Discussion
Sepsis, shock, vasoplegic syndrome, hypotension, septic shock
SEPSIS, SHOCK, DISEASE, VASODILATORY SHOCK, SEPTIC SHOCK, DISEASE
This exploratory post-hoc analysis of the phase 3 ATHOS-3 clinical trial was undertaken to determine whether there is a signal for benefit of intervening with AT II at lower doses of other vasopressor agents. While this analysis is only hypothesis-generating in nature, we found a narrow window of low background vasopressor dose at which adding AT II may be associated with better hemodynamic response and increased survival in patients with vasodilatory shock. Specifically, more patients achieved the hemodynamic target with AT II when initiated at low-NED (≤ 0.25 µg/kg/min) compared to high-NED (> 0.25 µg/kg/min). Further, amongst patients with low-NED at the time of study drug initiation, those randomized to AT II were significantly more likely to survive at 7 and 28 days compared to those randomized to placebo, and within the AT II arm, those randomized at low-NED were significantly more likely to survive compared to those randomized at high-NED. Importantly however, this analysis cannot establish the true beneficial window for intervention with AT II, but suggests that it may occur at lower NED, and may also be narrow.Vasodilatory shock is considered a medical emergency that requires hypotension-correcting interventions [While unable to demonstrate any causal relationship, our post-hoc analysis suggests that if started at a lower NED, AT II may be associated with increased survival compared with placebo. Importantly, this analysis demonstrates that there may be a narrow range of NED at which intervention with AT II may be beneficial and above which may be futile. These results are similar to an observational study which found increased hemodynamic benefit with addition of AT II at NED < 0.3 µg/kg/min and even more pronounced benefit when the NED was lower (< 0.2 µg/kg/min) [Reasons for why the addition of AT II at lower NED may be associated with improved outcomes are likely multifactorial but may include NED sparing, RAAS-specific mechanisms, and potentially beneficial interaction between vasopressor agents with differing mechanisms of action. In the ATHOS-3 trial, the addition of AT II lowered the requirement for background vasopressors throughout the majority of the 48-h treatment period [Additionally, RAAS disruption and AT II deficiency have been described to occur in septic shock and vasoplegic syndrome following cardiac surgery and to be significantly associated with adverse outcomes [Finally, while we were unable in this post-hoc analysis to determine whether there is any interaction between vasopressor agents, there may be a potentiating effect of AT II and vasopressin. Such an interaction was suggested in an observational study of AT II, in which pre-existing use of vasopressin at the time of AT II initiation was associated with a significantly higher rate of hemodynamic responsiveness to AT II (OR 6.05, 95% CI 1.98–18.6; The present analysis, although hypothesis-generating in scope, has potentially important clinical implications, as it adds to mounting evidence suggesting that the NED may be an important determinant of outcomes in shock and could be used to guide management strategies. The current Surviving Sepsis Campaign guidelines do not provide specific recommendations regarding timing for initiation of non-catecholamine vasopressors in patients with persistent hypotension, but the guideline authors state that their typical approach is to start vasopressin at a norepinephrine dose of 0.25–0.5 µg/kg/min [The current analysis has several strengths, including the use of data from a prospective randomized trial of patients with vasodilatory shock. Further, the analysis addresses an important clinical question, the most appropriate scenario for intervention with AT II, which is not currently defined. Finally, the present findings are consistent with those from other analyses suggesting that interventions with non-catecholamine agents at lower norepinephrine doses are associated with improved outcomes [We acknowledge several limitations. First, this is a post-hoc observational study of a phase 3 trial with a non-patient-centered primary outcome. Thus, no inferences of causality of AT II on the patient-centered outcomes reported herein can be drawn; the results should be considered exploratory, hypothesis-generating, and the interpretation of the results requires caution. Second, the study design of ATHOS-3 resulted in only one third of patients being enrolled at NED ≤ 0.25 µg/kg/min, limiting the generalizability of these data. Had the ATHOS-3 protocol allowed for earlier enrollment, additional analyses could have been conducted on this population of patients. However, the limited number of patients enrolled in ATHOS-3 below this threshold preclude further analysis of thresholds below 0.25 µg/kg/min. Further, the total number of patients in each subgroup was small and so the findings are subject to type I error. Third, it is possible that low-NED and high-NED do not correlate with early or late stage of disease. Disease trajectory may be such that low-NED may not necessarily be early in the shock state but could potentially be a sign of patient improvement. Therefore, no conclusions regarding timing can be drawn from this analysis. Finally, even within the placebo group, practice may have been variable with regard to vasopressors [