Purpose: Ketamine is a N-methyl-D-aspartate (NMDA) antagonist with strong analgesic properties. Its addition to the treatment of neuropathic pain may reduce pain intensity and improve overall quality of life. A systematic review and meta-analysis of randomized controlled trials was performed to investigate the addition of ketamine to the treatment of patients with neuropathic pain. Patients and Methods: GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach was used to rate the overall certainty of the evidence for each outcome. Eighteen (18) randomized controlled trials including 706 participants were included for further analysis. Results: Ketamine addition to standard treatment of neuropathic pain (NP) resulted in a statistically significant reduction of pain intensity at one week after the end of treatment with ketamine (MD − 2.14, 95% CI − 2.65 to − 1.63; p< 0.00001) and after 30 days after the end of treatment with ketamine (MD − 1.68, 95% CI − 2.25 to − 1.12; p< 0.00001) and a statistically significant increase in discomfort (RR 4.06; 95% CI 1.18 to 13.95; p=0.03), and psychedelic effects (RR 4.94; 95% CI 2.76 to 8.84; p< 0.00001). Conclusion: There is a statistically significant pain reduction by adding ketamine to the treatment of chronic NP when compared to the standard treatment. However, such pain reduction comes at the expense of adverse outcomes, especially psychedelic effects related to the administration of ketamine. However, the overall quality of certainty of evidence is low due to the clinical heterogeneity among the intervention characteristics of the trials analyzed (different administration routes, dosing regimen, therapy durations, different clinical characteristics of the population investigated). Future large multi-centered trials are necessary to confirm or not the results of the present review.

Cardiac surgeries are complex procedures aiming to re-establish coronary flow and correct valvular defects. Oxidative stress, caused by inflammation and ischemia-reperfusion injury, is associated with these procedures, increasing the risk of adverse outcomes. N-acetylcysteine (NAC) acts as an antioxidant by replenishing the glutathione stores, and emerging evidence suggests that NAC may reduce the risk of adverse perioperative outcomes. We conducted a systematic review and meta-analysis to investigate the addition of NAC to a standard of care among adult patients undergoing cardiac surgery. We searched four databases (PubMed, EMBASE, CENTRAL, LILACS) from inception to October 2018 and the grey literaure for randomized controlled trials (RCTs) investigating the effect of NAC on pre-defined outcomes including mortality, acute renal insufficiency (ARI), acute cardiac insufficiency (ACI), hospital length of stay (HLoS), intensive care unit length of stay (ICULoS), arrhythmia and acute myocardial infarction (AMI). Reviewers independently screened potentially eligible articles, extracted data and assessed the risk of bias among eligible articles. We used the GRADE approach to rate the overall certainty of evidence for each outcome. Twenty-nine RCTs including 2,486 participants proved eligible. Low to moderate certainty evidence demonstrated that the addition of NAC resulted in a non-statistically significant reduction in mortality (Risk Ratio (RR) 0.71; 95% Confidence Interval (CI) 0.40 to 1.25), ARI (RR 0.92; 95% CI 0.79 to 1.09), ACI (RR 0.77; 95% CI 0.44 to 1.38), HLoS (Mean Difference (MD) 0.21; 95% CI -0.64 to 0.23), ICULoS (MD -0.04; 95% CI -0.29 to 0.20), arrhythmia (RR 0.79; 95% CI 0.52 to 1.20), and AMI (RR 0.84; 95% CI 0.48 to 1.48). Among eligible trials, we observed heterogeneity in the population and interventions including patients with and without kidney dysfunction and interventions that differed in route of administration, dosage, and duration of treatment. This observed heterogeneity was not explained by our subgroup analyses. The addition of NAC during cardiac surgery did not result in a statistically significant reduction in clinical outcomes. A large randomized placebo-controlled multi-centre trial is needed to determine whether NAC reduces mortality. PROSPERO CRD42018091191.

KEY WORDS: Evidence-based medicine; MEDLINE; Databases, bibliographic; Medical subject headings; Anesthesiology

Introduction: Craniotomy, a common neurosurgical procedure, is frequently associated with substantial perioperative challenges and delayed recovery. While Enhanced Recovery After Surgery (ERAS) protocols have demonstrated clear benefits in multiple surgical fields, their application in neurosurgery, particularly elective craniotomy, remains emerging. Objective: This systematic review and meta-analysis aimed to evaluate the efficacy and safety of ERAS protocols in adult patients undergoing elective craniotomy, focusing on key outcomes such as length of hospital stay (LOS), postoperative pain, complications, and functional recovery. Methods: Following PRISMA guidelines, a comprehensive search was conducted in PubMed, Embase, Scopus, Web of Science, and the Cochrane Library up to June 2025. Eligible studies included adult patients (≥18 years) undergoing elective craniotomy and compared ERAS protocols to conventional perioperative care. Primary outcomes were LOS, postoperative complications, pain, early oral intake, and early mobilization. Data extraction and risk of bias assessment (RoB 2.0) were independently performed by two reviewers. Results: Nine randomized controlled trials (RCTs), totaling 1453 patients, were included. Meta-analysis showed that ERAS protocols significantly reduced length of hospital stay (mean difference: −2.17 days; 95% CI: −2.92 to −1.42; p < 0.00001) and decreased the incidence of postoperative nausea and vomiting (odds ratio [OR]: 0.29; 95% CI: 0.19 to 0.44; I² = 0%). ERAS protocols were associated with higher odds of early mobilization (OR: 6.88; 95% CI: 3.46 to 13.68) and early oral intake (OR: 14.04; 95% CI: 7.80 to 25.26). Postoperative complications were significantly reduced in the ERAS group (OR: 0.49; 95% CI: 0.24 to 0.99; p = 0.048; I² = 0%). While early urinary catheter removal showed a favorable trend (OR: 13.48), high heterogeneity (I² = 95.7%) limits interpretability. Postoperative pain on day 1 did not differ significantly between groups (mean difference: −0.37; 95% CI: −2.38 to 1.63; p = 0.72). The overall risk of bias was rated low to moderate across studies. Conclusions: ERAS protocols in elective craniotomy are associated with shorter hospital stays, lower complication rates, reduced PONV, and earlier return to function, without increasing adverse events. These findings support broader implementation of ERAS in neurosurgical practice. Further multicenter RCTs are warranted to standardize and refine ERAS components for craniotomy.