incisional hernia recurrence.</p> <p>Results</p> <p>The study included 56 patients with 100% follow-up. The median follow-up was 35 months (range 4–151). Recurrent incisional hernia was found in 8 of 56 patients (15%, 95% CI: 6–24). The overall complication rate was 13% (95% CI, 4–22). All complications were minor and needed no hospital admission.</p> <p>Conclusion</p> <p>This study with a long follow-up showed low recurrence and complication rates in patients undergoing incisional hernia repair with the open onlay technique.</p

Fraction of Inspired Oxygen During General Anesthesia for Non-Cardiac Surgery:Systematic Review and Meta-Analysis

BACKGROUND: Controversy exists regarding the effects of a high versus a low intraoperative fraction of inspired oxygen (FiO(2)) in adults undergoing general anesthesia. This systematic review and meta‐analysis investigated the effect of a high versus a low FiO(2) on postoperative outcomes. METHODS: PubMed and Embase were searched on March 22, 2022 for randomized clinical trials investigating the effect of different FiO(2) levels in adults undergoing general anesthesia for non‐cardiac surgery. Two investigators independently reviewed studies for relevance, extracted data, and assessed risk of bias. Meta‐analyses were performed for relevant outcomes, and potential effect measure modification was assessed in subgroup analyses and meta‐regression. The evidence certainty was evaluated using GRADE. RESULTS: This review included 25 original trials investigating the effect of a high (mostly 80%) versus a low (mostly 30%) FiO(2). Risk of bias was intermediate for all trials. A high FiO(2) did not result in a significant reduction in surgical site infections (OR: 0.91, 95% CI 0.81–1.02 [p = .10]). No effect was found for all other included outcomes, including mortality (OR = 1.27, 95% CI: 0.90–1.79 [p = .18]) and hospital length of stay (mean difference = 0.03 days, 95% CI −0.25 to 0.30 [p = .84). Results from subgroup analyses and meta‐regression did not identify any clear effect modifiers across outcomes. The certainty of evidence (GRADE) was rated as low for most outcomes. CONCLUSIONS: In adults undergoing general anesthesia for non‐cardiac surgery, a high FiO(2) did not improve outcomes including surgical site infections, length of stay, or mortality. However, the certainty of the evidence was assessed as low

Goal-directed haemodynamic therapy during general anaesthesia for noncardiac surgery:a systematic review and meta-analysis

BACKGROUND: During general anaesthesia for noncardiac surgery, there remain knowledge gaps regarding the effect of goal-directed haemodynamic therapy on patient-centred outcomes. METHODS: Included clinical trials investigated goal-directed haemodynamic therapy during general anaesthesia in adults undergoing noncardiac surgery and reported at least one patient-centred postoperative outcome. PubMed and Embase were searched for relevant articles on March 8, 2021. Two investigators performed abstract screening, full-text review, data extraction, and bias assessment. The primary outcomes were mortality and hospital length of stay, whereas 15 postoperative complications were included based on availability. From a main pool of comparable trials, meta-analyses were performed on trials with homogenous outcome definitions. Certainty of evidence was evaluated using Grading of Recommendations, Assessment, Development, and Evaluations (GRADE). RESULTS: The main pool consisted of 76 trials with intermediate risk of bias for most outcomes. Overall, goal-directed haemodynamic therapy might reduce mortality (odds ratio=0.84; 95% confidence interval [CI], 0.64 to 1.09) and shorten length of stay (mean difference=–0.72 days; 95% CI, –1.10 to –0.35) but with low certainty in the evidence. For both outcomes, larger effects favouring goal-directed haemodynamic therapy were seen in abdominal surgery, very high-risk surgery, and using targets based on preload variation by the respiratory cycle. However, formal tests for subgroup differences were not statistically significant. Goal-directed haemodynamic therapy decreased risk of several postoperative outcomes, but only infectious outcomes and anastomotic leakage reached moderate certainty of evidence. CONCLUSIONS: Goal-directed haemodynamic therapy during general anaesthesia might decrease mortality, hospital length of stay, and several postoperative complications. Only infectious postoperative complications and anastomotic leakage reached moderate certainty in the evidence

Hydroxyethyl starch 130/0.42 versus Ringer's acetate in severe sepsis.

To access publisher's full text version of this article. Please click on the hyperlink in Additional Links field.Hydroxyethyl starch (HES) [corrected] is widely used for fluid resuscitation in intensive care units (ICUs), but its safety and efficacy have not been established in patients with severe sepsis. In this multicenter, parallel-group, blinded trial, we randomly assigned patients with severe sepsis to fluid resuscitation in the ICU with either 6% HES 130/0.42 (Tetraspan) or Ringer's acetate at a dose of up to 33 ml per kilogram of ideal body weight per day. The primary outcome measure was either death or end-stage kidney failure (dependence on dialysis) at 90 days after randomization. Of the 804 patients who underwent randomization, 798 were included in the modified intention-to-treat population. The two intervention groups had similar baseline characteristics. At 90 days after randomization, 201 of 398 patients (51%) assigned to HES 130/0.42 had died, as compared with 172 of 400 patients (43%) assigned to Ringer's acetate (relative risk, 1.17; 95% confidence interval [CI], 1.01 to 1.36; P=0.03); 1 patient in each group had end-stage kidney failure. In the 90-day period, 87 patients (22%) assigned to HES 130/0.42 were treated with renal-replacement therapy versus 65 patients (16%) assigned to Ringer's acetate (relative risk, 1.35; 95% CI, 1.01 to 1.80; P=0.04), and 38 patients (10%) and 25 patients (6%), respectively, had severe bleeding (relative risk, 1.52; 95% CI, 0.94 to 2.48; P=0.09). The results were supported by multivariate analyses, with adjustment for known risk factors for death or acute kidney injury at baseline. Patients with severe sepsis assigned to fluid resuscitation with HES 130/0.42 had an increased risk of death at day 90 and were more likely to require renal-replacement therapy, as compared with those receiving Ringer's acetate. (Funded by the Danish Research Council and others; 6S ClinicalTrials.gov number, NCT00962156.)Danish Research Council 271-08-0691 09-066938 Rigshospitalet Research Council Scandinavian Society of Anesthesiology and Intensive Care Medicine ACTA Foundation Fresenius Kab