Preoperative Glucocorticoid Use in Major Hepatectomy - A Randomized Controlled Trial

Introduction:

Major hepatectomy lead to significant postoperative anatomical and physiological changes. The liver dictates the systemic metabolic environment and helps maintain homeostasis. When segments of liver are removed, it is challenged to regenerate and restore cellular volume, as well as continuing to perform mandated metabolic functions. Major hepatectomy can result in multiple complications (hemorrhage, biliary fistulae, wound infection, liver failure) with an overall complication rate up to 54% in some studies.

Recent studies purport that preoperative administration of GC may suppress the acute phase response during the early postoperative period. GCs are steroid hormones with a variety of immunological and biochemical functions (anti-inflammatory attenuation of the acute phase response by binding to intra-cytoplasmic GC receptors and therefore increased transcription of anti-inflammatory proteins interleukin-10 (IL-10), IL-1-receptor antagonist (IL-Ra), lipocortin-1 and neutral endopeptidase, or direct inhibition of activated transcription factors (nuclear factor kB, activator protein-1)). GC can also suppress gene expression by altering the chromatin structure and tightening DNA coils.

The acute phase response is a neuro-humoral and time-limited defensive mechanism, which aims to restore homeostasis. It is characterized by fever, leukocytosis, gluconeogenesis, as well as changes in lipid, carbohydrate and protein metabolism. Activation of the hypothalamus-pituitary-adrenal axis, coagulation and compliment pathways is also one of the salient features of the acute phase response. It is regulated by cytokine receptor antagonists (IL-1Ra) and soluble cytokine receptors. Cytokines are soluble, low molecular weight glycoproteins that act as inflammatory mediators and can be broadly divided into pro and anti-inflammatory cytokines. At low concentrations, they have a paracrine effect, while in high concentrations they act systemically. These pro-inflammatory cytokines (IL-1, IL-2, IL-6 and tumor necrosis factor (TNF) alpha) remain in the plasma for at least 24 hours after generation. They also attract leukocytes (neutrophils and macrophages) to the site of injury and are detrimental if produced in large amounts. Oka et al have demonstrated that increasing levels of IL-6 are directly related to an increased rate of postoperative complications.

In low doses, GC reduce short term mortality, reverse the shock process and improve hemodynamics in septic shock patients. In a meta-analysis of 17 RCTs, Annane et al found that 28-day mortality for a low-dose dexamethasone (DXA) group, versus control group was 35.3% vs. 38.5%. Shock reversal was also increased in the DXA group (66.9% vs. 58.6%) and the ICU stay was decreased by 4.49 days.