Pharmacotherapy最新文献

Critically ill patients with sepsis admitted to the intensive care unit (ICU) often present with or develop renal dysfunction requiring renal replacement therapy (RRT) in addition to antimicrobial therapy. While early and appropriate antimicrobials for sepsis have been associated with an increased probability of survival, adequate dosing is also required in these patients. Adequate dosing of antimicrobials refers to dosing strategies that achieve serum drug levels at the site of infection that are able to provide a microbiological and/or clinical response while avoiding toxicity from excessive antibiotic exposure. Therapeutic drug monitoring (TDM) is the recommended strategy to achieve this goal, however, TDM is not routinely available in all ICUs and for all antimicrobials. In the absence of TDM, clinicians are therefore required to make dosing decisions based on the clinical condition of the patient, the causative organism, the characteristics of RRT, and an understanding of the physicochemical properties of the antimicrobial. Pharmacokinetics (PK) of antimicrobials can be highly variable between critically ill patients and also within the same patient over the course of their ICU stay. The initiation of RRT, which can be in the form of intermittent hemodialysis, continuous, or prolonged intermittent therapy, further complicates the predictability of drug disposition. This variability highlights the need for individualized dosing. This review highlights the practical considerations for the clinician for antimicrobial dosing in critically ill patients receiving RRT.

Delirium occurs in critical illness and is associated with poor clinical outcomes, having a longstanding impact on survivors. Understanding the complexity of delirium in critical illness and its deleterious outcome has expanded since early reports. Delirium is a culmination of predisposing and precipitating risk factors that result in a transition to delirium. Known risks range from advanced age, frailty, medication exposure or withdrawal, sedation depth, and sepsis. Because of its multifactorial nature, different clinical phenotypes, and potential neurobiological causes, a precise approach to reducing delirium in critical illness requires a broad understanding of its complexity. Refinement in the categorization of delirium subtypes or phenotypes (i.e., psychomotor classifications) requires attention. Recent advances in the association of clinical phenotypes with clinical outcomes expand our understanding and highlight potentially modifiable targets. Several delirium biomarkers in critical care have been examined, with disrupted functional connectivity being precise in detecting delirium. Recent advances reinforce delirium as an acute, and partially modifiable, brain dysfunction, and place emphasis on the importance of mechanistic pathways including cholinergic activity and glucose metabolism. Pharmacologic agents have been assessed in randomized controlled prevention and treatment trials, with a disappointing lack of efficacy. Antipsychotics remain widely used after "negative" trials, yet may have a role in specific subtypes. However, antipsychotics do not appear to improve clinical outcomes. Alpha-2 agonists perhaps hold greater potential for current use and future investigation. The role of thiamine appears promising, yet requires evidence. Looking forward, clinical pharmacists should prioritize the mitigation of predisposing and precipitating risk factors as able. Future research is needed within individual delirium psychomotor subtypes and clinical phenotypes to identify modifiable targets that hold the potential to improve not only delirium duration and severity, but long-term outcomes including cognitive impairment.

Study objective: In critically ill patients, adequacy of early antibiotic exposure has been incompletely evaluated. This study characterized factors associated with inadequate cefepime exposure in the first 24 h of critical illness.

Design: Prospective cohort study.

Setting: Academic Medical Center.

Patients: Critically ill adults treated with cefepime. Patients with acute kidney injury or treated with kidney replacement therapy or extracorporeal membrane oxygenation were excluded.

Intervention: None.

Measurements: A nonlinear mixed-effects pharmacokinetic (PK) model was developed to estimate cefepime concentrations for each patient over time. The percentage of time the free drug concentration exceeded 8 mg/L during the first 24 h of therapy was calculated (%ƒT>8; appropriate for the susceptible breakpoint for Pseudomonas aeruginosa). Factors predictive of low %ƒT>8 were explored with multivariable regression.

Main results: In the 100 included patients, a one-compartment PK model was developed with first-order elimination with covariates for weight and estimated glomerular filtration rate based on creatinine and cystatin C (eGFRSCr-CysC). The median (interquartile range) %ƒT>8 for cefepime in the first 24 h of therapy based on this model was 85% (66%, 100%). Less than 100% ƒT>8 during first 24 h of therapy occurred in 70 (70%) individuals. Lower Sequential Organ Failure Assessment score (p = 0.032) and higher eGFRSCr-CysC (p < 0.001) predicted a lower %ƒT>8. Central nervous system infection source was protective (i.e., associated with a higher %ƒT>8; p = 0.008).

Conclusions: During early critical illness, cefepime concentrations were inadequate in a significant proportion of patients. Antimicrobial optimization is needed to improve the precision of pharmacotherapy in the critically ill patients.

Anticoagulant therapy is commonly associated with a high incidence of avoidable adverse events, especially in the acute care setting. This has led to several initiatives by key national health care stakeholders, including specific attention to The Joint Commission's National Patient Safety Goals, to improve anticoagulation management. The subject of special populations has long been identified as challenging by clinicians with the use of anticoagulants. This is driven in part by numerous variables that can contribute to hard outcomes such as bleeding, thrombosis, length of stay, hospital re-admission, morbidity, and mortality. Despite the notable effort to improve the use of anticoagulants with numerous clinical trials, guidelines, guidance statements, and other sources of published evidence, notable difficulties continue to challenge practitioners in managing this class of medications. This is especially the case with very diverse critically ill populations where countless variables exist, many of which were never explored in trials or have historically been frequently excluded. Trials evaluating anticoagulation therapy often can only account for small portions of variables that may affect thrombosis and hemostasis, and study methods often do not reflect the constantly changing dynamic conditions seen in unique critically ill patients. Clinicians providing care to the numerous critically ill populations are faced with conditions that lead to relatively small therapeutic windows, which makes designing safe optimal anticoagulation management plans difficult when dealing with complex patients and mechanical support devices. The approach to crafting a successful management plan for anticoagulant therapy must incorporate the numerous variables that are continuously assessed and revised during the patient's time in the intensive care unit. We explore considerations and approaches when developing, assessing, and implementing an individualized or precision-based management plan that involves the use of anticoagulants in the critically ill. The skills and thought process provided will assist clinicians in managing this unique, variable, and challenging population.

Prolonged intermittent renal replacement therapy (PIRRT) is gaining popularity as a renal replacement modality in intensive care units, but there is a relative lack of guidance regarding antimicrobial clearance and dosing when compared with other modalities. The objectives of this systematic review were to: (1) identify and describe the pharmacokinetics (PK) of relevant antimicrobials used in critically ill adults receiving PIRRT, (2) evaluate the quality of evidence supporting these data, and (3) propose dosing recommendations based on the synthesis of these data. A search strategy for multiple databases was designed and executed to identify relevant published evidence describing the PK of antimicrobials used in critically ill adults receiving PIRRT. Quality assessment, evaluation of reporting, and relevant data extraction were conducted in duplicate. Synthesis of PK/pharmacodynamic (PD) outcomes, dosing recommendations from study authors, and physicochemical properties of included antibiotics were assessed by investigators in addition to the quality of evidence to develop dosing recommendations. Thirty-nine studies enrolling 452 patients met criteria for inclusion and provided PK and/or PD data for 20 antimicrobials in critically ill adults receiving PIRRT. Nineteen studies describe both PK and PD outcomes. Vancomycin (12 studies, 171 patients), meropenem (7 studies, 84 patients), and piperacillin/tazobactam (5 studies, 56 patients) were the most frequent antimicrobials encountered. The quality of evidence was deemed strong for 7/20 antimicrobials, and strong dosing recommendations were determined for 9/20 antimicrobials. This systematic review updates and addresses issues of quality in previous systematic reviews on this topic. Despite an overall low quality of evidence, strong recommendations were able to be made for almost half of the identified antimicrobials. Knowledge gaps persist for many antimicrobials, and higher quality studies (i.e., population PK studies with assessment of PD target attainment) are needed to address these gaps.

Objectives: Extracorporeal membrane oxygenation (ECMO) plays an important role in providing temporary life support for patients with severe cardiac or pulmonary failure, but requires strict anticoagulation and monitoring. This network meta-analysis systematically explored the most effective anticoagulation and monitoring strategies for patients receiving ECMO.

Methods: MEDLINE, Embase, Web of Science, and the Cochrane Central Register of Controlled Trials were searched up to January 31, 2023, for studies comparing unfractionated heparin (UFH), argatroban (Arg), bivalirudin (Biv), and/or nafamostat mesylate (NM) in patients receiving ECMO. The primary outcomes included device-related thrombosis, patient-related thrombosis, and major bleeding events. The secondary outcomes included ECMO survival, ECMO duration, and in-hospital mortality.

Results: A total of 2522 patients from 23 trials were included in the study. Biv was associated with a decreased risk of device-related thrombosis (odd ratio [OR] 0.51, 95% confidence interval [CI]: 0.33-0.84) compared with UFH, whereas NM (OR 2.2, 95% CI: 0.24-65.0) and Arg (OR 0.92, 95% CI: 0.43-2.0) did not reduce the risk of device-related thrombosis compared with UFH. Biv was superior to Arg in decreasing the risk of device-related thrombosis (OR 0.14, 95% CI: 0.03-0.51). Biv reduced the risk of patient-related thrombosis compared with UFH (OR 0.44, 95% CI: 0.18-0.85); NM (OR 0.65, 95% CI: 0.14-3.3) and Arg (OR 3.1, 95% CI: 0.94-12.0) did not decrease risk of patient-related thrombosis compared with UFH. No significant difference was observed in the risk of major bleeding between three alternatives and UFH: Biv (OR 0.54, 95% CI: 0.23-1.3), Arg (OR 1.3, 95% CI: 0.34-5.8), and NM (OR 0.60, 95% CI: 0.13-2.6). NM showed a reduced risk of in-hospital mortality compared with UFH (OR 0.27, 95% CI: 0.091-0.77), whereas Arg (OR 0.43, 95% CI: 0.15-1.2) and Biv (OR 0.75, 95% CI: 0.52-1.1) did not decrease risk of in-hospital mortality.

Conclusions: Compared with UFH and Arg, Biv reduces the risk of thrombosis and appears to be a better choice for patients requiring ECMO. NM was associated with a reduced risk of in-hospital mortality.

Aortic valve replacement is a necessary management strategy for patients with severe aortic stenosis. The use of transaortic valve replacement (TAVR) has increased significantly over the last decade and now exceeds traditional surgical aortic valve replacement. Since the valve systems used in TAVR consist of bioprosthetic valve tissue encased in a metal stent frame, antithrombotic therapy recommendations cannot be extrapolated from prior data with differently constructed surgical bioprosthetic or mechanical valves. Data on the use of antithrombotic therapy with TAVR are a rapidly developing area of medicine. Choice of agents depends on several patient factors. Patients undergoing TAVR also have a relatively high incidence of subclinical valve thrombosis. The clinical impact of this phenomenon and the implications for antithrombotic therapy continue to evolve. It is critical for clinicians who treat patients undergoing TAVR to have a firm understanding of practice guidelines, the evolving evidence, and its implications for the use of antithrombotic therapy in these patients.

Lipoprotein(a), or Lp(a), is structurally like low-density lipoprotein (LDL) but differs in that it contains glycoprotein apolipoprotein(a) [apo(a)]. Due to its prothrombotic and proinflammatory properties, Lp(a) is an independent risk factor for atherosclerotic cardiovascular disease (ASCVD) and aortic valve stenosis. Lp(a) levels are genetically determined, and it is estimated that 20%-25% of the global population has an Lp(a) level ≥50 mg/dL (or ≥125 nmol/L). Diet and lifestyle interventions have little to no effect on Lp(a) levels. Lipoprotein apheresis is the only approved treatment for elevated Lp(a) but is time-intensive for the patient and only modestly effective. Pharmacological approaches to reduce Lp(a) levels and its associated risks are of significant interest; however, currently available lipid-lowering therapies have limited effectiveness in reducing Lp(a) levels. Although statins are first-line agents to reduce LDL cholesterol levels, they modestly increase Lp(a) levels and have not been shown to change Lp(a)-mediated ASCVD risk. Alirocumab, evolocumab, and inclisiran reduce Lp(a) levels by 20-25%, yet the clinical implications of this reduction for Lp(a)-mediated ASCVD risk are uncertain. Niacin also lowers Lp(a) levels; however, its effectiveness in mitigating Lp(a)-mediated ASCVD risk remains unclear, and its side effects have limited its utilization. Recommendations for when to screen and how to manage individuals with elevated Lp(a) vary widely between national and international guidelines and scientific statements. Three investigational compounds targeting Lp(a), including small interfering RNA (siRNA) agents (olpasiran, SLN360) and an antisense oligonucleotide (pelacarsen), are in various stages of development. These compounds block the translation of messenger RNA (mRNA) into apo(a), a key structural component of Lp(a), thereby substantially reducing Lp(a) synthesis in the liver. The purpose of this review is to describe current recommendations for screening and managing elevated Lp(a), describe the effects of currently available lipid-lowering therapies on Lp(a) levels, and provide insight into emerging therapies targeting Lp(a).