Mark P. Yeager’s research while affiliated with Geisel School of Medicine at Dartmouth and other places

Study objective A randomized controlled study demonstrated that an optimized intraoperative infection control program targeting basic preventive measures can reduce Staphylococcus aureus transmission and surgical site infections. In this study we address potential limitations of operating room heterogeneity of infections and compliance with behavioral interventions following adoption into clinical practice. Design A post-implementation prospective case-cohort study. Setting Twenty-three operating rooms at a large teaching hospital. Patients A total of 801 surgical patients [425 (53%) women; 350 (44%) ASA > 2, age 54.6 ± 15.9 years] were analyzed for the primary and 804 for the secondary outcomes. Interventions A multifaceted, evidence-based intraoperative infection control program involving hand hygiene, vascular care, and environmental cleaning improvements was implemented for 23 operating room environments. Bacterial transmission monitoring was used to provide monthly feedback for intervention optimization. Measurements S. aureus transmission (primary) and surgical site infection (secondary). Materials and methods The incidence of S. aureus transmission and surgical site infection before (3.5 months) and after (4.5 months) infection control optimization was assessed. Optimization was defined by a sustained reduction in anesthesia work area bacterial reservoir isolate counts. Poisson regression with robust error variances was used to estimate the incidence risk ratio (IRR) of intraoperative S. aureus transmission and surgical site infection for the independent variable of optimization. Main results Optimization was associated with decreased S. aureus transmission [24% before (85/357) to 9% after (42/444), IRR 0.39, 95% CI 0.28 to 0.56, P < .001] and surgical site infections [8% before (29/360) and 3% after (15/444) (IRR 0.42, 95% CI 0.23 to 0.77, P = .005; adjusted for American Society of Anesthesiologists' physical status, aIRR 0.45, 95% CI 0.25 to 0.82, P = .009]. Conclusion An optimized intraoperative infection control program targeting improvements in basic preventive measures is an effective and feasible approach for reducing S. aureus transmission and surgical site infection development.

Importance Surgical site infections increase patient morbidity and health care costs. The Centers for Disease Control and Prevention emphasize improved basic preventive measures to reduce bacterial transmission and infections among patients undergoing surgery. Objective To assess whether improved basic preventive measures can reduce perioperative Staphylococcus aureus transmission and surgical site infections. Design, Setting, and Participants This randomized clinical trial was conducted from September 20, 2018, to September 20, 2019, among 19 surgeons and their 236 associated patients at a major academic medical center with a 60-day follow-up period. Participants were a random sample of adult patients undergoing orthopedic total joint, orthopedic spine, oncologic gynecological, thoracic, general, colorectal, open vascular, plastic, or open urological surgery requiring general or regional anesthesia. Surgeons and their associated patients were randomized 1:1 via a random number generator to treatment group or to usual care. Observers were masked to patient groupings during assessment of outcome measures. Interventions Sustained improvements in perioperative hand hygiene, vascular care, environmental cleaning, and patient decolonization efforts. Main Outcomes and Measures Perioperative S aureus transmission assessed by the number of isolates transmitted and the incidence of transmission among patient care units (primary) and the incidence of surgical site infections (secondary). Results Of 236 patients (156 [66.1%] women; mean [SD] age, 57 [15] years), 106 (44.9%) and 130 (55.1%) were allocated to the treatment and control groups, respectively, received the intended treatment, and were analyzed for the primary outcome. Compared with the control group, the treatment group had a reduced mean (SD) number of transmitted perioperative S aureus isolates (1.25 [2.11] vs 0.47 [1.13]; P = .002). Treatment reduced the incidence of S aureus transmission (incidence risk ratio; 0.56; 95% CI, 0.37-0.86; P = .008; with robust variance clustering by surgeon: 95% CI, 0.42-0.76; P < .001). Overall, 11 patients (4.7%) experienced surgical site infections, 10 (7.7%) in the control group and 1 (0.9%) in the treatment group. Transmission was associated with an increased risk of surgical site infection (8 of 73 patients [11.0%] with transmission vs 3 of 163 [1.8%] without; risk ratio, 5.95; 95% CI, 1.62-21.86; P = .007). Treatment reduced the risk of surgical site infection (hazard ratio, 0.12; 95% CI, 0.02-0.92; P = .04; with clustering by surgeon: 95% CI, 0.03-0.51; P = .004). Conclusions and Relevance Improved basic preventive measures in the perioperative arena can reduce S aureus transmission and surgical site infections. Trial Registration ClinicalTrials.gov Identifier: NCT03638947

Background: Cortisol is a prototypical human stress hormone essential for life, yet the precise role of cortisol in the human stress response to injury or infection is still uncertain. Glucocorticoids (GCs) such as cortisol are widely understood to suppress inflammation and immunity. However, recent research shows that GCs also induce delayed immune effects manifesting as immune stimulation. In this study, we show that cortisol enhances the immune-stimulating effects of a prototypical proinflammatory cytokine, interferon-υ (IFN-υ). We tested the hypothesis that cortisol enhances IFN-υ-mediated proinflammatory responses of human mononuclear phagocytes (monocyte/macrophages [MOs]) stimulated by bacterial endotoxin (lipopolysaccharide [LPS]). Methods: Human MOs were cultured for 18 hours with or without IFN-υ and/or cortisol before LPS stimulation. MO differentiation factors granulocyte-macrophage colony stimulating factor (GM-CSF) or M-CSF were added to separate cultures. We also compared the inflammatory response with an acute, 4-hour MO incubation with IFN-υ plus cortisol and LPS to a delayed 18-hour incubation with cortisol before LPS exposure. MO activation was assessed by interleukin-6 (IL-6) release and by multiplex analysis of pro- and anti-inflammatory soluble mediators. Results: After the 18-hour incubation, we observed that cortisol significantly increased LPS-stimulated IL-6 release from IFN-υ-treated undifferentiated MOs. In GM-CSF-pretreated MOs, cortisol increased IFN-υ-mediated IL-6 release by >4-fold and release of the immune stimulant IFN-α2 (IFN-α2) by >3-fold, while suppressing release of the anti-inflammatory mediator, IL-1 receptor antagonist to 15% of control. These results were reversed by either the GC receptor antagonist RU486 or by an IFN-υ receptor type 1 antibody antagonist. Cortisol alone increased expression of the IFN-υ receptor type 1 on undifferentiated and GM-CSF-treated MOs. In contrast, an acute 4-hour incubation of MOs with IFN-υ and cortisol showed classic suppression of the IL-6 response to LPS. Conclusions: These results reveal a surprisingly robust proinflammatory interaction between the human stress response hormone cortisol and the immune activating cytokine IFN-υ. The results support an emerging physiological model with an adaptive role for cortisol, wherein acute release of cortisol suppresses early proinflammatory responses but also primes immune cells for an augmented response to a subsequent immune challenge. These findings have broad clinical implications and provide an experimental framework to examine individual differences, mechanisms, and translational implications of cortisol-enhanced immune responses in humans.

Background and objectives: Thoracic epidural analgesia can reduce postoperative pain and cardiopulmonary morbidity, but it is associated with a high rate of clinical failure. Up to 50% of clinical failure is thought to be related to technical insertion. In this study, patients undergoing thoracic surgery were randomized to one of two catheter insertion techniques: fluoroscopically guided or conventional loss of resistance with saline/air. Our primary aim was to examine whether fluoroscopic guidance could increase the incidence of correct catheter placement and improve postoperative analgesia. Our secondary aim was to assess the potential impact of correct epidural catheter positioning on length of stay in the postanesthesia care unit and total hospital length of stay. Methods: This randomized clinical trial was conducted at Dartmouth-Hitchcock Medical Center over 25 months (January 2012 to February 2014). Patients (N = 100) undergoing thoracic surgery were randomized to fluoroscopic guidance (n = 47) or to loss of resistance with saline/air (n = 53). Patients were followed for the primary outcomes of 24-hour morphine use, 24-hour numeric pain scores, and the incidence of epidural catheter positioning within the epidural space. Postanesthesia care unit and total hospital lengths of stay were evaluated as secondary outcome measurements and compared for patients with correct epidural catheter positioning and those without correct epidural catheter positioning. Results: One hundred patients were included in an intention-to-treat analysis. Numeric pain scores and 24-hour morphine consumption were no different between groups. Fluoroscopic guidance was associated with an increased incidence of epidural catheter placement within the epidural space compared with loss of resistance with air/saline [fluoroscopic guidance, epidural in 98% (46/47) versus loss of resistance with saline/air, epidural in 74% (39/53)]. There was a significant increase in correct catheter positioning with (odds ratio, 21.07; 95% confidence interval, 2.07-214.38; P = 0.010) or without (odds ratio, 16.15; 95% confidence interval, 2.03-128.47; P = 0.009) adjustment for potentially confounding variables. In an adjusted analysis, correctly positioned thoracic epidural catheters were associated with shorter postanesthesia care unit (5.87 ± 5.39 hours vs 4.30 ± 1.171 hours; P = 0.044) and total hospital length of stay (5.77 ± 4.94 days vs 4.93 ± 2.79 days; P = 0.031). Conclusions: Fluoroscopic guidance increases the incidence of epidural catheter positioning within the epidural space and may reduce postanesthesia care unit and hospital lengths of stay. Future work should validate the effectiveness of this approach.This clinical trial is registered with ClinicalTrials.gov (NCT02678039).

Glucocorticoids (GCs) are best known for their potent anti-inflammatory effects. However, an emerging model for glucocorticoid (GC) regulation of in vivo inflammation also includes a delayed, preparatory effect that manifests as enhanced inflammation following exposure to an inflammatory stimulus. When GCs are transiently elevated in vivo following exposure to a stressful event, this model proposes that a subsequent period of increased inflammatory responsiveness is adaptive because it enhances resistance to a subsequent stressor. In the present study, we examined the migratory response of human monocytes/macrophages following transient in vivo exposure to stress-associated concentrations of cortisol. Participants were administered cortisol for 6 hours to elevate in vivo cortisol levels to approximate those observed during major systemic stress. Monocytes in peripheral blood and macrophages in sterile inflammatory tissue (skin blisters) were studied before and after exposure to cortisol or placebo. We found that exposure to cortisol induced transient upregulation of monocyte mRNA for CCR2, the receptor for monocyte chemotactic protein-1 (MCP-1/CCL2) as well as for the chemokine receptor CX3CR1. At the same time, mRNA for the transcription factor IκBα was decreased. Monocyte surface expression of CCR2 but not CX3CR1 increased in the first 24 hours after cortisol exposure. Transient exposure to cortisol also led to an increased number of macrophages and neutrophils in fluid derived from a sterile inflammatory site in vivo. These findings suggest that the delayed, pro-inflammatory effects of cortisol on the human inflammatory responses may include enhanced localization of effector cells at sites of in vivo inflammation.

Background: Epidural catheters that are placed for post-operative analgesia have a significant failure rate in the first 24 hours. Beginning in 2011, we have used fluoroscopic guidance to place all non-obstetrical epidural catheters. In this retrospective analysis, we hypothesized that the characteristics of dye distribution on an epidurogram obtained immediately after catheter placement would predict clinical catheter function after surgery. Methods: The epidurograms and medical records of 303 consecutive patients who had epidural catheters placed for post-operative analgesia were reviewed. We extracted data on epidural dye distribution on the epidurograms and compared these results to the clinical function of the epidural catheters assessed on post-operative day 1 (POD1). Results: The three-dimensional pattern of epidural dye distribution (cephalad-caudad, right-left, anterior-posterior) had significant correlations with clinical function of an epidural catheter after surgery. Increased cephalad-caudad and anterior dye spread both correlated with decreased epidural solution infusion rates on POD1, whereas right- or left-sided dye distribution correlated with unilateral sensory deficits. A higher catheter placement on the neuraxis correlated with lower pain scores after thoracic surgery. Conclusions: An epidurogram obtained immediately after epidural catheter placement may have clinical utility for predicting clinical function of the catheter after surgery.