The Stress Hormone Cortisol Enhances Interferon-υ-Mediated Proinflammatory Responses of Human Immune Cells.

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.

Glucocorticoids enhance the in vivo migratory response of human monocytes.

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 6h 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 24h 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.

Hand hygiene knowledge and perceptions among anesthesia providers.

BACKGROUND: Health care worker compliance with hand hygiene guidelines is an important measure for health care-associated infection prevention, yet overall compliance across all health care arenas remains low. A correct answer to 4 of 4 structured questions pertaining to indications for hand decontamination (according to types of contact) has been associated with improved health care provider hand hygiene compliance when compared to those health care providers answering incorrectly for 1 or more questions. A better understanding of knowledge deficits among anesthesia providers may lead to hand hygiene improvement strategies. In this study, our primary aims were to characterize and identify predictors for hand hygiene knowledge deficits among anesthesia providers. METHODS: We modified this previously tested survey instrument to measure anesthesia provider hand hygiene knowledge regarding the 5 moments of hand hygiene across national and multicenter groups. Complete knowledge was defined by correct answers to 5 questions addressing the 5 moments for hand hygiene and received a score of 1. Incomplete knowledge was defined by an incorrect answer to 1 or more of the 5 questions and received a score of 0. We used a multilevel random-effects XTMELOGIT logistic model clustering at the respondent and geographic location for insufficient knowledge and forward/backward stepwise logistic regression analysis to identify predictors for incomplete knowledge. RESULTS: The survey response rates were 55.8% and 18.2% for the multicenter and national survey study groups, respectively. One or more knowledge deficits occurred with 81.6% of survey respondents, with the mean number of correct answers 2.89 (95% confidence interval, 2.78- 2.99). Failure of providers to recognize prior contact with the environment and prior contact with the patient as hand hygiene opportunities contributed to the low mean. Several cognitive factors were associated with a reduced risk of incomplete knowledge including providers responding positively to washing their hands after contact with the environment (odds ratio [OR] 0.23, 0.14-0.37, P < 0.001), disinfecting their environment during patient care (OR 0.54, 0.35-0.82, P = 0.004), believing that they can influence their colleagues (OR 0.43, 0.27-0.68, P < 0.001), and intending to adhere to guidelines (OR 0.56, 0.36-0.86, P = 0.008). These covariates were associated with an area under receiver operator characteristics curve of 0.79 (95% confidence interval, 0.74-0.83). CONCLUSIONS: Anesthesia provider knowledge deficits around to hand hygiene guidelines occur frequently and are often due to failure to recognize opportunities for hand hygiene after prior contact with contaminated patient and environmental reservoirs. Intraoperative hand hygiene improvement programs should address these knowledge deficits. Predictors for incomplete knowledge as identified in this study should be validated in future studies.

Transmission dynamics of gram-negative bacterial pathogens in the anesthesia work area.

BACKGROUND: Gram-negative organisms are a major health care concern with increasing prevalence of infection and community spread. Our primary aim was to characterize the transmission dynamics of frequently encountered gram-negative bacteria in the anesthesia work area environment (AWE). Our secondary aim was to examine links between these transmission events and 30-day postoperative health care-associated infections (HCAIs). METHODS: Gram-negative isolates obtained from the AWE (patient nasopharynx and axilla, anesthesia provider hands, and the adjustable pressure-limiting valve and agent dial of the anesthesia machine) at 3 major academic medical centers were identified as possible intraoperative bacterial transmission events by class of pathogen, temporal association, and phenotypic analysis (analytical profile indexing). The top 5 frequently encountered genera were subjected to antibiotic disk diffusion sensitivity to identify epidemiologically related transmission events. Complete multivariable logistic regression analysis and binomial tests of proportion were then used to examine the relative contributions of reservoirs of origin and within- and between-case modes of transmission, respectively, to epidemiologically related transmission events. Analyses were conducted with and without the inclusion of duplicate transmission events of the same genera occurring in a given study unit (first and second case of the day in each operating room observed) to examine the potential effect of statistical dependency. Transmitted isolates were compared by pulsed-field gel electrophoresis to disease-causing bacteria for 30-day postoperative HCAIs. RESULTS: The top 5 frequently encountered gram-negative genera included Acinetobacter, Pseudomonas, Brevundimonas, Enterobacter, and Moraxella that together accounted for 81% (767/945) of possible transmission events. For all isolates, 22% (167/767) of possible transmission events were identified by antibiotic susceptibility patterns as epidemiologically related and underwent further study of transmission dynamics. There were 20 duplicates involving within- and between-case transmission events. Thus, approximately 19% (147/767) of isolates excluding duplicates were considered epidemiologically related. Contaminated provider hand reservoirs were less likely (all isolates, odds ratio 0.12, 95% confidence interval 0.03-0.50, P = 0.004; without duplicate events, odds ratio 0.05, 95% confidence interval 0.01-0.49, P = 0.010) than contaminated patient or environmental sites to serve as the reservoir of origin for epidemiologically related transmission events. Within- and between-case modes of gram-negative bacilli transmission occurred at similar rates (all isolates, 7% between-case, 5.2% within-case, binomial P value 0.176; without duplicates, 6.3% between-case, 3.7% within-case, binomial P value 0.036). Overall, 4.0% (23/548) of patients suffered from HCAIs and had an intraoperative exposure to gram-negative isolates. In 8.0% (2/23) of those patients, gram-negative bacteria were linked by pulsed-field gel electrophoresis to the causative organism of infection. Patient and provider hands were identified as the reservoirs of origin and the environment confirmed as a vehicle for between-case transmission events linked to HCAIs. CONCLUSIONS: Between- and within-case AWE gram-negative bacterial transmission occurs frequently and is linked by pulsed-field gel electrophoresis to 30-day postoperative infections. Provider hands are less likely than contaminated environmental or patient skin surfaces to serve as the reservoir of origin for transmission events.

The epidemiology of Staphylococcus aureus transmission in the anesthesia work area.

BACKGROUND: Little is known regarding the epidemiology of intraoperative Staphylococcus aureus transmission. The primary aim of this study was to examine the mode of transmission, reservoir of origin, transmission locations, and antibiotic susceptibility for frequently encountered S aureus strains (phenotypes) in the anesthesia work area. Our secondary aims were to examine phenotypic associations with 30-day postoperative patient cultures, phenotypic growth rates, and risk factors for phenotypic isolation. METHODS: S aureus isolates previously identified as possible intraoperative bacterial transmission events by class of pathogen, temporal association, and analytical profile indexing were subjected to antibiotic disk diffusion sensitivity. The combination of these techniques was then used to confirm S aureus transmission events and to classify them as occurring within or between operative cases (mode). The origin of S aureus transmission events was determined via use of a previously validated experimental model and links to 30-day postoperative patient cultures confirmed via pulsed-field gel electrophoresis. Growth rates were assessed via time-to-positivity analysis, and risk factors for isolation were characterized via logistic regression. RESULTS: One hundred seventy S aureus isolates previously implicated as possible intraoperative transmission events were further subdivided by analytical profile indexing phenotype. Two phenotypes, phenotype P (patients) and phenotype H (hands), accounted for 65% of isolates. Phenotype P and phenotype H contributed to at least 1 confirmed transmission event in 39% and 28% of cases, respectively. Patient skin surfaces (odds ratio [OR], 8.40; 95% confidence interval [CI], 2.30-30.73) and environmental (OR, 10.89; 95% CI, 1.29-92.13) samples were more likely than provider hands (referent) to have phenotype P positivity. Phenotype P was more likely than phenotype H to be resistant to methicillin (OR, 4.38; 95% CI, 1.59-12.06; P = 0.004) and to be linked to 30-day postoperative patient cultures (risk ratio, 36.63 [risk difference, 0.174; 95% CI, 0.019-0.328]; P < 0.001). Phenotype P exhibited a faster growth rate for methicillin resistant and for methicillin susceptible than phenotype H (phenotype P: median, 10.32H; interquartile range, 10.08-10.56; phenotype H: median, 10.56H; interquartile range, 10.32-10.8; P = 0.012). Risk factors for isolation of phenotype P included age (OR, 14.11; 95% CI, 3.12-63.5; P = 0.001) and patient exposure to the hospital ward (OR, 41.11; 95% CI, 5.30-318.78; P < 0.001). CONCLUSIONS: Two S aureus phenotypes are frequently transmitted in the anesthesia work area. A patient and environmentally derived phenotype is associated with increased risk of antibiotic resistance and links to 30-day postoperative patient cultures as compared with a provider hand-derived phenotype. Future work should be directed toward improved screening and decolonization of patients entering the perioperative arena and improved intraoperative environmental cleaning to attenuate postoperative health care-associated infections.

The dynamics of Enterococcus transmission from bacterial reservoirs commonly encountered by anesthesia providers.

BACKGROUND: Enterococci, the second leading cause of health care-associated infections, have evolved from commensal and harmless organisms to multidrug-resistant bacteria associated with a significant increase in patient morbidity and mortality. Prevention of ongoing spread of this organism within and between hospitals is important. In this study, we characterized Enterococcus transmission dynamics for bacterial reservoirs commonly encountered by anesthesia providers during the routine administration of general anesthesia. METHODS: Enterococcus isolates previously obtained from bacterial reservoirs frequently encountered by anesthesiologists (patient nasopharynx and axilla, anesthesia provider hands, and the adjustable pressure-limiting valve and agent dial of the anesthesia machine) at 3 major academic medical centers were identified as possible intraoperative bacterial transmission events by class of pathogen, temporal association, and phenotypic analysis (analytical profile indexing). They were then subjected to antibiotic disk diffusion sensitivity for transmission event confirmation. Isolates involved in confirmed transmission events were further analyzed to characterize the frequency, mode, origin, location of transmission events, and antibiotic susceptibility of transmitted pathogens. RESULTS: Three hundred eighty-nine anesthesia reservoir isolates were previously identified by gross morphology and simple rapid tests as Enterococcus. The combination of further analytical profile indexing analysis and temporal association implicated 43% (166/389) of those isolates in possible intraoperative bacterial transmission events. Approximately, 30% (49/166) of possible transmission events were confirmed by additional antibiotic disk diffusion analysis. Two phenotypes, E5 and E7, explained 80% (39/49) of confirmed transmission events. For both phenotypes, provider hands were a common reservoir of origin proximal to the transmission event (96% [72/75] hand origin for E7 and 89% [50/56] hand origin for E5) and site of transmission (94% [16/17] hand transmission location for E7 and 86% [19/22] hand transmission location for E5). CONCLUSIONS: Anesthesia provider hand contamination is a common proximal source and transmission location for Enterococcus transmission events in the anesthesia work area. Future work should evaluate the impact of intraoperative hand hygiene improvement strategies on the dynamics of intraoperative Enterococcus transmission.

Reduction in intraoperative bacterial contamination of peripheral intravenous tubing through the use of a passive catheter care system.

BACKGROUND: Bacterial contamination of intravascular devices has been associated with increased morbidity and mortality in various hospital settings, including the perioperative environment. Catheter hub disinfection has been shown in an ex vivo model to attenuate intraoperative injection of bacterial organisms originating from the anesthesia provider's hands, providing the impetus for improvement in intraoperative disinfection techniques and compliance. In the current study, we investigated the clinical effectiveness of a new, passive catheter care station in reducing the incidence of bacterial contamination of open lumen patient IV stopcock sets. The secondary aim was to evaluate the impact of this novel intervention on the combined incidence of 30-day postoperative infections and IV catheter-associated phlebitis. METHODS: Five hundred ninety-four operating room environments were randomized by a computer-generated list to receive either a novel catheter care bundle (HubScrub and DOCit) or standard caps in conjunction with a sterile, conventional open lumen 3-way stopcock set (24 inch with 3-gang 4-way and T-Connector). Patients underwent general anesthesia according to usual practice and were followed prospectively for 30 postoperative days to identify the development of health care-associated infections (HCAIs) and/or phlebitis. The primary outcome was intraoperative bacterial contamination of the primary stopcock set used by the anesthesia provider(s). The secondary outcome was the combined incidence of 30-day postoperative infections and phlebitis. RESULTS: Five hundred seventy-two operating rooms were included in the final analysis. Study groups were comparable with no significant differences in patient, provider, anesthetic, or procedural characteristics. The catheter care station reduced the incidence of primary stopcock lumen contamination compared with standard caps (odds ratio [OR] 0.79, 95% confidence interval [CI] 0.63-0.98, P = 0.034) and was associated with a reduction in the combined incidence of HCAIs and IV catheter-associated phlebitis with and without adjustment for patient and procedural covariates (OR(adjusted) 0.589, 95% CI 0.353-0.984, P = 0.040). The risk-adjusted number needed to treat to eliminate 1 case of lumen contamination was 9 (95% CI 3.4-13.5) patients, whereas the risk-adjusted number needed to treat to eliminate 1 case of HCAI/catheter-associated phlebitis was 17 (95% CI 11.8-17.9) patients. CONCLUSION: Intraoperative use of a passive catheter care station significantly reduced open lumen bacterial contamination and the combined incidence of 30-day postoperative infections and phlebitis.

Multiple reservoirs contribute to intraoperative bacterial transmission.

BACKGROUND: Intraoperative stopcock contamination is a frequent event associated with increased patient mortality. In the current study we examined the relative contributions of anesthesia provider hands, the patient, and the patient environment to stopcock contamination. Our secondary aims were to identify risk factors for stopcock contamination and to examine the prior association of stopcock contamination with 30-day postoperative infection and mortality. Additional microbiological analyses were completed to determine the prevalence of bacterial pathogens within intraoperative bacterial reservoirs. Pulsed-field gel electrophoresis was used to assess the contribution of reservoir bacterial pathogens to 30-day postoperative infections. METHODS: In a multicenter study, stopcock transmission events were observed in 274 operating rooms, with the first and second cases of the day in each operating room studied in series to identify within- and between-case transmission events. Reservoir bacterial cultures were obtained and compared with stopcock set isolates to determine the origin of stopcock contamination. Between-case transmission was defined by the isolation of 1 or more bacterial isolates from the stopcock set of a subsequent case (case 2) that were identical to reservoir isolates from the preceding case (case 1). Within-case transmission was defined by the isolation of 1 or more bacterial isolates from a stopcock set that were identical to bacterial reservoirs from the same case. Bacterial pathogens within these reservoirs were identified, and their potential contribution to postoperative infections was evaluated. All patients were followed for 30 days postoperatively for the development of infection and all-cause mortality. RESULTS: Stopcock contamination was detected in 23% (126 out of 548) of cases with 14 between-case and 30 within-case transmission events confirmed. All 3 reservoirs contributed to between-case (64% environment, 14% patient, and 21% provider) and within-case (47% environment, 23% patient, and 30% provider) stopcock transmission. The environment was a more likely source of stopcock contamination than provider hands (relative risk [RR] 1.91, confidence interval [CI] 1.09 to 3.35, P = 0.029) or patients (RR 2.56, CI 1.34 to 4.89, P = 0.002). Hospital site (odds ratio [OR] 5.09, CI 2.02 to 12.86, P = 0.001) and case 2 (OR 6.82, CI 4.03 to 11.5, P < 0.001) were significant predictors of stopcock contamination. Stopcock contamination was associated with increased mortality (OR 58.5, CI 2.32 to 1477, P = 0.014). Intraoperative bacterial contamination of patients and provider hands was linked to 30-day postoperative infections. CONCLUSIONS: Bacterial contamination of patients, provider hands, and the environment contributes to stopcock transmission events, but the surrounding patient environment is the most likely source. Stopcock contamination is associated with increased patient mortality. Patient and provider bacterial reservoirs contribute to 30-day postoperative infections. Multimodal programs designed to target each of these reservoirs in parallel should be studied intensely as a comprehensive approach to reducing intraoperative bacterial transmission.

Prevention of intravenous bacterial injection from health care provider hands: the importance of catheter design and handling.

BACKGROUND: Device-related bloodstream infections are associated with a significant increase in patient morbidity and mortality in multiple health care settings. Recently, intraoperative bacterial contamination of conventional open-lumen 3-way stopcock sets has been shown to be associated with increased patient mortality. Intraoperative use of disinfectable, needleless closed catheter devices (DNCCs) may reduce the risk of bacterial injection as compared to conventional open-lumen devices due to an intrinsic barrier to bacterial entry associated with valve design and/or the capacity for surface disinfection. However, the relative benefit of DNCC valve design (intrinsic barrier capacity) as compared to surface disinfection in attenuation of bacterial injection in the clinical environment is untested and entirely unknown. The primary aim of the current study was to investigate the relative efficacy of a novel disinfectable stopcock, the Ultraport zero, with and without disinfection in attenuating intraoperative injection of potential bacterial pathogens as compared to a conventional open-lumen stopcock intravascular device. The secondary aims were to identify risk factors for bacterial injection and to estimate the quantity of bacterial organisms injected during catheter handling. METHODS: Four hundred sixty-eight operating room environments were randomized by a computer generated list to 1 of 3 device-injection schemes: (1) injection of the Ultraport zero stopcock with hub disinfection before injection, (2) injection of the Ultraport zero stopcock without prior hub disinfection, and (3) injection of the conventional open-lumen stopcock closed with sterile caps according to usual practice. After induction of general anesthesia, the primary anesthesia provider caring for patients in each operating room environment was asked to perform a series of 5 injections of sterile saline through the assigned device into an ex vivo catheter system. The primary outcome was the incidence of bacterial contamination of the injected fluid column (effluent). Risk factors for effluent contamination were identified in univariate analysis, and a controlled laboratory experiment was used to generate an estimate of the bacterial load injected for contaminated effluent samples. RESULTS: The incidence of effluent bacterial contamination was 0% (0/152) for the Ultraport zero stopcock with hub disinfection before injection, 4% (7/162) for the Ultraport zero stopcock without hub disinfection before injection, and 3.2% (5/154) for the conventional open-lumen stopcock. The Ultraport zero stopcock with hub disinfection before injection was associated with a significant reduction in the risk of bacterial injection as compared to the conventional open-lumen stopcock (RR = 8.15 × 10(-8), 95% CI, 3.39 × 10(-8) to 1.96 × 10(-7), P = <0.001), with an absolute risk reduction of 3.2% (95% CI, 0.5% to 7.4%). Provider glove use was a risk factor for effluent contamination (RR = 10.48, 95% CI, 3.16 to 34.80, P < 0.001). The estimated quantity of bacteria injected reached a clinically significant threshold of 50,000 colony-forming units per each injection series. CONCLUSIONS: The Ultraport zero stopcock with hub disinfection before injection was associated with a significant reduction in the risk of inadvertent bacterial injection as compared to the conventional open-lumen stopcock. Future studies should examine strategies designed to facilitate health care provider DNCC hub disinfection and proper device handling.

Effectiveness and feasibility of an evidence-based intraoperative infection control program targeting improved basic measures: a post-implementation prospective case-cohort study.

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.

Hand contamination of anesthesia providers is an important risk factor for intraoperative bacterial transmission.

BACKGROUND: We have recently shown that intraoperative bacterial transmission to patient IV stopcock sets is associated with increased patient mortality. In this study, we hypothesized that bacterial contamination of anesthesia provider hands before patient contact is a risk factor for direct intraoperative bacterial transmission. METHODS: Dartmouth-Hitchcock Medical Center is a tertiary care and level 1 trauma center with 400 inpatient beds and 28 operating suites. The first and second operative cases in each of 92 operating rooms were randomly selected for analysis. Eighty-two paired samples were analyzed. Ten pairs of cases were excluded because of broken or missing sampling protocol and lost samples. We identified cases of intraoperative bacterial transmission to the patient IV stopcock set and the anesthesia environment (adjustable pressure-limiting valve and agent dial) in each operating room pair by using a previously validated protocol. We then used biotype analysis to compare these transmitted organisms to those organisms isolated from the hands of anesthesia providers obtained before the start of each case. Provider-origin transmission was defined as potential pathogens isolated in the patient stopcock set or environment that had an identical biotype to the same organism isolated from hands of providers. We also assessed the efficacy of the current intraoperative cleaning protocol by evaluating isolated potential pathogens identified at the start of case 2. Poor intraoperative cleaning was defined as 1 or more potential pathogens found in the anesthesia environment at the start of case 2 that were not there at the beginning of case 1. We collected clinical and epidemiological data on all the cases to identify risk factors for contamination. RESULTS: One hundred sixty-four cases (82 case pairs) were studied. We identified intraoperative bacterial transmission to the IV stopcock set in 11.5 % (19/164) of cases, 47% (9/19) of which were of provider origin. We identified intraoperative bacterial transmission to the anesthesia environment in 89% (146/164) of cases, 12% (17/146) of which were of provider origin. The number of rooms that an attending anesthesiologist supervised simultaneously, the age of the patient, and patient discharge from the operating room to an intensive care unit were independent predictors of bacterial transmission events not directly linked to providers. CONCLUSION: The contaminated hands of anesthesia providers serve as a significant source of patient environmental and stopcock set contamination in the operating room. Additional sources of intraoperative bacterial transmission, including postoperative environmental cleaning practices, should be further studied.

Intraoperative ketamine reduces perioperative opiate consumption in opiate-dependent patients with chronic back pain undergoing back surgery.

BACKGROUND: Ketamine is an N-methyl-d-aspartate receptor antagonist that has been shown to be useful in the reduction of acute postoperative pain and analgesic consumption in a variety of surgical interventions with variable routes of administration. Little is known regarding its efficacy in opiate-dependent patients with a history of chronic pain. We hypothesized that ketamine would reduce postoperative opiate consumption in this patient population. METHODS: This was a randomized, prospective, double-blinded, and placebo-controlled trial involving opiate-dependent patients undergoing major lumbar spine surgery. Fifty-two patients in the treatment group were administered 0.5 mg/kg intravenous ketamine on induction of anesthesia, and a continuous infusion at 10 microg kg(-1) min(-1) was begun on induction and terminated at wound closure. Fifty patients in the placebo group received saline of equivalent volume. Patients were observed for 48 h postoperatively and followed up at 6 weeks. The primary outcome was 48-h morphine consumption. RESULTS: Total morphine consumption (morphine equivalents) was significantly reduced in the treatment group 48 h after the procedure. It was also reduced at 24 h and at 6 weeks. The average reported pain intensity was significantly reduced in the postanesthesia care unit and at 6 weeks. The groups had no differences in known ketamine- or opiate-related side effects. CONCLUSIONS: Intraoperative ketamine reduces opiate consumption in the 48-h postoperative period in opiate-dependent patients with chronic pain. Ketamine may also reduce opioid consumption and pain intensity throughout the postoperative period in this patient population. This benefit is without an increase in side effects.

Pretreatment with stress cortisol enhances the human systemic inflammatory response to bacterial endotoxin.

OBJECTIVE: There is continuing controversy regarding the effect of glucocorticoids on a systemic inflammatory process. Based ona model of glucocorticoid action that includes both pro- and anti-inflammatory effects, we used the human experimental endotoxemia model to test the hypothesis that a transient elevation of plasma cortisol to stress-associated levels would enhance a subsequent (delayed) systemic inflammatory response to bacterial endotoxin. DESIGN: Prospective, randomized, double-blind, placebo-controlled clinical investigation. SETTING: Academic medical center. SUBJECTS: Thirty-six healthy human volunteers. INTERVENTIONS: Participants were randomized to receive a 6-hr intravenous infusion of saline (control), an intermediate dose of cortisol (Cort80; 6.3 mg/hr/70 kg), or a high dose of cortisol (Cort160; 12.6 mg/hr/70 kg) on day 1. On day 2, participants received an intravenous injection of 2 ng/kg Escherichia coli endotoxin followed by serial measurements of plasma cytokine concentrations. MEASUREMENTS AND MAIN RESULTS: Baseline participant characteristics and cortisol and cytokine concentrations were similar in all three groups. The plasma cortisol response to endotoxemia on day 2 was similar in all three groups. The interleukin-6 response to endotoxemia was significantly increased in the Cort80 Group compared with the control Group (p = .004), whereas the interleukin-10 response was significantly suppressed (p = .034). Corresponding results for the Cort160 Group were not significantly different from control Group values. CONCLUSIONS: In this study, transient elevation of in vivo cortisol concentrations to levels that are observed during major systemic stress enhanced a subsequent, delayed in vivo inflammatory response to endotoxin. This appeared to be a dose-dependent effect that was more prominent at intermediate concentrations of cortisol than at higher concentrations of cortisol.

In vivo exposure to high or low cortisol has biphasic effects on inflammatory response pathways of human monocytes.

BACKGROUND: Recent studies demonstrate that glucocorticoids (GCs) have both supportive (stimulatory) and suppressive effects on immune responses, depending upon the GC concentration. Since some GC effects on inflammation are stimulatory, we hypothesized that acute in vivo GC depletion would decrease inflammatory responses of human monocytes. METHODS: Monocytes were isolated from healthy volunteer participants before and after in vivo treatment with; 1) IV saline, 2) IV high dose hydrocortisone (8 microg x kg(-1) x min(-1)) followed by oral hydrocortisone overnight, and 3) oral RU486 (200 mg at 0400 and 1600 h) to block the intracellular GC receptor and IV etomidate (1.5 mg x kg(-1) x h(-1)) for 12 h to prevent compensatory adrenal cortisol synthesis. Plasma adrenocorticotropic hormone, plasma, and salivary cortisol were measured serially. Monocytes were tested for; 1) cytokine responses, 2) expression of CD163, CD119, and CD54, and 3) mRNA levels of GC-responsive inflammatory mediators. All measurements were made with and without in vitro stimulation of monocytes by lipopolysaccharide. RESULTS: Cortisol and adrenocorticotropic hormone measurements demonstrated effective manipulation of in vivo cortisol. In vivo hypercortisolemia and in vivo GC depletion had reciprocal effects on monocyte mRNA levels of 4 important GC-responsive molecules: 1) GC receptor, CD163, interleukin-10, and suppressor of the cytokine synthesis-3. Monocyte cytokine responses and protein expression were not affected by GC depletion. CD163 expression was increased by hypercortisolemia. CONCLUSIONS: Short-term GC depletion affects mRNA levels of GC-responsive molecules but does not affect monocyte protein expression or cytokine responses.

Fluoroscopic Guidance Increases the Incidence of Thoracic Epidural Catheter Placement Within the Epidural Space: A Randomized Trial.

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).

Endotoxin induces rapid metalloproteinase-mediated shedding followed by up-regulation of the monocyte hemoglobin scavenger receptor CD163.

CD163, a monocyte and macrophage-specific surface glycoprotein, which is increased by interleukin-10 and glucocorticoids, is a scavenger receptor for hemoglobin/haptoglobin complexes. We report a rapid and highly reproducible rise in soluble CD163 in the plasma of human volunteers given intravenous lipopolysaccharide (LPS). We also show that LPS induces shedding of CD163 from the surface of isolated monocytes, identifying shedding from monocytes and macrophages as a likely mechanism for the endotoxemia-associated rise in plasma CD163 in vivo. Studies using the inhibitor TAPI-0 indicate that a metalloproteinase is responsible for LPS-mediated shedding of CD163. Finally, we demonstrate a marked increase in surface CD163 expression on circulating monocytes 24 h following experimental endotoxemia. These findings show that CD163 is rapidly mobilized in response to bacterial endotoxin. As hemoglobin can bind LPS and enhance its toxicity, it will be important to determine how cell surface and soluble CD163 influence inflammatory processes during sepsis.

A novel method for selective delivery of drugs to the pulmonary arteries.

Drug treatment of pulmonary hypertension may be limited by systemic hypotension. Selective action of a vasodilator drug in pulmonary arteries could be achieved by administering a vasodilator gas into systemic venous blood so that it dilates pulmonary arteries before immediate first-pass elimination via exhalation. This article presents in vivo data to show that a pharmacologically active gas can be delivered safely into systemic venous blood where it has a distribution pattern and physiologic effects similar to those observed when the gas is inhaled into pulmonary venous (systemic arterial) blood. This is a first step toward development of first-pass pulmonary clearance as a mechanism to concentrate drugs in pulmonary arteries.