Antibiotic Duration Following Abdominal Gunshot Injuries With Associated Pelvis or Spine Involvement: A 20-Year Single-Center Experience.

INTRODUCTION: Optimal antimicrobial prophylaxis duration following gunshot wounds (GSW) to the abdomen with an associated orthopedic fracture is unknown. This study evaluated the safety and efficacy of short versus long courses of prophylactic antibiotics following penetrating hollow viscus injury with communicating orthopedic fracture. METHODS: This retrospective study included adult patients admitted to the trauma service over a 20-y period who sustained an abdominal GSW with hollow viscus injury and communicating spine or pelvic fractures. Patients were stratified into cohorts based on prophylactic antibiotic duration: short course (SC, ≤48 h) and long course (>48 h). The primary outcome was the incidence of osteomyelitis and meningitis up to 1-y postinjury. Secondary outcomes included hospital length of stay and the incidence of multidrug-resistant organisms and Clostridioides difficile infections. Risk factors for osteomyelitis and meningitis were determined. RESULTS: A total of 125 patients were included with 45 (36%) in the SC group. Median prophylactic antibiotic durations were SC, 1 (interquartile range [IQR], 1-2) versus long course, 7 (IQR, 5-7) d (P < 0.001). There was no difference in osteomyelitis and meningitis incidence (2 [4.4%] versus 4 [5%], P = 0.77). Median hospital length of stay (7 [IQR, 6-11] versus 9 [IQR, 6-15] d, P = 0.072) and incidence of multidrug-resistant organisms (6 [13.3%] versus 13 [16.3%], P = 0.86) and Clostridioides difficile infections (0 [0%] versus 1 [1.3%], P = 0.77) were similar between groups. There were no independent risk factors identified for osteomyelitis or meningitis. CONCLUSIONS: A shorter course of antibiotic prophylaxis ≤48 h may be adequate following abdominal GSW that traverses a hollow viscus and results in pelvic fracture or spinal column injury.

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.

Reversal of apixaban and rivaroxaban with andexanet alfa prior to invasive or surgical procedures.

BACKGROUND: Outcomes following andexanet alfa reversal of factor Xa inhibitors in patients requiring urgent or emergent invasive procedures are lacking. This study aimed to describe efficacy and safety outcomes following andexanet alfa administration within 24 h of an invasive procedure. METHODS: This single-center, observational, retrospective study included patients who received andexanet alfa within 24 h of an invasive or surgical procedure. The primary outcome was hemostatic efficacy graded as excellent, good, or poor using similar definitions to the ANNEXA-4 criteria. Secondary outcomes included hospital discharge disposition, intensive care unit (ICU) and hospital length of stay, 30-day mortality, 30-day thromboischemic event rates, and serum coagulation assay changes pre- and postreversal. RESULTS: Forty-four patients met inclusion criteria; of these, 27 (62.8%) received apixaban and 16 (37.2%) were treated with rivaroxaban prior to admission. The indications for reversal were categorized as intracranial (n = 20 [45.5%]) or extracranial (n = 24 [54.5%]) sites. Majority of patients required emergent operative procedures (18 [40.9%]), followed by invasive device placement (10 [22.7%]) or arterial embolization (9 [20.5%]). Thirty-eight (86.4%) patients were able to be adequately graded for hemostatic efficacy. Overall, 30 (78.9%) patients achieved excellent or good hemostasis within 24 h after periprocedural administration of andexanet alfa (19 [82.6%] apixaban vs. 11 [78.6%] rivaroxaban; 12 [80.0%] intracranial events vs. 18 [78.3%] extracranial events). Discharge disposition was most often to a short- or long-term care facilities (27 [61.4%]). Thirty-day mortality and thromboischemic complications occurred in 15 (34.1%) and 12 (27.3%) patients, respectively. Prothrombin time and antifactor Xa assay results were significantly decreased after andexanet alfa administration (p < 0.05) while thromboelastogram assay values (reaction time, kinetic time, and activated clotting time) showed nonsignificant changes pre- versus postreversal. CONCLUSION: Andexanet alfa may be used for urgent or emergent reversal of apixaban and rivaroxaban peri-procedurally with promising hemostatic outcomes. Further prospective, comparative clinical research is warranted.

Andexanet alfa after 4-factor PCC administration for intracranial hemorrhage: a case series.

The ongoing controversy regarding optimal reversal agent for factor Xa-inhibitors is mainly due to lack of comparative data of andexanet alfa (AA) to 4-factor prothrombin complex concentrate (4F-PCC), institutional formulary restrictions, and navigation of clinical scenarios involving patients clinically worsen despite initial reversal efforts. The combination use of 4F-PCC and AA has not been evaluated in clinical trials and the outcomes of such patients with FXA-inhibitor associated intracranial hemorrhage (ICH) are unknown. A total of five patients, including four outside hospital transfers, received 4F-PCC prior to AA for FXa-inhibitor associated ICH (n = 3 apixaban, n = 2 rivaroxaban; n = 4 ICH, n = 1 TBI). The doses of 4F-PCC ranged from 25 to 60 units/kg and were administered within a range of 1.5-4.2 h prior to AA. One patient required surgical intervention with craniotomy and three patients underwent external ventricular drain placement. Two of the five patients developed an ischemic or thromboembolic complication within one week from 4F-PCC and AA administration. This case series discusses multiple unique patient cases in which 4F-PCC and AA were both administered for FXa-inhibitor associated ICH. The results highlight the potentially increased thrombotic risk associated with combination use. Ongoing post-marketing data collection of real patient case scenarios are essential to the establishment of consensus guidelines on how to prioritize initial reversal efforts and manage these patients during the course of their bleed.

Ketamine Stability over Six Months of Exposure to Moderate and High Temperature Environments.

Background: All medications should be stored within temperature ranges defined by manufacturers, but logistical and operational challenges of prehospital and military settings complicate adherence to these recommendations. Lorazepam and succinylcholine experience clinically relevant heat-related degradation, whereas midazolam does not. Because ketamine's stability when stored outside manufacturer recommendations is unknown, we evaluated the heat-related degradation of ketamine exposed to several temperature ranges. Methods: One hundred twenty vials of ketamine (50 mg/mL labeled concentration) from the same manufacturer lot were equally distributed and stored for six months in five environments: an active EMS unit in southwest Ohio (May-October 2019); heat chamber at constant 120 °F (C1); heat chamber fluctuating over 24 hours from 86 °F-120 °F (C2); heat chamber fluctuating over 24 hours from 40 °F-120 °F (C3); heat chamber kept at constant 70 °F (manufacturer recommended room temperature, C4). Four ketamine vials were removed every 30 days from each environment and sent to an FDA-accredited commercial lab for high performance liquid chromatography testing. Data loggers and thermistors allowed temperature recording every minute for all environments. Cumulative heat exposure was quantified by mean kinetic temperature (MKT), which accounts for additional heat-stress over time caused by temperature fluctuations and is a superior measure than simple ambient temperature. MKT was calculated for each environment at the time of ketamine removal. Descriptive statistics were used to describe the concentration changes at each time point. Results: The MKT ranged from 73.6 °F-80.7 °F in the active EMS unit and stayed constant for each chamber (C1 MKT: 120 °F, C2 MKT: 107.3 °F, C3 MKT: 96.5 °F, C4 MKT: 70 °F). No significant absolute ketamine degradation, or trends in degradation, occurred in any environment at any time point. The lowest median concentration occurred in the EMS-stored samples removed after 6 months [48.2 mg/mL (47.75, 48.35)], or 96.4% relative strength to labeled concentration. Conclusion: Ketamine samples exhibited limited degradation after 6 months of exposure to real world and simulated extreme high temperature environments exceeding manufacturer recommendations. Future studies are necessary to evaluate ketamine stability beyond 6 months.

Assessment of Detectable Serum Tobramycin Concentrations in Patients Receiving Inhaled Tobramycin for Ventilator-Associated Pneumonia.

BACKGROUND: Inhaled tobramycin can be used for empiric or definitive therapy of ventilator-associated pneumonia (VAP) in mechanically ventilated patients. This is believed to minimize systemic exposure and potential adverse drug toxicities including acute kidney injury (AKI). However, detectable serum tobramycin concentrations have been reported after inhaled tobramycin therapy with AKI. METHODS: This retrospective, observational study evaluated mechanically ventilated adult subjects admitted to ICUs at a large, urban academic medical center that received empiric inhaled tobramycin for VAP. Subjects were separated into detectable (ie, ≥ 0.6 mg/L) or undetectable serum tobramycin concentration groups, and characteristics were compared. Independent predictors for detectable serum tobramycin concentration and new onset AKI during or within 48 h of therapy discontinuation were assessed. RESULTS: Fifty-nine inhaled tobramycin courses in 53 subjects were included in the analysis, of which 39 (66.1%) courses administered to 35 (66.0%) subjects had detectable serum tobramycin concentrations. Subjects with detectable serum tobramycin concentrations were older (57.1 y ± 11.4 vs 45.9 ±15.0, P = .004), had higher PEEP (9.2 cm H2O [7.0-11.0] vs 8.0 [5.6-8.9], P = .049), chronic kidney disease stage ≥ 2 (10 [29.4%] vs 0 [0%], P = .009), and higher serum creatinine before inhaled tobramycin therapy (1.26 mg/dL [0.84-2.18] vs 0.76 [0.47-1.28], P = .004). Age (odds ratio 1.09 [95% CI 1.02-1.16], P = .009) and PEEP (odds ratio 1.47 [95% CI 1.08-2.0], P =.01) were independent predictors for detectable serum tobramycin concentration. Thirty-seven subjects had no previous renal disease or injury, of which 9 (24.3%) developed an AKI. Sequential Organ Failure Assessment score (odds ratio 1.72 [95% CI 1.07-2.76], P = .03) was the only independent predictor for AKI. CONCLUSIONS: Detectable serum tobramycin concentrations were frequently observed in critically ill, mechanically ventilated subjects receiving empiric inhaled tobramycin for VAP. Subject age and PEEP were independent predictors for detectable serum tobramycin concentration. Serum monitoring and empiric dose reductions should be considered in older patients and those requiring higher PEEP.

COPD Care Bundle in Emergency Department Observation Unit Reduces Emergency Department Revisits.

BACKGROUND: COPD exacerbations lead to accelerated decline in lung function, poor quality of life, and increased mortality and cost. Emergency department (ED) observation units provide short-term care to reduce hospitalizations and cost. Strategies to improve outcomes in ED observation units following COPD exacerbations are needed. We sought to reduce 30-d ED revisits for COPD exacerbations managed in ED observation units through implementation of a COPD care bundle. The study setting was an 800-bed, academic, safety-net hospital with 700 annual ED encounters for COPD exacerbations. Among those discharged from ED observation unit, the 30-d all-cause ED revisit rate (ie, the outcome measure) was 49% (baseline period: August 2014 through September 2016). METHODS: All patients admitted to the ED observation unit with COPD exacerbations were included. A multidisciplinary team implemented the COPD bundle using iterative plan-do-study-act cycles with a goal adherence of 90% (process measure). The bundle, adopted from our inpatient program, was developed using care-delivery failures and unmet subject needs. It included 5 components: appropriate inhaler regimen, 30-d inhaler supply, education on devices available after discharge, standardized discharge instructions, and a scheduled 15-d appointment. We used statistical process-control charts for process and outcome measures. To compare subject characteristics and process features, we sampled consecutive patients from the baseline (n = 50) and postbundle (n = 83) period over 5-month and 7-month intervals, respectively. Comparisons were made using t tests and chi-square tests with P < .05 significance. RESULTS: During baseline and postbundle periods, 410 and 165 subjects were admitted to the ED observation unit, respectively. After iterative plan-do-study-act cycles, bundle adherence reached 90% in 6 months, and the 30-d ED revisit rate declined from 49% to 30% (P = .003) with a system shift on statistical process-control charts. There was no difference in hospitalization rate from ED observation unit (45% vs 51%, P = .16). Subject characteristics were similar in the baseline and postbundle periods. CONCLUSIONS: Reliable adherence to a COPD care bundle reduced 30-d ED revisits among those treated in the ED observation unit.

Pharmacokinetics and Pharmacodynamics of Extended-Infusion Cefepime in Critically Ill Patients Receiving Continuous Renal Replacement Therapy: A Prospective, Open-Label Study.

STUDY OBJECTIVE: To evaluate extended-infusion (EI) cefepime pharmacokinetics (PK) and pharmacodynamic target attainment in critically ill patients receiving continuous venovenous hemofiltration (CVVH) or continuous venovenous hemodialysis (CVVHD). DESIGN: Prospective, open-label, PK study. SETTING: Intensive care units at a large, academic, tertiary-care medical center. PATIENTS: Ten critically ill adults who were receiving cefepime 2 g intravenously every 8 hours as a 4-hour infusion while receiving CVVH (eight patients) or CVVHD (two patients). INTERVENTION: Two sets of five serum cefepime concentrations were collected for each patient to assess pharmacokinetics before and during presumed steady state. Concurrent serum and CRRT effluent samples were collected at hours 1, 2, 3, 4, and 8 after the first cefepime dose and after either the fourth, fifth, or sixth (steady-state) cefepime doses. MEASUREMENTS AND MAIN RESULTS: Reversed-phase high-performance liquid chromatography was used to determine free cefepime concentrations. PK analyses included CRRT clearance, half-life, and sieving coefficient or saturation coefficient. Cefepime peak (4 hrs) concentrations, trough (8 hrs) concentrations (Cmin ), and minimum inhibitory concentration breakpoint of 8 µg/ml for the pathogen (MIC8 ) were used to evaluate attainment of pharmacodynamic targets: 100% of the dosing interval that free drug remains above MIC8 (100% fT > MIC8 ), 100% fT > 4 × MIC8 (optimal), percentage of time fT > 4 × MIC8 (%fT > 4 × MIC8 ) at steady state, and ratio of Cmin to MIC8 (fCmin /MIC8 ). Total CRRT effluent flow rate was a mean ± SD of 30.1 ± 5.4 ml/kg/hr, CRRT clearance was 39.6 ± 9.9 ml/min, and half-life was 5.3 ± 1.7 hours. Sieving coefficient or saturation coefficient were 0.83 ± 0.13 and 0.69 ± 0.22, respectively. First and steady-state dose Cmin were 23.4 ± 10.1 µg/ml and 45.2 ± 14.6 µg/ml, respectively. All patients achieved 100% fT > MIC8 on first and steady-state doses. First and steady-state dose 100% fT > 4 × MIC8 were achieved in 22% (2/9 patients) and 87.5% (7/8 patients) of patients, respectively. The mean %fT > 4 × MIC8 at steady state was 97.5%. The fCmin /MIC8 was 2.92 ± 1.26 for the first dose and 5.65 ± 1.83 at steady state. CONCLUSION: Extended-infusion cefepime dosing in critically ill patients receiving CRRT successfully attained 100% fT > MIC8 in all patients and an appropriate fCmin /MIC8 for both first and steady-state doses. All but one patient achieved 100% fT > 4 × MIC8 at steady state. No significant differences were observed in PK properties between first and steady-state doses among or between patients. It may be reasonable to initiate an empiric or definitive regimen of EI cefepime in critically ill patients receiving concurrent CRRT who are at risk for resistant organisms. Further research is needed to identify the optimal dosing regimen of EI cefepime in this patient population.

Recognition, Assessment, and Pharmacotherapeutic Treatment of Alcohol Withdrawal Syndrome in the Intensive Care Unit.

Alcohol withdrawal syndrome (AWS) is a complex neurologic disorder that develops after an acute reduction in or cessation of chronic alcohol consumption that alters neurotransmitter conduction. The incidence of AWS in the intensive care unit varies, but has been associated with poor outcomes. This is primarily driven by downregulation of gamma-aminobutyric acid (GABA) leading to autonomic excitability and psychomotor agitation. No clinical assessment tools have been validated to assess for AWS in the intensive care unit, particularly for patients requiring mechanical ventilation. The Clinical Institute Withdrawal Assessment for Alcohol Scale, Revised, may be considered to gauge the extent of withdrawal, but is not particular with acute presentations in this population. Symptom-triggered use of GABA agonist such as benzodiazepines remains the mainstay of pharmacotherapeutic intervention. Nonbenzodiazepine GABA agonists such as barbiturates and propofol as well as non-GABA adjunctive agents such as dexmedetomidine, ketamine, and antipsychotic agents may help reduce the need for symptom-triggered benzodiazepine dosing, but lack robust data. Agent selection should be based on patient-specific factors such as renal and hepatic metabolism, duration of action, and clearance. Institution-specific protocols directing GABA-acting medications and adjunctive medications for excitatory, adrenergic, and delirium assessments could be considered to improve patient outcomes and caregiver satisfaction.

Update on ultra-long-acting ß agonists in chronic obstructive pulmonary disease.

INTRODUCTION: For the last two decades, long-acting ß agonists (LABAs) have been a cornerstone in the management of chronic obstructive pulmonary disease (COPD). They relax airway smooth muscle and augment expiratory airflow, which reduces hyperinflation and improves dyspnea, functional capacity and quality of life. In recent years, Indacaterol, a LABA with an ultra-long duration of action (ultra-LABA), which only requires once-daily dosing, was approved by the FDA. The clinical efficacy of indacaterol is comparable, and, in some aspects better, than the currently available LABAs. AREAS COVERED: This article reviews the pharmacological properties, clinical efficacy, safety and potential role of the ultra-LABAs in COPD management. EXPERT OPINION: Ultra-LABAs are effective bronchodilators with a prolonged duration of action. By decreasing dosing frequency, ultra-LABAs potentially may improve respiratory medication adherence, which is associated with better survival and less healthcare utilization. In addition to their salubrious benefits, ß agonists may produce untoward effects. Increased mortality and hospitalizations among patients with left ventricular heart failure, who were treated with ß agonists, has caused concern about their use in patients with COPD and heart disease. Further experience and testing will determine the optimal role of ultra-LABAs in the management of COPD.