Pharmacokinetics of Levetiracetam Seizure Prophylaxis in Severe Traumatic Brain Injury.

BACKGROUND: Drug pharmacokinetics (PK) are altered in neurocritically ill patients, and optimal levetiracetam dosing for seizure prophylaxis is unknown. OBJECTIVE: This study evaluates levetiracetam PK in critically ill patients with severe traumatic brain injury (sTBI) receiving intravenous levetiracetam 1000 mg every 8 (LEV8) to 12 (LEV12) hours for seizure prophylaxis. METHODS: This prospective, open-label study was conducted at a level 1 trauma, academic, quaternary care center. Patients with sTBI receiving seizure prophylaxis with LEV8 or LEV12 were eligible for enrollment. Five sequential, steady-state, postdose serum levetiracetam concentrations were obtained. Non-compartmental analysis (NCA) and compartmental approaches were employed for estimating pharmacokinetic parameters and projecting steady-state trough concentrations. Pharmacokinetic parameters were compared between LEV8 and LEV12 patients. Monte Carlo simulations (MCS) were performed to determine probability of target trough attainment (PTA) of 6 to 20 mg/L. A secondary analysis evaluated PTA for weight-tiered levetiracetam dosing. RESULTS: Ten male patients (5 LEV8; 5 LEV12) were included. The NCA-based systemic clearance and elimination half-life were 5.3 ± 1.2 L/h and 4.8 ± 0.64 hours. A one-compartment model provided a higher steady-state trough concentration for the LEV8 group compared with the LEV12 group (13.7 ± 4.3 mg/L vs 6.3 ± 1.7 mg/L; P = 0.008). Monte Carlo simulations predicted regimens of 500 mg every 6 hours, 1000 mg every 8 hours, and 2000 mg every 12 hours achieved therapeutic target attainment. Weight-tiered dosing regimens achieved therapeutic target attainment using a 75 kg breakpoint. CONCLUSION AND RELEVANCE: Neurocritically ill patients exhibit rapid levetiracetam clearance resulting in a short elimination half-life. Findings of this study suggest regimens of levetiracetam 500 mg every 6 hours, 1000 mg every 8 hours, or 2000 mg every 12 hours may be required for optimal therapeutic target attainment. Patient weight of 75 kg may serve as a breakpoint for weight-guided dosing to optimize levetiracetam therapeutic target attainment for seizure prophylaxis.

Concomitant andexanet alfa and 4 F-PCC for Factor Xa inhibitor associated intracranial hemorrhage.

Andexanet alfa is the only FDA approved drug for acute reversal of life-threatening bleeding associated with oral factor Xa inhibitor agents. The case series investigates clinical outcomes of four patients receiving concomitant Andexanet alfa and Four Factor Prothrombin Concentrate Complex (4 F-PCC) for acute reversal of intracranial hemorrhage. Following administration, effective hemostasis was achieved in two patients (50%) and one patient (25%) experienced an acute ischemic stroke. Two patients (50%) expired prior to discharge without achieving hemostasis. This case series serves to further expand the limited data on the concomitant administration of Andexanet alfa and 4 F-PCC.

Sugammadex Efficacy and Dosing for Rocuronium Reversal Outside of Perioperative Settings.

Background: Sugammadex is approved for postoperative recovery from rocuronium neuromuscular blockade with train-of-four (TOF) guided dosing. Data for non-perioperative sugammadex efficacy and dosing are limited when TOF is not available and reversal is not immediate. Objective: This study evaluated the efficacy, safety, and dose of sugammadex when administered in the emergency department (ED) or intensive care unit (ICU) for delayed rocuronium reversal when TOF guidance was not consistently available. Methods: This single-center, retrospective cohort study included patients over a 6-year period who received sugammadex in the ED or ICU at least 30 minutes after rocuronium administration for rapid sequence intubation (RSI). Patients who received sugammadex for intra-operative neuromuscular blockade reversal were excluded. Efficacy was defined as successful reversal documented in progress notes, TOF assessment, or improvement in Glasgow Coma Scale (GCS). Dose was evaluated in patients with successful reversal by correlating sugammadex and rocuronium dose with reversal time after paralysis. Results: Thirty-four patients were included with 19 (55.9%) patients receiving sugammadex in the ED. Sugammadex indication was acute neurologic assessment in 31 (91.1%) patients. Twenty-nine patients (85.2%) had successful reversal documented. The remaining 5 patients had fatal neurologic injuries with GCS 3 limiting non-TOF efficacy assessment. The median (IQR) sugammadex dose was 3.4 (2.5-4.1) mg/kg administered 89 (56.3-158) minutes after rocuronium. No correlation was identified between sugammadex dose, rocuronium dose, and administration time. No adverse events were noted. Conclusion: This pilot investigation demonstrated safe and effective rocuronium reversal with sugammadex 3 to 4 mg/kg administered in the non-operative setting 1 to 2 hours after RSI. Larger, prospective studies are necessary to determine the safety in patients outside of the operating room when TOF is not available.

Intranasal Fentanyl and Midazolam Use in Children 3 Years of Age and Younger in the Emergency Department.

BACKGROUND: Although the efficacy and safety profiles of both intranasal fentanyl and midazolam are well studied in pediatric patients, few studies examine their use in younger children. OBJECTIVES: To examine and report our experiences in a pediatric emergency department (ED) with intranasal fentanyl and midazolam in children aged 3 years and younger. METHODS: This retrospective study investigated intranasal fentanyl and midazolam administration, alone and in combination, in children 3 years and younger treated in a pediatric ED. RESULTS: Of 6198 patients included, 1762 received intranasal fentanyl alone, 1115 received intranasal midazolam alone, and 3321 received combination therapy. The median (interquartile range [IQR]) patient age was 2.2 (1.5-3) years. Initial median (IQR) fentanyl dose was 2.7 (2-3) µg/kg, with 13.3% receiving a repeat dose. Initial median (IQR) midazolam dose was 0.3 (0.2-0.3) mg/kg, with 3.3% receiving a second dose. Children receiving both fentanyl and midazolam had median (IQR) initial doses of 2.8 (2.1-3) µg/kg and 0.3 (0.2-0.3) mg/kg, respectively. Of these, 3.2% received repeat doses of both medications. Laceration repairs (33.8%) and incision and drainage (22.2%) accounted for the majority of indications. Only 2.9% (n = 178) received additional opioids. No serious adverse events requiring a reversal agent or respiratory support were reported. CONCLUSIONS: Intranasal fentanyl and midazolam, alone and in combination, can provide analgesia and anxiolysis to children aged 3 years and younger in the ED setting. Further prospective studies are needed to better evaluate their safety and efficacy in this younger population.

Improving Communication Messages by Using Perceptual Mapping: Family Planning Survey in East Java and West Nusa Tenggara, Indonesia.

OBJECTIVES: Contraceptive methods vary in effectiveness, actions required of users, and side effects. This article aims to analyze the perceptions about contraceptive methods among family planning clients of the East Java and West Nusa Tenggara (NTB) provinces in Indonesia. METHODS: The data were obtained from the operational research of the Improving Contraceptive Method Mix Project in Indonesia, conducted in 2015-2016 in six districts in East Java and West Nusa Tenggara. The total sample size was 12,190 women aged 15-49 years. The perceptual mapping method uses cross-sectional surveys that require the respondent to rate the level to which they associate specific elements with each other, based on similarities and differences of perceived association. The correlation matrices for six contraceptive methods and five attributes were subjected to a multidimensional scaling analysis. RESULTS: The results showed injectable to be the most preferred method, which was positioned closest to the attributes 'easy to use' and 'easy to get', followed by pills. Implants ranked higher than other long-acting and permanent method. CONCLUSION: Injectables and pills were the most preferred because people believe that they were 'easy to use' and 'easy to get'. The least preferred methods were tubectomy and vasectomy because the respondents thought those were not close to any attributes at all. To increase the demand for the long-acting and permanent method choice in the provinces of East Java and West Nusa Tenggara, the attributes 'easy to use' and 'easy to get' should be emphasized in the long-acting and permanent method Information Education and Communication messages.

Blunt cerebrovascular injury in the geriatric population.

OBJECTIVE: Blunt cerebrovascular injury (BCVI) is associated with high rates of neurological morbidity and mortality. The detection and management of BCVI has improved with advances in imaging and sensitive screening protocols. Few studies have explored how these injuries specifically affect the geriatric population. The purpose of this retrospective analysis was to investigate the presentation and prognosis of BCVI in the elderly population and to assess its clinical implications in the management of these patients. METHODS: All patients presenting to the University of Cincinnati (UC) level I trauma center between February 2017 and December 2019 were screened for BCVI and entered into the prospectively maintained UC Neurotrauma Registry. Patients with BCVI confirmed by CT angiography underwent retrospective chart reviews to collect information regarding demographics, positive screening criteria, cause of injury, antithrombotic agent, injury location, Denver Grading Scale, hospital and ICU length of stay, and discharge disposition. Patients were divided into geriatric (age ≥ 65 years) and adult (age < 65 years) subgroups. Continuous variables were analyzed using the Student t-test and categorical variables with the Pearson chi-square test. RESULTS: Of 124 patients with BCVI, stratification by age yielded 23 geriatric and 101 adult patients. Injury in the geriatric group was associated with significantly higher mortality (p = 0.0194). The most common cause of injury in the elderly was falls (74%, 17/23; p < 0.0001), whereas motor vehicle accidents were most common in the adult group (38%, 38/100; p = 0.0642). With respect to the location of injury, carotid (p = 0.1171) and vertebral artery (p = 0.6981) injuries did not differ significantly for the geriatric group. The adult population presented more often with Denver grade I injuries (p < 0.0001), whereas the geriatric population presented with grade IV injuries (p = 0.0247). Elderly patients were more likely to be discharged to skilled nursing facilities (p = 0.0403) and adults to home or self-care (p = 0.0148). CONCLUSIONS: This study is the first to characterize BCVI to all cervical and intracranial vessels in the geriatric population. Older age at presentation is significantly associated with greater severity, morbidity, and mortality from injury, with no preference for the particular artery injured. These findings carry important clinical implications for adapting practice in an aging population.

Poor Knowledge and Nonuse of Long-Acting/Permanent Methods of Contraceptives in Six Districts in Indonesia.

This analysis aimed at examining the association between the level of knowledge about long-acting/permanent methods of contraceptives (LAPM) and nonuse of LAPM among currently married, nonpregnant, and fecund women aged 15 to 49 years intending to limit childbearing. Data were derived from a cross-sectional study in Tuban, Kediri, and Lumajang District (East Java Province) and Lombok Barat, Lombok Timur, and Sumbawa District (Nusa Tenggara Barat Province) in June 2012. Information was obtained from 4323 respondents. Using multivariate logistic regression, we found that women with moderate levels of LAPM knowledge were less likely to use LAPM than women with high levels of knowledge (adjusted odds ratio [aOR] = 2.01, 95% CI = 1.51-2.68). Women with low level of LAPM knowledge were less likely to use LAPM than women with high levels of knowledge (aOR = 4.25, 95% CI = 3.37-5.36). Efforts to strengthen counseling services and increased provider knowledge and counselling skills are important to improve women's knowledge about and use of LAPM.

Increasing the uptake of long-acting and permanent methods of family planning: A qualitative study with village midwives in East Java and Nusa Tenggara Barat Provinces, Indonesia.

OBJECTIVE: this analysis aims to explore midwives' insights into the provision of long-acting and permanent methods of contraception (LAPMs) in the selected areas of East Java and Nusa Tenggara Barat (NTB) Provinces, Indonesia. DESIGN: a qualitative study using in-depth interviews was conducted with 12 village midwives from 12 villages, to explore their perceptions and experiences in delivering family planning services. SETTING: the study was carried out in May-June 2013, as part of the baseline assessment in the Improving Contraceptive Method Mix (ICMM) study. We interviewed 12 village midwives working in 12 villages in six study districts: Tuban, Kediri, and Lumajang Districts in East Java Province; and Lombok Barat, Lombok Timur, and Sumbawa Districts in NTB Province. MEASUREMENT: an interview guideline was used in all interviews. It covered several topics, such as community perceptions of LAPMs, availability of contraception and related equipment, availability of human resources, and midwives' efforts to improve LAPM coverage. All interviews were recorded and transcribed. Content and thematic analyses were carried out by grouping and coding the information based on the identified themes and topics. FINDINGS: according to village midwives interviewed in this study, community-level acceptance of LAPMs has increased over time; however, some still prefer using short-acting methods for a long period. The reasons include lack of awareness about the benefits and side effects of LAPMs, fear of surgical procedures, rumored consequences (for example, that LAPMs would limit women's ability to perform hard physical labor), and religious beliefs. There were several challenges reported by village midwives in delivering LAPM services, such as confusion about midwives' eligibility to provide LAPM services, lack of Contraceptive Technology Update (CTU) and counseling trainings, and shortage of supporting equipment (such as exam tables and IUD and implant insertion kits). There were several strategies implemented by village midwives to improve LAPM use, including strengthening the counseling services, accompanying clients to higher health facilities to obtain LAPM services, and providing services for groups of clients. All village midwives emphasized the importance of strengthening collaboration among stakeholders to increase the uptake of LAPM services. KEY CONCLUSIONS: as midwives are the main family planning providers in Indonesia, efforts to address their challenges is essential. Enabling a supportive policy environment, strengthening promotional activities, increasing the number of training programs designed for village midwives-in addition to enhancing inter-sectoral collaboration-are some recommendations to improve LAPM uptake in study areas.

Increasing support for contraception as HIV prevention: stakeholder mapping to identify influential individuals and their perceptions.

BACKGROUND: Voluntary contraceptive use by HIV-positive women currently prevents more HIV-positive births, at a lower cost, than anti-retroviral drug (ARV) regimens. Despite this evidence, most prevention of mother-to-child transmission (PMTCT) programs focus solely on providing ARV prophylaxis to pregnant women and rarely include the prevention of unintended pregnancies among HIV-positive women. METHODOLOGY/PRINCIPAL FINDINGS: To strengthen support for family planning as HIV prevention, we systematically identified key individuals in the field of international HIV/AIDS-those who could potentially influence the issue-and sought to determine their perceptions of barriers to and facilitators for implementing this PMTCT strategy. We used a criteria-based approach to determine which HIV/AIDS stakeholders have the most significant impact on HIV/AIDS research, programs, funding and policy and stratified purposive sampling to conduct interviews with a subset of these individuals. The interview findings pointed to obstacles to strengthening linkages between family planning and HIV/AIDS, including the need for: resources to integrate family planning and HIV services, infrastructure or capacity to provide integrated services at the facility level, national leadership and coordination, and targeted advocacy to key decision-makers. CONCLUSIONS/SIGNIFICANCE: The individuals we identified as having regional or international influence in the field of HIV/AIDS have the ability to leverage an increasingly conducive funding environment and a growing evidence base to address the policy, programmatic and operational challenges to integrating family planning with HIV/AIDS. Fostering greater support for implementing contraception for HIV prevention will require the dedication, collaboration and coordination of many such actors. Our findings can inform a targeted advocacy campaign.