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.

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.

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.