Relationship Between Alternative Resuscitation Strategies, Host Response and Injury Biomarkers, and Outcome in Septic Shock: Analysis of the Protocol-Based Care for Early Septic Shock Study

Abstract

Objective The Protocol-based Care for Early Septic Shock (ProCESS) trial found no differences across alternative resuscitation strategies in all-cause mortality. A separate aim was to determine whether differences in resuscitation strategies affected trajectories of biomarkers of key pathways associated with downstream clinical outcomes of sepsis and whether there were differences in survival across treatment arms for patients with different baseline biomarker profiles. Design Secondary analysis of a large randomized clinical trial. Setting 31 US hospitals. Patients 628 patients with septic shock. Interventions Two resuscitation protocols versus usual care. Measurements and Main Results We measured a panel of biomarkers representing four pathophysiologic domains: inflammation (tumor necrosis factor, interleukin-6, and -10); coagulation (D-dimers, thrombin-anti-thrombin complex); oxidative stress (urine isoprostane) and tissue hypoxia (lactate) at 0, 6, 24 and 72 hours after treatment. We analyzed whether alternative resuscitation strategies affected biomarker trajectories over 72 hours and whether effects on 90-day hospital mortality varied by baseline (time 0) biomarker profiles—both using regression models with interaction terms for treatment arms. For all baseline biomarkers, higher concentrations were associated with increased risk of death by 90 days. However, there was no significant effect of treatment assignment on subsequent biomarker trajectories. We did find evidence for heterogeneity of treatment effect of protocol-based care on mortality for patients with different baseline [IL-6] and [IL-6]•[IL-10] profiles wherein patients with the lowest quartiles fared better with protocol-based care (Odds Ratios 0.32 [0.13, 075] p=0.01 and 0.32 [0.14, 0.73] p=0.01 respectively). Conclusions In patients with septic shock, alterations in inflammation, coagulation, oxidative stress and tissue hypoxia are common and associated with adverse outcomes but are not influenced by protocol-based resuscitation compared to usual care. However, contrary to expectation, protocol-based resuscitation appeared to be superior in patients with lower concentrations of inflammatory biomarkers. The mechanisms responsible for this effect are unclear.

Sepsis associated acute kidney injury

“…The resultant reduction in the mean systemic pressure and relative hypovolemic state, paired with decreased systemic vascular resistance, results in hypotension 8. Prompt resuscitation of the circulation with administration of intravenous fluids is a key component of sepsis management 104105106. However, excessive administration and accumulation of fluids in an attempt to treat hypotension or oliguria after AKI is common and harmful.…”

“…Recent studies have shown that protocolized resuscitation strategies did not improved outcomes, but a minimal degree of resuscitation is needed to mitigate the risk of adverse outcomes. Finally, clear evidence shows that in addition to the risks of under-resuscitation, in the setting of AKI, volume overload from aggressive over-resuscitation is also harmful, creating a J or U shaped curve for resuscitation and mortality 104105106114…”

Distant organ dysfunction in acute kidney injury

“…While these mechanisms may be distinct in animal models, they appear to be more complex and interrelated in clinical practice and sorting out causality is difficult. Inflammatory mediator levels vary widely (eg IL-6 can range from <10 to >1 million pg/ml in sepsis 96 ) and extracorporeal blood purification may fail to significantly modulate their plasma levels. Based on the current findings about different pathways linking kidney injury with distant organs, therapeutic strategies that target just a single molecule are less likely to succeed in reducing the AKI-induced distant organ dysfunctions.…”

“…95 Applying blood purification to all patients may be beneficial for some and have no effect or even be injurious to others (eg by removal of various antioxidants, micronutrients, electrolytes, antibiotics and other medications essential for optimal organ function and recovery during the process). Inflammatory mediator levels vary widely (eg IL-6 can range from <10 to >1 million pg/ml in sepsis 96 ) and extracorporeal blood purification may fail to significantly modulate their plasma levels. 97 Future investigations will need to evaluate whether a personalized approach that links the use of extracorporeal blood purification techniques to mediator levels and matches micronutrients, antibiotic and electrolyte loss to blood purification intensity improves outcomes in these patients.…”

Fluid resuscitation targeting sepsis-induced cardiovascular dysfunction: severity of disease as effect modifier

“…It is not known if EGDT further increases mortality compared with sick controls without EGDT due to effect heterogeneity that is determined by disease severity (Figure 1). In order to test EGDT for effect modification and treatment interactions, survival outcomes in the Protocolized Care for Early Septic Shock (ProCESS) trial were analyzed in relation to inflammatory, coagulation, oxidative stress, and tissue hypoxia biomarkers measured in patients enrolled (19). Whereas protocol-based resuscitation had no effects on baseline coagulation, oxidative stress, and tissue hypoxia biomarkers, patients with lower baseline concentrations of inflammatory biomarkers seemed to benefit from it.…”