Perioperative organ injury

Abstract

Despite the fact that a surgical procedure may have been performed for the appropriate indication and in a technically perfect manner, patients are threatened by perioperative organ injury. For example, stroke, myocardial infarction, acute respiratory distress syndrome, acute kidney injury, or acute gut injury are among the most common causes for morbidity and mortality in surgical patients. In the current review, the authors discuss the pathogenesis of perioperative organ injury, and provide select examples for novel treatment concepts that have emerged over the past decade. Indeed, the authors are of the opinion that research to provide mechanistic insight into acute organ injury and identification of novel therapeutic approaches for the prevention or treatment of perioperative organ injury represent the most important opportunity to improve outcomes of anesthesia and surgery.

Figure 1. Magnitude of perioperative mortality

The 3 leading causes of death in the Center for Disease Control’s (CDC) annual death table for the United States in 2006 were: #1. Diseases of heart (n=631,636), #2. Malignant neoplasms (n=559,888), and #3. Cerebrovascular diseases (n=137,119). Using the Nationwide Inpatient Sample (NIS) for the same year, Gawande and colleagues reported 189,690 deaths within 30 days of admission for inpatients having a surgical procedure. In magnitude, all-cause 30-day inpatient mortality following surgery approximated the third leading cause of death in the United States.

Figure 2. Activation of regulatory T-cells

Regulatory T-cells are a subpopulation of immuno-modulatory T-cells characterized by expression of the cell surface molecules cluster of differentiation (CD)4 and CD25, and by the presence of the transcription factor forkhead box P3 (FoxP3). Binding of interleukin (IL)-2 to CD25 induces proliferation of regulatory T-cells and is required to ensure their physiologic maintenance. FoxP3 expression is induced under hypoxic conditions and regulates target genes that govern immuno-modulatory functions. Neuroprotective effects are mediated by regulatory augmentation of T-cell proliferation and activity as well as by synthesis of anti-inflammatory cytokines such as IL-10 and transforming growth factor (TGF)-β. Therapeutic activation of regulatory T-cells has been successfully achieved through exogenous administration of IL-2 in clinical trials of primarily non-neurologic diseases.^, This approach may serve as a model for studying neuroprotective effects by regulatory T-cells in perioperative stroke.

Figure 3. Extracellular Adenosine Signaling and Its Termination

In inflammatory conditions, extracellular adenosine is derived predominantly from the enzymatic conversion of the precursor nucleotides ATP and ADP to AMP through the enzymatic activity of the ectonucleoside triphosphate diphosphohydrolase 1 (CD39) and the subsequent conversion of AMP to adenosine through ecto-5′-nucleotidase (CD73). Extracellular adenosine can signal through four distinct adenosine receptors: ADORA1 (A1), ADORA2A (A2A), ADORA2B (A2B), and ADORA3 (A3). An example of the functional role of extracellular adenosine signaling is A1-receptor activation during intravenous administration of adenosine for the treatment of supraventricular tachycardia. In addition, experimental studies implicate activation of A2A that is expressed on inflammatory cells such as neutrophils or lymphocytes in the attenuation of inflammation.^, Other experimental studies provide evidence of signaling events through A2B in tissue adaptation to hypoxia and attenuation of ischemia and reperfusion.^,, A clinical trial has shown that an oral agonist of the A3 adenosine receptor may be useful in the treatment of the dry-eye syndrome. Adenosine signaling is terminated by adenosine uptake from the extracellular space toward the intracellular space, predominantly through equilibrative nucleoside transporter 1 (ENT1) and equilibrative nucleoside transporter 2 (ENT2), followed by metabolism of adenosine to AMP through the adenosine kinase or to inosine through the adenosine deaminase. Blockade of equilibrative nucleoside transporters by dipyridamole is associated with increased extracellular adenosine concentrations and signaling (e.g., during pharmacologic stress echocardiography or in protection of tissue from ischemia). From: Purinergic signaling during inflammation; Holger K. Eltzschig, M.D., Ph.D., Michail V. Sitkovsky, Ph.D., and Simon C. Robson, M.D., Ph.D., N Engl J Med 2012; 367:2322-2333 © (2012) Massachusetts Medical Society. Reprinted with permission.

Figure 4. Veno–venous extracorporeal membrane oxygenation (VV-ECMO)

A bicaval, double-lumen central venous cannula is placed in the right internal jugular vein. Deoxygenated blood is collected from both the inferior and the superior vena cava. After passing through a centrifugal pump and a membrane oxygenator, the oxygenated blood is then returned to the right atrium through the cannula’s second lumen’s orifice. Various configurations are currently in use, including pumpless systems and alternative cannulation techniques.

Figure 5. Activation of hypoxia-inducible factor (HIF)-dependent gene expression via prolyl hydroxylase inhibition

Under hypoxic conditions (blue arrows), HIF-α and the constitutively expressed HIF-β bind and translocate into the cell nucleus. After binding to the DNA hypoxia response promoter element, the HIF heterodimer induces expression of hypoxia-sensitive genes. Under normoxic conditions (red arrows), prolyl hydroxylases (PHDs) hydroxylate HIF-α and thereby mark it for proteasomal degradation, effectively inhibiting HIF-dependent gene expression. Prevention of proteasomal HIF-α degradation using prolyl hydroxylase inhibitors, e.g., FG-2216, activates hypoxia-activated signaling pathways even under normoxic conditions.

Figure 6. Paneth cells and intestinal Mast cells release potent effectors to regulate local injury and systemic inflammation following intestinal ischemia/reperfusion

Most prominently, the Paneth cell-dependent pathway (blue) depends on release of interleukin (IL)-17 from Paneth cells localized at the base of small intestinal crypts. Mast cell responses (purple) use a number of pre-formed and de novo-synthesized products such as proteases (tryptase, mast cell protease (MCP)4), lipid mediators (leukotriens, prostaglandins) and cytokines (tumor necrosis factor (TNF)-α, IL-6).