Clinical Research Directory

Biological Effects of Hemoadsorption in Septic Shock

Septic shock is the most severe form of sepsis and continues to carry an in-hospital mortality of between 30% and 50% despite advances in compliance with the Surviving Sepsis Campaign care bundles. The pathophysiology of septic shock is dominated by an uncontrolled immuno-inflammatory response with massive release of mediators, pro- and anti-inflammatory cytokines5, DAMPs (damage-associated molecular patterns) and PAMPs (pathogen-associated molecular patterns), producing vasoplegia, endothelial dysfunction, glycocalyx damage and, in many patients, a subsequent immunoparalysis phase that increases the risk of nosocomial infections and late mortality. Endothelial damage and glycocalyx degradation are central elements in the pathophysiology of septic shock. The endothelial glycocalyx, a layer of proteoglycans and glycosaminoglycans approximately 0.5 µm thick on the luminal surface of the endothelium, regulates vascular permeability, leukocyte adhesion and the inflammatory response. During sepsis, the release of metalloproteinases, heparanase and other inflammatory mediators causes the shedding of syndecan-1, heparan sulfate and other glycocalyx molecules into the circulation. This process is associated with increased capillary permeability, interstitial edema, third-space fluid leakage, and progression to multiorgan failure. Elevated plasma syndecan-1 levels correlate with greater severity of septic shock, development of acute respiratory distress syndrome (ARDS), extrapulmonary organ dysfunction, and mortality. In parallel, the release of angiopoietin-2 by activated endothelial cells antagonizes Tie2 signaling, destabilizes the endothelial barrier and amplifies vascular dysfunction. Selective modulation of the immune response through extracorporeal adsorption of medium-sized mediators (5-60 kDa) is an adjunctive strategy whose biological rationale is well established and whose hemodynamic effect has been described by multiple authors. The HA380 HA cartridge (Jafron Biomedical), specifically, uses a synthetic neutral macroporous polymer resin with high affinity for cytokines in the 10-60 kDa range, especially IL-6, TNF-α, IL-8 and IL-10. The device is connected to an extracorporeal therapy circuit (in this protocol, always integrated into a continuous renal replacement therapy \[CRRT\] circuit) and operates for 4-6 hours per cartridge. Removal of proinflammatory cytokines (IL-6, TNF-α, IL-8) with HA380 also aims to reduce their effect on endothelial damage, and recent studies with other cytokine adsorbents have demonstrated the ability to remove circulating angiopoietin-2. Although the specific literature on the effect of HA380 on recovery of glycocalyx integrity is limited, reducing the burden of cytokines and endotoxic mediators could attenuate the glycocalyx degradation cascade and contribute to the hemodynamic stabilization observed in clinical studies. This mechanism provides an additional biological rationale for assessing biomarkers of endothelial dysfunction (angiopoietin-2, syndecan-1, soluble thrombomodulin) as secondary variables in the present study. Within the spectrum of septic shock, this protocol distinguishes two clinically and biologically relevant severity strata: 1) established septic shock as per Sepsis-3 criteria who, despite requiring vasopressor support and showing hyperlactatemia, do not meet the thresholds of refractoriness. 2) refractory septic shock, a particularly severe subgroup in which standard resuscitation measures-guided fluid therapy, vasopressors, source control, early antibiotic therapy, and hydrocortisone-are insufficient to reverse tissue hypoperfusion and progressive organ dysfunction. Primary objective To establish whether HA380 hemoadsorption yields a more desirable overall outcome than concurrent standard of care, within each severity stratum, using a pre-specified hierarchical ordinal DOOR endpoint.

Efficacy of the Alpha 2 Agonist Dexmedetomidine for Sympathetic Deactivation in REfractory Septic Shock

Septic shock is one of the most frequent reasons for admission to intensive care units and remains associated with a high mortality rate of approximatively 40% at 28 days. Nearly half of deaths attributable to septic shock occur within the first 3 days and are directly related to the consequences of circulatory failure leading to multiple organ dysfunction. In some patients, persistent shock despite adequate resuscitation leads to early death. This condition is referred to as refractory septic shock. Although its pathophysiology if multifactorial, refractory septic shock is largely characterized by profound vasoplegia and reduced responsiveness to vasopressor therapy. Current guidelines recommend norepinephrine as the first-line vasopressor. Vasopressin may be considered as a second-line agent, although the addition of vasopressin to norepinephrine has not consistently demonstrated a survival benefit compared with norepinephrine alone. Corticosteroids are also recommended in patients with refractory septic shock with a low level of evidence. Similarly, the addition of other vasopressors such as selepressin or angiotensin II may reduce catecholamine requirements but has not consistently demonstrated an improvement in mortality. More recently, a meta-analysis evaluating all non-adrenergic therapeutic strategies confirmed that none of these strategies individually provides a clear mortally benefit. However, when considered collectively, non-adrenergic approaches were associated with improved outcomes in patients with septic shock, supporting the concept that strategies aimed at bypassing or limiting excessive catecholaminergic stimulation may be beneficial in this population. In parallel, α2-adrenergic agonists are increasingly used as sedative agents in intensive care. Dexmedetomidine has been shown in experimental models to restore vascular responsiveness to vasopressors. Clinical studies conducted in patients with severe sepsis or septic shock have also suggested a potential benefit, including reduced vasopressor requirements and improved hemodynamic stability in the most severely ill patients. Therefore, dexmedetomidine may provide clinically relevant benefits through improved hemodynamic control during the acute phase of septic shock. By restoring vasopressor sensitivity, dexmedetomidine could potentially address an important therapeutic gap in the management of refractory septic shock. The underlying hypothesis is that the downregulation of adrenergic receptors observed during sepsis may be a direct consequence of sympathetic hyperactivation. Reversal of this phenomenon through "sympathetic deactivation" using α2-agonists may restore vascular responsiveness to vasopressors. To prepare the ADRESS trial, the investigator's team conducted a multicenter, randomized, double-blind pilot study (ADRESS Pilot). The primary objective of ADRESS Pilot was to assess the effect of dexmedetomidine on vascular responsiveness to phenylephrine in patients with septic shock and vasopressor resistance. Mortality was also evaluated as a secondary outcome. Thirty-two patients were randomized (16 per group). Due to the small sample size, an imbalance in baseline characteristics was observed, with greater vasopressor resistance in the dexmedetomidine group at the time of randomization, even before treatment administration. Patients allocated to the dexmedetomidine group had lower baseline responsiveness to phenylephrine, which limited the comparability of the groups and made the interpretation of the results particularly challenging. Nevertheless, 30-day and 90-day mortality were not significantly higher in the dexmedetomidine group. No significant differences were observed between groups in the occurrence of bradycardia or in heart rate. Several sensitivity analyses adjusting for baseline imbalances did not demonstrate a clear beneficial effect of dexmedetomidine. However, these findings may reflect insufficient statistical power, given the very small sample size of the study. Therefore, a larger and adequately powered trial is required to determine whether dexmedetomidine provides a clinical benefit in patients with refractory septic shock. Based on the results of ADRESS Pilot, the investigator propose to adapt the design of the ADRESS trial to increase the likelihood of detecting a potential treatment effect. Following the pilot study, the scientific committee decided to modify the study design from a double-blind to an open-label trial in order to reduce the risk of excessive sedation resulting from the addition of a sedative drug in patients already receiving continuous sedation. The target population consists of patients with refractory septic shock and a high risk of mortality. These patients are likely to derive the greatest benefit from a sympathetic deactivation strategy using dexmedetomidine in order to improve clinical outcomes.