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.

Prehospital Tranexamic Acid Administration During Aeromedical Transport After Injury.

BACKGROUND: Tranexamic acid (TXA) has been shown to reduce mortality in the treatment of traumatic hemorrhage. This effect seems most profound when given early after injury. We hypothesized that extending a protocol for TXA administration into the prehospital aeromedical setting would improve outcomes while maintaining a similar safety profile to TXA dosed in the emergency department (ED). MATERIALS AND METHODS: We identified all trauma patients who received TXA during prehospital aeromedical transport or in the ED at our urban level I trauma center over an 18-mo period. These patients had been selected prospectively for TXA administration using a protocol that selected adult trauma patients with high-risk mechanism and concern for severe hemorrhage to receive TXA. Patient demographics, vital signs, lab values including thromboelastography, blood administration, mortality, and complications were reviewed retrospectively and analyzed. RESULTS: One hundred sixteen patients were identified (62 prehospital versus 54 ED). Prehospital TXA patients were more likely to have sustained blunt injury (76% prehospital versus 46% ED, P = 0.002). There were no differences between groups in injury severity score or initial vital signs. There were no differences in complication rates or mortality. Patients receiving TXA had higher rates of venous thromboembolic events (8.1% in prehospital and 18.5% in ED) than the overall trauma population (2.1%, P < 0.001). CONCLUSIONS: Prehospital administration of TXA during aeromedical transport did not improve survival compared with ED administration. Treatment with TXA was associated with increased risk of venous thromboembolic events. Prehospital TXA protocols should be refined to identify patients with severe hemorrhagic shock or traumatic brain injury.

Continuous Infusion Ketamine for Adjunctive Analgosedation in Mechanically Ventilated, Critically Ill Patients.

OBJECTIVE: Ketamine is an N-methyl-D-aspartate antagonist with emerging evidence assessing its use as a continuous infusion agent to provide concomitant analgesia and sedation. The role of ketamine as adjunctive therapy in mechanically ventilated patients is unclear. This study sought to investigate the impact of adjunctive continuous infusion ketamine on concomitant analgesic and sedative dosing while providing goal comfort in mechanically ventilated patients. METHODS: This retrospective two-center intrapatient comparison study included mechanically ventilated adult ICU patients who received continuous infusion ketamine with at least one other analgesic or sedative infusion. The primary outcome assessed percent relative change in concomitant analgesic-sedative doses 24 hours after ketamine initiation. Secondary outcomes included percent of Richmond Agitation and Sedation Score (RASS) assessments at goal, adverse effects, and delirium incidence. Exploratory evaluation of independent factors associated with ketamine responders (50% or more relative reduction in analgesic-sedative dosing requirements at 24 hrs) and nonresponders (less than 50% relative reduction) was performed using multivariate logistic regression. RESULTS: Overall, 104 patients were included. A total of 160 concomitant analgesic-sedative infusions were used in combination with ketamine, most commonly fentanyl (98 [61.3%]) and propofol (46 [28.8%]). A 20% (interquartile range [IQR] -63.6 to 0.0, p<0.001) relative reduction in total analgesic-sedative infusion pharmacotherapy was achieved at 24 hours after ketamine initiation. Analgesic and sedative infusion doses decreased at 24 hours (fentanyl: pre, 175 µg/hr [IQR 100-200 µg/hr] vs post, 125 µg/hr [IQR 50-200 µg/hr], p<0.001; propofol: pre, 42.5 µg/kg/min [IQR 20.0-60.0 µg/kg/min] vs post, 20.0 µg/kg/min [IQR 3.8-31.3 µg/kg/min], p<0.001). Median percent time within goal RASS improved after ketamine initiation (pre, 7.1% [0-40%] vs post, 25% [0-66.7%], p=0.005). No differences were observed in secondary outcomes between responders and nonresponders, except a longer non-ICU hospital length of stay in responders. Independent factors associated with ketamine response included a lower body mass index, higher starting dose of ketamine, lower severity of illness, and need for multiple concomitant analgesic-sedative infusions before initiation of ketamine. CONCLUSIONS: Adjunctive continuous infusion ketamine promotes analgesic and sedative dose-sparing effects in mechanically ventilated patients while improving time spent within goal sedation range. Further prospective research is warranted.

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.

Stepwise approach to implementing ambulatory clinical pharmacy services.

PURPOSE: A methodological approach was developed to facilitate expansion of clinical pharmacist-managed anticoagulation services across an integrated health care delivery network. METHODS: A stepwise approach to the development and implementation of ambulatory care clinical pharmacy services was used to facilitate expansion of pharmacist-managed anticoagulation clinics in a university hospital setting and a community hospital within the same health network. RESULTS: The Health Alliance of Greater Cincinnati successfully created a care delivery model using clinical pharmacists to provide comprehensive anticoagulation management services at a university hospital and a community hospital. The incidence of thromboembolic events was significantly lower in the pharmacy anticoagulation service patients versus the patients in the usual care setting (p=0.005). A statistically significant decrease in minor bleeding events was observed in the pharmacist-managed group (p=0.038). Although a decrease in major bleeding events was observed, it was not statistically significant (p=0.075). International Normalized Ratio values of the patients managed by the pharmacy anticoagulation clinics were within the therapeutic range approximately 75% of the time. CONCLUSION: A stepwise approach to the development and implementation of ambulatory care clinical pharmacy services has facilitated the expansion of pharmacist-managed anticoagulation clinics across an integrated health system. This may serve as a valuable template for other systems as they strive to develop medication therapy management services.

An automated dispensing system for improving medication timing in the emergency department.

BACKGROUND: Numerous medical conditions require timely medication administration in the emergency department (ED). Automated dispensing systems (ADSs) store premixed common doses at the point-of-care to minimize time to administration, but the use of such automation to improved time to medication administration has not been studied. Since vancomycin is a commonly used empiric antimicrobial, we sought to quantify the effect of using an ADS on time to drug delivery in patients presenting to the ED. The study aimed to determine the efficacy of utilizing an ADS to improve time to administration of vancomycin and determine any negative effects on dosing appropriateness. METHODS: The institional review board approved the retrospective quality improvement study took place in a single, urban academic tertiary care ED with an annual census of 80 000. Study subjects were all patients receiving vancomycin for the management of sepsis between March 1 to September 30, 2008 and the same time period in 2009. The primary outcome was the proportion of patients who received vancomycin within one hour of bed placement and the secondary outcome was dosing appropriateness. RESULTS: Sixty-three patients had weight and dosing information available (29 before and 34 after intervention) and were included in the study. Before intervention, no patient received vancomycin in less than 60 minutes, while after intervention 14.7% of the patients received it in less than 60 minutes (difference in proportions 14.7%, 95% CI 0.39%-30.0%, P=0.04). A similar proportion of the patients received correct dosing before and after intervention (44.8% vs. 41.2%, difference in proportions 3.7%, 95% CI -20.0%-26.7%, P=0.770). CONCLUSION: The use of an ADS may improve the timing of medication administration in patients presenting to the ED without affecting dosing appropriateness.