Stenting for Traumatic Pseudoaneurysms of the Cervical Internal Carotid Artery: Case Report and Systematic Review.

BACKGROUND: The optimal stenting approach for traumatic pseudoaneurysms (PSA) of the extracranial internal carotid artery (ICA) remains underinvestigated. We present a case of a traumatic pseudoaneurysm of the extracranial ICA managed with stenting and review of prior published similar cases. METHODS: The systematic review followed PRISMA-S guidelines and included studies that investigated traumatic pseudoaneurysms of the extracranial ICA managed by stent placement. Statistical analysis assessed the association between the type of injury and stent type, dual antiplatelet therapy (DAPT) duration, and clinical presentation, and the association between stent type and DAPT duration. RESULTS: Our search yielded 82 publications with 135 patients with extracranial ICA PSA treated with stenting. The odds of neck hematoma presentation was 12.2 times greater for patients with penetrating rather than blunt injuries (P = 0.000002). Covered stents had 2.02 times higher odds of use for penetrating rather than blunt injuries compared to bare metal stents. (P = 0.0029). Shorter duration DAPT was seen with bare metal stents having 1.25 higher odds of DAPT duration less than one month compared to covered (P = 0.001). CONCLUSIONS: In traumatic extracranial ICA pseudoaneurysms, covered stents are used more commonly for penetrating injuries compared to blunt injuries. Penetrating injuries are more strongly associated with the presentation of a hematoma compared to blunt injuries. Stent type may influence the recommended DAPT duration. Surgeons should consider these findings when selecting stent type and DAPT duration with patients presenting with traumatic extracranial ICA pseudoaneurysm.

Subcutaneous infusion of high-dose benzathine penicillin G is safe, tolerable, and suitable for less-frequent dosing for rheumatic heart disease secondary prophylaxis: a phase 1 open-label population pharmacokinetic study.

Since 1955, the recommended strategy for rheumatic heart disease (RHD) secondary prophylaxis has been benzathine penicillin G [BPG; 1.2 MU (900 mg)] injections administered intramuscularly every 4 weeks. Due to dosing frequency, pain, and programmatic challenges, adherence is suboptimal. It has previously been demonstrated that BPG delivered subcutaneously at a standard dose is safe and tolerable and has favorable pharmacokinetics, setting the scene for improved regimens with less frequent administration. The safety, tolerability, and pharmacokinetics of subcutaneous infusions of high-dose BPG were assessed in 24 healthy adult volunteers assigned to receive either 3.6, 7.2, or 10.8 MU (three, six, and nine times the standard dose, respectively) as a single subcutaneous infusion. The delivery of the BPG to the subcutaneous tissue was confirmed with ultrasonography. Safety assessments, pain scores, and penicillin concentrations were measured for 16 weeks post-dose. Subcutaneous infusion of penicillin (SCIP) was generally well tolerated with all participants experiencing transient, mild infusion-site reactions. Prolonged elevated penicillin concentrations were described using a combined zero-order (44 days) and first-order (t1/2 = 12 days) absorption pharmacokinetic model. In simulations, time above the conventionally accepted target concentration of 20 ng/mL (0.02 µg/mL) was 57 days for 10.8 MU delivered by subcutaneous infusion every 13 weeks compared with 9 days of every 4-weekly dosing interval for the standard 1.2 MU intramuscular dose (i.e., 63% and 32% of the dosing interval, respectively). High-dose SCIP (BPG) is safe, has acceptable tolerability, and may be suitable for up to 3 monthly dosing intervals for secondary prophylaxis of RHD.

Routine bacterial culture of proximal bone specimens during minor amputation in patients with diabetes-related foot infections has little clinical utility in predicting re-operation or ulcer healing.

BACKGROUND: Trans-phalangeal and trans-metatarsal amputation, collectively termed 'minor amputations' are important procedures for managing infections of diabetes-related foot ulcers (DFU). Following minor amputation, international guidelines recommend a prolonged course of antibiotics if residual infected bone on intra-operative bone samples are identified, but the quality of the evidence underpinning these guidelines is low. In this study, we examined the concordance of microbiological results from proximal bone cultures compared to results from superficial wound swabs in relation to patient outcomes; with the aim of determining the utility of routinely obtaining marginal bone specimens. METHODS: Data was retrospectively collected on 144 individuals who underwent minor amputations for infected DFU at a large Australian tertiary hospital. Concordance was identified for patients with both superficial wound swabs and intra-operative bone samples available. Patient outcomes were monitored up to 6 months post-amputation. The primary outcome was complete healing at 6 months; and secondary outcome measures included further surgery and death. Mann Whitney U testing was performed for bivariate analyses of continuous variables, Chi-Squared testing used for categorical variables and a logistic regression was performed with healing as the dependent variable. RESULTS: A moderate-high degree of concordance was observed between microbiological samples, with 38/111 (35%) of patients having discordant wound swab and bone sample microbiology. Discordant results were not associated with adverse outcomes (67.2% with concordant results achieved complete healing compared with 68.6% patients with discordant results; P = 0.89). Revascularisation during admission (0.37 [0.13-0.96], P = 0.04) and amputation of the 5th ray (0.45 [0.21-0.94], P = 0.03) were independent risk factors for non-healing. CONCLUSION: There was a moderate-high degree of concordance between superficial wound swab results and intra-operative bone sample microbiology in this patient cohort. Discordance was not associated with adverse outcomes. These results suggest there is little clinical utility in routinely collecting proximal bone as an adjunct to routine wound swabs for culture during minor amputation for an infected DFU.

Population pharmacokinetic study of benzathine penicillin G administration in Indigenous children and young adults with rheumatic heart disease in the Northern Territory, Australia.

BACKGROUND: Benzathine penicillin G (BPG) is the cornerstone of secondary prophylaxis to prevent Streptococcus pyogenes infections, which precede acute rheumatic fever (ARF). The paucity of pharmacokinetic (PK) data from children and adolescents from populations at the highest risk of ARF and rheumatic heart disease (RHD) poses a challenge for determining the optimal dosing and frequency of injections and undermines efforts to develop improved regimens. METHODS: We conducted a 6 month longitudinal PK study of young people receiving BPG for secondary prophylaxis. Throat and skin swabs were collected for microbiological culture along with dried blood spot (DBS) samples for penicillin concentrations. DBSs were assayed using LC-MS/MS. Penicillin concentration datasets were analysed using non-linear mixed-effects modelling and simulations performed using published BMI-for-age and weight-for-age data. RESULTS: Nineteen participants provided 75 throat swabs, 3 skin swabs and 216 penicillin samples. Throat cultures grew group C and G Streptococcus. Despite no participant maintaining penicillin concentration >20 ng/mL between doses, there were no S. pyogenes throat infections and no ARF. The median (range) observed durations >20 ng/mL for the low- and high-BMI groups were 14.5 (11.0-24.25) and 15.0 (7.5-18.25) days, respectively. CONCLUSIONS: Few patients at highest risk of ARF/RHD receiving BPG for secondary prophylaxis maintain penicillin concentrations above the target of 20 ng/mL beyond 2 weeks during each monthly dosing interval. These PK data suggest that some high-risk individuals may get inadequate protection from every 4 week dosing. Future research should explore this gap in knowledge and PK differences between different populations to inform future dosing schedules.

Influence of sex on survival, neurologic outcomes, and neurodiagnostic testing after out-of-hospital cardiac arrest.

AIM: Previous studies evaluating the relationship between sex and post-resuscitation care and outcomes following out-of-hospital cardiac arrest (OHCA) are conflicting. We investigated the association between sex and outcomes as well as neurodiagnostic testing in a prospective multicenter international registry of patients admitted to intensive care units following OHCA. METHODS: OHCA survivors enrolled in the International Cardiac Arrest Registry (INTCAR) from 2012 to 2017 were included. We assessed the independent association between sex and survival to hospital discharge, good neurologic outcome (Cerebral Performance Category 1 or 2), neurodiagnostic testing, and withdrawal of life-sustaining therapy (WLST). RESULTS: Of 2407 eligible patients, 809 (33.6%) were women. Baseline characteristics differed by sex, with less bystander CPR and initial shockable rhythms among women. Women were less likely to survive to hospital discharge, however significance abated following adjusted analysis (30.1% vs 42.7%, adjusted OR 0.85, 95% CI 0.67-1.08). Women were less likely to have good neurologic outcome at discharge (21.4% vs 34.0%, adjusted OR 0.74, 95% CI 0.57-0.96) and at six months post-arrest (16.7% vs 29.4%, adjusted OR 0.73, 95% CI 0.54-0.98) that persisted after adjustment. Neuroimaging (75.5% vs 74.3%, p = 0.54) and other neurophysiologic testing (78.8% vs 78.6%, p = 0.91) was similar across sex. Women were more likely to undergo WLST (55.6% vs 42.8%, adjusted OR 1.35, 95% CI 1.09-1.66). CONCLUSIONS: Women with cardiac arrest have lower odds of good neurologic outcomes and higher odds of WLST, despite comparable rates of neurodiagnostic testing and after controlling for baseline differences in clinical characteristics and cardiac arrest features.

Quality of benzathine penicillin G: A multinational cross-sectional study.

Benzathine penicillin G (BPG) is used as first-line treatment for most forms of syphilis and as secondary prophylaxis against rheumatic heart disease (RHD). Perceptions that poor quality of BPG is linked to reported adverse effects and therapeutic failure may impact syphilis and RHD control programs. Clinical networks and web-based advertising were used to obtain vials of BPG from a wide range of countries. The quality of BPG was assessed using a high performance liquid chromatography assay capable of detecting relevant impurities and degradation products. Tests for water content, presence of heavy metals and physical characteristics of BPG, including particle size analysis and optical microscopy, also were conducted. Thirty-five batches of BPG were sourced from 16 countries across 4 WHO regions. All batches passed the US Pharmacopeia requirements for BPG injection (content), with no evidence of breakdown products or other detected contaminants. Water content and heavy metal analysis (n = 11) indicated adherence to regulatory standards and Good Manufacturing Practice. Particle size analysis (n = 20) found two batches with aggregated particles (>400 µm) that were dispersed following sonication. Current batches of BPG were of satisfactory pharmaceutical quality but aggregated particles were found in a modest proportion of samples. Future studies should focus on the physical characteristics of BPG which may contribute to variations in plasma penicillin concentrations an observed needle blockages in clinical practice. Pharmacopeial monographs could be revised to include standards on particle size and crystal morphology of BPG.

Subcutaneous administration of benzathine benzylpenicillin G has favourable pharmacokinetic characteristics for the prevention of rheumatic heart disease compared with intramuscular injection: a randomized, crossover, population pharmacokinetic study in healthy adult volunteers.

BACKGROUND: Benzathine penicillin G has been used as monthly deep intramuscular (IM) injections since the 1950s for secondary prevention of acute rheumatic fever and rheumatic heart disease (RHD). Injection frequency and pain are major programmatic barriers for adherence, prompting calls for development of better long-acting penicillin preparations to prevent RHD. We hypothesized that subcutaneous (SC) administration of benzathine penicillin G could delay penicillin absorption when compared with IM injections. METHODS: To compare the pharmacokinetic profile and tolerability of benzathine penicillin G according to different routes of administration, 15 healthy males participated in a randomized crossover study to receive benzathine penicillin G by either SC or IM routes, with a 10 week washout period before the second dose by the alternative route. Ultrasound guidance confirmed injection location. Penicillin concentrations and pain scores were measured for 6 weeks following injections. RESULTS: SC administration was well tolerated with no significant differences in pain scores. Following SC injection, the principal absorption half-life (95% CI) was 20.1 (16.3-29.5) days and 89.6% (87.1%-92.0%) of the drug was directed via this pathway compared with 10.2 (8.6-12.5) days and 71.3% (64.9%-77.4%) following IM administration. Lower peak and higher trough penicillin concentrations resulted following SC injection. Simulations demonstrated that SC infusion of higher doses of benzathine penicillin G could provide therapeutic penicillin concentrations for 3 months. CONCLUSIONS: SC administration of benzathine penicillin G is safe and significantly delays penicillin absorption. High-dose benzathine penicillin G via the SC route would fulfil many product characteristics required for the next generation of longer-acting penicillins for use in RHD.

Functional outcomes associated with varying levels of targeted temperature management after out-of-hospital cardiac arrest - An INTCAR2 registry analysis.

INTRODUCTION: Targeted temperature management (TTM) after out-of-hospital cardiac arrest (OHCA) has been recommended in international guidelines since 2005. The TTM-trial published in 2013 showed no difference in survival or neurological outcome for patients randomised to 33 °C or 36 °C, and many hospitals have changed practice. The optimal utilization of TTM is still debated. This study aimed to analyse if a difference in temperature goal was associated with outcome in an unselected international registry population. METHODS: This is a retrospective observational study based on a prospective registry - the International Cardiac Arrest Registry 2. Patients were categorized as receiving TTM in the lower range at 32-34 °C (TTM-low) or at 35-37 °C (TTM-high). Primary outcome was good functional status defined as cerebral performance category (CPC) of 1-2 at hospital discharge and secondary outcome was adverse events related to TTM. A logistic regression model was created to evaluate the independent effect of temperature by correcting for clinical and demographic factors associated with outcome. RESULTS: Of 1710 patients included, 1242 (72,6%) received TTM-low and 468 (27,4%) TTM-high. In patients receiving TTM-low, 31.3% survived with good outcome compared to 28.8% in the TTM-high group. There was no significant association between temperature and outcome (p = 0.352). In analyses adjusted for baseline differences the OR for a good outcome with TTM-low was 1.27, 95% CI (0.94-1.73). Haemodynamic instability leading to discontinuation of TTM was more common in TTM-low. CONCLUSIONS: No significant difference in functional outcome at hospital discharge was found in patients receiving lower- versus higher targeted temperature management.

Correction to: Variability in functional outcome and treatment practices by treatment center after out-of-hospital cardiac arrest: analysis of International Cardiac Arrest Registry.

The original version of this article unfortunately contained a mistake.

Severe adverse events following benzathine penicillin G injection for rheumatic heart disease prophylaxis: cardiac compromise more likely than anaphylaxis.

OBJECTIVE: Secondary prophylaxis through long-term antibiotic administration is essential to prevent the progression of acute rheumatic fever to rheumatic heart disease (RHD). Benzathine penicillin G (BPG) has been shown to be the most efficacious antibiotic for this purpose; however, adverse events associated with BPG administration have been anecdotally reported. This study therefore aimed to collate case reports of adverse events associated with BPG administration for RHD prophylaxis. STUDY DESIGN: A literature review was used to explore reported adverse reactions to BPG and inform development of a case report questionnaire. This questionnaire was circulated through professional networks to solicit retrospective reports of adverse events from treating physicians. Returned surveys were tabulated and thematically analysed. Reactions were assessed using the Brighton Collaboration case definition to identity potential anaphylaxis. RESULTS: We obtained 10 case reports from various locations, with patients ranging in age from early-teens to adults. All patients had clinical or echocardiogram-obtained evidence of valvular disease. The majority of patients (80%) had received BPG prior to the event with no previous adverse reaction. In eight cases, the reaction was fatal; in one case resuscitation was successful and in one case treatment was not required. Only three cases met Level 1 Brighton criteria consistent with anaphylaxis. CONCLUSION: These results indicate that anaphylaxis is not a major cause of adverse reactions to BPG. An alternative mechanism for sudden death following BPG administration in people with severe RHD is proposed.

A population pharmacokinetic study of benzathine benzylpenicillin G administration in children and adolescents with rheumatic heart disease: new insights for improved secondary prophylaxis strategies.

BACKGROUND: Benzathine benzylpenicillin G (BPG) is recommended as secondary prophylaxis to prevent recurrence of acute rheumatic fever and subsequent rheumatic heart disease (RHD). Following intramuscular injection, BPG is hydrolysed to benzylpenicillin. Little is known of the pharmacokinetics of benzylpenicillin following BPG in populations at risk of RHD. METHODS: We conducted a longitudinal pharmacokinetic study of children and adolescents receiving secondary prophylaxis throughout six monthly cycles of BPG. Dried blood spot samples were assayed with LC-MS/MS. Benzylpenicillin concentrations were analysed using non-linear mixed-effects modelling with subsequent simulations based on published BMI-for-age and weight-for-age data. RESULTS: Eighteen participants contributed 256 concentrations for analysis. None had benzylpenicillin concentrations >0.02 mg/L for the full time between doses. The median duration above this target was 9.8 days for those with a lower BMI (<25 kg/m2), who also had lower weights, and 0 days for those with a higher BMI (≥25 kg/m2). Although fat-free mass was a key determinant of benzylpenicillin exposure after a standard dose of BPG, having a higher BMI influenced absorption and almost doubled (increase of 86%) the observed t½. CONCLUSIONS: Few children and adolescents receiving BPG as secondary prophylaxis will achieve concentrations >0.02 mg/L for the majority of the time between injections. The discordance of this observation with reported efficacy of BPG to prevent rheumatic fever implies a major knowledge gap relating to pharmacokinetic/pharmacodynamic relationships between benzylpenicillin exposure and clinical outcomes.

Antimicrobial stewardship opportunities among inpatients with diabetic foot infections: microbiology results from a tertiary hospital multidisciplinary unit.

Among 125 inpatients with diabetic foot infections managed by a multidisciplinary foot ulcer unit, knowledge of methicillin-resistant Staphylococcus aureus colonisation status assisted decision-making to prescribe appropriately or with-hold empiric anti-methicillin-resistant Staphylococcus aureus therapy. Despite adherence to national guidelines, apparent overuse of anti-pseudomonal therapy was frequent, providing potential antimicrobial stewardship opportunities.

Early withdrawal of life support after resuscitation from cardiac arrest is common and may result in additional deaths.

AIM: "Early" withdrawal of life support therapies (eWLST) within the first 3 calendar days after resuscitation from cardiac arrest (CA) is discouraged. We evaluated a prospective multicenter registry of patients admitted to hospitals after resuscitation from CA to determine predictors of eWLST and estimate its impact on outcomes. METHODS: CA survivors enrolled from 2012-2017 in the International Cardiac Arrest Registry (INTCAR) were included. We developed a propensity score for eWLST and matched a cohort with similar probabilities of eWLST who received ongoing care. The incidence of good outcome (Cerebral Performance Category of 1 or 2) was measured across deciles of eWLST in the matched cohort. RESULTS: 2688 patients from 24 hospitals were included. Median ischemic time was 20 (IQR 11, 30) minutes, and 1148 (43%) had an initial shockable rhythm. Withdrawal of life support occurred in 1162 (43%) cases, with 459 (17%) classified as eWLST. Older age, initial non-shockable rhythm, increased ischemic time, shock on admission, out-of-hospital arrest, and admission in the United States were each independently associated with eWLST. All patients with eWLST died, while the matched cohort, good outcome occurred in 21% of patients. 19% of patients within the eWLST group were predicted to have a good outcome, had eWLST not occurred. CONCLUSIONS: Early withdrawal of life support occurs frequently after cardiac arrest. Although the mortality of patients matched to those with eWLST was high, these data showed excess mortality with eWLST.

Variability in functional outcome and treatment practices by treatment center after out-of-hospital cardiac arrest: analysis of International Cardiac Arrest Registry.

PURPOSE: Functional outcomes vary between centers after out-of-hospital cardiac arrest (OHCA) and are partially explained by pre-existing health status and arrest characteristics, while the effects of in-hospital treatments on functional outcome are less understood. We examined variation in functional outcomes by center after adjusting for patient- and arrest-specific characteristics and evaluated how in-hospital management differs between high- and low-performing centers. METHODS: Analysis of observational registry data within the International Cardiac Arrest Registry was used to perform a hierarchical model of center-specific risk standardized rates for good outcome, adjusted for demographics, pre-existing functional status, and arrest-related factors with treatment center as a random effect variable. We described the variability in treatments and diagnostic tests that may influence outcome at centers with adjusted rates significantly above and below registry average. RESULTS: A total of 3855 patients were admitted to an ICU following cardiac arrest with return of spontaneous circulation. The overall prevalence of good outcome was 11-63% among centers. After adjustment, center-specific risk standardized rates for good functional outcome ranged from 0.47 (0.37-0.58) to 0.20 (0.12-0.26). High-performing centers had faster time to goal temperature, were more likely to have goal temperature of 33 °C, more likely to perform unconscious cardiac catheterization and percutaneous coronary intervention, and had differing prognostication practices than low-performing centers. CONCLUSIONS: Center-specific differences in outcomes after OHCA after adjusting for patient-specific factors exist. This variation could partially be explained by in-hospital management differences. Future research should address the contribution of these factors to the differences in outcomes after resuscitation.

Variation in Sedation and Neuromuscular Blockade Regimens on Outcome After Cardiac Arrest.

OBJECTIVES: Sedation and neuromuscular blockade protocols in patients undergoing targeted temperature management after cardiac arrest address patient discomfort and manage shivering. These protocols vary widely between centers and may affect outcomes. DESIGN: Consecutive patients admitted to 20 centers after resuscitation from cardiac arrest were prospectively entered into the International Cardiac Arrest Registry between 2006 and 2016. Additional data about each center's sedation and shivering management practice were obtained via survey. Sedation and shivering practices were categorized as escalating doses of sedation and minimal or no neuromuscular blockade (sedation and shivering practice 1), sedation with continuous or scheduled neuromuscular blockade (sedation and shivering practice 2), or sedation with as-needed neuromuscular blockade (sedation and shivering practice 3). Good outcome was defined as Cerebral Performance Category score of 1 or 2. A logistic regression hierarchical model was created with two levels (patient-level data with standard confounders at level 1 and hospitals at level 2) and sedation and shivering practices as a fixed effect at the hospital level. The primary outcome was dichotomized Cerebral Performance Category at 6 months. SETTING: Cardiac arrest receiving centers in Europe and the United states from 2006 to 2016 PATIENTS:: Four-thousand two-hundred sixty-seven cardiac arrest patients 18 years old or older enrolled in the International Cardiac Arrest Registry. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The mean age was 62 ± 15 years, 36% were female, 77% out-of-hospital arrests, and mean ischemic time was 24 (± 18) minutes. Adjusted odds ratio (for age, return of spontaneous circulation, location of arrest, witnessed, initial rhythm, bystander cardiopulmonary resuscitation, defibrillation, medical history, country, and size of hospital) was 1.13 (0.74-1.73; p = 0.56) and 1.45 (1.00-2.13; p = 0.046) for sedation and shivering practice 2 and sedation and shivering practice 3, respectively, referenced to sedation and shivering practice 1. CONCLUSION: Cardiac arrest patients treated at centers using as-needed neuromuscular blockade had increased odds of good outcomes compared with centers using escalating sedation doses and avoidance of neuromuscular blockade, after adjusting for potential confounders. These findings should be further investigated in prospective studies.

Large-aperture plasma-assisted deposition of inertial confinement fusion laser coatings.

Plasma-assisted electron-beam evaporation leads to changes in the crystallinity, density, and stresses of thin films. A dual-source plasma system provides stress control of large-aperture, high-fluence coatings used in vacuum for substrates 1m in aperture.