Amiodarone but not propafenone impairs bioenergetics and autophagy of human myocardial cells.

Cardiac and extra-cardiac side effects of common antiarrhythmic agents might be related to drug-induced mitochondrial dysfunction. Supratherapeutic doses of amiodarone have been shown to impair mitochondria in animal studies, whilst influence of propafenone on cellular bioenergetics is unknown. We aimed to assess effects of protracted exposure to pharmacologically relevant doses of amiodarone and propafenone on cellular bioenergetics and mitochondrial biology of human and mouse cardiomyocytes. In this study, HL-1 mouse atrial cardiomyocytes and primary human cardiomyocytes derived from the ventricles of the adult heart were exposed to 2 and 7 µg/mL of either amiodarone or propafenone. After 24 h, extracellular flux analysis and confocal laser scanning microscopy were used to measure mitochondrial functions. Autophagy was assessed by western blots and live-cell imaging of lysosomes. In human cardiomyocytes, amiodarone significantly reduced mitochondrial membrane potential and ATP production, in association with an inhibition of fatty acid oxidation and impaired complex I- and II-linked respiration in the electron transport chain. Expectedly, this led to increased anaerobic glycolysis. Amiodarone increased the production of reactive oxygen species and autophagy was also markedly affected. In contrast, propafenone-exposed cardiomyocytes did not exert any impairment of cellular bioenergetics. Similar changes after amiodarone treatment were observed during identical experiments performed on HL-1 mouse cardiomyocytes, suggesting a comparable pharmacodynamics of amiodarone among mammalian species. In conclusion, amiodarone but not propafenone in near-therapeutic concentrations causes a pattern of mitochondrial dysfunction with affected autophagy and metabolic switch from oxidative metabolism to anaerobic glycolysis in human cardiomyocytes.

Incidence of surgical site infections after cervical spine surgery: results of a single-center cohort study adhering to multimodal preventive wound control protocol.

PURPOSE: The incidence of surgical site infections is considered a relevant indicator of perioperative and postoperative care quality. The aim of this study is to analyze and evaluate SSIs after elective cervical spine surgery under the guidance of our preventive multimodal wound protocol. METHODS: A monocentric observational cohort study analyzed 797 patients who underwent cervical spine surgery from 2005 to 2010 (mean age 51.58 ± 11.74 year, male 56.09%, mean BMI 26.87 ± 4.41, ASA score 1-2 in 81.68% of patients), fulfilling the entry criteria: (1) cervical spine surgery performed by neurosurgeons (degenerative disease 85.19%, trauma 11.04%, tumor 3.76%), (2) elective surgery, (3) postoperative care in our neurointensive care unit. Our preventive wound control protocol management focused mainly on antibiotic prophylaxis, wound hygiene regime, and drainage equipment. All wound complications and surgical site infections were monitored up for 1 year after surgery. RESULTS: We had only 2 (0.25%) patients with SSI after cervical spine surgery-one organ/space infection (osteomyelitis, primary due to liquorrhea) after anterior surgical approach, and one deep surgical site infection (due to dehiscence) after posterior approach. We had 17 (2.13%) patients with some wound complications (secretion 7, dehiscence 4, hematoma 1, edema 3, and liquorrhea 2) that were not classified as SSI according to the CDC guidelines. CONCLUSION: Concerning our study population of patients undergoing elective cervical surgery, with ASA scores 1-2 in 81.68% of our patients, the incidence of SSI was 0.14% after anterior surgical approach, 1.4% after posterior surgical approach, and 0.25% altogether in the referred cohort.

Individualized perioperative management in transoral spine surgery: a single-center cohort study evaluating surgical wound complications and wound infections.

BACKGROUND: Transoral spine surgery is specific due to both its surgical approach and the spectrum of diseases it targets. Patients with high age and elevated clinical frailty scores are often involved, and there are reports of increased risks of surgical site infection (SSI) due to extended exposures requiring maxilotomy or mandibulotomy. Our case series describes surgical wound complications under the meticulous application of individualized perioperative multimodal management. METHODS: Our primary outcome was the occurrence of SSI and the secondary outcome was the occurrence of other noninfectious wound complications evaluated in 22 adult patients who consecutively underwent the transoral spine surgery from 2001 to 2018 (trauma - C2, cervical nonunion: 6 patients, 27%; tumor: 4 patients, 18%; osteomyelitis: 6 patients, 27%; other non-traumatic cases: 6 patients, 27%). Structuralized data comprising parameters related to nosocomial infections after spine surgery were continuously processed and put into specialized database of preventive multimodal nosocomial infection control protocol that was used as a main source of analyzed parameters. The mean age of studied cohort was 54.9 [Formula: see text] 15.5 years, with 68% males, mean body mass index (BMI) 24.9 [Formula: see text] 5.22, and the mean clinical frailty score was 2.59 [Formula: see text] 1.07. There were 7 patients (32%) who only had the transoral approach and 15 patients (68%) having this approach followed by additional posterior approach. We observed SSI from all wound complications for up to one year after surgery. RESULTS: There were 4 (18%) superficial wound complications from transoral approach, but none of them were infected. We had 2 patients (13%) with deep wound infections after subsequent posterior approach, but only one (4.5%) was classified as SSI. CONCLUSIONS: We describe the wound complications and the incidence of SSI in a series of 22 patients after the transoral surgery. Considering the average values of the clinical frailty score reaching 2.59, American Society of Anesthesiologists score of 2.73, and the BMI of 26.87, the transoral spine surgery did not seem to be a considerable risk for SSI in the analyzed cohort, provided preventive perioperative multimodal management is properly individualized and followed.

Risk factors associated with surgical site infections after thoracic or lumbar surgery: a 6-year single centre prospective cohort study.

BACKGROUND: Surgical site infection (SSI) is a risk in every operation. Infections negatively impact patient morbidity and mortality and increase financial demands. The aim of this study was to analyse SSI and its risk factors in patients after thoracic or lumbar spine surgery. METHODS: A six-year single-centre prospective observational cohort study monitored the incidence of SSI in 274 patients who received planned thoracic or lumbar spinal surgery for degenerative disease, trauma, or tumour. They were monitored for up to 30 days postoperatively and again after 1 year. All patients received short antibiotic prophylaxis and stayed in the eight-bed neurointensive care unit (NICU) during the immediate postoperative period. Risk factors for SSI were sought using multivariate logistic regression analysis. RESULTS: We recorded 22 incidences of SSI (8.03%; superficial 5.84%, deep 1.82%, and organ 0.36%). Comparing patients with and without SSI, there were no differences in age (p=0.374), gender (p=0.545), body mass index (p=0.878), spine diagnosis (p=0.745), number of vertebrae (p=0.786), spine localization (p=0.808), implant use (p=0.428), American Society of Anesthesiologists (ASA) Score (p=0.752), urine catheterization (p=0.423), drainage (p=0.498), corticosteroid use (p=0.409), transfusion (p=0.262), ulcer prophylaxis (p=0.409) and diabetes mellitus (p=0.811). The SSI group had longer NICU stays (p=0.043) and more non-infectious hospital wound complications (p<0.001). SSI risk factors according to our multivariate logistic regression analysis were hospital wound complications (OR 20.40, 95% CI 7.32-56.85, p<0.001) and warm season (OR 2.92, 95% CI 1.03-8.27, p=0.044). CONCLUSIONS: Contrary to the prevailing literature, our study did not identify corticosteroids, diabetes mellitus, or transfusions as risk factors for the development of SSI. Only wound complications and warm seasons were significantly associated with SSI development according to our multivariate regression analysis.

The role of vitamin D in primary and secondary prevention in orthopaedic patients.

The article discusses the effect of vitamin D on primary and secondary prevention of fractures and its effect on conditions after selected orthopaedic procedures. Fractures can be divided into traumatic, fatigue and pathological according to the cause. One of the complications of fracture is the formation of a nonunion. In addition to dealing with fractures, a total joint replacement is another common procedure in orthopaedic surgery. Because insufficient muscle strength can increase the risk of falls and thus result in a fracture, these topics are also mentioned in this article. Due to the impact of vitamin D deficiency on various musculoskeletal disorders, orthopaedic surgeons should pay more attention to the patients vitamin D status and be familiar with different strategies for preventing hypovitaminosis D, although clear evidence-based medical recommendations are still insufficient.

Vitamin D for prevention of sternotomy healing complications: REINFORCE-D trial.

BACKGROUND: Most cardiac surgery patients undergo median sternotomy during open heart surgery. Sternotomy healing is an arduous, very complex, and multifactorial process dependent on many independent factors affecting the sternum and the surrounding soft tissues. Complication rates for median sternotomy range from 0.5 to 5%; however, mortality rates from complications are very variable at 7-80%. Low calcidiol concentration below 80 nmol/L results in calcium absorptive impairment and carries a risk of bone loss, which is considered as a risk factor in the sternotomy healing process. The primary objective of this clinical trial is to compare the incidence of all postoperative sternotomy healing complications in two parallel patient groups administered cholecalciferol or placebo. The secondary objectives are focused on general patient recovery process: sternal bone healing grade at the end of the trial, length of hospitalization, number of days spent in the ICU, number of days spent on mechanical lung ventilation, and number of hospital readmissions for sternotomy complications. METHODS: This clinical trial is conducted as monocentric, randomized, double-blind, placebo-controlled, with planned enrollment of 600 patients over 4 years, approximately 300 in the placebo arm and 300 in the treatment arm. Males and females from 18 to 95 years of age who fulfill the indication criteria for undergoing cardiac surgery with median sternotomy can be included in this clinical trial, if they meet the eligibility criteria. DISCUSSION: REINFORCE-D is the first monocentric trial dividing patients into groups based on serum calcidiol levels, and with dosing based on serum calcidiol levels. This trial may help to open up a wider range of postoperative healing issues. TRIAL REGISTRATION: EU Clinical Trials Register, EUDRA CT No: 2016-002606-39 . Registered on September 8, 2016.

Azithromycin added to hydroxychloroquine for patients admitted to intensive care due to coronavirus disease 2019 (COVID-19)-protocol of randomised controlled trial AZIQUINE-ICU.

BACKGROUND: Novel coronavirus SARS-CoV-2 is known to be susceptible in vitro to exposure to hydroxychloroquine and its effect has been found to be potentiated by azithromycin. We hypothesise that early administration of hydroxychloroquine alone or in combination with azithromycin can prevent respiratory deterioration in patients admitted to intensive care due to rapidly progressive COVID-19 infection. METHODS: Design: Prospective, multi-centre, double-blind, randomised, controlled trial (RCT). PARTICIPANTS: Adult (> 18 years) within 24 h of admission to the intensive care unit with proven or suspected COVID-19 infection, whether or not mechanically ventilated. Exclusion criteria include duration symptoms of febrile disease for ≥ 1 week, treatment limitations in place or moribund patients, allergy or intolerance of any study treatment, and pregnancy. INTERVENTIONS: Patients will be randomised in 1:1:1 ratio to receive Hydroxychloroquine 800 mg orally in two doses followed by 400 mg daily in two doses and azithromycin 500 mg orally in one dose followed by 250 mg in one dose for a total of 5 days (HC-A group) or hydroxychloroquine + placebo (HC group) or placebo + placebo (C-group) in addition to the best standard of care, which may evolve during the trial period but will not differ between groups. Primary outcome is the composite percentage of patients alive and not on end-of-life pathway who are free of mechanical ventilation at day 14. SECONDARY OUTCOMES: The percentage of patients who were prevented from needing intubation until day 14, ICU length of stay, and mortality (in hospital) at day 28 and 90. DISCUSSION: Although both investigational drugs are often administered off label to patients with severe COVID-19, at present, there is no data from RCTs on their safety and efficacy. In vitro and observational trial suggests their potential to limit viral replication and the damage to lungs as the most common reason for ICU admission. Therefore, patients most likely to benefit from the treatment are those with severe but early disease. This trial is designed and powered to investigate whether the treatment in this cohort of patients leads to improved clinical patient-centred outcomes, such as mechanical ventilation-free survival. TRIAL REGISTRATION: Clinical trials.gov: NCT04339816 (Registered on 9 April 2020, amended on 22 June 2020); Eudra CT number: 2020-001456-18 (Registered on 29 March 2020).

Pharmacokinetic aspects of beta-lactam antibiotic therapy in intensive care unit patients: A one-center experience with TDM.

Early and appropriate antibiotic therapy remains the key intervention for successful treatment of infection in critically ill patients, particularly in the current era of increasing antibiotic resistance. Optimization of the antimicrobial dosing regimens to achieve therapeutic plasma concentrations and concentrations at the site of infection is crucial for maximizing the therapeutic response and minimizing the risk of organ toxicity and is also an important tool to avoid the resistance emergence. Beta-lactam antibiotics have been considered relatively safe and, as opposed to aminoglycosides, therapeutic drug monitoring as a tool conventionally used primarily to minimize toxicity in drugs with narrow therapeutic window or complex pharmacokinetics, has not been provided routinely yet. However, emerging data suggest that optimal antibiotic exposure may not be achieved with traditional dosing strategies in a significant number of critically ill patients and, on the contrary, concerns about insufficient plasma concentrations leading to microbiological and clinical failure are warranted. The treatment of infections in the intensive care unit (ICU) patients is often challenging because of disease complexity, pathophysiologic alterations they undergo and reduced susceptibility of nosocomial pathogens. Therefore, it is of paramount importance to update current recommendations on dosing of beta-lactam antibiotics in severe infections and therapeutic drug monitoring may be regarded as the only exact method to ensure pharmacodynamics target achievement. Na Homolce Hospital is one of the first medical institutions in the Czech Republic where the practice of routine TDM of beta-lactam antibiotics in ICU-patients has been established. In this paper, we introduce our experience and first case reports.

Kinetic characteristics of propofol-induced inhibition of electron-transfer chain and fatty acid oxidation in human and rodent skeletal and cardiac muscles.

INTRODUCTION: Propofol causes a profound inhibition of fatty acid oxidation and reduces spare electron transfer chain capacity in a range of human and rodent cells and tissues-a feature that might be related to the pathogenesis of Propofol Infusion Syndrome. We aimed to explore the mechanism of propofol-induced alteration of bioenergetic pathways by describing its kinetic characteristics. METHODS: We obtained samples of skeletal and cardiac muscle from Wistar rat (n = 3) and human subjects: vastus lateralis from hip surgery patients (n = 11) and myocardium from brain-dead organ donors (n = 10). We assessed mitochondrial functional indices using standard SUIT protocol and high resolution respirometry in fresh tissue homogenates with or without short-term exposure to a range of propofol concentration (2.5-100 µg/ml). After finding concentrations of propofol causing partial inhibition of a particular pathways, we used that concentration to construct kinetic curves by plotting oxygen flux against substrate concentration during its stepwise titration in the presence or absence of propofol. By spectrophotometry we also measured the influence of the same propofol concentrations on the activity of isolated respiratory complexes. RESULTS: We found that human muscle and cardiac tissues are more sensitive to propofol-mediated inhibition of bioenergetic pathways than rat's tissue. In human homogenates, palmitoyl carnitine-driven respiration was inhibited at much lower concentrations of propofol than that required for a reduction of electron transfer chain capacity, suggesting FAO inhibition mechanism different from downstream limitation or carnitine-palmitoyl transferase-1 inhibition. Inhibition of Complex I was characterised by more marked reduction of Vmax, in keeping with non-competitive nature of the inhibition and the pattern was similar to the inhibition of Complex II or electron transfer chain capacity. There was neither inhibition of Complex IV nor increased leak through inner mitochondrial membrane with up to 100 µg/ml of propofol. If measured in isolation by spectrophotometry, propofol 10 µg/ml did not affect the activity of any respiratory complexes. CONCLUSION: In human skeletal and heart muscle homogenates, propofol in concentrations that are achieved in propofol-anaesthetized patients, causes a direct inhibition of fatty acid oxidation, in addition to inhibiting flux of electrons through inner mitochondrial membrane. The inhibition is more marked in human as compared to rodent tissues.

[Optimal way of administration of high dose intravenous furosemide - continuous infusion or bolus?]. / Optimální zpusob podání vysokodávkového i.v. furosemidu - kontinuálne nebo bolusove?

INTRODUCTION: Furosemide is a loop diuretic used in states of volume overload. The need for high doses is due to its reduced efficacy caused by lower concentration of furosemide achieved at the site of action in the renal tubule lumen and adaptation mechanisms. High doses have been associated with the development of ionic dysbalance, direct toxicity and intravascular volume fluctuations. The way of furosemide administration (intermitent versus continuously) to influence efficacy and safety is contradictory evaluated in EBM. AIM: The aim of this study is to analyze the available data for evaluation of the efficacy and safety of intermittent versus continuous dose regimens. METHODS: A systematic search on PubMed from 1990 to 2013 using the keywords - furosemide, loop diuretic, bolus, continuous infusion, efficacy, safety, heart failure, ICU, critical care. CONCLUSION: The pharmacokinetic and pharmacodynamic knowledge of furosemide create a theoretical assumption for the preference of continuous infusions before intermittent boluses. Assessement of available studies, however, yet in clinical practice did not proof the advantage of one over the other route of administration.

NT-proBNP and BNP values in cardiac patients with different degree of left ventricular systolic dysfunction.

We investigated the performance of brain natriuretic peptides (BNP and NT-proBNP) in detecting various degrees of left ventricular systolic dysfunction. The NT-proBNP assay (Roche) and the BNP assay (Bayer Shionoria) were performed in 46 patients (mean age 50 years; range 20-79 years) with various types of heart disease (chronic heart failure due to coronary artery disease, cardiomyopathy, acquired valve disease, congenital heart diseases) and different impairment of left ventricular systolic dysfunction was assessed by echocardiography. Patients were divided into four groups according to the left ventricular ejection fraction (LVEF) correlated with clinical severity. Significant differences in medians of NT-proBNP and BNP values between all groups were determined (P= 0.0161 for NT-proBNP and P=0.0180 for BNP). For identifying patients with severe systolic dysfunction (LVEF<40%), receiver operating characteristic (ROC) analysis for both BNP and NT-proBNP was performed. The diagnostic performances expressed as areas under the curve were of 0.69 for NT-proBNP (cut off value 367 pg/ml) and 0.60 for BNP (cut off value 172 pg/ml). However, the BNP showed higher sensitivity (85 % vs. 63 %) and a higher positive predictive value (69 % vs 55 %) than the NT-proBNP. The negative predictive values of BNP and NT-proBNP were similar (70 % and 71 % respectively). Brain natriuretic peptides are promising markers for the diagnosis of severe left ventricular systolic dysfunction.

The relevance of brain natriuretic peptides investigation in various cardiovascular diseases.

BACKGROUND: Brain natriuretic peptides are relevant markers of heart impairment. AIM: We investigated the relevance of investiging brain natriuretic peptides (NT-proBNP, BNP) in monitoring different types of cardiovascular disease (chronic heart failure due to coronary artery disease, cardiomyopathy, acquired valve disease, congenital heart diseases). METHODS: The NT-proBNP assay (Roche) was performed on 280 patients (mean age 49 years; range 20-89 years) and 48 healthy controls (mean age 43 years; range 13-65 years) and BNP assay (Bayer Shionoria) was performed in a subgroup of 42 patients (mean age 50 years; range 20-79 years). Patients were divided into four groups characterized by severity of heart failure according to the New York Heart Association classification. RESULTS: NT-proBNP concentrations differed in patients with cardiovascular diseases from controls (median 371 ng/l versus 41.5 ng/l, p < 0.0001). The cut off value of NT-proBNP determined in 280 patients with cardiovascular diseases was at 130 ng/l (AUC-area under curve = 0.93; sensitivity 98 %; specificity 79 %). Comparison of NT-proBNP and BNP values in patients showed significant correlation (r = 0.93; p < 0.0001). NT-proBNP showed significant differences between groups. CONCLUSIONS: Measurement of brain natriuretic peptides is useful and relevant in various types of heart diseases including congenital.