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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 mug kgmin 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. [ABSTRACT FROM AUTHOR]

Objective: To determine the plasma concentration of cortisol that is needed for maximal suppression of the systemic inflammatory response to cardiac surgery with cardiopulmonary bypass.Design: Prospective, randomized, double-blind clinical study of cardiac surgical patients.Setting: Operating room and inpatient care facility of a university medical center.Subjects: Sixty elective cardiac surgical patients scheduled for coronary artery bypass graft, cardiac valve replacement, or both.Interventions: Patients were randomized to receive one of three different hydrocortisone doses, by intravenous infusion, for 6 hrs before, during, and immediately after surgery while also receiving etomidate to suppress endogenous cortisol production.Measurements and Main Results: Serial determinations of plasma interleukin-6 were studied as a marker of systemic inflammation. Measurements of interleukin-10 were used as a marker of the compensatory antiinflammatory response. Plasma cortisol concentrations in an untreated control group rose from 17 microg/dL before surgery to a mean of 43 microg/dL by 4 hrs after surgery. A dose of hydrocortisone (4 microg/kg/min for 6 hrs) that maintained plasma cortisol between 40 and 50 microg/dL, starting 60-90 mins before surgery, significantly suppressed plasma interleukin-6 after surgery compared with control while significantly increasing plasma interleukin-10 during surgery. Plasma interleukin-6 after surgery was not suppressed further by increasing the dose of hydrocortisone to 8 microg/kg/min, although the mean peak plasma interleukin-10 concentration increased further compared with the group that received the 4 microg/kg/min hydrocortisone dose.Conclusions: At the doses studied, cortisol-induced suppression of plasma interleukin-6 during and after cardiac surgery appears to be a saturable phenomenon at the concentration of plasma cortisol that is normally achieved after surgery in untreated patients. [ABSTRACT FROM AUTHOR]

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., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

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 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., (Copyright © 2016 Elsevier Inc. All rights reserved.)

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., (© 2015 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

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.

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.

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.

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.

Background: Hand hygiene (HH) is considered a primary intervention to avoid transmission of bacteria in health care settings and to prevent health care-associated infections. Despite efforts to decrease the incidence of health care-associated infections by improving HH, HH compliance rates vary widely depending on the hospital environment., Methods: We used intraoperative video observation to map temporal patterns of anesthesia provider hand contact with anesthesia work environment (AWE) surfaces and to assess HH compliance. Serial bacterial cultures of high contact objects were subsequently used to characterize bacterial transmission over time., Results: Using World Health Organization criteria, we found a large number of HH opportunities and a low rate of HH compliance by anesthesia providers (mean, 2.9%). We observed an inverse correlation between provider hand hygiene compliance during induction and emergence from anesthesia (3.2% and 4.1%, respectively) and the magnitude of AWE surface contamination (103 and 147 CFU, respectively) at these time points. We found no correlation between frequency of hand contact with the AWE and bacterial contamination., Conclusions: Compliance with current HH recommendations by anesthesia providers is not feasible. However, there does appear to be a correlation between HH compliance rates and bacterial contamination of the AWE, an observation that should stimulate further work to design new methods for control of bacterial transmission in operating rooms., (Copyright © 2014 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Mosby, Inc. All rights reserved.)

Spaced out: This paper investigates potassium-ion storage in vanadium pentoxide nanofibers (VNFs, K0.33 V2 O5 ) with a layered architecture. In situ XRD experiments reveal that the interplanar space of VNF expands/contracts upon extraction/insertion of potassium ions during the redox process., (Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Hausmannite Mn3 O4 octahedral nanoparticles of 18.3 ± 7.0 nm with (101) facets have been prepared by an oxygen-mediated growth. The electrochemical properties of the Mn3 O4 particles as pseudocapacitive cathode materials were characterized both in half-cells and in button-cells. The Mn3 O4 nanoparticles exhibited a high mass-specific capacitance of 261 F g(-1), which was calculated from cyclic voltammetry analyses, and a capacitive retention of 78% after 10,000 galvanostatic charge-discharge cycles. The charge-transfer mechanisms of the Mn3 O4 nanoparticles were further studied by using synchrotron-based in situ X-ray absorption near edge spectroscopy and XRD. Both measurements showed concurrently that throughout the potential window of 0-1.2 V (vs. Ag/AgCl), a stable spinel structure of Mn3 O4 remained, and a reversible electrochemical conversion between tetrahedral [Mn(II) O4 ] and octahedral [Mn(III) O6 ] units accounted for the redox activity. Density functional theory calculations further corroborated this mechanism by confirming the enhanced redox stability afforded by the abundant and exposed (101) facets of Mn3 O4 octahedra., (Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

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.

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.

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.

Purpose: We evaluated the differential impact of stress-associated vs high pharmacologic concentrations of hydrocortisone pretreatment on heart rate variability (HRV) during a subsequent systemic inflammatory stimulus., Materials and Methods: Healthy volunteers were randomized to receive placebo (Control) and hydrocortisone at 1.5 μg/kg per minute (STRESS) or at 3.0 μg/kg per minute (PHARM) as a 6-hour infusion. The STRESS dose was chosen to replicate the condition of physiologic adrenal cortical output during acute systemic stress. The PHARM dose was chosen to induce a supraphysiologic concentration of cortisol. The next day, all subjects received 2 ng/kg Escherichia coli endotoxin (lipopolysaccharide). Heart rate variability was analyzed with the statistic approximate entropy (ApEn). A lower ApEn correlates with decreased HRV., Results: At the 3-hour nadir, the decrease in ApEn in the STRESS group was significantly less compared to placebo (P < .03), whereas ApEn in the PHARM group was not statistically different. We also found that the maximal decrease in ApEn preceded maximal increase in heart rate in all groups. The decrease in R-R interval was maximal at 4 hours, whereas the ApEn nadir was 1 hour earlier at 3 hours., Conclusions: Pretreatment with a stress dose of hydrocortisone but not a higher pharmacologic dose maintained a significantly higher ApEn after endotoxin exposure when compared to a placebo. In addition, decreases in ApEn preceded increases in heart rate., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Natural and synthetic glucocorticoids (GCs) have been used for decades to suppress inflammation. In this paper, we re-examine the role of the endogenous GC, cortisol, as a primary homeostatic regulator of the human inflammatory response to injury. Our data show that cortisol regulation of innate immunity can be both pro-inflammatory and anti-inflammatory. Using a human model of in vivo cortisol depletion, we first show that baseline (diurnal) cortisol concentrations do not exert an anti-inflammatory effect. This is the first clue that cortisol regulation of inflammation is not represented by a linear dose-response relationship. We next show in surgical patients that cortisol does exert an acute anti-inflammatory effect over a carefully regulated range of physiologic cortisol concentrations. Finally, transient pre-treatment of healthy humans with cortisol induces a bi-phasic response during a later, delayed systemic inflammatory response: an intermediate cortisol concentration augments inflammation while a high cortisol concentration is neither pro- nor anti-inflammatory. Based on these findings and the work of others, we propose a new paradigm that identifies cortisol regulation of human inflammation as both dualistic-it is pro- and anti-inflammatory-and dynamic, it evolves over time.

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.

Background: Prior clinical studies have used injection port lumen culture as a marker of intravenous (IV) fluid system contamination. We hypothesized that culturing injected saline (effluent) is a more sensitive method of detecting IV fluid system bacterial contamination than lumen culture. To test this hypothesis, we compared the incidence of lumen contamination with effluent contamination in a simulated setting. We also measured the effect of a novel injection port protective device (Port Guide; Matrix Tooling, Inc, Wood Dale, IL) on contamination., Methods: In this ex vivo study, 33 providers performed 5 injections of 1 mL sterile saline into each of 4 injection port designs: (1) stopcock, (2) stopcock with Port Guide, (3) stopcock with disinfectable needleless closed connector (DNCC), and (4) stopcock with DNCC and Port Guide. The primary outcome was the rate of effluent contamination with simultaneously contaminated injection port lumen., Results: Bacterial organisms were recovered from the effluent in 17 of the 132 injection ports evaluated. Of those 17 injection ports with contaminated effluent, 4 injection port lumens were simultaneously contaminated (24%). Additionally, use of the stopcock with Port Guide significantly reduced effluent contamination., Conclusion: Effluent culture is a more sensitive marker of IV fluid system contamination than injection port lumen culture. A novel protective device on the stopcock (Port Guide) significantly reduced IV fluid system bacterial contamination., (Copyright © 2010 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Mosby, Inc. All rights reserved.)

Post-mortem analyses and epidemiological studies strongly indicate metals have a participatory role in neurodegenerative diseases, but whether these roles are pathogenic and not simply subsidiary mechanisms is currently unclear. For Parkinson's disease (PD), iron content in the afflicted brain region, the substantia nigra pars compacta (SNpc), has been consistently reported elevated whereas copper levels have been decreased. Both metals exhibit deleterious functions that occur during the late stages of PD, but mutations involving the regulation of these two metals have not been associated with PD. The pathogenesis of PD is undoubtedly multifaceted and may consist of various etiological factors participating in slow disease ascension. However, the extent to which certain factors may contribute to PD is unclear. To study whether iron and/or copper may facilitate a parkinsonian state, a computational model of neuronal metal regulation was initially developed and then the system was perturbed, corresponding to proposed etiological pathways for PD from the literature, in order to determine which iron- and copper-based pathogeneses would elicit a parkinsonian system. We report that a defective glutathione system and/or inhibited cellular iron efflux have the neurotoxic capacities to initiate a system characteristic of PD; furthermore, these capacities are greatly enhanced with mutated alpha-synuclein proteins., (Copyright 2010 Elsevier B.V. All rights reserved.)

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.

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.

The scientific knowledge base that supports clinical decisions about perioperative fluid management continues to evolve. However, despite these advancements in the understanding of the physiology of fluid replacement, the definition of ''optimal'' perioperative fluid management remains a matter of clinical judgment. With an appreciation of the many factors, both sensible and insensible, that contribute to changes in blood and extracellular fluid volume during surgery, clinicians have tried to create reproducible and generally applicable formulas for replacement of fluid during surgery. These formulas have been challenged recently by the introduction of new tools for monitoring cardiopulmonary function, by the implementation of monitor-guided protocols for fluid management, and, more recently, by clinical data suggesting that fluid restriction may improve surgical outcomes in some clinical settings. The relative ease of pre-identified fluid replacement protocols is being slowly replaced by data-guided interventions that take into account a variety of factors. Clinicians are therefore required to tailor their fluid replacement strategies based on preoperative patient characteristics, the type of surgery and even the type of anesthetic that is utilized. Some of the benefits of this new approach range from relatively ''minor'' outcomes such as diminished nausea after surgery to preventing postoperative complications such as wound breakdown and cardiopulmonary failure.

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.

During the first half of the 20th century, physiologists were interested in the adrenal glands primarily because adrenalectomized animals failed to survive even mild degrees of systemic stress. It eventually became clear that hormones secreted by the adrenal cortex were critical for survival and, in this context, adrenal cortical hormones were widely considered to support or stimulate important responses to stress or injury. With the purification and manufacture of adrenal cortical hormones in the 1930s and 1940s, clinicians suddenly discovered the potent anti-inflammatory actions of glucocorticoids (GCs). This dramatic, and unexpected, discovery has dominated clinical and laboratory research into GC actions throughout the second half of the 20th century. More recent research is again reporting GC-induced stimulatory effects on a variety of inflammatory response components. These effects are usually observed at low GC concentrations, close to concentrations that are observed in vivo during basal, unstimulated states. For example, GC-mediated stimulation has been reported for the hepatic acute-phase response, for cytokine secretion, expression of cytokine/chemokine receptors, and for the pro-inflammatory mediator, macrophage migration inhibition factor. It seems clear that the long-held clinical view that GCs act solely as anti-inflammatory agents needs to be re-assessed. Varying doses of GCs do not lead simply to varying degrees of inflammation suppression, but rather GCs can exert a full range of effects from permissive to stimulatory to suppressive.

Although haptoglobin polymorphism has been shown to be a genetic risk factor in coronary artery disease, its mechanisms of action are incompletely defined. Recently, a macrophage scavenger receptor for the uptake of haptoglobin-hemoglobin (Hp-Hb) complexes was cloned and designated CD163. Macrophage expression of CD163 is increased by glucocorticoids, IL-10 and IL-6. To better understand the in vivo response of CD163 to an inflammatory stimulus and glucocorticoid treatment, we studied 18 patients who underwent elective coronary artery bypass graft (CABG) surgery with cardiopulmonary bypass (CPB). We report a rapid increase in plasma levels of soluble CD163 by 1 h post-declamping the aorta during CABG surgery with CPB. Furthermore, we demonstrate significant increases in monocyte CD163 on post-operative day 1; 14-fold for patients pre-treated with methylprednisolone and 3-fold for those who did not receive exogenous glucocorticoids. These findings show CD163 to be rapidly mobilized in response to systemic inflammatory stimuli and to be affected significantly by glucocorticoids in vivo. The proposed role of CD163 as a Hp-Hb scavenger and anti-inflammatory molecule, in conjunction with the results of this study, make CD163 an intriguing target for potential manipulation of the acute response to inflammation.

Tumor necrosis factor (TNF) has been implicated in the development and pathogenicity of infectious diseases and autoimmune disorders, such as septic shock and arthritis. The zinc-finger protein tristetraprolin (TTP) has been identified as a major regulator of TNF biosynthesis. To define its intracellular location and examine its regulation of TNF, a quantitive intracellular staining assay specific for TTP was developed. We establish for the first time that in peripheral blood leukocytes, expression of endogenous TTP is confined to the cytoplasm. Baseline expression of TTP was higher in monocytes than in lymphocytes or neutrophils. After in vitro incubation with lipopolysaccharide (LPS), leukocyte TTP levels increased rapidly, peaking after approximately 2 hours. Monocytes showed the greatest response to LPS stimulation and lymphocytes the least. TTP levels were also studied in leukocytes isolated from healthy volunteers infused with a bolus dose of LPS. TTP expression and initial upregulation in response to LPS infusion were consistent with the in vitro data. Neutrophil TTP levels responded first, reaching an initial peak within 1 hour, monocyte levels peaked next at 2 hours, followed by lymphocytes at 4 hours. This response paralleled plasma TNF levels, which peaked 2 hours after infusion and were no longer detectable after 12 hours. A second rise in intracellular TTP levels, which did not parallel plasma TNF levels, was observed in all leukocyte populations, starting 12 hours after infusion. These data establish the cytoplasmic location of TTP, supporting a major role for this protein in regulating TNF production, and suggest that TTP levels are not regulated solely by TNF.

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.

Unlabelled: We previously reported that a continuous insulin infusion improves neutrophil phagocytic function after cardiac surgery in diabetic patients. These data suggested that hyperglycemia impairs neutrophil function, and because nondiabetic patients also experience hyperglycemia during cardiac surgery, we hypothesized that a continuous insulin infusion would improve glucose control and neutrophil function in nondiabetic cardiac surgical patients. Patients were randomized to receive either no insulin (Control group) or a continuous insulin infusion (Insulin group), with glucose measurements every 10 min during cardiopulmonary bypass (CPB). Blood glucose was significantly lower in the Insulin group immediately after surgery but not during surgery. When assessed as the percentage of phagocytic cells, neutrophil function was similar in the Control and Insulin groups at baseline (55% and 57%, respectively) and after CPB (38% and 43%, respectively). However, a quantitative determination of neutrophil phagocytic activity showed that whole blood neutrophil phagocytic capacity increased significantly in both groups at 60 min after CPB when compared with their respective baseline values and that the increase in total neutrophil phagocytic capacity was significantly more in the Insulin group compared with the Control group (P = 0.036). This observation was primarily due to a larger increase in the peripheral blood neutrophil count and not to increased activation of neutrophils., Implications: IV insulin, as used in this study, had effects on blood glucose only after cardiac surgery, when it was associated with an increased neutrophil count and a greater total capacity of peripheral blood neutrophils to ingest foreign particles.

Objective: To measure the effects of glucocorticoids on the systemic inflammatory response and clinical recovery after cardiac surgery., Design: Randomized, prospective, double-blind, placebo-controlled clinical trial with concurrent comparison groups., Setting: University medical center., Participants: Patients scheduled for elective coronary artery bypass graft surgery using normothermic cardiopulmonary bypass (CPB) and a standardized anesthetic., Interventions: Participants randomly received either methylprednisolone, 15 mg/kg intravenously 1 hour before surgery and 0.3 mg/kg intravenously every 6 hours x 4 doses, or placebo. Comparison groups included cardiac surgical patients who received etomidate to lower endogenous cortisol during surgery and healthy volunteers who received methylprednisolone only., Measurements and Main Results: Patients who received methylprednisolone had a significant reduction in circulating interleukin (IL)-6 at 60 minutes after CPB (p < 0.05) and on the morning of the 1st (p < 0.01) and 3rd (p < 0.05) postoperative days and a significant increase in circulating IL-10 at 60 minutes after CPB (p < 0.01) compared with the placebo group. Etomidate, given to lower cortisol during surgery, was associated with significantly decreased IL-6 and IL-10 responses to surgery compared with the placebo group, whereas methylprednisolone alone, given to healthy nonsurgical volunteers, had no effect on these cytokines. After adjusting for age, there were no significant differences in postoperative length of hospital stay between the methylprednisolone-treated (4.6 days) and placebo (6.1 days) groups or in the duration of mechanical ventilation (9.9 hours and 15.6 hours). No patient treated with methylprednisolone had nausea and vomiting on the 1st postoperative day compared with 33% of placebo-treated patients (p = 0.02). Glucose was significantly higher after methylprednisolone treatment at 1 hour after CPB (276 mg/dL v 210 mg/dL; p = 0.001) and at 2 hours (289 mg/dL v 213 mg/dL; p = 0.009) and 8 hours (247 mg/dL v 196 mg/dL; p = 0.02) after surgery. There were no differences in pain scores and no significant intergroup differences in lung peak expiratory flow rate or alveolar-arterial oxygen gradients after surgery., Conclusion: This study shows significant effects of glucocorticoids on the production of IL-6 and IL-10 in response to cardiac surgery but only minor effects on clinical recovery., (Copyright 2002, Elsevier Science (USA). All rights reserved.)

Objective: To measure predefined clinical effects resulting from the use of epidural anesthesia and analgesia during and after cardiac surgery., Design: Prospective, randomized, nonblinded clinical trial., Setting: Single academic medical center., Participants: Sixty patients scheduled for elective cardiac surgery with cardiopulmonary bypass., Interventions: Sixty participants were randomly assigned to 1 of 2 study groups: (1) A control group received general anesthesia during surgery and intravenous opiate analgesia after surgery. (2) A treatment group received thoracic epidural anesthesia combined with general anesthesia during surgery and epidural analgesia for the first 24 postoperative hours., Measurements and Main Results: Primary study measurements were planned to evaluate recovery from surgery and included time to tracheal extubation, duration of postoperative intensive care unit stay, duration of postoperative hospitalization, pain control, urinary free cortisol, cardiopulmonary complication rate, and total hospital charges. No statistically significant differences between the 2 study groups were found in these main measurements., Conclusions: The clinical course of elective cardiac surgical patients who receive epidural anesthesia during surgery and epidural analgesia after surgery is comparable to that of patients managed with general anesthesia alone during surgery followed by parenteral opiate analgesia after surgery., (Copyright 2002, Elsevier Science (USA). All rights reserved.)

Unlabelled: Opioids, including fentanyl, are often administered to patients who may be at risk for the consequences of impaired immune function. We performed a clinical study to test the effects of the synthetic opioid fentanyl on human immune function. Participants received an IV fentanyl initial dose of 3 microg/kg followed by a 2-h IV infusion of 1.2 microg x kg(-1) x h(-1). Peripheral blood was drawn before and after fentanyl administration to test for neutrophil phagocytic function, neutrophil antibody-dependent cell cytotoxicity, natural killer cell cytotoxicity, percentage of lymphocyte populations, T-lymphocyte proliferative response, and in vivo antibody response to a pneumococcal vaccine inoculation given at the end of the fentanyl infusion. Fentanyl exposure under the conditions of this study caused a rapid and significant increase in natural killer cell cytotoxicity, which was coincident with an increase in the percentage of CD16(+) and CD8(+) cells in peripheral blood. Fentanyl did not significantly affect any of the other immune measurements., Implications: Many previous studies have suggested that opioid drugs can impair immune resistance in patients who may be at risk for infection. This study suggests that the opioid fentanyl, when given to healthy humans without coexisting diseases, does not suppress immune resistance. On the basis of these results, the use of fentanyl should not be restricted because of concerns that it may suppress immune function.

Unlabelled: Impaired in vivo immunity is often observed after major surgery and is multifactorial. We conducted a randomized clinical study to determine the independent effects of general anesthesia (GA) and of lumbar epidural anesthesia (LEA) on human immune function in the absence of surgical trauma. Nineteen healthy volunteers were randomized to receive GA with thiopental and isoflurane, LEA with lidocaine, or no anesthesia (Control). Serial blood samples were tested for antibody responses to antigen inoculation, neutrophil and mononuclear cell antibody-dependent cell cytotoxicity (ADCC), natural killer cell cytotoxicity, and neutrophil phagocytic activity. Antibody responses were similar in the three groups. Mononuclear cell ADCC increased in the LEA group at the end of the anesthetic (P < 0.05 at effector/target [E/T] ratios of 10:1, 25:1, and 50:1). Natural killer cell cytotoxicity increased at the end of the anesthetic in both the LEA group (P < 0.05 at all E/T ratios) and the GA group (P < 0.05 at an E/T ratio of 5:1 and 10:1). No significant changes were observed for neutrophil ADCC or phagocytosis. General or epidural anesthesia alone, in the absence of surgery, seems to have only transient and minor effects on human immune function., Implications: General or epidural anesthesia alone, in the absence of surgery, seems to have only transient and minor effects on human immune function.

Objective: Determine the in vivo localization pattern of indium-111-labeled lymphocytes after a standardized extremity injury or standardized laparotomy and after sterile inflammation of the central nervous system., Design: Prospective animal study with concurrent controls., Setting: Animal research laboratory., Subjects: Male Lewis rats weighing 150-175 g., Interventions: Indium-111-labeled splenic lymphocytes were injected into animals after a standardized hind limb trauma or laparotomy and after induction of sterile central nervous system inflammation., Measurements and Main Results: Lymphoid and non-lymphoid organs were removed at fixed intervals after lymphocyte injection and the proportion of injected lymphocytes/gram of tissue was determined using a quantitative radionuclide calculation. Results from treated animals were compared with results from untreated control animals. Muscle injury caused early localization of lymphocytes to injured hind limbs, liver, and spleen compared with controls, whereas laparotomy decreased lymphocyte localization in the thymus and colon. Encephalitis increased localization to the central nervous system with no effect on other tissues., Conclusions: These results identify a sensitive method to track in vivo leukocyte localization and specifically demonstrate that lymphocyte localization is altered in both traumatic and nontraumatic models of inflammation.

Background and Objectives: Studies show that pain may cause neuroinflammatory changes in the spinal cord. These inflammatory changes could be caused by circulating factors such as plasma cytokines or could be a primary neuroimmune response of the central nervous system following peripheral nerve injury. To identify the possible effects of peripheral trauma and pain on the cytokine environment of the spinal cord, interleukin-6 (IL-6) and interleukin-10 (IL-10) concentrations in plasma and cerebrospinal fluid (CSF) were measured before and after hip replacement surgery., Methods: The investigation used a prospective, observational design to measure cytokine levels in samples of plasma and CSF by enzyme-linked immunosorbent assay (ELISA). Samples were taken from surgical patients before and after surgery under general anesthesia or spinal anesthesia performed with or without a spinal catheter. Reference samples were also obtained from healthy control subjects., Results: Both plasma and CSF levels of IL-6 increased substantially after major surgery with either general or spinal anesthesia. No significant correlation was observed between plasma IL-6 and CSF IL-6 levels, suggesting a central origin for increased CSF cytokine levels. IL-10 did not change in plasma or CSF after surgery. Plasma and CSF IL-6 and IL-10 cytokine levels were very low or undetectable in healthy controls., Conclusions: Major orthopedic surgery leads to elevated CSF levels of the proinflammatory cytokine, IL-6. The origin of increased CSF IL-6 may be central because there was no significant correlation with plasma levels.

Unlabelled: Diabetic patients are at increased risk of wound infection after major surgery, but the effect of perioperative glucose control on postoperative wound infection rates after surgery is uncertain. We tested the effect of an insulin infusion on perioperative neutrophil function in diabetic patients scheduled for coronary artery bypass surgery. Participants (n = 26) were randomly allocated to receive either aggressive insulin therapy (AIT) or standard insulin therapy (SIT) during surgery. Blood was drawn for neutrophil testing before surgery, 1 h after the completion of cardiopulmonary bypass, and on the first postoperative day. Neutrophil phagocytic activity decreased to 75% of baseline activity in the AIT group and to 47% of baseline activity in the SIT group (P < 0.05 between groups). No important differences in neutrophil antibody-dependent cell cytotoxicity were found. This study documents a potentially beneficial effect of continuous insulin therapy in diabetic patients who require major surgery., Implications: A continuous insulin infusion and glucose control during surgery improves white cell function in diabetic patients and may increase resistance to infection after surgery.

Peripheral nerve injury commonly leads to neuropathic pain states fostered, in part, by neuroimmunologic events. We used two models of neuropathic pain (L5 spinal nerve cryoneurolysis (SPCN) and chronic constriction injury (CCI)) to assess the role of spinal glial activation responses in producing pain behaviors. Scoring of glial responses subjectively encompassed changes in cell morphology, cell density and intensity of immunoreactivity with specific activation markers (OX-42 and anti-glial fibrillary acidic protein (GFAP) for microglia and astrocytes, respectively). Glial responses were compared with tactile sensitivity (mechanical allodynia) at 1, 3 or 10 days following SPCN and with thermal hyperalgesia at 10 days in the CCI group. Neuropathic pain behaviors preceded and did not closely correlate with microglial responses in either model. Perineural application of bupivacaine prior to SPCN prevented spinal microglial responses but not pain behaviors. Spinal astrocytic responses to SPCN were early, robust and not altered by bupivacaine. The current findings support the use of bupivacaine as a tool to suppress microglial activation and challenge the putative role of microglia in initiating or potentiating pain behaviors which result from nerve injury.

Objective: To assess the impact of regional supplemented general anesthesia (RSGEN) on regional myocardial function during abdominal aortic surgery (AAS)., Design: Prospective randomized study., Setting: Single academic medical center., Participants: Seventy-three patients scheduled for infrarenal aortic aneursymectomy., Interventions: Patients received standardized intraoperative anesthetic management consisting of either general anesthesia (GA; n = 37) or general anesthesia supplemented by epidural anesthesia (RSGEN; n = 36)., Measurements and Main Results: Hemodynamic measurements and transesophageal echocardiograms (TEE) were obtained at eight intraoperative times. The electrocardiogram (ECG) was continuously recorded using Holter monitoring. Of the 56 patients with interpretable TEE recordings, 8 of 30 (27%) GA patients and 7 of 26 (27%) RSGEN patients developed new segmental wall motion abnormalities (SWMAs). There was no treatment effect on either the incidence (p = 0.23) or the intensity (p = 0.34) of SWMAs. Cross-clamping of the aorta was associated with the onset of new SWMAs (odds ratio, 8.2; 95% CI, 1.1 to 64; p = 0.04). Among the 63 patients with interpretable Holter recordings, 9 of 34 (26%) GA patients and 9 of 29 (31%) RSGEN patients exhibited intraoperative ischemia. There was no treatment effect on the incidence (p = 0.22) or intensity (p = 0.67) of ECG ischemia., Conclusion: Despite providing modest hemodynamic depression, RSGEN did not reduce the incidence or intensity of either regional myocardial dysfunction or ECG ischemia. New SWMAs were temporally associated with cross-clamping of the aorta and tended to resolve with unclamping.

Intrathecal (i.t.) catheterization in the rat has been used extensively for drug delivery in various experimental paradigms. These indwelling i.t. catheters have been associated with inflammatory processes and tissue reactions external to the spinal cord in numerous clinical and animal studies. The purpose of this study was to determine whether i.t. catheter placement produced glial activation and changes in specific cytokine expression, i.e. neuroimmune activation, within the spinal cord which might cause altered sensory processing. Rats underwent i.t. catheterization or sham surgery and were killed at 3 or 14 days postsurgery (n> or =3 per group). Spinal cord segments were taken at the cervical level, tip of the catheter and distal to the catheter (thoracic levels). Immunohistochemistry was used to examine spinal localization of the cytokines, interleukin (IL)-6, IL-10 and glial activation (OX-42 for microglia and anti-glial fibrillary acidic protein for astrocytes). At 3 and 14 days after i.t. catheterization, there was an elevation in OX-42 and GFAP expression as compared to control (n=3) and sham surgery (n=4) groups. IL-10-like immunoreactivity was significantly increased in both the dorsal and ventral horns 14 days after i.t. placement as compared to the sham and normal groups. Conversely, IL-6-like immunoreactivity was not significantly different from sham or normal groups. These cytokine findings are discussed in the context of a differential role of specific cytokines in the potential generation of pain states or in the production of analgesia. This study demonstrated that i.t. catheterization induces robust neuroimmune activation that manifests as increases in glial markers and specific cytokine expression. This method should be controlled for, or alternate methods used for, drug delivery in nociceptive animal models that require spinally administered agents.

Background: Opioids are used by patients who have conditions ranging from the acute pain of surgery and chronic cancer pain to substance abuse. Despite their widespread use and considerable experimental data about them, little is known about how opioids may alter in vivo immunity in humans. This study was designed to evaluate the in vivo effect of morphine on human peripheral blood immune functions., Methods: Healthy volunteers underwent continuous exposure to morphine for 36 h including a 24-h intravenous infusion in the hospital. Peripheral blood was drawn for immune function studies at five measurement times before, during, and after morphine exposure. Peripheral blood mononuclear cells were tested for acute and gamma-interferon-stimulated natural killer cell cytotoxicity (NKCC), antibody-dependent cell cytotoxicity, antibody Fc receptor expression, and human immunodeficiency virus infectivity., Results: Significant suppression of NKCC was observed at 2 and 24 h after the onset of intravenous morphine exposure. Suppression of NKCC persisted for 24 h after termination of morphine infusion in a "high"-dose study group. gamma-Interferon-stimulated NKCC and antibody-dependent cell cytotoxicity were also decreased after 24 h of intravenous morphine exposure. No effect on Fc receptor expression was observed. Mean virus antigen production after lymphocyte infection with human immunodeficiency virus was not increased (p24 100 ng/ml after morphine vs. 43 ng/ml before morphine; P = 0.17)., Conclusions: These results suggest that morphine administration, at doses within the range of analgesic use, can cause measurable suppression of some components of the human cellular immune system.

Despite undergoing a curative resection, many patients with colorectal cancer will develop and die of metastatic disease. It has been shown clinically and experimentally that surgery causes a transient period of immunosuppression, and it is postulated that this may encourage both the implantation of surgically disseminated tumor cells and the growth of existing micrometastases. The present study used natural killer cell cytotoxicity (NKCC) and tumor burden to evaluate perioperative modulation of immunocompetence in a murine model. We measured NKCC and tumor burden responses to a standardized surgical stress (SSS) alone, and to either morphine sulfate (MS) (15 mg/kg subcutaneously x 4 doses), ketorolac (a prostaglandin synthetase--prostaglandin E2--inhibitor) (2.5 mg/kg subcutaneously x 4 doses), or interleukin 2 (2,000 units intraperitoneally x 3 doses) administration with the SSS. In this model, we found that both low-dose interleukin-2 (IL-2) and ketorolac reversed the NKCC suppression associated with surgery, whereas morphine resulted in further depression of NKCC. In addition, IL-2 significantly decreased tumor incidence, whereas continuous MS exposure markedly increased tumor burden after surgery. These data suggest that IL-2 and ketorolac may be effective agents for the restoration of perioperative immune competence, whereas the use of continuous morphine might have significant deleterious effects.