Out-of-Hospital Intranasal Ketamine as an Adjunct to Fentanyl for the Treatment of Acute Traumatic Pain: A Randomized Clinical Trial.

STUDY OBJECTIVE: To evaluate if out-of-hospital administration of fentanyl and intranasal ketamine, compared to fentanyl alone, improves early pain control after injury. METHODS: We conducted an out-of-hospital randomized, placebo-controlled, blinded, parallel group clinical trial from October 2017 to December 2021. Participants were male, aged 18 to 65 years, receiving fentanyl to treat acute traumatic pain prior to hospital arrival, treated by an urban fire-based emergency medical services agency, and transported to the region's only adult Level I trauma center. Participants randomly received 50 mg intranasal ketamine or placebo. The primary outcome was the proportion with a minimum 2-point reduction in self-described pain on the verbal numerical rating scale 30 minutes after study drug administration assessed by 95% confidence interval overlap. Secondary outcomes were side effects, pain ratings, and additional pain medications through the first 3 hours of care. RESULTS: Among the 192 participants enrolled, 89 (46%) were White, (median age, 36 years; interquartile range, 27 to 53 years), with 103 receiving ketamine and 89 receiving placebo. There was no difference in the proportion experiencing improved pain 30 minutes after treatment (46/103 [44.7%] ketamine versus 32/89 [36.0%] placebo; difference in proportions, 8.7%; 95% confidence interval, -5.1% to 22.5%; P=.22) or at any time point through 3 hours. There was no difference in secondary outcomes or side effects. CONCLUSION: In our sample, we did not detect an analgesic benefit of adding 50 mg intranasal ketamine to fentanyl in out-of-hospital trauma patients.

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.

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.

Clinical Experience, Characteristics, and Performance of an Acetaminophen Absorption Test in Critically Ill Patients.

BACKGROUND: Altered drug and nutrient absorption presents a unique challenge in critically ill patients. Performing an acetaminophen absorption test (AAT) has been used as a marker for gastric motility and upper small bowel absorption; thus, it may provide objective data regarding enteral absorptive ability in critically ill patients. STUDY QUESTION: What is the clinical experience with AAT when used as a surrogate marker for enteral absorption in critically ill patients? STUDY DESIGN: This single-center, retrospective, cohort study evaluated serum acetaminophen concentrations within 180 minutes following 1-time enteral administration of an AAT. Patients admitted to the surgical and medical intensive care units and medical intensive care units over a 7-year period were evaluated. Groups were defined as positive (acetaminophen concentration of ≥10 mg/L) or negative (acetaminophen concentration of <10 mg/L) AAT. MEASURES AND OUTCOMES: The outcomes were to describe the clinical experience, characteristics, and performance of AAT. RESULTS: Forty-eight patients were included. Patients were 58.5 ± 14 years of age, mostly male (58.3%), and admitted to the surgical intensive care unit (66.7%). Median hospital length of stay was 47.5 (27-78.8) days. Thirty-four patients (70.8%) had a positive AAT [median concentration, 14 (12-18) mg/L]. Median time to first detectable concentration was 37 (33-64) minutes. AAT characteristics were similar between the groups including total dose, weight-based dose, time to first and second assays, drug formulation, and site of administration between groups. There were no independent risk factors identified on regression analysis for negative AAT. CONCLUSIONS: An acetaminophen dose of 15 mg/kg with 2 coordinated serum concentrations approximately 30 and 60 minutes after administration is a reasonable construct for AAT. Future research is needed to assess AAT utility, safety, and clinical outcomes for predicting patient ability to absorb enteral feeds and medications.

Evaluating the Utility of High Sensitivity Troponin in Blunt Cardiac Injury.

INTRODUCTION: Screening for blunt cardiac injury (BCI) includes obtaining a serum troponin level and an electrocardiogram for patients diagnosed with a sternal fracture. Our institution has transitioned to the use of a high sensitivity troponin I (hsTnI). The aim of this study was to determine whether hsTnI is comparable to troponin I (TnI) in identifying clinically significant BCI. MATERIALS AND METHODS: Trauma patients presenting to a level I trauma center over a 24-mo period with the diagnosis of sternal fracture were screened for BCI. Any initial TnI more than 0.04 ng/mL or hsTnI more than 18 ng/L was considered positive for potential BCI. Clinically significant BCI was defined as a new-bundle branch block, ST wave change, echocardiogram change, or need for cardiac catheterization. RESULTS: Two hundred sixty five patients with a sternal fracture were identified, 161 underwent screening with TnI and 104 with hsTnI. For TnI, the sensitivity and specificity for detection of clinically significant BCI was 0.80 and 0.79, respectively. For hsTnI, the sensitivity and specificity for detection of clinically significant BCI was 0.71 and 0.69, respectively. A multivariate analysis demonstrated the odds ratio for significant BCI with a positive TnI was 14.4 (95% confidence interval, 3.9-55.8, P < 0.0001) versus an odds ratio of 5.48 (95% confidence interval 1.9-15.7, P = 0.002) in the hsTnI group. CONCLUSIONS: The sensitivity of hsTnI is comparable to TnI for detection of significant BCI. Additional investigation is needed to determine the necessity and interval for repeat testing and the need for additional diagnostic testing.

Ketamine in Critically Ill Patients: Use, Perceptions, and Potential Barriers.

Objective: To evaluate practitioner use of ketamine and identify potential barriers to use in acutely and critically ill patients. To compare characteristics, beliefs, and practices of ketamine frequent users and non-users. Methods: An online survey developed by members of the Society of Critical Care Medicine (SCCM) Clinical Pharmacy and Pharmacology Section was distributed to physician, pharmacist, nurse practitioner, physician assistant and nurse members of SCCM. The online survey queried SCCM members on self-reported practices regarding ketamine use and potential barriers in acute and critically ill patients. Results: Respondents, 341 analyzed, were mostly adult physicians, practicing in the United States at academic medical centers. Clinicians were comfortable or very comfortable using ketamine to facilitate intubation (80.0%), for analgesia (77.9%), procedural sedation (79.4%), continuous ICU sedation (65.8%), dressing changes (62.4%), or for asthma exacerbation and status epilepticus (58.8% and 40.4%). Clinicians were least comfortable with ketamine use for alcohol withdrawal and opioid detoxification (24.7% and 23.2%). Most respondents reported "never" or "infrequently" using ketamine preferentially for continuous IV analgesia (55.6%) or sedation (61%). Responses were mixed across dosing ranges and duration. The most common barriers to ketamine use were adverse effects (42.6%), other practitioners not routinely using the medication (41.5%), lack of evidence (33.5%), lack of familiarity (33.1%), and hospital/institutional policy guiding the indication for use (32.3%). Conclusion: Although most critical care practitioners report feeling comfortable using ketamine, there are many inconsistencies in practice regarding dose, duration, and reasons to avoid or limit ketamine use. Further educational tools may be targeted at practitioners to improve appropriate ketamine use.

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.

The Association of Norepinephrine Utilization With Mortality Risk in Trauma Patients.

INTRODUCTION: While the pillars of trauma resuscitation are surgical hemostasis and blood product administration, norepinephrine (NE) can be used as an adjunct. The goal of this study was to evaluate the relationship between the maximum dose of NE, timing of NE administration, and mortality in trauma patients. METHODS: Patients admitted between January 2013 and January 2021 treated with NE were reviewed. Univariate and multivariate logistic regression were used to assess whether maximum NE dose was independently associated with mortality. Optimal dosage rates for NE were determined via Youden Index. Subgroup analyses comparing those who received NE within versus after the first 24 h of admission were conducted. RESULTS: Three hundred fifty-first trauma patients were included, with 217 (62%) surviving. Patients who died received an average maximum dose of 16.7 mcg/min compared to 9.1 mcg/min in survivors (P = 0.0003). Mortality rate increased with dosage (P < 0.0001), with doses greater than 20 mcg/min having 79% mortality. Those who received NE within the first 24 h had an inflection point in mortality at 16 mcg/min (Youden = 0.45) (OR 1.06; 95% CI 1.03-1.10). For patients who received NE after the first 24 h, an inflection point in mortality was at 10 mcg/min (Youden = 0.34) (OR 1.09; 95% CI 1.04-1.14). CONCLUSIONS: Higher maximum doses of NE were associated with increased mortality. Patients initiated on NE more than 24 h into their admission displayed an inflection point at a lower dose than those initiated later. This suggests that trauma patients initiated on NE after 24 h from injury may have a dire prognosis.

Tracheostomy decreases continuous analgesia and sedation requirements.

BACKGROUND: The goals of sedation in the critically ill surgical patient are to minimize pain, anxiety, and agitation without hindering cardiopulmonary function. One potential benefit of tracheostomy during endotracheal intubation is the reduction of sedation and analgesia; however, there are little data to support this supposition. We hypothesized that patients undergoing tracheostomy would have a rapid reduction in sedation and analgesia following tracheostomy. METHODS: A retrospective review of tracheostomies performed at a single Level I trauma center from January 2013 to June 2018 was completed. An evaluation of Glasgow Coma Scale, Richmond Agitation-Sedation Scale, and Confusion Assessment Method for the intensive care unit 72 hours pretracheostomy to 72 hours posttracheostomy was performed. The total daily dose of sedation, anxiolytic, and analgesic medications administered were recorded. Mixed-effects models were used to evaluate longitudinal drug does over time (hours). RESULTS: Four hundred sixty-eight patients included for analysis with a mean age of 58.8 ± 18.3 years. There was a significant decrease in propofol and fentanyl utilization from 24 hours pretracheostomy to 24 hours posttracheostomy in both dose and number of patients receiving these continuous intravenous medications. Similarly, total morphine milligram equivalents (MME) use and continuous midazolam significantly decreased from 24 hours pretracheostomy to 24 hours posttracheostomy. By contrast, intermittent enteral quetiapine and methadone administration increased after tracheostomy. Importantly, Richmond Agitation-Sedation Scale, Glasgow Coma Scale, and Confusion Assessment Method scoring were also significantly improved as early as 24 hours posttracheostomy. Total MME use was significantly elevated in patients younger than 65 years and in male patients pretracheostomy compared with female patients. Patients admitted to the medical intensive care unit had significantly higher MME use compared with those in the surgical intensive care unit pretracheostomy. CONCLUSION: Tracheostomy allows for a rapid and significant reduction in intravenous sedation and analgesia medication utilization. Posttracheostomy sedation can transition to intermittent enteral medications, potentially contributing to the observed improvements in postoperative mental status and agitation. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level III.

Retrospective Evaluation of Intrapleural Tissue Plasminogen Activator With or Without Dornase Alfa for the Treatment of Traumatic Retained Hemothorax: A 6-Year Experience.

BACKGROUND: Intrapleural fibrinolytic instillation is second-line treatment for retained hemothorax. Dornase alfa (DNase) has demonstrated efficacy in parapneumonic effusion, but the lack of deoxyribonucleoproteins limits direct extrapolation to traumatic retained hemothorax treatment. OBJECTIVE: This study evaluated the effectiveness of intrapleural tissue plasminogen activator (tPA) with and without DNase in the treatment of retained traumatic hemothorax. METHODS: This retrospective cohort study included patients aged 16 years and older admitted to a level 1 trauma center from January 2013 through July 2019 with retained hemothorax and one or more intrapleural tPA instillations. Exclusion criteria were tPA for other indications or concomitant empyema. The primary endpoint was treatment failure defined as the need for operative intervention. RESULTS: Fifty patients were included (tPA alone: 28; tPA with DNase: 22). Baseline characteristics were similar between groups, including time to diagnosis (6.5 [interquartile range (IQR), 4-15.5] days vs 6 [IQR, 6.3-10.8] days, P = 0.52). Median tPA dose per treatment (6 [IQR, 6-6.4] mg vs 10 [IQR, 8.4-10] mg, P < 0.001) and cumulative tPA (18 [IQR, 6.5-24] mg vs 30 [IQR, 29.5-40], P < 0.001) dose were significantly lower in the tPA alone group. Treatment failure was similar between groups. Chest tube output, retained hemothorax reduction, and bleeding incidences were similar between groups. Multivariate logistic regression demonstrated no significant risk factors for treatment failure. CONCLUSIONS AND RELEVANCE: Dornase alfa added to tPA may not reduce the need for operation to treat retained hemothorax. Further studies should be directed at optimal tPA dose determination and economic impact of inappropriate DNase use.

Multicenter Retrospective Review of Ketamine Use in the ICU.

The response of ICU patients to continuously infused ketamine when it is used for analgesia and/or sedation remains poorly established. OBJECTIVES: To describe continuous infusion (CI) ketamine use in critically ill patients, including indications, dose and duration, adverse effects, patient outcomes, time in goal pain/sedation score range, exposure to analgesics/sedatives, and delirium. DESIGN SETTING AND PARTICIPANTS: Multicenter, retrospective, observational study from twenty-five diverse institutions in the United States. Patients receiving CI ketamine between January 2014 and December 2017. MAIN OUTCOMES AND MEASURES: Chart review evaluating institutional and patient demographics, ketamine indication, dose, administration, and adverse effects. Pain/sedation scores, cumulative doses of sedatives and analgesics, and delirium screenings in the 24 hours prior to ketamine were compared with those at 0-24 hours and 25-48 hours after. RESULTS: A total of 390 patients were included (median age, 54.5 yr; interquartile range, 39-65 yr; 61% males). Primary ICU types were medical (35.3%), surgical (23.3%), and trauma (17.7%). Most common indications were analgesia/sedation (n = 357, 91.5%). Starting doses were 0.2 mg/kg/hr (0.1-0.5 mg/kg/hr) and continued for 1.6 days (0.6-2.9 d). Hemodynamics in the first 4 hours after ketamine were variable (hypertension 24.0%, hypotension 23.5%, tachycardia 19.5%, bradycardia 2.3%); other adverse effects were minimal. Compared with 24 hours prior, there was a significant increase in proportion of time spent within goal pain score after ketamine initiation (24 hr prior: 68.9% [66.7-72.6%], 0-24 hr: 78.6% [74.3-82.5%], 25-48 hr: 80.3% [74.6-84.3%]; p < 0.001) and time spent within goal sedation score (24 hr prior: 57.1% [52.5-60.0%], 0-24 hr: 64.1% [60.7-67.2%], 25-48 hr: 68.9% [65.5-79.5%]; p < 0.001). There was also a significant reduction in IV morphine (mg) equivalents (24 hr prior: 120 [25-400], 0-24 hr: 118 [10-363], 25-48 hr: 80 [5-328]; p < 0.005), midazolam (mg) equivalents (24 hr prior: 11 [4-67], 0-24 hr: 6 [0-68], 25-48 hr: 3 [0-57]; p < 0.001), propofol (mg) (24 hr prior: 942 [223-4,018], 0-24 hr: 160 [0-2,776], 25-48 hr: 0 [0-1,859]; p < 0.001), and dexmedetomidine (µg) (24 hr prior: 1,025 [276-1,925], 0-24 hr: 285 [0-1,283], 25-48 hr: 0 [0-826]; p < 0.001). There was no difference in proportion of time spent positive for delirium (24 hr prior: 43.0% [17.0-47.0%], 0-24 hr: 39.5% [27.0-43.8%], 25-48 hr: 0% [0-43.7%]; p = 0.233). Limitations to these data include lack of a comparator group, potential for confounders and selection bias, and varying pain and sedation practices that may have changed since completion of the study. CONCLUSIONS AND RELEVANCE: There is variability in the use of CI ketamine. Hemodynamic instability was the most common adverse effect. In the 48 hours after ketamine initiation compared with the 24 hours prior, proportion of time spent in goal pain/sedation score range increased and exposure to other analgesics/sedatives decreased.

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.

Applying Cefepime Population Pharmacokinetics to Critically Ill Patients Receiving Continuous Renal Replacement Therapy.

Patients admitted to the intensive care unit (ICU) may need continuous renal replacement therapy (CRRT) due to acute kidney injury or worsening of underlying chronic kidney disease. This will affect their antimicrobial exposure and may have a significant impact on the treatment. We aim to develop a cefepime pharmacokinetic (PK) model in CRRT ICU patients and generate the posterior predictions for a group and assess their therapy outcomes. Adult patients, who were admitted to the ICU, received cefepime, and had its concentration measured while on CRRT were included from three different data sets. In two data sets, samples were collected from the predialyzer, postdialyzer ports, and effluent fluid at different times within the same dosing interval. The third data set had only cefepime plasma concentration measured as part of clinical service. Patients' demographics, cefepime regimens and concentration, CRRT parameters, and therapy outcomes were recorded. NPAG was used for population PK and posterior predictions. A total of 125 patients were included. Cefepime was described by a five-compartment model, and the CRRT flow rates described the rates of cefepime transfer between compartments. The posterior predictions were generated for the third data set and the median (range) fT>MIC was 100% (27%-100%) and fT>4×MIC was 64% (0%-100%). The mortality rate was 53%. There was no difference in target attainment in terms of clinical cure and 30-day mortality. This model can be used as a precision dosing tool in CRRT patients. Future studies may address other PK/PD targets in a larger population.

Intercostal liposomal bupivacaine injection for rib fractures: A prospective randomized controlled trial.

BACKGROUND: Blunt chest wall injury accounts for 15% of trauma admissions. Previous studies have shown that the number of rib fractures predicts inpatient opioid requirements, raising concerns for pharmacologic consequences, including hypotension, delirium, and opioid dependence. We hypothesized that intercostal injection of liposomal bupivacaine would reduce analgesia needs and improve spirometry metrics in trauma patients with rib fractures. METHODS: A prospective, double-blinded, randomized placebo-control study was conducted at a Level I trauma center as a Food and Drug Administration investigational new drug study. Enrollment criteria included patients 18 years or older admitted to the intensive care unit with blunt chest wall trauma who could not achieve greater than 50% goal inspiratory capacity. Patients were randomized to liposomal bupivacaine or saline injections in up to six intercostal spaces. Primary outcome was to examine pain scores and breakthrough pain medications for 96-hour duration. The secondary endpoint was to evaluate the effects of analgesia on pulmonary physiology. RESULTS: One hundred patients were enrolled, 50 per cohort, with similar demographics (Injury Severity Score, 17.9 bupivacaine 17.6 control) and comorbidities. Enrolled patients had a mean age of 60.5 years, and 47% were female. Rib fracture number, distribution, and targets for injection were similar between groups. While both groups displayed a decrease in opioid use over time, there was no change in mean daily pain scores. The bupivacaine group achieved higher incentive spirometry volumes over Days 1 and 2 (1095 mL, 1063 mL bupivacaine vs. 900 mL, 866 mL control). Hospital and intensive care unit lengths of stay were similar and there were no differences in postinjection pneumonia, use of epidural catheters or adverse events bet ween groups. CONCLUSION: While intercostal liposomal bupivacaine injection is a safe method for rib fracture-related analgesia, it was not effective in reducing pain scores, opioid requirements, or hospital length of stay. Bupivacaine injection transiently improved incentive spirometry volumes, but without a reduction in the development of pneumonia. LEVEL OF EVIDENCE: Therapeutic/care management, Level II.

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.

Comparison of Ceftriaxone and Antipseudomonal ß-Lactam Antibiotics Utilized for Potential AmpC ß-Lactamase-Producing Organisms.

Background: Induction of antibiotic resistance is associated with increased morbidity and mortality in AmpC ß-lactamase producing Enterobacteriaceae. The use of ceftriaxone is controversial for treatment of these organisms due to concerns for inducible resistance. This study was designed to compare treatment failure rates between ceftriaxone and antipseudomonal ß-lactam antibiotics when used as definitive therapy for organisms most commonly associated with chromosomal AmpC ß-lactamase production. Methods: A retrospective, single-center cohort study was performed enrolling patients hospitalized with monomicrobial Enterobacter, Citrobacter, or Serratia spp. infections. The primary objective compared proportion of treatment failure between groups. All patients received either ceftriaxone or an antipseudomonal ß-lactam alone within 24 hours of culture finalization, and with a duration of at least 72 hours for definitive treatment. Treatment failure was defined as either clinical failure (abnormal white blood cell count or temperature on day 7 or 14 post-antibiotics) or microbiologic failure (regrowth of the same organism at same site within 14 or 21 days). Results: Of 192 total patients, treatment failure was observed in 24/71 patients (34%) receiving ceftriaxone and in 42/121 patients (35%) receiving antipseudomonal ß-lactam (P = .98). No difference was observed between clinical or microbiologic failure rates between groups. The ceftriaxone group had significantly more patients undergoing treatment for urinary tract infections (51% vs 17%, P < .001), but treatment failure rates remained similar between groups when comparing infections of all other sources. Conclusion: Ceftriaxone has comparable treatment failure rates to antipseudomonal ß-lactams for susceptible Enterobacteriaceae infections and may be considered as a therapeutic option. Further, prospective research is needed to validate optimal dosing and application in all sites of infection.

Impact of antithrombin III and enoxaparin dosage adjustment on prophylactic anti-Xa concentrations in trauma patients at high risk for venous thromboembolism: a randomized pilot trial.

The impact of antithrombin III activity (AT-III) on prophylactic enoxaparin anti-factor Xa concentration (anti-Xa) is unknown in high-risk trauma patients. So too is the optimal anti-Xa-adjusted enoxaparin dosage. This prospective, randomized, pilot study sought to explore the association between AT-III and anti-Xa goal attainment and to preliminarily evaluate two enoxaparin dosage adjustment strategies in patients with subprophylactic anti-Xa. Adult trauma patients with Risk Assessment Profile (RAP) ≥ 5 prescribed enoxaparin 30 mg subcutaneously every 12 h were eligible. AT-III and anti-Xa were drawn 8 h after the third enoxaparin dose and compared between patients with anti-Xa ≥ 0.1 IU/mL (goal; control group) or anti-Xa < 0.1 IU/mL (subprophylactic; intervention group). The primary outcome was difference in baseline AT-III. Subsequently, intervention group patients underwent 1:1 randomization to either enoxaparin 40 mg every 12 h (up to 50 mg every 12 h if repeat anti-Xa < 0.1 IU/mL) (enox12) or enoxaparin 30 mg every 8 h (enox8) with repeat anti-Xa assessments. The proportion of patients achieving goal anti-Xa after dosage adjustment were compared. A total of 103 patients were included. Anti-Xa was subprophylactic in 50.5%. Baseline AT-III (median [IQR]) was 87% [80-98%] in control patients versus 82% [71-96%] in intervention patients (p = 0.092). Goal trough anti-Xa was achieved on first assessment in 38.1% enox12 versus 50% enox8 patients (p = 0.67), 84.6% versus 53.3% on second assessment (p = 0.11), and 100% vs. 54.5% on third trough assessment (p = 0.045). AT-III activity did not differ between high-risk trauma patients with goal and subprophylactic enoxaparin anti-Xa concentrations, although future investigation is warranted. Enoxaparin dose adjustment rather than frequency adjustment may be associated with a higher proportion of patients achieving goal anti-Xa over time.

Hitting the Vasopressor Ceiling: Finding Norepinephrine Associated Mortality in the Critically Ill.

BACKGROUND: There is no consensus on what dose of norepinephrine corresponds with futility. The purpose of this study was to investigate the maximum infusion and cumulative doses of norepinephrine associated with survival for patients in medical and surgical intensive care units (MICU and SICU). MATERIALS AND METHODS: A retrospective review was conducted of 661 critically ill patients admitted to a large academic medical center who received norepinephrine. Univariate, multivariate, and area under the curve analyses with optimal cut offs for maximum infusion rate and cumulative dosage were determined by Youden Index. RESULTS: The population was 54.9% male, 75.8% white, and 58.7 ± 16.1 y old with 384 (69.8%) admitted to the MICU and 166 (30.2%) admitted to the SICU, including 38 trauma patients. Inflection points in mortality were seen at 18 mcg/min and 17.6 mg. The inflection point was higher in MICU patients at 21 mcg/min and lower in SICU patients at 11 mcg/min. MICU patients also had a higher maximum cumulative dosage of 30.7 mg, compared to 2.7 mg in SICU patients. In trauma patients, norepinephrine infusions up to 5 mcg/min were associated with a 41.7% mortality rate. CONCLUSION: A maximum rate of 18 mcg/min and cumulative dose of 17.6 mg were the inflection points for mortality risk in ICU patients, with SICU patients tolerating lower doses. In trauma patients, even low doses of norepinephrine were associated with higher mortality. These data suggest that MICU, SICU, and trauma patients differ in need for, response to, and outcome from escalating norepinephrine doses.

Impact of Weight on Anti-Xa Attainment in High-Risk Trauma Patients on Enoxaparin Chemoprophylaxis.

BACKGROUND: Serum anti-factor Xa (anti-Xa) concentration may guide low molecular weight heparin chemoprophylaxis in trauma patients. Higher total body weight (TBW) is a risk factor for subprophylactic anti-Xa and venous thromboembolism (VTE). The purpose of this study was to evaluate TBW differences in patients with subprophylactic versus prophylactic trough anti-Xa. METHODS: This retrospective study included adults admitted to the trauma service who received enoxaparin chemoprophylaxis, trough anti-Xa assessment, and screening duplex ultrasound. Initial enoxaparin dose was determined per trauma team weight-tiered protocol with subsequent 10 mg increase if anti-Xa was subprophylactic. Patients were stratified into subprophylactic (anti-Xa <0.1 IU/ml) and prophylactic (anti-Xa ≥0.1 IU/mL) groups. The primary outcome was difference in TBW. Secondary outcomes were weight-adjusted enoxaparin dose (mg/kg), VTE, red blood cell (pRBC) transfusions. RESULTS: A total of 887 patients were included with 681 (76.8%) having subprophylactic anti-Xa. The subprophylactic group had significantly younger age, higher proportion male sex, higher Injury Severity Score (ISS), higher BMI, and longer length of hospital stay. The subprophylactic group had higher TBW (median [IQR], 87.8 [74-102] kg vs. 78.9 [68-91.8] kg; P < 0.001) which equated to a lower weight-adjusted dose (0.34 [0.3-0.41] mg/kg vs. 0.38 (0.33-0.44) mg/kg; P < 0.001). There were no differences in VTE (10.4% vs. 9.2%; P = 0.71) or pRBC administration (17.0% vs. 16.0%; P = 0.81). CONCLUSIONS: TBW is higher and weight-adjusted enoxaparin dose is lower in high-risk trauma patients with subprophylactic anti-Xa concentrations. These data suggest TBW should be considered when determining the optimal prophylactic enoxaparin dose in high-risk trauma patients.

Cefepime Population Pharmacokinetics and Target Attainment in Critically Ill Patients on Continuous Renal Replacement Therapy.

Sepsis causes half of acute kidney injuries in the intensive care unit (ICU). ICU patients may need continuous renal replacement therapy (CRRT), which will affect their antimicrobial exposure. We aimed to build a cefepime population pharmacokinetic (PK) model in CRRT ICU patients and perform simulations to assess target attainment. Patients who were ≥18 years old, were admitted to the ICU, and received cefepime 2 g every 8 h as a 4-h infusion while on CRRT were enrolled prospectively. Samples were collected from the predialyzer ports, postdialyzer ports, and effluent fluid at 1, 2, 3, 4, and 8 h after the first dose and at steady state. Age, sex, weight, urine output, and CRRT parameters were recorded. Pmetrics was used for population PK and simulations. The target exposure was 100% of the dosing interval during which the free beta-lactam concentration is above the MIC (fT>MIC). Ten patients were included; their mean age was 53 years, and mean weight was 119 kg. Seventy percent were males. Cefepime was described by a five-compartment model. The downtime was applied to the CRRT flow rates, which were used to describe the rates of transfer between the compartments. At MICs of ≤8 mg/liter, intermittent infusion of 2 g cefepime every 8 h achieved good target attainment both early in therapy and at steady state. Only extended- and continuous-infusion regimens achieved good target attainment at MICs of 16 mg/liter. In conclusion, 2 g cefepime infused over 30 min followed by extended infusion of 2 g every 8 h achieved good target attainment at MICs of ≤16 mg/liter with different CRRT flow rates and may be considered in resistant bacterial infections.