David A Zygun’s research while affiliated with Alberta Health Services and other places

We evaluated the cost-effectiveness of a bundled intervention including an antimicrobial stewardship program (ASP), procalcitonin (PCT) testing, and rapid blood culture identification (BCID), compared with pre-implementation standard care in critically ill adult patients with sepsis. We conducted a decision tree model-based cost-effectiveness analysis alongside a previously published pre- and post-implementation quality improvement study. We adopted a public Canadian healthcare payer’s perspective. Two intensive care units in Alberta with 727 adult critically ill patients were included. Our bundled intervention was compared with pre-implementation standard care. We collected healthcare resource use and estimated unit costs in 2022 Canadian dollars (CAD) over a time horizon from study entry to hospital discharge or death. We calculated the incremental net monetary benefit (iNMB) of the intervention group compared with the pre-intervention group. The primary outcome was cost per sepsis case. Secondary outcomes included readmission rates, Clostridioides difficile infections, mortality, and lengths of stay. Uncertainty was investigated using cost-effectiveness acceptability curves, cost-effectiveness plane scatterplots, and sensitivity analyses. Mean (standard deviation [SD]) cost per index hospital admission was CAD $83,251 ($107,926) for patients in the intervention group and CAD $87,044 ($104,406) for the pre-intervention group, though the difference ($3,793 [$7,897]) was not statistically significant. Costs were higher in the pre-intervention group for antibiotics, readmissions, and C. difficile infections. The intervention group had a lower mean expected cost; $110,580 ($108,917) compared with pre-intervention ($125,745 [$113,210]), with a difference of $15,165 ($8278). There were no statistically significant differences in quality adjusted life years (QALYs) between groups. The iNMB of the intervention group compared with pre-intervention was greater than $15,000 for willingness-to-pay (WTP) per QALY values of between$0 and $100,000. In our sensitivity analysis, the intervention was most likely to be cost-effective in roughly 56% of simulations at all WTP thresholds. Our bundled intervention of ASP, PCT, and BCID among adult critically ill patients with sepsis was potentially cost-effective, but with substantial decision uncertainty.

We examined the effect of an antimicrobial stewardship program (ASP), procalcitonin testing and rapid blood-culture identification on hospital mortality in a prospective quality improvement project in critically ill septic adults. Secondarily, we have reported antimicrobial guideline concordance, acceptance of ASP interventions, and antimicrobial and health-resource utilization.

Background Health technology reassessment (HTR) is a process to manage existing health technologies to ensure ongoing optimal use. A model to guide HTR was developed; however, there is limited practical experience. This paper addresses this knowledge gap through the completion of a multi-phase HTR of red blood cell (RBC) transfusion practices in the intensive care unit (ICU). Objective The HTR consisted of three phases and here we report on the final phase: the development, implementation, and evaluation of behavior change interventions aimed at addressing inappropriate RBC transfusions in an ICU. Methods The interventions, comprised of group education and audit and feedback, were co-designed and implemented with clinical leaders. The intervention was evaluated through a controlled before-and-after pilot feasibility study. The primary outcome was the proportion of potentially inappropriate RBC transfusions (i.e., with a pre-transfusion hemoglobin of 70 g/L or more). Results There was marked variability in the monthly proportion of potentially inappropriate RBC transfusions. Relative to the pre-intervention phase, there was no significant difference in the proportion of potentially inappropriate RBC transfusions post-intervention. Lessons from this work include the importance of early and meaningful engagement of clinical leaders; tailoring the intervention modalities; and, efficient access to data through an electronic clinical information system. Conclusions It was feasible to design, implement, and evaluate a tailored, multi-modal behavior change intervention in this small-scale pilot study. However, early evaluation of the intervention revealed no change in technology use leading to reflection on the important question of how the HTR model needs to be improved.

Importance Growing interest in microbial dysbiosis during critical illness has raised questions about the therapeutic potential of microbiome modification with probiotics. Prior randomized trials in this population suggest that probiotics reduce infection, particularly ventilator-associated pneumonia (VAP), although probiotic-associated infections have also been reported. Objective To evaluate the effect of Lactobacillus rhamnosus GG on preventing VAP, additional infections, and other clinically important outcomes in the intensive care unit (ICU). Design, Setting, and Participants Randomized placebo-controlled trial in 44 ICUs in Canada, the United States, and Saudi Arabia enrolling adults predicted to require mechanical ventilation for at least 72 hours. A total of 2653 patients were enrolled from October 2013 to March 2019 (final follow-up, October 2020). Interventions Enteral L rhamnosus GG (1 × 10¹⁰ colony-forming units) (n = 1321) or placebo (n = 1332) twice daily in the ICU. Main Outcomes and Measures The primary outcome was VAP determined by duplicate blinded central adjudication. Secondary outcomes were other ICU-acquired infections including Clostridioides difficile infection, diarrhea, antimicrobial use, ICU and hospital length of stay, and mortality. Results Among 2653 randomized patients (mean age, 59.8 years [SD], 16.5 years), 2650 (99.9%) completed the trial (mean age, 59.8 years [SD], 16.5 years; 1063 women [40.1%.] with a mean Acute Physiology and Chronic Health Evaluation II score of 22.0 (SD, 7.8) and received the study product for a median of 9 days (IQR, 5-15 days). VAP developed among 289 of 1318 patients (21.9%) receiving probiotics vs 284 of 1332 controls (21.3%; hazard ratio [HR], 1.03 (95% CI, 0.87-1.22; P = .73, absolute difference, 0.6%, 95% CI, –2.5% to 3.7%). None of the 20 prespecified secondary outcomes, including other ICU-acquired infections, diarrhea, antimicrobial use, mortality, or length of stay showed a significant difference. Fifteen patients (1.1%) receiving probiotics vs 1 (0.1%) in the control group experienced the adverse event of L rhamnosus in a sterile site or the sole or predominant organism in a nonsterile site (odds ratio, 14.02; 95% CI, 1.79-109.58; P < .001). Conclusions and Relevance Among critically ill patients requiring mechanical ventilation, administration of the probiotic L rhamnosus GG compared with placebo, resulted in no significant difference in the development of ventilator-associated pneumonia. These findings do not support the use of L rhamnosus GG in critically ill patients. Trial Registration ClinicalTrials.gov Identifier: NCT02462590

Background: Neurological injury can alter the systemic immune system, modifying the functional capacity of immune cells and causing a dysfunctional balance of cytokines, although mechanisms remain incompletely understood. The objective of this study was to assess the temporal relationship between changes in the activation status of circulating invariant natural killer T (iNKT) cells and the balance of plasma cytokines among critically ill patients with neurological injury. Methods: We conducted an exploratory prospective observational study of adult (18 years or older) intensive care unit (ICU) patients with acute neurological injury (n = 20) compared with ICU patients without neurological injury (n = 22) and healthy controls (n = 10). Blood samples were collected on days 1, 2, 4, 7, 14, and 28 following ICU admission to analyze the activation status of circulating iNKT cells by flow cytometry and the plasma concentration of inflammation-relevant immune mediators, including T helper 1 (TH1) and T helper 2 (TH2) cytokines, by multiplex bead-based assay. Results: Invariant natural killer T cells were activated in both ICU patient groups compared with healthy controls. Neurological patients had decreased levels of multiple immune mediators, including TH1 cytokines (interferon-γ, tumor necrosis factor-α, and interleukin-12p70), indicative of immunosuppression. This led to a greater than twofold increase in the ratio of TH2/TH1 cytokines early after injury (days 1 - 2) compared with healthy controls, a shift that was also observed for ICU controls. Systemic TH2/TH1 cytokine ratios were positively associated with iNKT cell activation in the neurological patients and negatively associated in ICU controls. These relationships were strongest for the CD4+ iNKT cell subset compared with the CD4- iNKT cell subset. The relationships to individual cytokines similarly differed between patient groups. Forty percent of the neurological patients developed an infection; however, differences for the infection subgroup were not identified. Conclusions: Critically ill patients with neurological injury demonstrated altered systemic immune profiles early after injury, with an association between activated peripheral iNKT cells and elevated systemic TH2/TH1 cytokine ratios. This work provides further support for a brain-immune axis and the ability of neurological injury to have far-reaching effects on the body's immune system.

Background Although damage control (DC) surgery is widely assumed to reduce mortality in critically injured patients, survivors often suffer substantial morbidity, suggesting that it should only be used when indicated. The purpose of this systematic review was to determine which indications for DC have evidence that they are reliable and/or valid (and therefore in which clinical situations evidence supports use of DC or that DC improves outcomes). Methods We searched 11 databases (1950–April 1, 2019) for studies that enrolled exclusively civilian trauma patients and reported data on the reliability (consistency of surgical decisions in a given clinical scenario) or content (surgeons would perform DC in that clinical scenario or the indication predicted use of DC in practice), construct (were associated with poor outcomes), or criterion (were associated with improved outcomes when DC was conducted instead of definitive surgery) validity for suggested indications for DC surgery or DC interventions. Results Among 34,979 citations identified, we included 36 cohort studies and three cross-sectional surveys in the systematic review. Of the 59 unique indications for DC identified, 10 had evidence of content validity [e.g., a major abdominal vascular injury or a packed red blood cell (PRBC) volume exceeding the critical administration threshold], nine had evidence of construct validity (e.g., unstable patients with combined abdominal vascular and pancreas gunshot injuries or an iliac vessel injury and intraoperative acidosis), and six had evidence of criterion validity (e.g., penetrating trauma patients requiring > 10 U PRBCs with an abdominal vascular and multiple abdominal visceral injuries or intraoperative hypothermia, acidosis, or coagulopathy). No studies evaluated the reliability of indications. Conclusions Few indications for DC surgery or DC interventions have evidence supporting that they are reliable and/or valid. DC should be used with respect for the uncertainty regarding its effectiveness, and only in circumstances where definitive surgery cannot be entertained.

Background: Although damage control (DC) surgery is widely assumed to reduce mortality in critically injured patients, survivors often suffer substantial morbidity, suggesting that it should only be used when indicated. The purpose of this systematic review was to determine which indications for DC have evidence that they are reliable and/or valid (and therefore in which clinical situations evidence supports use of DC or that DC improves outcomes). Methods: We searched 11 databases (1950-April 1, 2019) for studies that enrolled exclusively civilian trauma patients and reported data on the reliability (consistency of surgical decisions in a given clinical scenario) or content (surgeons would perform DC in that clinical scenario or the indication predicted use of DC in practice), construct (were associated with poor outcomes), or criterion (were associated with improved outcomes when DC was conducted instead of definitive surgery) validity for suggested indications for DC surgery or DC interventions. Results: Among 34,979 citations identified, we included 36 cohort studies and three cross-sectional surveys in the systematic review. Of the 59 unique indications for DC identified, 10 had evidence of content validity [e.g., a major abdominal vascular injury or a packed red blood cell (PRBC) exceeding the critical administration threshold], nine had evidence of construct validity (e.g., unstable patients with combined abdominal vascular and pancreas gunshot injuries or an iliac vessel injury and intraoperative acidosis), and six had evidence of criterion validity (e.g., penetrating trauma patients requiring >10 U PRBCs with an abdominal vascular and multiple abdominal visceral injuries or intraoperative hypothermia, acidosis, or coagulopathy). No studies evaluated the reliability of indications. Conclusions: Few indications for DC surgery or DC interventions have evidence supporting that they are reliable and/or valid. DC should be used with respect for the uncertainty regarding its effectiveness, and only in circumstances where definitive surgery cannot be entertained.

Background Severe traumatic brain injury (TBI) is a significant cause of death and disability. The objective of this study was to provide an overview of whether adherence to brain trauma foundation (BTF) guidelines improved outcomes following TBI utilizing intracranial pressure (ICP) monitoring. Methods This cohort study between 2000 and 2013 involved 1848 patients who sustained severe blunt TBI. Outcomes were correlated with whether or not ICP monitoring was utilized based on BTF guidelines. Results The BTF guideline adherence rate for utilizing ICP monitoring in patients with TBI was 30% in 1848 patients. Adherence rates positively correlated with younger age, high injury severity scores, lower Glasgow Coma Scores, abnormal computed tomography scans of the head, performance of a craniotomy, neurocritical care unit admission, the lack of alcohol intoxication, and the absence of a cardiac arrest. Greater adherence to BTF guidelines was associated with higher mortality rates (OR 2.01, 95% CI: 1.56–2.59, P < 0.001), and increase ICU and hospital lengths of stay ( P < 0.001). Conclusion Adherence rates to BTF guidelines for ICP monitoring in patients with severe TBI were low. Further, these rates varied across centers and were correlated with higher mortality and morbidity rates. Although ICP insertion may be an indicator of TBI severity, the current BTF criteria for insertion of ICP monitors may fail to identify patients likely to benefit.