Bernhard Riedel

Statin Therapy within the Perioperative Period

STATINS are highly effective in lowering serum cholesterol concentrations through 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase inhibition and thus are central to the primary and secondary prevention of cardiovascular disease. More than 50% of patients undergoing major vascular surgery and 80% undergoing cardiac surgery are on chronic statin therapy. 1,2 Statins also exert numerous lipid-independent or “pleiotropic” effects (effects that were not expected during drug development) as a result of their ability to inhibit the inflammatory response, reduce thrombosis, enhance fibrinolysis, decrease platelet reactivity, inhibit cell growth, reduce ischemia–reperfusion injury, and restore endothelial function. These beneficial effects result predominantly from the modulation of the complex interplay between the pathologic triad of inflammation, dynamic obstruction, and thrombosis. 3 This triad is integral to the surgical stress response and central to postoperative outcomes. However, recent reports noted that patients who undergo postoperative statin withdrawal experience increased cardiac morbidity when compared with patients who undergo early postoperative readministration of statins or with patients not treated with statins. 1,4 These facts raise several important questions for the anesthesiologist regarding statin therapy during the perioperative period: (1) Do statins modify perioperative risk? (2) Is continuation or discontinuation of statin therapy during the perioperative period associated with additional risk? (3) Do the potential benefits of statin therapy outweigh the potential risks? This review of the literature explores the risks and benefits associated with perioperative statin therapy.

The pathophysiology and management of perioperative pulmonary hypertension with specific emphasis on the period following cardiac surgery.

Pulmonary hypertension, right ventricular dysfunction, and RV failure are common occurrences following CPB. The endothelium is now recognized as an important organ and is central to the pathophysiology and management of this condition. Current progress has arisen from the development of newer methods and the refinement of older methods attempting to protect the endothelium. Modern methods attempting to preserve endothelial function (thereby preventing pulmonary vasoconstriction and RV dysfunction) include new pharmacological inhibitors of the inflammatory response to CPB, improved myocardial protection using substrate enhanced cardioplegia, improved cardioplegia delivery techniques combined with monitoring by myocardial contrast TEE, and new minimally invasive surgical techniques not requiring extracorporeal support. Progress in therapeutic methods attempting to reverse pulmonary hypertension, RV dysfunction, and support of the failing right ventricle include the application of nitric oxide, prostacyclin, other pulmonary selective vasodilators, and improved ventricular assist devices that provide support to the right ventricle until recovery of the myocardium occurs or serve as a bridge to transplantation.

Association between Endothelial Dysfunction and Acute Brain Dysfunction during Critical Illness

Background:Acute brain dysfunction (delirium and coma) during critical illness is prevalent and costly, but the pathophysiology remains unclear. The relationship of acute brain dysfunction with endothelial function, which is impaired in critical illness and may contribute to alterations in cerebral blood flow and blood–brain barrier permeability, has not been studied. This study sought to determine whether systemic endothelial dysfunction is associated with acute brain dysfunction during critical illness. Methods:In this prospective cohort study, adult medical/surgical intensive care unit patients in shock and/or respiratory failure were enrolled. Endothelial function was assessed at enrollment using peripheral artery tonometry to calculate the reactive hyperemia index, with lower reactive hyperemia index indicative of worse endothelial function. Patients were assessed for coma and delirium with the Richmond Agitation–Sedation Scale and Confusion Assessment Method for the Intensive Care Unit. Multivariable linear regression was used to analyze the association between reactive hyperemia index and (1) delirium/coma-free days among all patients and (2) delirium duration among survivors, both over a 14-day period. Results:One hundred forty-seven patients with median age of 57 yr and median Acute Physiology and Chronic Health Evaluation II score of 26 were enrolled. After adjusting for age, severity of illness, severe sepsis, preexisting cognitive function, medical versus surgical intensive care unit admission, and prehospital statin use, lower reactive hyperemia index (worse systemic endothelial function) was associated with fewer delirium/coma-free days (P = 0.02) and more delirium days (P = 0.05). Conclusions:In this study, critically ill patients with lower vascular reactivity indicative of worse systemic endothelial function had increased duration of acute brain dysfunction.

Cerebral protection: inflammation, endothelial dysfunction, and postoperative cognitive dysfunction.

Purpose of review Postoperative cognitive dysfunction (POCD) is a well recognized perioperative syndrome, with approximately 15% of patients over the age of 60 years displaying objectively measured decrease in cognitive function as a consequence of anesthesia and surgery. The exact cause, however, remains unknown. This review aims to update anesthesiologists on the recent advancements in the understanding of the pathophysiology of POCD. Recent findings Recent evidence suggests that the observed predilection to POCD is likely mediated by a neuro-inflammatory response – with surgery being a major contributing factor. The blood–brain barrier, a highly specialized endothelial layer, is exquisitely sensitive to an inflammatory insult and implicated in the cause of other neurocognitive syndromes also characterized by neuro-inflammation such as cerebral malaria. Inflammatory changes may disrupt the blood–brain barrier and facilitate migration of macrophages into the brain, damaging synapses and neurones and ultimately lead to POCD. This review explores the important question of causality – the potential relationship between inflammation, endothelial dysfunction, and postoperative cognitive decline. Summary Recent research points to a central role of a neuro-inflammatory cascade in POCD, with endothelial dysfunction potentially aggravating the insult. Investigating the genomic and molecular mechanisms that underlie the intervariation in the inflammatory response to surgery, improving the identification of appropriate endothelial and inflammatory biomarkers, and developing endothelial modulatory and anti-inflammatory (prevention and resolution) strategies are key areas of future translational research. This is important as the elderly, who show increased susceptibility to this and other perioperative illness syndromes, represent an ever-increasing proportion of patients presenting for surgery.

Epidural space identification: A meta-analysis of complications after air versus liquid as the medium for loss of resistance

BACKGROUND: The best method for identifying the epidural space for neuraxial blocks is controversial. We conducted this meta-analysis to test the hypothesis that loss of resistance with liquid reduces complications with epidural placement. METHODS: The MEDLINE, EMBASE, and Cochrane databases were searched for prospective, randomized studies comparing air versus liquid as the medium for loss of resistance during epidural space identification in adults. Data were abstracted from 5 studies (4 obstetric and 1 nonobstetric) (n = 4422 patients) that met inclusion criteria and analyzed for the following 6 outcomes: difficult catheter insertion, paresthesia, intravascular catheter insertion, accidental dural puncture, postdural puncture headache, and partial block. RESULTS: The overall risk differences for adverse outcome between the different mediums were not statistically different for the obstetric population. A small, but statistically significant, risk difference for postdural puncture headache was observed when fluid was used during epidural placement for chronic pain management. CONCLUSION: Larger studies that overcome limitations of heterogeneity across studies and a relatively infrequent occurrence of complications are required to determine the optimal medium for loss of resistance during epidural block.

Tumor Endothelial Markers Define Novel Subsets of Cancer-Specific Circulating Endothelial Cells Associated with Antitumor Efficacy

Circulating endothelial cells (CEC) are derived from multiple sources, including bone marrow (circulating endothelial progenitors; CEP), and established vasculature (mature CEC). Although CECs have shown promise as a biomarker for patients with cancer, their utility has been limited, in part, by the lack of specificity for tumor vasculature and the different nonmalignant causes that can impact CEC. Tumor endothelial markers (TEM) are antigens enriched in tumor versus nonmalignant endothelia. We hypothesized that TEMs may be detectable on CEC and that these circulating TEM(+) endothelial cells (CTEC) may be a more specific marker for cancer and tumor response than standard CEC. We found that tumor-bearing mice had a relative increase in numbers of circulating CTEC, specifically with increased levels of TEM7 and TEM8 expression. Following treatment with various vascular-targeting agents, we observed a decrease in CTEC that correlated with the reductions in tumor growth. We extended these findings to human clinical samples and observed that CTECs were present in patients with esophageal cancer and non-small cell lung cancer (N = 40), and their levels decreased after surgical resection. These results demonstrate that CTECs are detectable in preclinical cancer models and patients with cancer. Furthermore, they suggest that CTECs offer a novel cancer-associated marker that may be useful as a blood-based surrogate for assessing the presence of tumor vasculature and antiangiogenic drug activity.

β2-Adrenoceptors on tumor cells play a critical role in stress-enhanced metastasis in a mouse model of breast cancer.

Chronic stress accelerates metastasis - the main cause of death in cancer patients - through the activation of β-adrenoceptors (βARs). We have previously shown that β2AR signaling in MDA-MB-231(HM) breast cancer cells, facilitates invadopodia formation and invasion in vitro. However, in the tumor microenvironment where many stromal cells also express βAR, the role of β2AR signaling in tumor cells in metastasis is unclear. Therefore, to investigate the contribution of β2AR signaling in tumor cells to metastasis in vivo, we used RNA interference to generate MDA-MB-231(HM) breast cancer cells that are deficient in β2AR. β2AR knockdown in tumor cells reduced the proportion of cells with a mesenchymal-like morphology and, as expected, reduced tumor cell invasion in vitro. Conversely, overexpression of β2AR in low metastatic MCF-7 breast cancer cells induced an invasive phenotype. Importantly, we found that knockdown of β2AR in tumor cells significantly reduced the impact of stress on metastasis in vivo. These findings highlight a crucial role for β2AR tumor cell signaling in the adverse effects of stress on metastasis, and indicate that it may be necessary to block β2AR on tumor cells to fully control metastatic progression.

Perioperative events influence cancer recurrence risk after surgery

Surgery is a mainstay treatment for patients with solid tumours. However, despite surgical resection with a curative intent and numerous advances in the effectiveness of (neo)adjuvant therapies, metastatic disease remains common and carries a high risk of mortality. The biological perturbations that accompany the surgical stress response and the pharmacological effects of anaesthetic drugs, paradoxically, might also promote disease recurrence or the progression of metastatic disease. When cancer cells persist after surgery, either locally or at undiagnosed distant sites, neuroendocrine, immune, and metabolic pathways activated in response to surgery and/or anaesthesia might promote their survival and proliferation. A consequence of this effect is that minimal residual disease might then escape equilibrium and progress to metastatic disease. Herein, we discuss the most promising proposals for the refinement of perioperative care that might address these challenges. We outline the rationale and early evidence for the adaptation of anaesthetic techniques and the strategic use of anti-adrenergic, anti-inflammatory, and/or antithrombotic therapies. Many of these strategies are currently under evaluation in large-cohort trials and hold promise as affordable, readily available interventions that will improve the postoperative recurrence-free survival of patients with cancer.

Preoperative Microvascular Dysfunction: A Prospective, Observational Study Expanding Risk Assessment Strategies in Major Thoracic Surgery

BACKGROUND Brachial artery reactivity testing (BART)--a surrogate test of microvascular function--predicts cardiac risk in the nonsurgical population and associates it with adverse outcome after vascular surgery. This pilot study investigated BART-derived variables, including flow-mediated dilation (FMD), in preoperative risk stratification for major thoracic surgery. METHODS After institutional review board approval, BART was performed in 63 patients before major thoracic surgery. Ultrasonography recorded two-dimensional images and Doppler flow signals of the brachial artery preoperatively at baseline and after induced reactive hyperemia. Variables derived using BART were correlated with preoperative risk factors, established risk scores, and postoperative complications. RESULTS The median preoperative FMD value in patients without postoperative complications was 11.5%. This value was used to delineate all patients into two groups: low (FMD < 11.5%) and high (FMD ≥ 11.5%) FMD cohorts. Patients in the low FMD group experienced more postoperative complications: 54% versus 30% had one or more adverse postoperative event, and 11% versus 0% had three or more adverse postoperative events (p < 0.001), respectively. The low FMD group required longer intensive care unit (3.9 ± 2.0 days versus 0.9 ± 0.3 days; p = 0.015) and hospital (14.0 ± 3.3 days versus 6.8 ± 0.6 days; p = 0.007) stays. This cutoff point for FMD accurately predicted 71% of the patients with adverse postoperative events, achieving 71.4% (95% confidence interval, 54.7 to 88.2) sensitivity and 48.6% (95% confidence interval, 32.0 to 65.1) specificity. CONCLUSIONS Using BART, preoperative microvascular dysfunction can be identified in patients at increased risk for postoperative complications. These data suggest that larger observational studies and studies exploring preoperative optimization strategies aimed at improving microvascular function are warranted.

Endothelial progenitor cell mobilization by preoperative exercise: a bone marrow response associated with postoperative outcome

BACKGROUND Preoperative anaemia is associated with increased morbidity in patients undergoing major surgery. Whether erythrocytes are the only bone-marrow-derived cell lineage that associates with increased surgical complications is unknown. This prospective observational trial studied the mobilization of endothelial progenitor cells (EPCs) in response to exercise in association with postoperative complications. METHODS After IRB approval, 60 subjects undergoing major thoracic surgery were exercised to exhaustion (peak V̇(O₂)). Peripheral blood collected before and after peak exercise was quantified for EPC lineages by fluorescence-activated cell sorter analysis. Complication analysis was based on the Clavien-Dindo classification. RESULTS Exhaustive exercise increased EPC [CD45-133+34+ cells=150 (0.00-5230) to 220 (0.00-1270) cells μl(-1); median change (range)=20 (-4,180-860) cells μl(-1); P=0.03] but not mature endothelial cell (EC) subpopulations. Pre-exercise levels [odds ratio (OR)=0.86, 95% confidence interval (CI): 0.37-2.00, P=0.72), change after exercise as a continuous variable (OR=0.95, 95% CI: 0.41-2.22, P=0.91) and a positive response after exercise (change >0 cells μl(-1); OR=0.41, 95% CI: 0.13-1.28, P=0.12) were not statistically significantly associated with the incidence of postoperative complications. Post-hoc receiver operating characteristic curve analyses revealed that subjects with a CD45-133+34+ increase ≥60 cells μl(-1) in response to exercise suffered fewer postoperative complications [86% sensitivity, 48% specificity and AUC=0.67 (95% CI: 0.52-0.81)]. CONCLUSIONS Preoperative exercise induces EPC into the peripheral circulation. Subjects with a poor EPC response had a pre-existing propensity for postoperative complications. This warrants further research into the role of bone marrow function as a critical component to endothelial repair mechanisms. CLINICAL TRIAL REGISTRATION IRB 2003-0434 (University of Texas M.D. Anderson Cancer Center, Houston, TX, USA).