Introduction and Aim: There have been few studies to evaluate the monitoring of plasmatic concentrations of vancomycin in septic patients and their association with acute kidney injury (AKI) and death. This study aimed to evaluate the prevalence of adequate, subtherapeutic, and toxic serum concentrations of vancomycin in hospitalized septic patients and to associate the adequacy of therapeutic monitoring with clinical outcomes. Methodology: This was a cohort-unicentric study that evaluated septic patients aged >18 years using vancomycin admitted to clinical and surgical wards of a Brazilian university center from August 2016 to July 2017 in a daily and uninterrupted way. We excluded patients with AKI prior to the introduction of vancomycin or with AKI development <48 hours after use, patients with AKI of other etiologies, stage V chronic kidney disease, and pregnant women. Results: We evaluated 225 patients, and 135 were included. Evaluation of serum concentration of vancomycin was realized in 94.1%, and of those, 59.3% presented toxic concentrations. The prevalence of AKI was 27.4% and happened on average on the ninth day of vancomycin usage. Between the fourth and sixth days, vancomycin serum concentration of >21.5 mg/L was a predictor of AKI, with area under the curve of 0.803 (95% CI 0.62-0.98, p=0.005), preceding the diagnosis of AKI by at least 3 days. Of these patients, 20.7% died, and serum concentrations of vancomycin between the fourth and sixth days were identified as risk factors associated with negative outcomes. Conclusion: Serum concentration of vancomycin is an excellent predictor of AKI in patients admitted to wards, preceding the diagnosis of AKI by at least 72 hours. Toxic concentrations of vancomycin are associated with AKI, and AKI was a risk factor for death. Also, serum concentration of vancomycin >21.5 mg/L was the only variable associated with death in the Cox model.

Introduction: The incidence of acute kidney injury (AKI) related to vancomycin is variable, and several risk factors related to the treatment and patients may explain the nephrotoxicity. The role of urinary biomarkers in AKI related to vancomycin is unknown.Objective: The aim of this study was to evaluate the role of urinary IL-18, KIM-1, NGAL, TIMP-2, and IGFBP7 as diagnostic and prognostic predictors of AKI related to vancomycin.Methods: A prospective cohort study of patients receiving vancomycin and admitted to wards of a public university hospital from July 2019 to May 2020 was performed. We excluded patients that had AKI before starting vancomycin, hemodynamic instability, inability to collect urine, and chronic kidney disease stage 5.Results: Ninety-four patients were included, and the prevalence of AKI was 24.5%, while the general mortality was 8.7%. AKI occurred 11 ± 2 days after the first vancomycin dose. The most frequent KDIGO stage was 1 (61%). There was no difference between patients who developed and did not develop AKI due to gender, length of hospital stay, dose, and time of vancomycin use. Logistic regression identified age (OR 6.6, CI 1.16–38.22, p = 0.03), plasmatic vancomycin concentrations between 96 and 144 h (OR 1.18, CI 1.04-1.40, p = 0.04), and urinary NGAL levels between 96 and 144 h (OR 1.123, CI 1.096–1.290, p = 0.03) as predictors of AKI. The time of vancomycin use (OR 4.61, CI 1.11–22.02, p = 0.03), higher plasmatic vancomycin concentrations between 192 and 240 h (OR 1.02, CI 0.98–1.06, p = 0.26), and higher cell cycle arrest urinary biomarkers TIMP-2 multiplied by IGFBP-7 between 144 and 192 h (OR 1.33, CI 1.10–1.62, p = 0.02; OR 1.19, CI 1.09–1.39, p = 0.04, respectively) were identified as prognostic factors for non-recovery of kidney function at discharge.Conclusion: AKI related to vancomycin was frequent in patients hospitalized in wards. Age, plasmatic vancomycin concentrations, and NGAL between 96 and 144 h were identified as predictors of AKI related to vancomycin use. Plasmatic vancomycin concentrations and urinary NGAL were predictors of AKI diagnosis within the next 5 days. The urinary biomarkers of cell cycle arrest TIMP-2 and IGFBP-7 and the duration of vancomycin use were associated with non-recovery of kidney function at hospital discharge moment.

The impact of serum concentrations of vancomycin is a controversial topic. Results: 182 critically ill patients were evaluated using vancomycin and 63 patients were included in the study. AKI occurred in 44.4% of patients on the sixth day of vancomycin use. Vancomycin higher than 17.53 mg/L between the second and the fourth days of use was a predictor of AKI, preceding AKI diagnosis for at least two days, with an area under the curve of 0.806 (IC 95% 0.624–0.987, p = 0.011). Altogether, 46.03% of patients died, and in the Cox analysis, the associated factors were age, estimated GFR, CPR, and vancomycin between the second and the fourth days. Discussion: The current 2020 guidelines recommend using Bayesian-derived AUC monitoring rather than trough concentrations. However, due to the higher number of laboratory analyses and the need for an application to calculate the AUC, many centers still use therapeutic trough levels between 15 and 20 mg/L. Conclusion: The results of this study suggest that a narrower range of serum concentration of vancomycin was a predictor of AKI in critically ill septic patients, preceding the diagnosis of AKI by at least 48 h, and it can be a useful monitoring tool when AUC cannot be used.

Considering the increase of cardiovascular risk with the progression of the atherogenic process and the effectiveness of physical training as a strategy to control/manage the cardiac dysfunction in populations exposed to elevated risks, the aim of this study was to evaluate the cardiovascular and autonomic effects of an aerobic exercise training protocol in an experimental model of atherosclerosis. Considering the cardioprotective effects already known about physical training the hypothesis of this study is that the aerobic exercise training will promote systemic benefits on hemodynamics and autonomic in a model of atherosclerosis. For this, sixteen ApoE‐knockout mice, 15 months old, were divided in 2 groups (n=8, each): sedentary group (APOE 15) and moderate intensity exercise training group (APOE 15T). The exercise training lasted for 6 weeks (5 days/week, 1 hour/day, intensity 60–75% of the maximum treadmill test). At the end of the protocol, the animals were submitted to echocardiography analysis and cannulation for a direct recording of the arterial blood pressure (AP), and then, baroreflex sensitivity and cardiovascular autonomic modulation were evaluated. The aerobic exercise training improved running capacity (APOE 15: 594.90±46.95; APOE 15T: 878.6±68.54 s) and cardiac diastolic function (E/A: APOE 15: 1.10±0.05; APOE 15T: 1.70±0.24), as well as decreased diastolic blood pressure (DAP: APOE 15: 107.0±5.202; APOE 15T: 95.12±0.79 mmHg) and induced resting bradycardia (HR: APOE 15: 704±21; APOE 15T: 613±20 bpm) associated with heart rate variability increase (Var‐PI: APOE 15:1.25±0.09; APOE 15T: 8.81±1.98 ms2; SD‐Pl: APOE 15: 1.09±0.06; APOE 15T: 2.77±0.37 ms). In addition, greater cardiac parasympathetic modulation (RMSSD: APOE 15: 0.99±0.06; APOE 15T: 1.41±0.10 ms) and baroreflex sensitivity improvement (Alpha Index: APOE 15: 0.31±0.044; APOE 15T: 0.66±0.10 ms/mmHg) were also observed. In conclusion, aerobic exercise training may be considered an important non‐pharmacological strategy for the management of cardiovascular risk induced by atherosclerosis, improving running capacity, diastolic function as well as the hemodynamic status and autonomic modulation.

Ketamine hydrochloride is a drug widely used to treat depression, the most mentally disabling disease in the world. However, there is increasing evidence of cardiovascular damage resulting from the chronic use of ketamine. While regular practice of physical activity has been increasingly recommended as an adjunct in the treatment of depression, physical training promotes beneficial effects on the cardiovascular system. Therefore, the hypothesis of this study is that physical training can mitigate and/or prevent the harmful effects of ketamine on the cardiovascular system. Thus, the aim of this study was to evaluate the effects of aerobic physical training on cardiac morphometry and function, hemodynamic parameters and baroreflex sensitivity in Wistar rats treated with ketamine hydrochloride. For this, 24 Wistar rats were divided into 4 groups (n=6 in each): control (S), trained (T), sedentary treated with ketamine hydrochloride (SK) and trained treated with ketamine hydrochloride (TK). The treatment with ketamine hydrochloride was performed 3 times a week, for 6 weeks (ip, 10mg/kg). The physical training was aerobic on a treadmill (50‐70% of the maximum running capacity, 1 hour/day, 5 days/week, 6 weeks). At the end of the protocol, the animals were submitted to echocardiography analysis and cannulation for direct recording of the arterial pressure (AP) and then, baroreflex sensitivity was evaluated. The results demonstrate that chronic treatment with ketamine hydrochloride induces reduction in left ventricular shortening fraction (S: 35.4±1.7; T: 35.7±2.3; SK: 31.5±1.6; TK: 27.9±1.3), increase in systolic (S: 147±2.2; T: 153±2.5; SK: 161±2.8; TK: 155±2.8) and diastolic (S: 97±2.2; T: 103±0.8; SK: 107±3.6; TK: 103±1.5) arterial pressure, increased heart rate (S: 361±2.4; T: 365±8.1; SK: 401±18.1; TK: 354±10.0), and impaired baroreflex tachycardic response (S: 3.0±0.18; T: 3.1±0.18; SK: 2.3±0.06; TK: 3.1±0.10). On the other hand, aerobic physical training seems to be promising to prevent hemodynamic damage, since ketamine‐trained animals did not present such damages. In addition, TF promoted resting bradycardia (groups T and TK). These results demonstrate the protective role of physical training, preventing the onset of cardiovascular damage after chronic use of ketamine hydrochloride, suggesting that physical training should be recommended as an adjunct to the treatment of patients using this drug.