Annals of Pharmacotherapy最新文献

Objective: Summarize the studies evaluating the use of subcutaneous (SQ) insulin in the management of diabetic ketoacidosis (DKA) in adults and pediatrics.

Data sources: A PubMed literature search was conducted for articles published between 2000 and the end of May 2024 which contained the following terms in their title: (1) subcutaneous, glargine, or basal and (2) ketoa*.

Study selection and data extraction: Review articles, guidelines, meta-analysis, commentaries, studies not related to the acute management of DKA, studies evaluating continuous SQ insulin, animal studies, if the time to DKA resolution was not clearly defined, and studies where basal insulin was administered greater than 6 hours after the insulin infusion was started were excluded.

Data synthesis: The electronic search identified 58 articles. Following the initial screening 38 articles were excluded and 3 were added after bibliography review. Of the 23 articles assessed for eligibility, 7 were excluded. Sixteen articles were included. Five studies compared SQ rapid/short-acting insulin and intravenous (IV) insulin infusions in adults, 4 compared SQ rapid/short-acting insulin and IV insulin infusions in pediatrics, 4 evaluated IV insulin infusions with or without SQ basal insulin in adults, and 3 evaluated IV insulin infusions with or without SQ basal insulin in pediatrics.

Relevance to patient care and clinical practice: In comparison with IV insulin infusions, rapid/short-acting SQ insulin regimens were associated with reduced ICU admission rates, hospital length of stay, and hospitalization costs. IV insulin infusion regimens that included a single SQ basal insulin dose upon therapy initiation were associated with reduced concurrent IV insulin infusion durations.

Conclusion: Studies reviewed suggest that SQ insulin regimens may be as effective and safe as IV insulin infusions in the management of DKA and are associated with the conservation of resources. Providers may refer to this review when establishing or modifying their DKA management protocols.

Background: Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are first-line treatment for type 2 diabetes. Evidence has shown a 3- to 5-fold increase in the risk of genitourinary infections with their use due to inhibition of renal glucose reabsorption, resulting in glucosuria. Increased glucosuria is thought to increase the risk of genitourinary infections at a greater degree in patients with a significantly elevated HbA1c (≥10%), and initiation of SGLT2i is often delayed in these patients. While a limited body of evidence exists indicating that A1c level is not an independent risk factor for SGLT2i-induced genitourinary infection, pragmatically this concern remains a barrier to SGLT2i utilization.

Objective: Evaluate the real-world genitourinary (GU) infection rate in patients receiving SGLT2i with a baseline HbA1c ≥10% compared to patients with a baseline HbA1c <10%.

Methods: This retrospective cohort study evaluated data from 5542 adult patients treated between January 2013 and January 2023, who were prescribed an SGLT2i. Data collected included sex, age, race/ethnicity, renal function, date of SGLT2i start, number of SGLT2i orders, name and dose of SGLT2i, HbA1c, and a predetermined set of diagnosis codes related to bacterial and fungal genitourinary infections. The primary outcome was the overall GU infection rate after SGLT2i initiation within groups of baseline HbA1c of ≥10% and <10%, and the secondary outcome was total GU infections within these same groups.

Results: The primary outcome was equivalent between those with HbA1c <10% and HbA1c ≥10% (0.0064 ± 0.0565 vs 0.0030 ± 0.0303 infection per month [mean ± standard deviation]; P < 0.0001 for both lower and upper bounds). There was no statistically significant difference in total GU infections between the same groups (0.027 ± 0.21 vs 0.015 ± 0.14, P = 0.11). Female gender and prior recurrent infection were associated with increased GU infection after SGLT2i.

Conclusion and relevance: A baseline HbA1c ≥ 10% was not significantly associated with an increased risk of GU infection following the initiation of SGLT2i compared to those with a baseline HbA1c of <10%.

Parkinsonism induced by dopamine receptor antagonists, traditionally considered completely reversible following offending drug withdrawal, may unmask a degenerative parkinsonism in the patients with an underlying subclinical disease. In elderly patients, parkinsonism induced by the calcium channel blockers such as piperazine derivates cinnarizine and flunarizine may persist following drug discontinuation resulting in a permanent nonprogressive syndrome fulfilling the criteria for tardive parkinsonism. Whether this outcome occurs also following exposure to dopamine receptor antagonists such as neuroleptics and benzamide derivates or represents a class effect of the voltage-gated L-type calcium channel blockers, such as cinnarizine and flunarizine, due to their complex pharmacodynamic properties remains to be established.

Background: Midazolam (MZ) is commonly used in critically ill neurosurgical patients. Neuro-penetration of MZ and its metabolite, 1-hydroxy-midazolam (1-OH-MZ), is not well characterized.

Objective: This study evaluated correlations between serum and cerebrospinal fluid (CSF) concentrations of MZ and 1-OH-MZ and assessed implications on patient sedation.

Methods: Adults in the neurosurgical intensive care unit (ICU) with external ventricular drains receiving MZ via continuous infusion were prospectively studied. Serum and CSF samples were obtained 12-24 h and 72-96 h after initiation, and concentrations were determined in duplicate by high-performance liquid chromatography with tandem mass spectrometry. Bivariate correlation analyses used Pearson coefficient.

Results: A total of 31 serum and CSF samples were obtained from 18 subjects. At sampling, mean MZ infusion rate was 3.9 ± 4.4 mg/h, and previous 12-h cumulative dose was 51.4 ± 78.2 mg. Mean concentrations of MZ and 1-OH-MZ in serum and CSF were similar between timepoints. Similarly, ratios of 1-OH-MZ to MZ in serum and CSF remained stable over time. Serum MZ (126.2 ± 89.3 ng/mL) showed moderate correlation (r² = 0.68, P < 0.001) with serum 1-OH-MZ (17.7 ± 17.6 ng/mL) but not CSF MZ (3.9 ± 2.5 ng/mL; r² = 0.24, P = 0.005) or CSF 1-OH-MZ (2.5 ± 0.6 ng/mL; r² = 0.47, P = 0.30). CSF MZ did not correlate with CSF 1-OH-MZ (r² = 0.003, P < 0.001). Mean serum ratio of 1-OH-MZ to MZ (0.14 ± 0.2 ng/mL) did not correlate with CSF ratio (1.06 ± 0.83 ng/mL; r² = 0.06, P = 0.19). Concentrations and ratios were unrelated to MZ infusion rate or 12-h cumulative dose. Sedation was weakly correlated with CSF 1-OH-MZ, but not with serum MZ, serum 1-OH-MZ, or CSF MZ.

Conclusion and relevance: Continuous infusions of MZ result in measurable concentrations of MZ and 1-OH-MZ in CSF; however, CSF concentrations of MZ and 1-OH-MZ poorly represent serum concentrations or dosages. Accumulation of MZ and 1-OH-MZ in serum or CSF over time was not evident. Concentrations of MZ and 1-OH-MZ do not predict sedation levels, reinforcing that pharmacodynamic assessments are warranted.

Objective: To compare efficacy and safety outcomes for ketamine anesthesia + electroconvulsive therapy (ECT) versus nonketamine anesthesia + ECT in treatment-resistant depression (TRD) patients.

Data sources: PubMed and Embase were searched from the earliest date through November 27, 2023.

Study selection and data extraction: Relevant randomized controlled trials (RCTs) of ketamine + ECT versus nonketamine anesthesia + ECT that reported data on remission (odds ratio [OR]), defined as a Hamilton Depression Rating Scale (HAM-D) and Montgomery-Asburg Depression Rating Scale (MADRS) score <8-10) and mean differences (MDs) in HAM-D scores after several ECT sessions were compared using inverse variance methods. The risk of bias (RoB) was assessed using the Cochrane RoB tool.

Data synthesis: Seventeen RCTs (RoB: Low N = 12, Moderate N = 2, High N = 3) with 1181 total patients met inclusion criteria. Patients receiving ECT experienced greater clinical remission (OR: 1.78, [95% confidence interval (CI): 1.08-2.93], I² = 11%, N = 9) and lower HAM-D scores after the third through sixth ECT sessions as well as the eighth ECT session when ketamine versus nonketamine anesthesia was used. Ketamine use with ECT significantly increased fear with hallucinations (OR: 1.99, [95% CI: 1.11-3.58], I² = 0%, N = 7) than with nonketamine anesthesia.

Relevance to patient care and clinical practice: Selecting ketamine-based anesthesia could more quickly and profoundly enhance the beneficial effects of ECT for patients with severe TRD, but the balance of benefits to harm is unclear as there may be additional adverse events.

Conclusion: Ketamine is a promising anesthesia adjunct to ECT that may enhance antidepressant effects in exchange for more adverse events.

Background: Thrombolysis is recommended in the setting of massive pulmonary embolism (PE) for reperfusion of vessels but carries a serious concern for increased bleed risk. In October 2022, our institution adopted tenecteplase as the formulary thrombolytic. Previous literature is unclear regarding the bleed risk of tenecteplase in massive PE, and no study has yet compared safety outcomes with the current standard of care, alteplase.

Objective: The objective of this study was to compare the incidence of bleeding with tenecteplase versus alteplase in massive PE patients.

Methods: This was a retrospective, observational cohort study that included adults who received tenecteplase or alteplase for massive PE. The primary outcome was major bleeding as defined by the International Society on Thrombosis and Hemostasis (ISTH). Secondary outcomes included incidence of symptomatic intracranial hemorrhage (ICH), in-hospital mortality, administration of reversal agents, and length of stay.

Results: A total of 44 patients met inclusion criteria with 20 patients in the alteplase cohort and 24 in the tenecteplase cohort. Seventeen percent of tenecteplase patients compared with 5% of alteplase patients experienced bleeding. The mortality rate was 83% vs 75%, respectively. In addition, 1 patient in the tenecteplase cohort experienced a symptomatic ICH and 2 patients required initiation of massive transfusion protocol.

Conclusion and relevance: Although this study was limited in sample size, these results suggest that there may be reason for concern of higher bleeding rates in patients treated with tenecteplase in the setting of massive PE.

Background: Alcohol withdrawal syndrome (AWS) is a complication of alcohol use disorder that manifests as a range of symptoms. Symptom-triggered benzodiazepines (BZDs) are often used as first-line treatment of AWS. However, recent literature suggests phenobarbital (PHB) may be safer and more efficacious, but studies are limited by exclusion of patients with neurological injuries.

Objective: We aimed to evaluate the safety of PHB compared to BZDs for the management of AWS among patients with primary neurologic injuries.

Methods: Retrospective cohort study of patients with primary neurologic injuries admitted to an ICU who received PHB or symptom-triggered BZD for AWS between December 2013 and February 2020. The primary outcome was incidence of oversedation, defined as Richmond Agitation Sedation Scale (RASS) scores from -5 to -3 within 24 hours of initial PHB or BZD dose. Secondary outcomes included largest decrease in RASS, need for mechanical ventilation, and additional sedative use within 24 hours of initial PHB or BZD dose. A multivariable analysis was performed to evaluate the association of PHB administration with the primary outcome.

Results: Among 600 patients treated for AWS, 84 patients were included in our analysis (PHB, n = 56; BZD, n = 28). In the unadjusted analysis, there were no differences between the PHB and BZD groups for the primary outcome of oversedation (21.4 vs. 7.1%, P = 0.13), or secondary outcomes of decrease in RASS (P = 0.34), or new ventilator requirement (P = 0.55). Patients who received PHB had higher rates of additional sedative use (P < 0.01). Multivariable regression revealed an increase in oversedation among intubated patients (P = 0.014), while PHB administration was not independently associated with oversedation (P = 0.516).

Conclusion and relevance: Phenobarbital did not independently increase the risk of oversedation compared to BZD for AWS in patients with primary neurologic injuries. Future studies should determine optimal dosing of PHB in this population.

Objective: This review aims to systematically summarize the available data on efficacy and safety of therapeutic enoxaparin in obese patients and to identify gaps to guide future research.

Data sources: Medline and Embase were systematically searched for eligible studies (last searched December 20, 2023). Studies were included if they reported on therapeutic dosing regimens, adverse bleeding, thrombotic outcomes, or antifactor Xa (AFXa) monitoring in obese adult patients.

Study selection and data extraction: The systematic review management tool Covidence was used to manage the study selection and data extraction process. The reference list from eligible studies was screened to determine any additional eligible studies.

Data synthesis: Sixteen studies were included in the analysis. Studies used a variety of doses, indications, and study designs making comparison difficult. Twelve studies reported the incidence of thrombotic events (median = 1.3% [interquartile range [IQR] = 0.3%-2.3%]) and all studies reported the incidence of bleeding events (median = 5.7% [IQR = 2.4%-14.5%]). Two of the 8 studies analyzing the influence of weight/body mass index (BMI) or dose per kg on AFXa levels reported statistically significant results. One study concluded that BMI did not affect achievement of target AFXa levels. However, the second study found that dosing using actual body weight was an independent predictor of supratherapeutic AFXa levels in the obese population.

Relevance to patient care and clinical practice: This is the first comprehensive review with a focus on therapeutic dosing of enoxaparin in obesity and has been conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement. Seven of the included studies were published since 2018 indicating that new evidence on this topic is emerging.

Conclusion: There was inadequate evidence to support an optimal dosing strategy in obese patients due to the heterogeneity of the studies. The AFXa monitoring may be appropriate to guide dosing in this population. Further research is required to determine a suitable dosing regimen.

Background: Immune thrombocytopenic purpura (ITP) in adults typically develops slowly and insidiously. The ITP medications might be linked to psychological disorders, but the connection is not well-understood.

Objective: This study aimed to examine the association between ITP medication use and the risk of depression among participants in the National Health and Nutrition Examination Survey (NHANES) from 2005 to 2018.

Methods: Using data from 70 190 NHANES participants, we conducted a cross-sectional study, excluding individuals under 18 years, with hypertension, HIV, hepatitis C, and various comorbidities. A total of 17 299 individuals were included in the analysis of this study. We identified 2 populations within this study: those using ITP medications, including prednisone, dexamethasone, and rituximab and those not using ITP drugs. Depression status was assessed using the Patient Health Questionnaire-9 (PHQ-9), and the relationship between ITP medication use and depression was analyzed through multivariate logistic regression.

Results: There was no significant association between ITP medication use and an increased risk of depression after adjusting for demographic and health-related variables. Notably, among the study participants, 1.8% of the non-depressed population were on ITP medication compared with 0.3% in the depressed population. The analysis revealed varying depression risks associated with different sociodemographic factors. For instance, the correlation between ITP medication and depression risk was influenced by a combination of age, race, income, and smoking status.

Conclusion and relevance: The study suggests that ITP medication use does not independently increase the risk of depression. This finding is crucial for guiding clinical decisions and managing patient expectations regarding ITP treatment and its psychological impacts.

Background: Alzheimer's disease (AD) is a neurodegenerative condition leading to memory loss, cognitive impairment, and neuropsychiatric symptoms. Second-generation antipsychotics (SGAs) are commonly used to manage these neuropsychiatric symptoms, but their safety profile in patients with AD requires further investigation.

Objective: The objective was to evaluate the safety of SGAs in patients with AD by analyzing adverse drug reactions (ADRs) using the US Food and Drug Administration Adverse Event Reporting System (FAERS) database.

Methods: This study conducted a comprehensive analysis of FAERS data from 2014 to 2023, focusing on ADRs in patients with AD treated with SGAs such as risperidone, quetiapine, olanzapine, clozapine, and aripiprazole. Descriptive, disproportionality, time, and dose analysis were performed using the Bayesian confidence propagation neural network, Weibull, and physiologically based pharmacokinetic model.

Results: Out of 1289 patients with AD treated with SGAs, the most common ADRs involved the nervous system, gastrointestinal system, and cardiac disorders. Disproportionality analysis identified significant positive signals in cardiac, renal, and vascular systems. Quetiapine, risperidone, and olanzapine showed more positive signals compared with clozapine and aripiprazole. Time analysis indicated that cardiovascular ADRs occurred randomly, whereas renal ADRs increased with prolonged use. Dose analysis suggested that small doses of SGAs did not elevate the risk of multiple cardiac, renal, or vascular ADRs.

Conclusion and relevance: The study underscores the importance of monitoring for ADRs, particularly in the cardiac and renal systems, when using SGAs in patients with AD. Future research incorporating more comprehensive clinical data is warranted to support safe and rational drug utilization.