Loading Dose Group Research Articles

Evaluation of preprocedural statin loading on clinical outcomes in patients undergoing elective percutaneous coronary intervention.

High-dose statin therapy before percutaneous coronary intervention (PCI) is thought to reduce the occurrence of Peri-procedural Myocardial Infarction (PPMI), which is associated with increased mortality and prolonged hospitalization, especially in statin naïve patients. This study aims to investigate the effect of rosuvastatin loading dose on PPMI and major adverse cardiac and cerebrovascular events (MACCE) in patients undergoing elective PCI, considering their statin use. One hundred sixty-five patients with stable coronary artery disease (CAD) without heart failure (HF) or chronic kidney disease (CKD) were included in the study. They were divided into two groups: patients already on statin treatment (n:126) and statin naive patients (n:39). Both groups were randomly assigned to high-dose (40 mg) rosuvastatin (n:86) or a non- loading dose group (n:79). The primary endpoint was the incidence of PPMI, and the secondary endpoint was MACCE. The mean age of study population was 59 ± 9.4 years with 77% being male (n = 127). The median follow-up (FU) time was 368 day. Thirty patients were diagnosed with PPMI after PCI (19 in the high-dose group and 11 in the no-loading-dose group). Meanwhile, less than half of study population (77 patients, 46.7%) had complex lesion type (B2, C) and 88 of those (53.3%) had simple lesion type (A, B1). PPMI was observed more frequently in statin-naive patients (23%) than in statin users (17%), although the difference was not statistically significant. Only two patients (1.2%) experienced MACCE during the FU period. One of these patients, who had a type C lesion, belonged to group A2 and underwent Target Vessel Revascularization (TVR) on the 391st day. The other patient, with a type B1 lesion, was in group A1 and was hospitalized due to Acute Coronary Syndrome (ACS) on the 40th day of FU. Pre-procedural administration of high dose rosuvastatin in patients with stable coronary artery disease did not decrease PPMI, independent of chronic statin use.

A Retrospective Study Evaluating Neonatal Vancomycin Loading Doses to Achieve a Therapeutic Target

Background: Vancomycin is a glycopeptide antibiotic that has been used to treat hospital-acquired gram-positive infections for more than 5 decades. However, the literature is divided regarding the therapeutic advantages of vancomycin loading doses in neonates. Objectives: This study aimed to investigate the effect of vancomycin loading doses on therapeutic target attainment in neonates with sepsis. Methods: A retrospective cohort study was conducted to compare the vancomycin target attainment (area under the curve 0–24 hours/minimum inhibitory concentration ≥400) in neonates before and after the 2019 change in vancomycin prescription guidelines at a neonatal unit in Cape Town, South Africa. As the standard of care, Bayesian modelling software was used to compute the area under the curve from the trough concentrations. Results: Two hundred ten neonates were included. Multivariate regression analysis showed a 2-fold increase in the odds of target attainment among neonates receiving a loading dose of vancomycin. Early target attainment (within 8–12 hours of treatment initiation) was significantly higher in the loading dose group compared with the no loading dose group [97/105 (92.4%) versus 64/105 (61.0%); P < 0.001]. However, the overall proportion of neonates achieving target attainment at 24 hours was similar between groups [73/105 (69.5%) in the loading dose group versus 62/105 (59.0%) in the no loading dose group; P = 0.110]. The nephrotoxicity rates were low [2/105 (1.9%) in the loading dose group and 2/105 (1.9%) in the no loading dose group]. Conclusions: The addition of a vancomycin loading dose to neonates may facilitate early therapeutic target attainment.

Two-Year Results of 0.01% Atropine Eye Drops and 0.1% Loading Dose for Myopia Progression Reduction in Danish Children: A Placebo-Controlled, Randomized Clinical Trial.

We investigated the two-year safety and efficacy of 0.1% loading dose and 0.01% low-dose atropine eye drops in Danish children for reduction in myopia progression in an investigator-initiated, placebo-controlled, double-masked, randomized clinical trial. Ninety-seven six- to twelve-year old myopic participants were randomized to 0.1% loading dose for six months and then 0.01% for eighteen months (loading dose group, N = 33), 0.01% for two years (0.01% group, N = 32) or placebo for two years (placebo, N = 32). Axial length (AL) and spherical equivalent refraction (SER) were primary outcomes. Secondary outcomes included adverse events and reactions, choroidal thickness, and other ocular biometrical measures. Outcomes were measured from baseline and at six-month intervals. Individual eyes nested by participant ID were analyzed with linear-mixed model analysis. Data were analyzed with intention-to-treat. Mean AL was 0.08 mm less (95% confidence interval (CI): -0.01; 0.17, p-value = 0.08) in the 0.1% loading dose and 0.10 mm less (95% CI: 0.01; 0.19, p-value = 0.02) in the 0.01% group after two years of treatment compared to placebo. Mean SER progression was 0.12 D (95% CI: -0.10; 0.33) less in the loading dose and 0.26 D (95% CI: 0.04; 0.48) less in the 0.01% groups after two years of treatment compared to placebo (p-value = 0.30 and 0.02, respectively). In total, 17 adverse events were reported in the second-year follow-up, and all were rated as mild. Adjusting for iris color did not affect treatment effect estimates. Intra-ocular pressure increased over two years comparably between all groups but remained within normal limits. Two-year treatment with 0.01% low-dose atropine eye drops is a safe and moderately efficacious intervention in Danish children for reducing myopia progression.

Safety and efficacy of 0.01% and 0.1% low-dose atropine eye drop regimens for reduction of myopia progression in Danish children: a randomized clinical trial examining one-year effect and safety

BackgroundTo investigate the efficacy and safety of 0.1% and 0.01% low-dose atropine eye drops in reducing myopia progression in Danish children.MethodsInvestigator-initiated, placebo-controlled, double-masked, randomized clinical trial. Ninety-seven six- to twelve-year old myopic participants were randomized to 0.1% loading dose for six months followed by 0.01% for six months (loading dose group, Number (N) = 33), 0.01% for twelve months (0.01% group, N = 32) or vehicle for twelve months (placebo, N = 32). Primary outcomes were axial length and spherical equivalent refraction. Secondary outcomes included adverse events and reactions, choroidal thickness and ocular biometry. Outcomes were measured at baseline and three-month intervals. Data was analyzed with linear-mixed model analysis according to intention-to-treat.ResultsMean axial elongation was 0.10 mm less (95% confidence interval (CI): 0.17; 0.02, adjusted-p = 0.06) in the 0.1% loading dose and 0.07 mm less (95% CI: 0.15; 0.00, adjusted-p = 0.16) in the 0.01% group at twelve months compared to placebo. Mean spherical equivalent refraction progression was 0.24 D (95% CI: 0.05; 0.42) less in the loading dose and 0.19 D (95% CI: 0.00; 0.38) less in the 0.01% groups at twelve months, compared to placebo (adjusted-p = 0.06 and 0.14, respectively). A total of 108 adverse events were reported during the initial six-month loading dose period, primarily in the loading dose group, and 14 were reported in the six months following dose switching, all deemed mild except two serious adverse events, unrelated to the intervention.ConclusionsLow-dose atropine eye drops are safe over twelve months in otherwise healthy children. There may be a modest but clinically relevant reduction in myopia progression in Danish children after twelve months treatment, but the effect was statistically non-significant after multiple comparisons adjustment. After dose-switching at six months the loading dose group approached the 0.01% group, potentially indicating an early “rebound-effect”.Trial registrationthis study was registered in the European Clinical Trials Database (EudraCT, number: 2018-001286-16) 05/11/2018 and first posted at www.clinicaltrials.gov (NCT03911271) 11/04/2019, prior to initiation.

Impact of antimicrobial stewardship program-driven educational intervention for vancomycin loading dose on mortality

BackgroundAlthough the loading dose (LD) of vancomycin (VCM) contributes to its efficacy, it may not be conducted adequately. Herein, the objective was to evaluate the effect of LD on patient prognosis using therapeutic drug monitoring by pharmacists and elucidate the impact of an antimicrobial stewardship program (ASP)-driven educational intervention on the LD implementation rate and patient prognosis. Materials and methodsFirst, a retrospective cohort study was conducted involving 121 adult patients administered with VCM and compared with 28-day mortality in LD and non-LD groups. To avoid confounding, the propensity score method was employed. Second, post-training with ASP-driven lectures, a questionnaire survey was conducted for healthcare workers, including physicians, nurses, and pharmacists. The rates of VCM LD implementation and 28-day mortality were compared during a period of one year and 9 months between the pre-ASP (n = 38) and post-ASP (n = 33) groups. ResultsAfter propensity score matching, the 28-day mortality in the LD group was significantly improved, suggesting that the early increase in blood levels of VCM due to an LD is an important factor influencing patient prognosis. After the lecture, a questionnaire survey revealed that the understanding rates of "well" and "slightly well" for educational lectures exceeded 80% of all healthcare workers. The rate of LD implementation significantly increased to 63.6% (21/33) in the post-ASP group compared with 31.6% (12/38) in the pre-ASP group (p = 0.007), and the 28-day mortality declined from 23.7% (9/38) to 6.1% (2/33) (p = 0.041). ConclusionThis method of ASP-driven educational intervention would facilitate LD implementation, improving patient prognosis.

Heparin Loading Dose in Patients Undergoing Extracorporeal Cardiopulmonary Resuscitation

To study the differences in hemorrhagic and embolic complications among extracorporeal cardiopulmonary resuscitation (ECPR) patients who received and did not receive a loading dose of heparin. This study is a controlled before-after monocentric retrospective study. The emergency department of the Aerospace Center Hospital (ASCH). The authors studied a total of 28 patients who, after a cardiac arrest, underwent ECPR in the emergency department of the ASCH from January 2018 to May 2022. The authors compared the hemorrhagic and embolic complications and prognosis of the 2 groups based on whether they received a loading dose of heparin anticoagulation therapy before catheterization (a loading-dose group and a non-loading dose- group). There were 12 patients in the loading-dose group and 16 in the nonloading-dose group. There was no statistically significant difference in age, sex, underlying diseases, causes of cardiac arrest, and hypoperfusion time between the 2 groups. The incidence of hemorrhagic complications was 75% in the loading-dose group and 67.5% in the nonloading-dose group. The difference between the 2 groups was not statistically significant (p > 0.05). The incidence of life-threatening massive hemorrhage in the loading-dose group was 50%, and in the nonloading-dose group, it was 12.5%. The difference between the 2 groups was statistically significant (p=0.03). The incidence of embolic complications in the loading-dose group and nonloading-dose group was 8.3% and 12.5%, respectively, and the difference between the 2 groups was not statistically significant (p > 0.05). The survival rates of the 2 groups were 8.3% v 18.8%, respectively, and the difference between the 2 groups was not statistically significant (p > 0.05). In conclusion, in the authors' study of patients undergoing ECPR, administering a loading dose of heparin was associated with an increased risk of early fatal hemorrhage. However, stopping this loading dose did not raise the risk of embolic complications. It also did not lower the risk of total hemorrhage and transfusion.

Investigation of Effect of the Colistin Loading Dosage on the clinical, Microbiological, and Laboratory Results in Acinetobacter baumannii Ventilator-Associated Pneumonia /Pneumonia.

Materials and Methods Adult patients administered colistin with and without LD for MDR Acinetobacter baumannii VAP/pneumonia in intensive care units (ICUs) in a tertiary teaching hospital between 1 January 2018 and 31 December 2019 were included in this retrospective cohort study. The primary endpoint was an assessment of clinical and microbiological success between treatment groups. Secondary endpoints included 14- and 30-day mortality and development of nephrotoxicity. Results A total of 101 patients were included (colistin with LD, n = 57; colistin without LD, n = 44). No significant difference in clinical success was observed between groups (73.7% versus 77.3%; p=0.670). In patients receiving colistin with LD, the microbiological success rate increased from 65.9% to 71.9%, but there was no statistically significantly difference (p=0.510). In terms of using combination therapies with carbapeneme and/or tigecycline, there was no significant difference between treatment groups (p=0.30). The rates of 14- and 30-day mortality were similar between groups. The colistin with LD group had a higher rate of nephrotoxicity compared to the other group (52.6% versus 20.5% p=0.001). The clinical and microbiological response times were found significantly higher in the colistin with LD group (p=0.001; p=0.017). Conclusion Colistin with LD was associated with a higher risk of nephrotoxicity and was not related to clinical success, microbiological success, and prolonged survival. Randomized comparative studies are needed to confirm the efficacy of LD colistin regimen on MDR Acinetobacter infection.

The necessity of a loading dose when prescribing intravenous colistin in critically ill patients with CRGNB-associated pneumonia: a multi-center observational study

BackgroundThe importance or necessity of a loading dose when prescribing intravenous colistin has not been well established in clinical practice, and approximate one-third to half of patients with carbapenem-resistant gram-negative bacteria (CRGNB) infection did not receive the administration of a loading dose. The aim of this study is to investigate the efficacy and risk of acute kidney injury when prescribing intravenous colistin for critically ill patients with nosocomial pneumonia caused by CRGNB.MethodsThis was a multicenter, retrospective study that recruited ICU-admitted patients who had CRGNB-associated nosocomial pneumonia and were treated with intravenous colistin. Then, we classified the patients into colistin loading dose (N = 85) and nonloading dose groups (N = 127). After propensity-score matching for important covariates, we compared the mortality rate, clinical outcome and microbiological eradication rates between the groups (N = 67).ResultsThe loading group had higher percentages of patients with favorable clinical outcomes (55.2% and 35.8%, p = 0.037) and microbiological eradication rates (50% and 27.3%, p = 0.042) at day 14 than the nonloading group. The mortality rates at days 7, 14 and 28 and overall in-hospital mortality were not different between the two groups, but the Kaplan–Meier analysis showed that the loading group had a longer survival time than the nonloading group. Furthermore, the loading group had a shorter length of hospital stay than the nonloading group (52 and 60, p = 0.037). Regarding nephrotoxicity, there was no significant difference in the risk of developing acute kidney injury between the groups.ConclusionsThe administration of a loading dose is recommended when prescribing intravenous colistin for critically ill patients with nosocomial pneumonia caused by CRGNB.

High-Dose Vitamin D Supplementation Can Correct Hypovitaminosis D Prior to Total Knee Arthroplasty.

Vitamin D deficiency in the perioperative surgical period is associated with inferior surgical outcomes. There are no established preoperative supplementation regimens in the orthopedic literature. The purpose of this study is to compare the efficacy between 2 different supplementation regimens of vitamin D prior to total knee arthroplasty. We conducted a retrospective analysis of 174 patients identified as vitamin D deficient (25(OH)D < 30 ng/mL) who received one of 2 vitamin D supplementation protocols: (1) daily supplementation with D3 on a sliding scale from 1000 to 6000 IU or (2) a loading dose of 50,000 IU D3 weekly for 4 weeks then 2000 IU/d. Serum vitamin D levels were measured at 3 months and 1 month preoperatively. Mean patient age was 65.5(±8.6) years, and 54.6% were female. Deficiency was corrected in 73.3% of patients in the loading dose group and 42.4% of patients in the daily, low-dose group [χ2 (1, N= 174)= 16.53, P < .001]. Patients in the loading dose group also achieved a greater average correction in vitamin D levels. This is the first study to compare preoperative vitamin D supplementation protocols. A loading dose regimen of 50,000 IU weekly for 4 weeks followed by a maintenance dose of 2000 IU/d more effectively corrects vitamin D deficiency compared to a low-dose, daily regimen among total knee arthroplasty patients. We recommend this regimen for deficiency correction in patients who have been screened to be deficient in vitamin D preoperatively.

Impact of a vancomycin loading dose on the achievement of target vancomycin exposure in the first 24 h and on the accompanying risk of nephrotoxicity in critically ill patients.

BackgroundThe advocated pharmacokinetic/pharmacodynamic (PK/PD) target for vancomycin, AUC/MIC ≥ 400 mg·h/L, may not be reached with a conventional fixed starting dose of 1000 mg in critically ill patients, but increasing the dose may cause nephrotoxicity.ObjectivesTo evaluate the effect of a weight-based loading dose of 25 mg/kg vancomycin on PK/PD target attainment in the first 24 h (AUC0–24) in critically ill patients and to evaluate whether this increases the risk of acute kidney injury (AKI).Patients and methodsA prospective observational before/after study was performed in ICU patients, comparing the percentage of vancomycin courses with AUC0–24 ≥ 400 mg·h/L and the incidence of AKI, defined as worsening of the risk, injury, failure, loss of kidney function and end-stage kidney disease (RIFLE) score. The conventional dose group received 1000 mg of vancomycin as initial dose; the loading dose group received a weight-based loading dose of 25 mg/kg. A population PK model developed using non-linear mixed-effects modelling was used to estimate AUC0–24 in all patients.ResultsOne hundred and four courses from 82 patients were included. With a loading dose, the percentage of courses achieving AUC0–24 ≥ 400 mg·h/L increased significantly from 53.8% to 88.0% (P = 0.0006). The percentage of patients with new-onset AKI was not significantly higher when receiving a 25 mg/kg loading dose (28.6% versus 37.8%; P = 0.48). However, the risk of AKI was significantly higher in patients achieving AUC0–24 > 400 mg·h/L compared with patients achieving AUC < 400 mg·h/L (39.0% versus 14.8%; P = 0.031).ConclusionsA weight-based loading dose of 25 mg/kg vancomycin led to significantly more patients achieving AUC0–24 ≥ 400 mg·h/L without increased risk of AKI. However, some harm cannot be ruled out since higher exposure was associated with increased risk of AKI.

Management of hyperkalemia in chronic heart failure using sodium zirconium cyclosilicate.

BackgroundSodium zirconium cyclosilicate (SZC), a newly‐developed selective potassium binder, has been clinically available to treat hyperkalemia. SZC might be a promising option to manage hyperkalemia, particularly in patients with heart failure, who often require potassium‐sparing medications. However, the optimal initial dose of SZC therapy at a loading dose (30 g per day for the initial 2 days) versus a maintenance dose (5 g per day) remains unknown.MethodsConsecutive patients with heart failure and hyperkalemia who received 2‐day SZC therapy were retrospectively included. Safety and efficacy of SZC therapy were compared between the two strategies (maintenance versus loading).ResultsWe had 16 patients (76 years old, 11 men) who received 2‐day SZC therapy (4 maintenance dose group and 12 loading dose group). Serum potassium decreased 0.7 mEqL/L by 2‐day maintenance dose therapy and 1.3 mEq/L by 2‐day loading dose therapy. Following 2‐day SZC therapy, 25% of patients had hypokalemia, which was defined as serum potassium <4.0 mEq/L. Baseline lower serum potassium level was associated with the post‐SZC hypokalemia.ConclusionsSZC immediately decreases approximately 1.0 mEq/L of serum potassium in patients with heart failure and hyperkalemia. However, caution should be exercised when utilizing SZC at a loading dose specifically in those with mild hyperkalemia to prevent iatrogenic hypokalemia.

Effect of vancomycin loading dose on clinical outcome in critically ill patients with methicillin-resistant Staphylococcus aureus pneumonia.

BackgroundVancomycin is the treatment of choice for serious methicillin-resistant Staphylococcus aureus (MRSA) infections. Current guidelines recommend giving an initial loading dose (LD) of 25–30 mg/kg to rapidly increase the serum concentration. However, high-quality evidence for the clinical benefit of LD is lacking. Herein, we aim to examine the association between vancomycin LD and clinical outcome.MethodsA retrospective cohort study was conducted on adult patients treated for MRSA pneumonia with vancomycin in medical intensive care units from April 2016 to August 2018. MRSA pneumonia was defined by the Centers for Disease Control and National Healthcare Safety Network definition. The primary outcome was the clinical cure of pneumonia. Secondary outcome measures included time to pharmacokinetic (PK) target attainment, microbiological cure, acute kidney injury, and all-cause mortality.ResultsA total of 81 patients were included; of these 22 (27.2%) received LD. The mean initial dose was significantly higher in the LD group. Clinical cure was similar in both groups (68.2% vs. 66.1% in the LD and non-LD groups, respectively; P=0.860). No significant difference was observed in the microbiological cure, all-cause mortality, and incidence of acute kidney injury. Furthermore, no difference was observed in terms of time to PK target attainment (69.2 vs. 63.4 h in the LD and non-LD groups, respectively; P=0.624). Vancomycin minimum inhibitory concentration of <2 mg/L was identified as an independent predictive factor for clinical cure in multivariable analysis, whereas vancomycin LD was not.ConclusionsInitial LD is not associated with better clinical outcome or rapid pharmacological target attainment in critically ill patients with MRSA pneumonia. Further studies are warranted to provide better evidence for this widely recommended practice.

Efficacy and safety of vancomycin loading doses in critically ill patients with methicillin-resistant Staphylococcus aureus infection

Background:While vancomycin loading doses may facilitate earlier pharmacokinetic–pharmacodynamic target attainment, the impact of loading doses on clinical outcomes remains understudied. Critically ill patients are at highest risk of morbidity and mortality from methicillin resistant Staphylococcus aureus (MRSA) infection and hypothesized to most likely benefit from a loading dose. We sought to determine the association between receipt of a vancomycin loading dose and clinical outcomes in a cohort of critically ill adults.Methods:Four hundred and forty-nine critically ill patients with MRSA cultures isolated from blood or respiratory specimens were eligible for the study. Cohorts were established by receipt of a loading dose (⩾20 mg/kg actual body weight) or not. The primary outcome was clinical failure, a composite outcome of death within 30 days of first MRSA culture, blood cultures positive ⩾7 days, white blood cell count up to 5 days from vancomycin initiation, temperature up to 5 days from vancomycin initiation, or substitution (or addition) of another MRSA agent.Results:There was no difference in the percentage of patients experiencing clinical failure between the loading dose and no loading dose groups (74.8% versus 72.8%; p = 0.698). Secondary outcomes were also similar between groups, including mortality and acute kidney injury, as was subgroup analysis based on site of infection. Exploratory analyses, including assessment of loading dose based on quartiles and a multivariable logistic regression model showed no differences.Conclusion:Use of vancomycin loading doses was not associated with improved clinical outcomes in critically ill patients with MRSA infection.

Loading dose and efficacy of continuous or extended infusion of beta-lactams compared with intermittent administration in patients with critical illnesses: A subgroup meta-analysis and meta-regression analysis.

The role of continuous/extended beta-lactam infusions (CEIs) in improving clinical outcomes among critically ill patients remains controversial. Therefore, we aimed to compare the clinical efficacy of CEI versus intermittent administration (IA) of beta-lactams by performing a systematic review and meta-analysis. PubMed, the Cochrane Library and Embase were searched from inception until December 2018 for studies comparing clinical outcomes of CEI versus IA in critically ill patients. The meta-analysis included 18 randomized controlled trials (RCTs) and 13 non-RCTs. For CEI versus IA, the summary relative risk (RR) for overall mortality and clinical cure was 0.82 (95% confidence interval [CI]: 0.72-0.94) and 1.31 (95% CI: 1.15-1.49), respectively. Subgroup and meta-regression analyses of the loading dose revealed a significantly increased clinical cure rate in the loading-dose group (RR: 1.44, 95% CI: 1.22-1.69), which remained significant after adjustments for beta-lactam type, and association between clinical cure and loading dose for clinical cure (RR: 1.47, 95% CI: 1.20-1.80; p=.001). Subgroup analysis of administration type indicated that both groups had low mortality and high clinical cure rates; however, the heterogeneity analysis did not support an association across continuous infusion and extended infusion groups. Subgroup analysis of the Acute Physiology and Chronic Health Evaluation (APACHE) score was conducted; according to APACHE scores≥16, overall mortality and clinical cure significantly differed between CEI and IA. CEIs with loading-dose treatment may significantly improve the clinical outcomes in critically ill sepsis or septic shock patients.

Efficacy and safety of levosimendan in elderly patients with severe heart failure

Objective: To investigate the efficacy and safety of different dosage regimens of levosimendan in elderly patients with severe heart failure. Methods: Thirty-two patients 75 years or older were randomly divided into a loading dose group (16 cases) in which levosimendan was maintained at 0.1 μg·kg(-1)·min(-1) for 24 h after loaded with 6 μg/kg, and a maintenance dose group (16 cases) with same schedule without loading dose. The amino-terminal brain natriuretic peptide (NT-proBNP) before and after treatment was detected. Left ventricular ejection fraction (LVEF), stroke volume (SV), stroke volume index (SVI) by echocardiograph were monitored. Adverse events, the length of stay in ICU and 28-day mortality were recorded. Results: The NT-proBNP level in loading group after treatment was 1 950 (922,6 481)ng/L, which was improved than that before treatment [4 018(2 716,9 637)ng/L, P<0.05]. The result was similar in maintenance group [1 390 (599,3 297)ng/L vs. 4 576 (2 681,10 682)ng/L, P<0.05]. LVEF in loading group before and after treatment was (39.4±8.8) % vs. (48.9±9.2) % respectively, while in maintenance group it was (40.4±8.8) % vs. (48.7±12.0) % (both P<0.05). SV were also improved after treatment in both groups compared with baseline levels (P<0.05). NT-proBNP started to decline on day 3 in the loading group, while on day 7 in the maintenance group. SVI recovered on day 14 in the loading group [ (29.4±6.5) ml/m(2) vs. (27.3±6.7) ml/m(2),P<0.05], while it did not change much in the maintenance group. There was no significant differences as to the length of stay in ICU [ (11.1±4.4) d in loading group vs. (9.6±3.5) d in maintenance group] and 28-day mortality rates were comparable (2/16 in loading group vs. 1/16 in maintenance group) . The adverse events were 7 vs. 2 cases in loading group and maintenance group respectively, which were mild and all alleviated. Conclusion: The application of levosimendan only with maintenance dose improves cardiac function in very elderly patients with severe heart failure. Adverse events are mild and manageable.

Population Pharmacokinetic Model-Based Evaluation of Circadian Variations in Plasma 5-Fluorouracil Concentrations During Long-Term Infusion in Rats: A Comparison With Oral Anticancer Prodrugs

Circadian fluctuations in the plasma concentration of 5-fluorouracil impede the accurate estimation of target therapeutic concentrations in the long-term infusion or oral 5-fluorouracil-based prodrug regimen. We evaluated the circadian patterns of plasma 5-fluorouracil concentrations in rats using population pharmacokinetic model. Rats were divided into 2 groups, and a continuous infusion (50 mg/m2/h) for 48 h was initiated with or without a bolus injection of 60 mg/kg 5-fluorouracil. In the group not administered a loading dose, significant circadian variation of plasma 5-fluorouracil concentration was observed. In contrast, in the loading dose group, this circadian variation disappeared. Additionally, decreased hepatic dihydropyrimidine dehydrogenase activity was observed. Population model analysis revealed that the concentrations of 5-fluorouracil followed a 24-h cosine circadian curve, representing an overall 1.8-fold increase from a nadir to a peak, with a relative amplitude (% of mesor) of 28%. The circadian 5-fluorouracil clearance pattern in the infusion-regimen was consistent with previously reported pattern for capecitabine and uracil-tegafur. In the recently modified regimen omitting the bolus injection of 5-fluorouracil, the circadian variations should be considered for blood sampling time points in therapeutic drug monitoring. The chronomodulated chemotherapy using oral prodrug administration could be established based on accumulating evidence in the infusion-regimen.

Relationship Status between Vancomycin Loading Dose and Treatment Failure in Patients with MRSA Bacteremia: It's Complicated.

IntroductionA one-time vancomycin loading dose of 25–30 mg/kg is recommended in the current iteration of the vancomycin consensus guidelines in order to more rapidly achieve target serum concentrations and hasten clinical improvement. However, there are few clinical data to support this practice, and the extents of its benefits are largely unknown.MethodsA multicenter, retrospective, cohort study was performed to assess the impact of a vancomycin loading dose (≥ 20 mg/kg) on clinical outcomes and rates of nephrotoxicity in patients with methicillin-resistant Staphylococcus aureus (MRSA) bacteremia. The study matched patients in a 1:1 fashion based on age, Pitt bacteremia score, and bacteremia source. The primary outcome was composite treatment failure (30-day mortality, bacteremia duration ≥ 7 days after vancomycin initiation, persistent signs and symptoms of infection ≥ 7 days after vancomycin initiation, or switch to an alternative antimicrobial agent). Secondary outcomes included duration of bacteremia, length of stay post-bacteremia onset, and nephrotoxicity.ResultsA total of 316 patients with MRSA bacteremia were included. Median first doses in the loading dose and non-loading dose groups were 23.0 mg/kg and 14.3 mg/kg, respectively (P < 0.001). No difference was found in composite failure rates between the non-loading dose and loading dose groups (40.5% vs. 36.7%; P = 0.488) or in the incidence of nephrotoxicity (12.7% vs. 16.5%; P = 0.347). While multivariable regression modeling showed receipt of a vancomycin loading dose on a mg/kg basis was not significantly associated with composite failure [aOR 0.612, 95% CI (0.368–1.019)]; post hoc analyses demonstrated that initial doses ≥ 1750 mg were independently protective against failure [aOR 0.506, 95% CI (0.284–0.902)] without increasing the risk for nephrotoxicity [aOR 0.909, 95% CI (0.432–1.911)].ConclusionThese findings suggest that initial vancomycin doses above a certain threshold may decrease clinical failures without increasing toxicity and that weight-based dosing might not be the optimal strategy.Electronic supplementary materialThe online version of this article (10.1007/s40121-019-00268-3) contains supplementary material, which is available to authorized users.

The clinical efficacy and safety of vancomycin loading dose: A systematic review and meta-analysis.

Background:The clinical significance of using vancomycin loading dose remains controversial. A systematic review and meta-analysis were performed to assess the clinical efficacy and safety of vancomycin loading dose in the treatment of infections.Methods:The Pubmed, Embase, Web of Science, and Cochrane Library databases were searched from their inception up to 5 May 2019. Randomized controlled trials (RCTs) and other observational studies were included if they provided clinical outcomes or trough concentrations of vancomycin loading dose (20–30 mg/kg) and conventional-dose (10–20 mg/kg) in the treatment of infections. Achievement of therapeutic concentration (serum trough concentrations of vancomycin reached 15–20 mg/L before the second dose), clinical response (clinical improvement or culture-negative), nephrotoxicity (serum creatinine increase ≥0.5 mg/dL or ≥50% increasing from the baseline), other adverse events (including pruritus, flushing, rash, and/or red man syndrome), and mortality were analyzed. Heterogeneity was identified using the Cochrane I2 statistic, and P-value <.10 or I2-values >50% indicated significant heterogeneity. Pooled estimates of the intervention effects were determined by the odds ratios (ORs) and 95% confidence intervals (CIs) in Review Manager program, version 5.3.5.Results:Two RCTs and 7 cohort studies including 2816 infected patients were selected for the analysis, in which serum trough concentrations of vancomycin following the use of vancomycin loading dose or other outcomes were available. Loading dose group had a significantly higher compliance rate of serum trough concentration of 15 to 20 mg/L (OR = 3.06; 95% CI = 1.15–8.15; P = .03) and significantly lower incidence of nephrotoxicity (OR = 0.59, 95% CI = 0.40–0.87; P = .008; I2 = 29%) compared with control group. No significant difference was noted between loading dose group and control group in terms of other adverse events and clinical response (OR = 1.98, 95% CI = 0.80–4.93; P = .14; I2 = 0%). The use of vancomycin loading doses in patients can indeed increase the achievement of therapeutic concentration.Conclusion:Vancomycin loading dose increases the achievement of therapeutic concentration without bringing extra risk of nephrotoxicity. However, well-designed large-scale RCTs remain needed to validate the clinical efficacy of vancomycin loading dose and to further evaluate other adverse reactions and mortality.PROSPERO registration number CRD42018093927

Efficacy and mechanism of loading dose clopidogrel in patients with transient ischemic attack and minor stroke

Objective: To assess outcome, safety and possible mechanism of loading dose clopidogrel in patients with transient ischemic attack (TIA) and minor stroke. Methods: We reviewed patients with confirmed TIA and minor stroke admitted between July 2016 and December 2017 into the First Affiliated Hospital of Soochow University. Loss-of-function allele carriers of CYP2C19 were included and randomly divided into loading dose group (first dose of 300 mg clopidogrel) and standard dose group (first dose of 75 mg clopidogrel), 100 mg aspirin was gave at the same time, followed by aspirin 100 mg/d plus clopidogrel 75 mg/d maintaining for 20 days. Platelet aggregation (maximum aggregation ratio, MAR) induced by Adenosine diphosphate (ADP) was examined before and 3 days after administration. The National Institutes of Health Stroke Scale (NIHSS) score method was employed to assess the NIHSS scores before and after treatment in each group of patients; the modified Rankin Scale (mRS) was used to assess the 3-month functional outcome. Results: There was no significant difference in baseline data between the two groups (P>0.05).The proportion of early neurological function improvement in the two groups was 75.0% and 54.8%, and the difference was statistically significant (χ(2)=4.498, P=0.034). The 3-month prognosis was 79.5% and 61.3%, and the difference was statistically significant (χ(2)=4.000, P=0.045). Adverse events: 1 case in the loading dose group, 1 case in the standard dose group, the difference was not statistically significant (2.3% vs 1.6%, χ(2)=0.061, P=0.806). After 3 days of antiplatelet therapy, the MAR of the loading dose group decreased (11%±8%), and the MAR of the standard dose group decreased (9%±4%), the difference was statistically significant (P=0.013).In the loading dose group, there were 32 (72.7%)CYP2C19*2 carriers and 42 (95.5%)CYP2C19*2+*3 carriers; early neurological function improvement in 33 cases, accounting for 93.8% and 76.2%, respectively, and the difference was statistically significant (χ(2)=4.122, P=0.042). There were 35 patients with good prognosis in 3 months, accounting for 96.9% and 81.0%, respectively. The difference was statistically significant (χ(2)=4.310, P=0.038); MAR of CYP2C19*2 carrier was decreased (15%±5%), and MAR of CYP2C19*2+*3 carrier was decreased (12%±8%). The difference was statistically significant (P=0.039). Conclusions: Loading dose clopidogrel can improve the clinical prognosis of minor stroke/TIA without increasing the risk of bleeding. Loading dose clopidogrel may improve the prognosis of minor stroke/TIA by decreasing MAR of CYP2C19*2 carriers.

Warfarin loading dose guided by pharmacogenetics is effective and safe in cardioembolic stroke patients - a randomized, prospective study.

Warfarin treatment is commonly started with a fixed loading dose that might be associated with an increased risk of bleeding. An individual maintenance dose can then be estimated based on a pharmacogenetic algorithm. Starting treatment with the estimated dose implies a longer time to reach the therapeutic range. Our goal was to compare the safety and efficacy of initiating warfarin treatment with a loading dose guided by pharmacogenetics versus a maintenance dose. The primary endpoint was time in the therapeutic range (TTR) in the first 10 days of treatment. Secondary endpoints were time to the first international normalized ratio (INR) in therapeutic range (2.0-3.0) and occurrence of serious adverse events. Consenting cardioembolic stroke patients were genotyped for CYP2C9 (cytochrome P450 2C9 gene) and VKORC1 (vitamin K epoxide reductase complex, subunit 1 gene) polymorphisms and a maintenance warfarin dose was estimated. Patients were randomized into two groups. The loading dose group (LDG) patients received twice the estimated dose in the first 2 days of treatment. The maintenance dose group (MDG) patients received the estimated dose directly from day one. The TTR in the first 10 days was significantly higher in the LDG than in the MDG (50.5% vs. 38.3%, p = 0.003). The time to the first INR in this range was significantly shorter in the LDG (5.24 vs. 7.3 days). There were no significant differences in the INR above this range or serious adverse events. Warfarin loading dose guided by pharmacogenetics after recent cardioembolic stroke improved the efficacy of warfarin initiation without increasing the risk of adverse events.