Comment on: Preoperative high dose of dexamethasone in emergency laparotomy: randomized clinical trial

BJS, https://doi.org/10.1093/bjs/znae130, published 19 July 2024

The recent article by Cihoric et al.1 makes a substantial contribution to better understanding of the effects of high-dose dexamethasone (1 mg/kg) in emergency laparotomy surgery, specifically reporting significant reductions in inflammatory markers. The study’s secondary endpoints of decreased complications, lower 90-day mortality and improved functional outcomes are also promising.

These results align with previous findings in  elective surgery cohorts, such as the DECS2, SIRS3, PACMAN4, PADDI5, albumin-dexamethasone trials6, and a meta-analysis of functional outcomes7. Interestingly, several of these studies used lower corticosteroid doses with similar effectiveness. Furthermore, high-dose steroid therapy was not without potential risks in the DECS and SIRS trials, with increased postoperative myocardial enzyme2,3 and blood glucose levels in the steroid groups2,3,5, though these findings did not translate to increased morbidity or mortality.

A critical question therefore arises: is very high-dose dexamethasone necessary to achieve these beneficial outcomes? Further research into optimal dosing, administration timing, and identifying high-risk patients is needed to balance efficacy and safety, ensuring clinical acceptability and widespread adoption.

Cihoric et al.1 found that patients receiving dexamethasone had reduced vasopressor requirements and a significantly less positive postoperative fluid balance, suggesting that a mechanism for its effectiveness may be through microcirculatory protection and prevention of interstitial fluid overload. This effect is likely due to reducing cytokine-induced damage to the microcirculation, including the endothelium and its glycocalyx layer, which regulate vasomotor tone, coagulation, and permeability, which is essential for optimal microcirculatory perfusion. Preoperative and postoperative endothelial dysfunction are linked to higher complications after surgery, with surgical stress exacerbating glycocalyx damage through inflammation, sepsis, ischaemia-reperfusion injury, and excessive fluid resuscitation. The role of steroids in microcirculatory protection is supported by reduced respiratory complications, acute kidney injury, and surgical site infections in the PACMAN4 and DECS2 trials.

The FEAST7 trial, a landmark study on intravenous fluid in inflammatory states, shifted our understanding of fluid resuscitation. Fluid boluses lead to natriuretic peptide release, causing vasodilation, glycocalyx disruption, and capillary leak syndromes. Fluid restriction was protective, suggesting that early vasopressor use in septic shock to avoid excessive fluid resuscitation might be beneficial. Mechanistically, noradrenaline and adrenaline also reduce endothelial cell permeability in vitro8 and improve lymphatic flow in large animal models9, which requires further elucidation in surgical patients.

Crystalloid solutions have short intravascular dwell times, leading to interstitial oedema. Synthetic colloid solutions may increase morbidity and mortality in critically ill patients10, whereas albumin may decrease organ dysfunction by stabilizing the glycocalyx, reducing capillary permeability and fluid extravasation. Our recent feasibility trial6 found that combining dexamethasone and albumin reduced glycocalyx injury markers and postoperative complications. Further research is needed to explore whether this combination, or its individual components offer additive protective effects and if timing is critical to maintain endothelial integrity.

We advocate that managing the inflammatory response and protecting the microcirculation are key therapeutic targets, and corticosteroid therapy has demonstrated potential benefits in elective and emergency surgery. Future research should focus on the efficacy and safety of lower steroid doses, different dosing regimens, microcirculatory care bundles, and better targeting of patient cohorts to optimize perioperative anti-inflammatory strategies and improve surgical outcomes.