Desirability of Outcome Ranking and Response Adjusted for Antibiotic Risk (DOOR/RADAR) Post Hoc Analysis Supports Equipoise for Antibiotic Initiation Strategies in Intensive Care Unit-Acquired Pneumonia.

Background: Pneumonia is the most common intensive care unit (ICU)-acquired infection and source of potential sepsis in ICU populations but can be difficult to diagnose in real-time. Despite limited data, rapid initiation of antibiotic agents is endorsed by society guidelines. We hypothesized that a post hoc analysis of a recent randomized pilot study would show no difference between two antibiotic initiation strategies. Patients and Methods: The recent Trial of Antibiotic Restraint in Presumed Pneumonia (TARPP) was a pragmatic cluster-randomized pilot of antibiotic initiation strategies for patients with suspected ICU-acquired pneumonia. Participating ICUs were cluster-randomized to either an immediate initiation protocol or a specimen-initiated protocol where a gram stain was required for initiation of antibiotics. Patients in the study were divided into one of seven mutually exclusive outcome rankings (desirability of outcome ranking; DOOR): (1) Survival, No Pneumonia, No adverse events; (2) Survival, Pneumonia, No adverse events; (3) Survival, No Pneumonia, ventilator-free-alive days ≤14; (4) Survival, Pneumonia, ventilator-free-alive days ≤14; (5) Survival, No Pneumonia, Subsequent episode of suspected pneumonia; (6) Survival, Pneumonia, Subsequent episode of suspected pneumonia; and (7) Death. These rankings were further refined using the duration of antibiotics prescribed for pneumonia (response adjusted for antibiotic risk; RADAR). Results: There were 186 patients enrolled in the study. After applying the DOOR analysis, a randomly selected patient was equally likely to have a better outcome in specimen-initiated arm as in the immediate initiation arm (DOOR probability: 50.8%; 95% confidence interval [CI], 42.7%-58.9%). Outcome probabilities were similar after applying the RADAR analysis (52.5%; 95% CI, 44.2%-60.6%; p = 0.31). Conclusions: We found that patients for whom antibiotic agents were withheld until there was objective evidence (specimen-initiated group) had similar outcome rankings to patients for whom antibiotic agents were started immediately. This supports the findings of the TARPP pilot trial and provides further evidence for equipoise between these two treatment strategies.

Provider Perceptions of Antibiotic Initiation Strategies for Hospital-Acquired Pneumonia.

Background: The practice of rapidly initiating antibiotic therapy for patients with suspected infection has recently been criticized yet remains commonplace. Provider comfort level has been an understudied aspect of this practice. Hypothesis: We hypothesized that there would be no significant differences in provider comfort level between the two treatment groups. Methods: We prospectively surveyed critical care intensivists who provided care for patients enrolled in the Trial of Antibiotic Restraint in Presumed Pneumonia (TARPP), which was a multicenter cluster-randomized crossover trial that evaluated an immediate antibiotic initiation protocol compared with a protocol of specimen-initiated antibiotic initiation in ventilated patients with suspected new-onset pneumonia. At the end of each enrollment arm, physicians at each center were surveyed regarding their overall comfort level with the recently completed treatment arm, and perception of adherence. Both a paired and unpaired analysis was performed. Results: We collected 51 survey responses from 31 unique participants. Providers perceived a higher rate of adherence to the immediate initiation arm than the specimen-initiated arm (Always Adherent: 37.5% vs. 11.1%; p = 0.045). Providers were less comfortable waiting for objective evidence of infection in the specimen-initiated arm than with starting antibiotic agents immediately (Very Comfortable: 83.3% vs. 40.7%; p = 0.004). For the smaller paired analysis, there was no longer a difference in comfort level. Conclusions: There may be differences in provider comfort levels and perceptions of adherence when considering two different antibiotic initiation strategies for suspected pneumonia in ventilated patients. These findings should be considered when planning future studies.

Vascular imaging immediately after tourniquet removal does not increase vasospasm risk.

BACKGROUND: Prehospital tourniquet use is now standard in trauma patients with diagnosed or suspected extremity vascular injuries. Tourniquet-related vasospasm is an understudied phenomenon that may confound management by causing erroneous arterial pressure indices (APIs) and abnormalities on computed tomography angiography (CTA) that do not reflect true arterial injuries. We hypothesized that shorter intervals between tourniquet removal and CTA imaging and longer total tourniquet times would be correlated with a higher likelihood of false positive CTA. MATERIALS AND METHODS: We performed a single-institution retrospective cohort study of patients presenting to a busy, urban Level 1 Trauma Center with prehospital tourniquets from 2019 to 2021. Patients who presented with a tourniquet disengaged upon arrival or who died prior to admission to the Trauma Unit were excluded. Tourniquet duration, time between tourniquet removal and CTA imaging (CTA interval), CTA findings, and management of extremity arterial injuries were extracted. The proportion of false positive injuries on CTA was assessed for correlation with increasing time interval from tourniquet removal to CTA imaging and correlation with increasing total tourniquet time using multivariable logistic regression. RESULTS: 251 patients were identified with prehospital tourniquets. 127 underwent CTA of the affected extremity, 96 patients had an abnormal CTA finding, and 57 (45% of total CTA patients) had false positive arterial injuries on imaging. Using multivariable logistic regression, neither the CTA interval nor the tourniquet duration was associated with false positive CTA injuries. Female sex was associated with false positive injuries on CTA (OR 2.91, 95% CI: 1.01 - 8.39). Vasospasm was cited as a possible explanation by radiologists in 40% of false positive CTA reports. CONCLUSIONS: Arterial vasospasm is a frequent finding on CTA after tourniquet use for extremity trauma, but concerns regarding tourniquet-related vasospasm should not alter trauma patient management. Neither the duration of tourniquet application nor the time interval since removal is associated with decreased CTA accuracy, and any delay in imaging does not appear to reduce the likelihood of vasospasm. These findings are important for supporting expedited care of trauma patients with severe extremity injuries.

Comparison of phenobarbital monotherapy to a benzodiazepine-based regimen for management of alcohol withdrawal syndrome in trauma patients.

BACKGROUND: Alcohol withdrawal syndrome (AWS) is associated with increased morbidity and mortality in the trauma population. Benzodiazepines (BZDs) are standard of care for AWS; however, given the risk of delirium with BZDs and reports of BZD-refractory withdrawal, phenobarbital (PHB) has emerged as an alternative therapy for AWS. Safety and efficacy studies of PHB for AWS in trauma patients are lacking. Our aim was to compare a BZD versus PHB protocol in the management of AWS in trauma patients. METHODS: We performed a retrospective cohort study at a level 1 trauma center of patients at risk for AWS managed with either a BZD or a low-dose oral PHB regimen. Patients were excluded if they were taking BZDs or barbiturates before admission, received propofol or dexmedetomidine before initiation of the study drug, presented with delirium tremens or seizures, or died or discharged within 24 hours of presentation. The primary outcome was complicated AWS (seizures or alcohol withdrawal delirium/delirium tremens). Secondary outcomes included uncomplicated AWS; therapy escalation; oversedation; delirium-, intensive care unit-, and ventilator-free days; and length of stay. RESULTS: A total of 411 patients were identified; 118 received BZD, and 293 received PHB. The odds of developing complicated AWS with PHB versus BZD-based therapy were not statistically significant (odds ratio [OR], 0.52; 95% confidence interval [CI], 0.21-1.39); however, patients receiving PHB were less likely to develop uncomplicated AWS (OR, 0.08; 95% CI, 0.04-0.14) and less likely to require escalation of therapy (OR, 0.45; 95% CI, 0.24-0.84). The PHB group had a length of stay 3.1 days shorter than the BZD group ( p = 0.002). There was no difference in intensive care unit-, ventilator-, or delirium-free days. CONCLUSION: A PHB-based protocol for the management of AWS is a safe and effective alternative to BZD-based regimens in trauma patients. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level IV.

The Effect of Propofol on Peri-Induction Hemodynamics and Resuscitation in Operative Penetrating Trauma.

BACKGROUND: Hemorrhaging trauma patients may be disproportionately affected by choice of induction agent during rapid sequence intubation (RSI). Etomidate, ketamine, and propofol are safe in the trauma population-at-large but have not been assessed in patients with ongoing hemorrhage. We hypothesize that in hemorrhaging patients with penetrating injury, propofol deleteriously affects peri-induction hypotension compared to etomidate and ketamine. METHODS: Retrospective cohort study. Primary outcome was the effect of induction agent on peri-induction systolic blood pressure. Secondary outcomes were the incidence of peri-induction vasopressor use and quantity of peri-induction blood transfusion requirements. Linear multivariate regression modeling assessed the effect of induction agent on the variables of interest. RESULTS: 169 patients were included, 146 received propofol and 23 received etomidate or ketamine. Univariate analysis revealed no difference in peri-induction systolic blood pressure (P = .53), peri-induction vasopressor administration (P = .62), or transfusion requirements within the first hour after induction (PRBC P = .24, FFP P = .19, PLT P = .29). Choice of RSI agent did not independently predict peri-induction systolic blood pressure or blood product administration. Rather, only presenting shock index independently predicted peri-induction hypotension. CONCLUSIONS: This is the first study to directly assess the peri-induction effects of anesthetic induction agent choice in penetrating trauma patients undergoing emergent hemorrhage control surgery. Propofol does not appear to worsen peri-induction hypotension regardless of dose. Patient physiology is most predictive of peri-induction hypotension.

Identifying temporal variations in burn admissions.

BACKGROUND: Variations in admission patterns have been previously identified in non-elective surgical services, but minimal data on the subject exists with respect to burn admissions. Improved understanding of the temporal pattern of burn admissions could inform resource utilization and clinical staffing. We hypothesize that burn admissions have a predictable temporal distribution with regard to the time of day, day of week, and season of year in which they present. STUDY DESIGN: A retrospective, cohort observational study of a single burn center from 7/1/2016 to 3/31/2021 was performed on all admissions to the burn surgery service. Demographics, burn characteristics, and temporal data of burn admissions were collected. Bivariate absolute and relative frequency data was captured and plotted for all patients who met inclusion criteria. Heat-maps were created to visually represent the relative admission frequency by time of day and day of week. Frequency analysis grouped by total body surface area against time of day and relative encounters against day of year was performed. RESULTS: 2213 burn patient encounters were analyzed, averaging 1.28 burns per day. The nadir of burn admissions was from 07:00 and 08:00, with progressive increase in the rate of admissions over the day. Admissions peaked in the 15:00 hour and then plateaued until midnight (p<0.001). There was no association between day of week in the burn admission distribution (p>0.05), though weekend admissions skewed slightly later (p = 0.025). No annual, cyclical trend in burn admissions was identified, suggesting that there is no predictable seasonality to burn admissions, though individual holidays were not assessed. CONCLUSION: Temporal variations in burn admissions exist, including a peak admission window late in the day. Furthermore, we did not find a predictable annual pattern to use in guiding staffing and resource allocation. This differs from findings in trauma, which identified admission peaks on the weekends and an annual cycle that peaks in spring and summer.

Components of Existing National Surgical Site Infection Surveillance Programs Based on a Case Series of Low- and Middle-Income Countries: Building Blocks for Success and Opportunities for Improvement.

Background: Surgical site infection (SSI) surveillance programs are recommended to be included in national infection prevention and control (IPC) programs, yet few exist in low- or middle-income countries (LMICs). Our goal was to identify components of surveillance in existing programs that could be replicated elsewhere and note opportunities for improvement to build awareness for other countries in the process of developing their own national surgical site infection surveillance (nSSIS) programs. Methods: We administered a survey built upon the U.S. Centers for Disease Control and Prevention's framework for surveillance system evaluation to systematically deconstruct logistical infrastructure of existing nSSIS programs in LMICs. Qualitative analyses of survey responses by thematic elements were used to identify successful surveillance system components and recognize opportunities for improvement. Results: Three respondents representing countries in Europe and Central Asia, sub-Saharan Africa, and South Asia designated as upper middle-income, lower middle-income, and low-income responded. Notable strengths described by respondents included use of local paper documentation, staggered data entry, and limited data entry fields. Opportunities for improvement included outpatient data capture, broader coverage of healthcare centers within a nation, improved audit processes, defining the denominator of number of surgical procedures, and presence of an easily accessible, free SSI surveillance training program for healthcare workers. Conclusions: Outpatient post-surgery surveillance, national coverage of healthcare facilities, and training on how to take local SSI surveillance data and integrate it within a broader nSSIS program at the national level remain areas of opportunities for countries looking to implement a nSSIS program.

Trial of antibiotic restraint in presumed pneumonia: A Surgical Infection Society multicenter pilot.

BACKGROUND: Pneumonia is the most common intensive care unit-acquired infection in the trauma and emergency general surgery population. Despite guidelines urging rapid antibiotic use, data supporting immediate antibiotic initiation in cases of suspected infection are limited. Our hypothesis was that a protocol of specimen-initiated antibiotic initiation would have similar compliance and outcomes to an immediate initiation protocol. METHODS: We devised a pragmatic cluster-randomized crossover pilot trial. Four surgical and trauma intensive care units were randomized to either an immediate initiation or specimen-initiated antibiotic protocol for intubated patients with suspected pneumonia and bronchoscopically obtained cultures who did not require vasopressors. In the immediate initiation arm, antibiotics were started immediately after the culture regardless of patient status. In the specimen-initiated arm, antibiotics were delayed until objective Gram stain or culture results suggested infection. Each site participated in both arms after a washout period and crossover. Outcomes were protocol compliance, all-cause 30-day mortality, and ventilator-free alive days at 30 days. Standard statistical techniques were applied. RESULTS: A total of 186 patients had 244 total cultures, of which only the first was analyzed. Ninety-three patients (50%) were enrolled in each arm, and 94.6% were trauma patients (84.4% blunt trauma). The median age was 50.5 years, and 21% of the cohort was female. There were no differences in demographics, comorbidities, sequential organ failure assessment, Acute Physiology and Chronic Health Evaluation II, or Injury Severity Scores. Antibiotics were started significantly later in the specimen-initiated arm (0 vs. 9.3 hours; p < 0.0001) with 19.4% avoiding antibiotics completely for that episode. There were no differences in the rate of protocol adherence, 30-day mortality, or ventilator-free alive days at 30 days. CONCLUSION: In this cluster-randomized crossover trial, we found similar compliance rates between immediate and specimen-initiated antibiotic strategies. Specimen-initiated antibiotic protocol in patients with a suspected hospital-acquired pneumonia did not result in worse clinical outcomes compared with immediate initiation. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level II.

Acute pain consult and management is associated with improved mortality in rib fracture patients.

INTRODUCTION: Traumatic rib fractures result in significant patient morbidity and mortality, which increases with patient age and number of rib fractures. A dedicated acute pain service (APS) providing expertize in multimodal pain management may reduce these risks and improve outcomes. We aimed to test the hypothesis that protocolized APS consultation decreases mortality and morbidity in traumatic rib fracture patients. METHODS: This is a retrospective observational, propensity-matched cohort study of adult patients with trauma with rib fractures from 2012 to 2015, at a single, large level 1 trauma center corresponding to introduction and incorporation of APS consultation into the institutional rib fracture pathway. Using electronic medical records and trauma registry data, we identified adult patients presenting with traumatic rib fractures. Patients with hospital length of stay (LOS) ≥2 days were split into two cohorts based on presence of APS consult using 1:1 propensity matching of age, gender, comorbidities and injury severity. The primary outcome was difference in hospital mortality. Secondary outcomes included LOS and pulmonary morbidity. RESULTS: 2486 patients were identified, with a final matched cohort of 621 patients receiving APS consult and 621 control patients. The mortality rate was 1.8% among consult patients and 6.6% among control patients (adjusted OR 0.25, 95% CI 0.13 to 0.50; p=0.001). The average treatment effect of consult on mortality was 4.8% (95% CI 1.2% to 8.5%;. p<0.001). APS consultation was associated with increased intensive care unit (ICU) LOS (1.19 day; 95% CI 0.48 to 1.90; p=0.001) and hospital LOS (1.61 days; 95% CI 0.81 to 2.41 days; p<0.001). No difference in pulmonary complications was observed. DISCUSSION: An APS consult in rib fracture patients is associated with decreased mortality and no difference in pulmonary complications yet increased ICU and hospital LOS.

The Effect of Comorbidities on Wound Healing.

Wound healing is affected by several factors. Preexisting diagnoses may significantly alter, delay, or inhibit normal wound healing. This is most commonly seen with chronic disorders, such as diabetes and renal failure, but also occurs secondary to aging and substance abuse. Less commonly, genetic or inflammatory disorders are the cause of delayed wound healing. In some cases, it is not the illness, but the treatment that can inhibit wound healing. This is seen in patients getting chemotherapy, radiation, steroids, methotrexate, and a host of other medications. Understanding these processes may help treat or avoid wound healing problems.

Optimization of glioblastoma multiforme stem cell isolation, transfection, and transduction.

It has been postulated that brain tumor stem cells (TSCs) may be the population of cells responsible for the maintenance and recurrence of glioblastoma multiforme (GBM). The purpose of this study was to optimize a reproducible protocol for generating TSCs for their subsequent transfection or transduction. Patient GBMs were enzymatically and mechanically dissociated and tumor spheres were resuspended in appropriate media and analyzed to ensure they met stem cell criteria. These cells were then transfected with a plasmid or transduced with a viral vector to introduce a previously absent gene and then allowed to form tumor spheres. Tumor spheres were generated from patient GBMs without contamination. These cells met stringent criteria as stem cells, including multipotentiality and self-renewal. High efficiency transfection and transduction of tumor spheres was possible, even at the core of the sphere. This allowed for the introduction of new genes to the TSCs, as evidenced by fluorescent microscopy and Western blot analysis. This study is a guide to optimize the generation of patient derived GBM tumor spheres without RBC and dead cell contamination. GBM TSCs within tumor spheres can easily be transfected with plasmids or transduced with a virus. This is important from a therapeutic perspective if gene replacement is to be successful in replacing genes lost in GBM progression or to knock down or silence genes that are over-expressed in malignant brain tumors.

EGFR signaling is differentially activated in patient-derived glioblastoma stem cells.

Evidence suggests that stem-like cells are responsible for initiation, maintenance and recurrence of solid tumors, including Glioblastoma Multiforme (GBM). GBM is an intractable, highly lethal tumor of the central nervous system. Although epidermal growth factor receptor (EGFR) is highly expressed in many GBMs, anti-EGFR therapies have been unsuccessful as treatment. Few studies have examined EGFR activation in GBM stem cells (GSCs) to determine if patient-specific GSCs are amenable to anti-EGFR therapy pre-clinically. We hypothesized that EGFR activation in GSCs varied between patients and was an important determinant of responsiveness to anti-EGFR therapy. Cell cycle and apoptosis analysis was performed on tumor-spheres by immuncytochemistry in the presence and absence of the AG1478. Second messenger pathways operative in these processes were elucidated by immunoblotting. EGFR activated AKT and inactivated GSK3beta in EGFR+/PTEN+ GSCs. AG1478 and erlotinib significantly decreased the total number of tumor-spheres that EGFR+/ PTEN+ GSCs generated and the rate of sphere formation. Inhibition of EGFR signaling by AG1478 increased GSC senescence and apoptosis, likely via inhibition of AKT and activation of GSK3beta. Sphere formation by EGFR-/ PTEN- GSCs was independent of EGF stimulation, but dependant on B27 growth supplement. Our data suggest that EGFR+/PTEN+ GSCs are susceptible to anti-EGFR therapy in vitro.