Search

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.A post-implementation prospective case-cohort study.Twenty-three operating rooms at a large teaching hospital.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.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.S. aureus transmission (primary) and surgical site infection (secondary).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.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].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.

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

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

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

BACKGROUND: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 an

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.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.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, P0.001), 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, P0.001), 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).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.

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).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.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.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.

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).

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. (Anesth Analg 2011;112:98‐105)

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.Prospective, randomized, double-blind, placebo-controlled clinical investigation.Academic medical center.Thirty-six healthy human volunteers.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.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.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 1949, Hench et al. surprised most of the medical community by reporting that glucocorticoids (GCs) suppress inflammation in humans.1 Their report, and a subsequent half century of research, effectively eclipsed decades of previous work by Selye and others who observed, in animals, stimulatory effects from GCs.2 Given the range of symptoms and pathophysiologic events that are caused by inflammation, it is not surprising that clinicians and researchers have chosen to search primarily for the antiinflammatory effect of GCs. Recently, human inflammatory responses have gained new levels of clinical significance with the emergence of the Systemic Inflammatory Response Syndrome (SIRS) and related conditions as a leading cause of death in hospitalized patients.3 No widely accepted treatment for this highly lethal condition is available, and overall mortality from SIRS continues to increase.4 Recent studies suggest that some patients may benefit from GC therapy of SIRS if they are in a (patho)physiologic state termed “relative adrenocortical insufficiency” but these studies have not been confirmed and it is still unclear which patients may benefit from GC treatment and whether the benefit is due to suppression of inflammation. Interestingly, Selye used the term “relative adrenocortical insufficiency” as early as 19405 in a conceptual framework in which cortisol was understood to stimulate the resistance of an organism to the effects of injury. Studies completed within the past 15 yr have used modern laboratory methods to reveal, at the cellular and molecular level, and often in a dose-dependent manner, stimulatory as well as suppressive effects of GCs on immune activity (Sapolsky et al. for recent review and definitions6). Perhaps most importantly, several studies report biphasic effects of GCs on the release of inflammatory mediators such as tumor necrosis factor-α (TNF-a), interleukin-6 (IL-6),7 acute phase proteins,8 and plasma macrophage migration inhibitory factor in vivo.9 These studies raise an important clinical question: Do all in vivo concentrations of cortisol have suppressive effects on human innate immune responses or do GC effects on immunity vary depending upon GC concentration? In this study we hypothesized that diurnal concentrations of cortisol support innate immune responses and that acute in vivo GC depletion would consequently act to decrease inflammatory responsiveness of circulating immune effector cells. Experimentally, we first either increased or decreased in vivo cortisol concentrations. Peripheral blood monocytes were then examined for their responses to the in vivo treatments and to further stimulation in vitro.

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.

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.

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.

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.

To measure the effects of glucocorticoids on the systemic inflammatory response and clinical recovery after cardiac surgery.Randomized, prospective, double-blind, placebo-controlled clinical trial with concurrent comparison groups.University medical center.Patients scheduled for elective coronary artery bypass graft surgery using normothermic cardiopulmonary bypass (CPB) and a standardized anesthetic.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.Patients who received methylprednisolone had a significant reduction in circulating interleukin (IL)-6 at 60 minutes after CPB (p0.05) and on the morning of the 1st (p0.01) and 3rd (p0.05) postoperative days and a significant increase in circulating IL-10 at 60 minutes after CPB (p0.01) 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.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.

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.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.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]; P0.001). 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; P0.001).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.

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 cerebro-spinal 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.

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% Cl, 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.

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.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.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.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 =

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.

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.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.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.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.

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.

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.

Interactions between opiates and the human immune system have important clinical implications. To further evaluate these interactions, we studied in vitro and in vivo effects of morphine sulfate (morphine) and beta-endorphin (Bend) on antibody-dependent cell cytotoxicity (ADCC), natural killer cell cytotoxicity (NKCC), and effector cell expression of antibody Fc receptors. Morphine and Bend had no potent in vivo or in vitro effect on FcR expression nor did they have a significant in vitro effect on ADCC by monocytes or polymorphonuclear cells. Bend enhancement of NKCC in vitro was inhibited by coincubation of effector cells with morphine. After taking 90 to 150 mg of oral morphine, study volunteers demonstrated a significant decrease in ADCC by peripheral blood mononuclear cells. The same individuals demonstrated a consistent increase in NKCC and no change in the expression of Fc receptors. Effector cells from these individuals responded normally to in vitro incubation with interferon-gamma (IFN-gamma).

Decreased cardiac output and increased plasma thromboxane have been observed during aortic cross-clamping under general anesthesia. Amelioration of these changes has been reported by preoperative administration of cyclooxygenase inhibitors, but heterogeneity in patients' intravascular volume status has confounded analysis of the drugs' effects in previous studies. We studied hemodynamic conditions in 24 volume-loaded (pulmonary capillary wedge pressure greater than 10 mm Hg) patients undergoing abdominal aortic aneurysm repair under general plus epidural anesthesia, after preoperative double-blind administration of either ibuprofen 800 mg (n = 12) or placebo (n = 12). The hemodynamic response to aortic cross-clamping was similar in both groups. Pulse and mean arterial pressure remained unchanged; cardiac index decreased after aortic cross-clamping from 2.4 +/- 0.1 (mean +/- standard error of the mean [SEM]) to 2.1 +/- 0.1 1/min/m2 in the ibuprofen group and from 2.5 +/- 0.1 to 2.3 +/- 0.2 1/min/m2 in the placebo group (p less than 0.01 versus preclamp values in both groups, multivariate analysis of variance [MANOVA]), but improved after declamping. Both left and right ventricular stroke work indexes followed a similar pattern. Plasma 6-keto prostaglandin Fl alpha (6-k-PGF1 alpha) increased transiently from a baseline level of 304 +/- 44 to 2083 +/- 698 pg/ml plasma in mixed venous blood 30 minutes after incision in the placebo group (p less than 0.05), but no other significant change in plasma 6-keto prostaglandin Fl alpha or in thromboxane B2 occurred in either group at any other time.(ABSTRACT TRUNCATED AT 250 WORDS)

Recent studies have brought additional clarity to the mechanisms by which glucocorticoid (GC) steroid hormones exert both suppressive and permissive effects on immune responses. Widely used for their immunosuppressive and anti-inflammatory actions, stress-elevated and therapeutic levels of GCs suppress defense mechanisms that would otherwise overshoot and damage the organism. Basal levels, on the other hand, are essential for permissive effects that prime defense mechanisms for more efficient action against a challenge. Both suppressive and permissive actions on immunity and inflammation have been documented in intact organisms. Suppressive actions are often due to inhibition by GCs of the production of cytokines and other mediators, whereas permissive effects include both induction of cytokine receptors and enhancement of activity of certain cytokines. GCs interact with both innate and adaptive immune responses. This is exemplified by immune–adrenal crosstalk wherein exposure to endotoxin stimulates the hypothalamic–pituitary–adrenal (HPA) axis and GC production, largely via endotoxin-induced cytokines. These stress-induced levels of GCs are, in turn, essential for survival in the face of endotoxic shock. GCs influence adaptive immunity in many ways. They inhibit antigen-specific T-lymphocyte activation, slow or redirect the maturation of macrophages and dendritic cells, favor Th2 over Th1 responses, and enhance the development as well as actions of specialized T-regulatory cells. GCs also induce T-cell apoptosis selectively on different T-cell populations, and can protect thymocytes from apoptosis induced by activation of the T-cell receptor. Moreover, experiments with rats that are highly susceptible to autoimmune disorders demonstrate the importance of a normal stress-induced increase in GC levels for the physiological control of autoimmunity. At the molecular level, at least three mechanisms contribute to GC effects on immunity and inflammation. Transactivation and transrepression are the “classical” mechanisms whereby ligand-activated glucocorticoid receptors (GRs) bind to DNA sequences called GC response elements and either activate or repress transcription of the targeted gene. Transactivation of genes encoding inhibitory proteins and transrepression of inflammatory genes have been described. However, the majority of anti-inflammatory effects are due to so-called cross-talk in which GC-liganded GRs interact with transcription factor proteins such as nuclear factor-κB (NF-κB) and activator protein-1(AP-1), interfering with their ability to activate transcription of target genes.

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.

c C H HE PROBLEM OF perioperative cardiac morbidity has been studied for more than a century.1,2 Now, with approxmately one third of the 40 million annual inpatient procedures eing performed on patients at risk for coronary artery disease CAD),3 estimates are that up to 50,000 patients per year ustain a perioperative myocardial infarction and that, of those, substantial percentage will die.4 A variety of pharmacologic nterventions have been tested in efforts to limit perioperative ardiac morbidity that is caused by CAD including beta-blockng agents, alpha2-agonists, calcium channel blockers, and niroglycerin. Of these, beta-blockers have shown the most conistent and well-documented efficacy for decreasing adverse erioperative cardiac events.5 Although clinicians traditionally onsider that effects on myocardial oxygen supply and demand rovide the primary benefit of beta-blocking drugs for this atient population, the complexity of the interactions among he sympathetic nervous system (SNS), the heart, and the innate nflammatory immune response may provide other explanaions for the benefit of perioperative beta-blockade. Until the middle of the last decade, most clinical studies of erioperative cardiac morbidity studied early postoperative cariac events including ischemia, infarction, or heart failure. In 996, Mangano and colleagues6 published their results from a arefully conducted randomized clinical trial suggesting that a eta1-adrenergic receptor blocking drug, atenolol, decreased he incidence of fatal cardiac events and improved survival for p to 2 years after surgery. The study population included atients with known or suspected CAD who were scheduled for ajor surgery under general anesthesia. After randomization, atients received either placebo or atenolol immediately before nd for up to 7 postoperative days. For those patients who eceived atenolol, the length of time between surgery and a first ardiac advent (congestive heart failure, myocardial infarction, nstable angina, cardiac surgery) or death was significantly ncreased leading to a survival benefit that was not immediately pparent but that evolved over the first 6 to 8 months after urgery. More recently, Poldermans et al7 published their reults from a similar clinical trial that was conducted exclusively n vascular surgical patients who had preoperative evidence of AD (assessed by stress echocardiography). Patients randomly eceived either “standard care” or standard care plus the beta1eceptor blocker, bisoprolol, for 30 days after surgery with isoprolol administration beginning at least 1 week before urgery. During the first 30 days after surgery, 18 patients in the tandard care group had a myocardial infarction or cardiac eath compared with 2 in the bisoprolol-treated group (p .001), suggesting an immediate benefit from perioperative eta1-blockade. However, during long-term follow-up, with b

Objective: To test the effect in normal human volunteers of transient systemic inflammation on the variability in time-series behaviors of widely divergent physiologic measures of the human inflammatory response. Design: Prospective study of human volunteers who were tested on 2 consecutive days, a control day and a treatment day. Each participant served as his or her own control. Setting: Critical care facility of a university medical center. Subjects: Subjects were eight healthy human volunteers. Interventions: Participant subjects were tested on both a baseline day with no intervention and on a treatment day when they received 4 ng/kg intravenous Escherichia coli endotoxin. Measurements and Main Results: Continuous electrocardiographic recordings and serial blood sampling (performed every 5 mins) were used to create time-series of heart rate (R-R intervals), neutrophil function (phagocytosis), and plasma cortisol concentrations. For each primary measure, we recorded a significant increase in the regularity (decreased variability) of the functional measurement as assessed by the statistical entity, approximate entropy. Conclusions: Increased regularity, or decreased variability, of organ functions is a generalized response to systemic inflammation that occurs in widely divergent systems during endotoxemia.

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.

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.

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.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 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.

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.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.

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 (P0.05 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 (P0.05 at all E/T ratios) and the GA group (P0.05 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.General or epidural anesthesia alone, in the absence of surgery, seems to have only transient and minor effects on human immune function.

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 (P0.05 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.A continuous insulin infusion and glucose control during surgery improves white cell function in diabetic patients and may increase resistance to infection after surgery.