Evaluation of Individualized Cefepime Dosing Strategy Using Population Pharmacokinetics.

The use of population pharmacokinetics (PK) to optimize cefepime dosing could be an effective strategy, given the increasing prevalence of resistant gram-negative organisms. The objective of this study is to retrospectively compare dosing using a PK approach (intervention) vs traditional dosing (control) for cefepime in patients with hospital-acquired pneumonia (HAP) or ventilator-associated pneumonia (VAP). Adult hospitalized patients with HAP or VAP receiving cefepime for ≥72 hours were screened first from August 2018 to January 2019 to be included in the intervention group, then screened during the preintervention period from August 2017 to July 2018 for the control group. Clinical improvement on day 7 of cefepime therapy was achieved in 72% of the patients in the intervention group and 70% of the patients in the control group (P = .8110). However, the clinical cure rate in the intervention group was higher than that of the control group (50% vs 36.5%; P = .0034). Cefepime dosing using population PK appears to be a novel, effective, and safe dosing strategy for patients with HAP or VAP.

Association of opioid exposure during intensive care unit stays with post-discharge opioid use: A retrospective study and literature review.

OBJECTIVE: To evaluate whether pain management strategies within intensive care unit (ICU) settings contribute to chronic opioid use upon hospital discharge in opioid-naive patients requiring invasive mechanical ventilation. DESIGN: A retrospective, observational study. SETTING: An 18-bed mixed ICU at a community teaching hospital located in Brooklyn, New York. PARTICIPANTS: This study included mechanically ventilated patients requiring continuous opioid infusion from April 25, 2017 to May 16, 2019. Patients were excluded if they received chronic opioid therapy at home or expired during this hospital admission. Eligible patients were identified using an electronic health record data query. MAIN OUTCOME MEASURE(S): The proportion of ICU patients who continued to require opioids upon ICU and hospital discharge. RESULTS: A total of 196 ICU patients were included in this study. Of these, 22 patients were transferred to a regular floor while receiving a fentanyl transdermal patch. However, the fentanyl patch treatment was continued only for three patients (2 percent) at hospital discharge. CONCLUSIONS: This retrospective study suggested that high-dose use of opioids in mechanically ventilated, opioid-naive ICU patients was not associated with continued opioid use upon hospital discharge.

Treatment With Tocilizumab for Patients With COVID-19 Infections: A Case-Series Study.

Tocilizumab (TCZ), a humanized monoclonal antibody targeting the interleukin-6 receptor, holds the potential for treating coronavirus disease 2019 (COVID-19) patients, particularly those at high risk of cytokine storm syndrome. However, data regarding the clinical impact of treatment with TCZ in patients with COVID-19 are limited. This study was conducted to evaluate the safety and effectiveness of TCZ as an adjunct therapy for the treatment of severe COVID-19 infection. This was a retrospective observational chart review of confirmed COVID-19 patients who received TCZ, along with other COVID-19 therapies. The outcomes of interest included changes in vital signs such as temperature and laboratory biomarkers, duration of mechanical ventilation, adverse events possibly associated with TCZ, and intensive care unit and hospital lengths of stay. This study included 38 patients with an average age of 63 years (IQR, 48-70 years). The average dose of TCZ given was 519 ± 61 mg. Median C-reactive protein significantly decreased following TCZ administration (189.9 vs 54.8 mg/L, P = .003). Nineteen of all febrile patients before the initiation of TCZ (73%) became fever free on the fourth day of TCZ treatment. Following TCZ treatment, 11 patients developed infections because of multidrug-resistant bacteria, and elevated liver transaminases were observed in 6 patients. The preliminary findings of this study suggested TCZ appeared to ameliorate COVID-19-related cytokine storm syndrome. However, large randomized, controlled trials are needed to investigate whether treatment with TCZ is associated with better outcomes in COVID-19.

Clinical and economic impact of the use of dexmedetomidine for sedation in the intensive care unit compared to propofol.

Background Despite the advantages of dexmedetomidine (DEX) over propofol (PRO) including minimal respiratory depression and the potential for preventing and/or treating intensive care unit (ICU) delirium, PRO has been the preferred agent due to its lower cost. However, the acquisition cost of DEX has considerably decreased as a generic version of DEX has recently become available. Objective To evaluate clinical and economic outcomes of DEX-based sedation compared to PRO in the ICU. Setting A retrospective cohort study of 86 ICU patients who received either DEX or PRO for a period ≥ 12 h. Method Patients were matched by age, sex, and Sequential Organ Failure Assessment scores in a 1:1 ratio. Main outcome measure Clinical outcomes included the duration of mechanical ventilation (MV), ICU and hospital length of stay (LOS), and requirements of concomitant sedatives and opioids. Economic outcomes included the ICU and hospital costs as well as the cost of sedatives or combined sedatives and opioids per patient. Results There were no significant differences in ICU and hospital LOS and time on MV in both groups (median ICU LOS 7 [DEX] vs. 9 [PRO] days, p = 0.07; median hospital LOS 12 [DEX] vs. 14 [PRO] days, p = 0.261; median time of MV 144 [DEX] vs. 158 [PRO] hours, p = 0.176). DEX-based sedation compared to PRO was associated with similar ICU and hospital costs (US$ 67,561 vs. 78,429, p = 0.39; US$ 71,923 vs. 71,084, p = 0.1). Conclusion The clinical outcomes and economic impact associated with DEX- and PRO-based sedation were similar.

Possible GoLytely-Associated Cardiac Arrest: A Case Report and Literature Review.

PURPOSE: To report a case of sudden cardiac arrest possibly associated with the administration of GoLytely® (polyethylene glycol 3350 and electrolytes). SUMMARY: A 60-year-old male with a history of hypertension, hyperlipidemia, type 2 diabetes, and coronary artery disease presented to the emergency department with complaints of constipation and lower abdominal pain over the past week, and the inability to urinate over the past day. The patient had received GoLytely as treatment to alleviate symptoms of constipation and abdominal pain. However, several hours after administration of the bowel prep solution, the patient suffered an episode of cardiac arrest. After ruling out other possible etiologies, GoLytely was suspected as a possible cause of cardiac arrest. The patient had suffered an anoxic brain injury and remained intubated and unconscious until he eventually expired, 20 days after the event. CONCLUSION: Although GoLytely appears to be a safe agent with fewer side effects, clinicians need to be mindful of potential life-threatening adverse events following GoLytely administration and monitor patients closely during and after administration.

Evaluation of Potential Drug-Drug Interactions With Direct Oral Anticoagulants in a Large Urban Hospital.

OBJECTIVE: The aim of this study is to assess patterns of potential drug-drug interactions (DDIs) with direct oral anticoagulants (DOACs) in an inpatient hospital setting. METHODS: A retrospective chart review was conducted at the Brookdale University Hospital and Medical Center (BUHMC) from January 2014 to November 2016. All adult patients admitted to the BUHMC who were treated with a DOAC for at least 3 days were screened. Among them, those who received selected interacting drugs at any time during the course of DOAC therapy were included in this study. RESULTS: This study included 165 patients with an average of 73 years (standard deviation [SD] = 12.3) and 233 cases. The most commonly used concomitant drug with a DOAC was aspirin (58%), followed by amiodarone (16%) and P2Y12 inhibitors (11%). The combined use of dual antiplatelet therapy and a DOAC was identified in 18 (6%) cases. Approximately one-third of the cases encountered were classified as the "avoidance" category. CONCLUSIONS: Despite computerized DDI alerts, potentially significant DDIs with DOACs still occur. While the present study provides insight into the current patterns of DDIs, further studies are needed to evaluate clinical outcomes of the potential DDIs with DOACs in practice.

What's new in the treatment of multidrug-resistant gram-negative infections?

Eradicating multi-drug resistant (MDR) organisms has been a major challenge in healthcare settings worldwide. Newly approved drugs and those currently in the pipeline may have a promising solution to this issue. The purposes of this review are to describe the various resistance mechanisms of Gram-negative bacteria and to provide a summary of the current literature available on the newer agents, such as ceftazidime/avibactam, ceftolozane/tazobactam, meropenem/vaborbactam, and other emerging agents used for the treatment of MDR Gram-negative infections. Given that MDR organisms confer resistance to treatment by various methods, including enzymatic degradation, efflux pumps, and porin mutation, an understanding of mechanisms of bacterial resistance combined with information on newer antimicrobial agents against MDR Gram-negative bacteria will further assist clinicians in determining the best suitable therapy for the treatment of various complicated infections.

Current Practice Patterns in the Management Of Alcohol Withdrawal Syndrome.

OBJECTIVE: The aim of this study was to examine current practice patterns surrounding the management of alcohol withdrawal syndrome (AWS) in the Northeast region of the United States. METHODS: A survey questionnaire with several treatment options related to current practice in the management of AWS was developed. All hospitals with 100 beds or more located in the Northeast region were selected, and 512 surveys were mailed to pharmacy directors of those hospitals. RESULTS: Responses from 90 hospitals in nine states were included in the analyses. For the treatment of mild, moderate, and severe AWS, most institutions utilized protocols or guidelines (66%, 73%, and 67%, respectively). However, two-thirds of the hospitals indicated that guidelines or protocols were not in place to treat benzodiazepine (BZD)-refractory AWS. A BZD-only treatment strategy was selected as the first choice for mild and moderate AWS (74% and 54%, respectively), whereas a BZD regimen in combination with a variety of other agents, including haloperidol, dexmedetomidine, phenobarbital, or propofol, was frequently used in the treatment of severe and BZD-refractory AWS. CONCLUSION: The findings suggest that considerable heterogeneity exists, particularly in the treatment of severe and BZD-refractory AWS, among hospitals in the Northeast. Given that current guidelines focus mainly on BZD therapy, the results of this survey highlight the need for updated practice guidelines utilizing other treatment strategies.

Effect of Modafinil on Cognitive Function in Intensive Care Unit Patients: A Retrospective Cohort Study.

Modafinil therapy, a nonamphetamine cognition-enhancing agent, holds the potential to improve recovery from cognitive impairment after intensive care unit (ICU) admission. To date, however, there is a paucity of data on modafinil use in the ICU setting. The purpose of this study was to explore the role of modafinil for improvement in cognition in ICU patients. This retrospective cohort study evaluated a total of 60 ICU patients with any ventilatory support who started on modafinil during their ICU stay from January 1, 2010, to March 19, 2016. The requirements of opioids and sedatives, as well as the lowest and average scores of the Glasgow Coma Scale (GCS) and Riker Sedation-Agitation Scale (SAS), were recorded during 48 hours before and after the start of modafinil therapy in 6-hour periods. The average daily modafinil dose of 170 mg was given for a median duration of 9 days. Modafinil administration was associated with a small, nonsignificant increase in GCS by 0.34 points after controlling for age, baseline severity of illness, and changes in sedation and analgesia over time (95%CI, -0.34 to 0.73 points; P = .0743). No major modafinil-associated adverse effects were observed. Modafinil administration did not significantly improve cognitive function in ICU patients within 48 hours of initiation. However, because of lack of robust evidence, the impact of modafinil on overall patient outcomes in the ICU remains unclear and needs further investigation.

Continuous Lidocaine Infusion as Adjunctive Analgesia in Intensive Care Unit Patients.

Despite a paucity of data, the role of intravenous lidocaine (IVLI) as adjunctive analgesia in the intensive care unit (ICU) seems promising due to a low potential to contribute to respiratory depression. A retrospective chart review was conducted to evaluate the safety and effectiveness of IVLI for the treatment of pain in ICU patients with varying degrees of organ dysfunction from March 2014 to March 2016. The primary outcomes included the time to a ≥20% reduction in pain scores after the initiation of IVLI and the difference in opioid requirements as well as pain scores prior to and during IVLI therapy. Other variables included the presence of IVLI-related adverse events and the dosage and duration of IVLI. A total of 21 ICU patients were included from 2 different hospitals. The mean time to a ≥20% reduction in pain scores from the start of IVLI was 3.3 hours (SD = 2.2). The median morphine dose equivalents required during 6, 12, and 24 hours pre-IVLI were significantly higher compared to the same time periods after IVLI (18.3 vs 10 mg, P = .002; 41.8 vs 18.3 mg, P = .002; 93.5 vs 30.5 mg, P = .037). Neurological adverse effects of lidocaine were noted in 3 patients, but the effects were reversed on IVLI discontinuation. This report suggests that IVLI as an adjunctive agent in the treatment of acute pain may be a potential option in ICU patients who are refractory to opioids or those in whom opioid-induced respiratory depression is a concern.

Practice Patterns and Opinions on Current Clinical Practice Guidelines Regarding the Management of Delirium in the Intensive Care Unit.

OBJECTIVE: The aim of this study was to determine current delirium practices in the intensive care unit (ICU) setting and evaluate awareness and adoption of the 2013 Pain, Agitation, and Delirium (PAD) guidelines with emphasis on delirium management. DESIGN, SETTING, AND PARTICIPANTS: A large-scale, multidisciplinary, online survey was administered to physician, pharmacist, nurse, and mid-level practitioner members of the Society of Critical Care Medicine (SCCM) between September 2014 and October 2014. A total of 635 respondents completed the survey. MEASUREMENTS AND MAIN RESULTS: Nonpharmacologic interventions such as early mobilization were used in most ICUs (83%) for prevention of delirium. A majority of respondents (97%) reported using pharmacologic agents to treat hyperactive delirium. Ninety percent of the respondents answered that they were aware of the 2013 PAD guidelines, and 75% of respondents felt that their delirium practices have been changed as a result of the new guidelines. In addition, logistic regression analysis of this study showed that respondents who use delirium screening tools were twice more likely to be fully aware of key components of the updated guidelines (odds ratio [OR] = 2.07, 95% confidence interval [CI] = 1.20-3.60). CONCLUSIONS: Most critical care practitioners are fully aware and knowledgeable of key recommendations in the new guidelines and have changed their delirium practices accordingly.

Rational Use of Second-Generation Antipsychotics for the Treatment of ICU Delirium.

Delirium, described as an acute neuropsychiatric syndrome, occurs commonly in critically ill patients and leads to many negative outcomes including increased mortality and long-term cognitive deficits. Despite the lack of clinical data supporting the use of antipsychotics for the management of intensive care unit (ICU) delirium, pharmacological interventions are often needed to control acutely agitated patients. Given that the most current guidelines do not advocate the use of haloperidol for either the prevention or treatment of ICU delirium due to a lack of evidence, second-generation antipsychotics (SGAs) have been commonly used as alternatives to haloperidol for ICU patients with delirium. Nonetheless, the evidence supporting the use of SGAs to treat ICU delirium remains limited. This review is designed to assess the available clinical evidence and highlights the different neuropharmacological and safety properties of SGAs in order to guide the rational use of SGAs for the treatment of ICU delirium.

Barbiturates for the treatment of alcohol withdrawal syndrome: A systematic review of clinical trials.

PURPOSE: To perform a systematic review of the clinical trials concerning the use of barbiturates for the treatment of acute alcohol withdrawal syndrome (AWS). MATERIALS AND METHODS: A literature search of MEDLINE, EMBASE, and the Cochrane Library, together with a manual citation review was conducted. We selected English-language clinical trials (controlled and observational studies) evaluating the efficacy and safety of barbiturates compared with benzodiazepine (BZD) therapy for the treatment of AWS in the acute care setting. Data extracted from the included trials were duration of delirium, number of seizures, length of intensive care unit and hospital stay, cumulated doses of barbiturates and BZDs, and respiratory or cardiac complications. RESULTS: Seven studies consisting of 4 prospective controlled and 3 retrospective trials were identified. Results from all the included studies suggest that barbiturates alone or in combination with BZDs are at least as effective as BZDs in the treatment of AWS. Furthermore, barbiturates appear to have acceptable tolerability and safety profiles, which were similar to those of BZDs in patients with AWS. CONCLUSIONS: Although the evidence is limited, based on our findings, adding phenobarbital to a BZD-based regimen is a reasonable option, particularly in patients with BZD-refractory AWS.

Possible Hepatotoxicity Associated With Daptomycin: A Case Report and Literature Review.

PURPOSE: To report a case of isolated daptomycin-induced acute liver injury without elevations in creatine kinase (CK) levels or kidney dysfunction. SUMMARY: A 49-year-old female with a history of pancreatitis, lupus, diabetes, congestive heart failure, hypertension, and chronic pain syndrome presented to the emergency department with alteration in mental status and acute liver failure. The patient had been treated with daptomycin for methicillin-resistant Staphylococcus aureus (MRSA) endocarditis for 3 weeks. After ruling out other possible etiologies, daptomycin was suspected as a cause of acute liver failure. Her liver failure resolved gradually following withdrawal of daptomycin. CONCLUSION: Although hepatic abnormalities caused by daptomycin are rare, a handful of cases with daptomycin-induced liver injury have been reported in the literature. Of note, in most cases, patients on daptomycin therapy developed liver damage with elevations in CK levels. Our case report suggests possible severe liver injury associated with high-dose and long-term daptomycin treatment in the absence of rhabdomyolysis. Future research is warranted to further investigate the relationship between daptomycin use and liver injury, yet it is reasonable to monitor liver function tests at baseline and weekly thereafter along with CK levels, especially in patients requiring long-term daptomycin therapy.

Emerging Role of Melatonin and Melatonin Receptor Agonists in Sleep and Delirium in Intensive Care Unit Patients.

Delirium, an acute state of mental confusion, can lead to many adverse sequelae in intensive care unit (ICU) patients. Although the etiology of ICU delirium is often multifactorial, and at times not fully understood, sleep deprivation is considered to be a major contributing factor to its development. It has been postulated that administration of exogenous melatonin and melatonin receptor agonists such as ramelteon may prevent delirium by promoting nocturnal sleep in ICU patients. The purpose of this review is to summarize the pharmacology of melatonin and melatonin receptor agonists and investigate their potential roles in sleep promotion and delirium prevention in ICU patients. Although few studies evaluating the impact of melatonergic agents on sleep and delirium in the ICU have been completed, some data suggest their potential positive effects on sleep and delirium. However, large-scale randomized controlled trials are warranted to determine the optimal role of melatonergic agents in the prevention of ICU delirium.

Recent advances in the development of specific antidotes for target-specific oral anticoagulants.

Warfarin, a vitamin K antagonist, has been the only orally available anticoagulant for > 60 years. During the past decade, the U.S. Food and Drug Administration has approved several target-specific oral anticoagulants (TSOACs) for the prophylaxis and treatment of arterial and venous thromboembolism and stroke prevention in patients with nonvalvular atrial fibrillation. These new agents have several advantages over warfarin including more predictable pharmacokinetics and pharmacodynamics, fewer food and drug interactions, and lack of need for routine coagulation monitoring. However, unlike warfarin, currently no antidotes are available to reverse the anticoagulant effect of TSOACs. Specific antidotes for TSOACs may not be needed in most situations due to their short half-life, yet the absence of antidotes for these agents is a concern, especially in emergent situations such as life-threatening major bleeding or nonelective major surgery. Several specific antidotes for TSOACs including idarucizumab, andexanet alfa, and aripazine have been developed and have shown promise in early clinical trials evaluating their efficacy and safety. In this narrative review, the progress made in developing specific antidotes for TSOACs is summarized based on the latest available preclinical and clinical data.

Role of dexmedetomidine for the prevention and treatment of delirium in intensive care unit patients.

OBJECTIVE: To review recent clinical studies regarding the role of dexmedetomidine for prevention and treatment of delirium in intensive care unit (ICU) patients. DATA SOURCES: MEDLINE and PubMed searches (1988-Feburary 2013) were conducted, using the key words delirium, dexmedetomidine, Precedex, agitation, α-2 agonists, critical care, and intensive care. References from relevant articles were reviewed for additional information. STUDY SELECTION AND DATA EXTRACTION: Clinical trials comparing dexmedetomidine with other sedatives/analgesics or with antipsychotics for delirium were selected. Studies that evaluated the use of dexmedetomidine for sedation for more than 6 hours were included in this review. DATA SYNTHESIS: Dexmedetomidine is a highly selective α-2 receptor agonist that provides sedation, anxiolysis, and modest analgesia with minimal respiratory depression. Its mechanism of action is unique compared with that of traditional sedatives because it does not act on γ-aminobutyric acid receptors. In addition, dexmedetomidine lacks anticholinergic activity and promotes a natural sleep pattern. These pharmacologic characteristics may explain the possible anti delirium effects of dexmedetomidine. Eight clinical trials, including 5 double-blind randomized trials, were reviewed to evaluate the impact of dexmedetomidine on ICU delirium. CONCLUSIONS: Currently available evidence suggests that dexmedetomidine is a promising agent, not only for prevention but also for treatment of ICU-associated delirium. However, larger, well-designed trials are warranted to define the role of dexmedetomidine in preventing and treating delirium in the ICU.

A simple HPLC method with pulsed EC detection for the analysis of creatine.

The objective of this study was to develop a simple and sensitive LC method for the determination of creatine in aqueous solutions as well as in rat plasma using electrochemical detection. The chromatographic system consisted of a GP50 gradient pump, an ED40 pulsed electrochemical detector, and an AI-450 chromatography automation system (Dionex). The mobile phase consisted of a mixture of water, acetonitrile, 0.01 M sodium acetate, and 1.0 M sodium hydroxide (2.5:2.5:90:5, V/V/V/V) at a flow rate of 1.0 ml/min. The chromatographic separation was achieved at 45 degrees C on a column with a polyhydroxylated glucose and sulfonated stationary phase. The retention times of creatine and creatinine was 3.50 and 4.73 min, respectively, with creatine fully resolved from its major degradation product, creatinine. The standard curves were linear over the concentration range of 0-20 microg/ml. Within-day and day-to-day relative standard deviations (R.S.D.) were less than 10%. This method was used to study dissolution characteristics of various creatine salts in water.

Solid-state properties of creatine monohydrate.

Creatine monohydrate (CM) is a nutritional supplement and an ergogenic aid for athletes. It appears to increase lean body mass, high-intensity power output and strength in healthy humans. The crystal structure of creatine monohydrate has previously been reported. However, little information is available on its solid-state properties. In this investigation, creatine monohydrate was subjected to Thermal Analyses, Karl-Fisccher Titrimetry (KFT), Scanning Electron Microscopy (SEM), and Variable Temperature X-ray Powder Diffractometry (VTXRD) to characterize its solid-state properties. The results of this study suggested that commercially available creatine monohydrate dehydrates at about 97-125 degrees C. A phase transition after dehydration was confirmed by X-ray diffraction studies. This dehydrated phase at a temperature above 230 degrees C undergoes intramolecular cyclization with a loss of an additional mole of water to form creatinine. Creatinine finally melts with decomposition at about 290 degrees C. VTXRD, confirmed that the above solid-state thermal transformation was kinetically driven, and occurred within a narrow temperature range. Mass Spectrometric (MS) studies further indicated a possible dimerization of creatinine formed during the solid-state transformation.