Postoperative systemic inflammatory dysregulation and corticosteroids: a narrative review.

In some patients, the inflammatory-immune response to surgical injury progresses to a harmful, dysregulated state. We posit that postoperative systemic inflammatory dysregulation forms part of a pathophysiological response to surgical injury that places patients at increased risk of complications and subsequently prolongs hospital stay. In this narrative review, we have outlined the evolution, measurement and prediction of postoperative systemic inflammatory dysregulation, distinguishing it from a healthy and self-limiting host response. We reviewed the actions of glucocorticoids and the potential for heterogeneous responses to peri-operative corticosteroid supplementation. We have then appraised the evidence highlighting the safety of corticosteroid supplementation, and the potential benefits of high/repeated doses to reduce the risks of major complications and death. Finally, we addressed how clinical trials in the future should target patients at higher risk of peri-operative inflammatory complications, whereby corticosteroid regimes should be tailored to modify not only the a priori risk, but also further adjusted in response to markers of an evolving pathophysiological response.

Postoperative systemic inflammation after major abdominal surgery: patient-centred outcomes.

Postoperative systemic inflammation is strongly associated with surgical outcomes, but its relationship with patient-centred outcomes is largely unknown. Detection of excessive inflammation and patient and surgical factors associated with adverse patient-centred outcomes should inform preventative treatment options to be evaluated in clinical trials and current clinical care. This retrospective cohort study analysed prospectively collected data from 3000 high-risk, elective, major abdominal surgery patients in the restrictive vs. liberal fluid therapy for major abdominal surgery (RELIEF) trial from 47 centres in seven countries from May 2013 to September 2016. The co-primary endpoints were persistent disability or death up to 90 days after surgery, and quality of recovery using a 15-item quality of recovery score at days 3 and 30. Secondary endpoints included: 90-day and 1-year all-cause mortality; septic complications; acute kidney injury; unplanned admission to intensive care/high dependency unit; and total intensive care unit and hospital stays. Patients were assigned into quartiles of maximum postoperative C-reactive protein concentration up to day 3, after multiple imputations of missing values. The lowest (reference) group, quartile 1, C-reactive protein ≤ 85 mg.l-1 , was compared with three inflammation groups: quartile 2 > 85 mg.l-1 to 140 mg.l-1 ; quartile 3 > 140 mg.l-1 to 200 mg.l-1 ; and quartile 4 > 200 mg.l-1 to 587 mg.l-1 . Greater postoperative systemic inflammation had a higher adjusted risk ratio (95%CI) of persistent disability or death up to 90 days after surgery, quartile 4 vs. quartile 1 being 1.76 (1.31-2.36), p < 0.001. Increased inflammation was associated with increasing decline in risk-adjusted estimated medians (95%CI) for quality of recovery, the quartile 4 to quartile 1 difference being -14.4 (-17.38 to -10.71), p < 0.001 on day 3, and -5.94 (-8.92 to -2.95), p < 0.001 on day 30. Marked postoperative systemic inflammation was associated with increased risk of complications, poor quality of recovery and persistent disability or death up to 90 days after surgery.

The early in-vivo effects of a single anti-emetic dose of dexamethasone on innate immune cell gene expression and activation in healthy volunteers.

Dexamethasone is often administered to surgical patients for anti-emetic prophylaxis. This study examined the early (up to 24 h) in-vivo effects of dexamethasone (8 mg) to demonstrate the magnitude and temporal nature of changes on circulating peripheral blood mononuclear cell gene expression and activation in 10 healthy male volunteers. Blood samples were drawn at baseline, 2 h, 4 h and 24 h. Gene expression was measured using quantitative real-time polymerase chain reaction. Cytokine expression was measured using multiplex immuno-assays. Innate immune cell phenotypes were examined with flow cytometry. Dexamethasone resulted in rapid transient changes in immunophilin (p = 0.0247), plasminogen activator inhibitor-1 (p = 0.0004), forkhead box P3 (p = 0.0068) and dual specific phosphatase-1 (p = 0.0157) gene expression at 4 h compared with pre-dexamethasone. Plasma interleukin-10 levels increased within 2 h (p = 0.0071) and returned to baseline at 24 h. Reductions in classical (p = 0.0009) and intermediate monocytes (p = 0.0178) and dendritic cells (p = 0.0012) were followed by increases in the level of these populations at 24 h compared with pre-dexamethasone (classical monocytes p = 0.0073, intermediate monocytes p = 0.0271, dendritic cells p = 0.0142). There was a profound reduction in the mean fluorescence intensity of the maturation marker, human histocompatibility leucocyte antigen, at 24 h in all monocyte subsets (p = 0.0002 for classical and non-classical monocytes, p = 0.0001 for intermediate monocytes) and dendritic cells (p = 0.0001). This study confirms rapid transient effects of 8 mg dexamethasone on innate immune cells with the potential to alter the inflammatory response to surgery and provides support for the hypothesis that intra-operative administration may be both immunosuppressive and immune-activating in the immediate peri-operative period.

Data on the modulatory effects of a single bolus dexamethasone on the surface marker expression of various leucocyte subsets.

Dexamethasone is frequently administered to surgical patients for anti-emetic prophylaxis. We have examined the immunomodulatory effects of a single bolus of dexamethasone on circulating peripheral blood mononuclear cells (PBMCs) in the same 10 healthy male volunteers, previously used in our investigation on early in vivo effects of a single anti-emetic dose of dexamethasone on innate immune cell gene expression and activation [1]. Blood samples were drawn at baseline, 2 h, 4 h and 24 h. Immune cell phenotypes were examined with flow cytometry. In this data article the expression strength of markers involved in immune activation and immunosuppression as well as maturation, migration, cell death and responsiveness to signalling on monocyte and cDC subsets, as well as NK cells, CD4+ and CD8+ T cells and regulatory T cells (Treg) are presented. These data improve our understanding of the immunomodulatory effects of the glucocorticoid dexamethasone in-vivo, which may be important for the optimisation of treatment regimens as well as the evaluation of new indications for glucocorticoid treatment.

The effect of hair colour on anaesthetic requirements and recovery time after surgery.

Patients with red hair are much more likely to have a variant of the melanocortin-1 receptor gene and this may affect sensitivity to general anaesthetics and pain response. We did a prospective, matched cohort study of 468 healthy adult patients undergoing general anaesthesia for elective surgery. All patients received an inhalational general anaesthetic. Anaesthetic drugs and doses used, hypnotic depth, recovery times, pain scores and quality of recovery scores were recorded. More men than women had red hair, so we did subgroup and multivariable analyses to account for this imbalance. There was no significant difference in recovery times, pain scores or quality of recovery scores in those with red hair. After adjusting for age, sex, American Society of Anesthesiologists physical status and duration of surgery, the recovery ratio for time to eye-opening in redheads was comparable to those with black or brown hair, 0.82 (0.57-1.19), P=0.30. We found no evidence that patient hair colour affects anaesthetic requirements or recovery characteristics in a broad range of surgical procedures.

Relationship between journal impact factor and levels of evidence in anaesthesia.

Evidence-based medicine uses a hierarchy of publication types according to their vulnerability to bias. A widely used measure of journal "quality" is its impact factor, which describes the citation rate of its publications. We investigated the relationship between impact factor for eight anaesthesia journals and publication type with respect to their level of evidence 1-4 using Spearman rank correlation (rho). There were 1418 original publications during 2001 included in the analysis. The number (%) of publication types according to evidence-based medicine level were: level 1:6 (0.4%), level 2:533 (38%) level 3:329 (23%), level 4:550 (39%). There was no correlation between journal ranking according to impact factor and publication type (rho =-0.03, P=0.25). The correlation between journal rank and the proportion of publications that were randomized trials was -0.35 (P<0.001). The correlation between journal rank and number of publications was 0.65 (P<0.001). The correlation between journal rank and number of level 1 or 2 studies was 0.58 (P<0.001). The overall level of evidence published in anaesthesia journals was high. Journal rank according to impact factor is related to the number of publications, but not the proportion of publications that are evidence-based medicine level 1 or 2.