Vasopressor Responsiveness 101: Prediction of Responsiveness to Angiotensin II Infusion*

The hormonal response to shock is usually a well-orchestrated complex integration of multiple hormone systems that includes principally catecholamines, vasopressin, and renin-angiotensin system (RAS) hormones and peptides. The response to shock is rapid, and precise, and then tapers off appropriately in hypovolemic hypotension and shock. However, vasodilatory shock (most often due to septic shock) upsets this orchestra and creates disharmony among the key players. The consequent endocrine disharmony creates dysfunctional responses to vasopressors and may increase the risk of poor outcomes. Vasopressor unresponsiveness could mark the severity of illness or could increase septic shock mortality. Relative hyporesponsiveness to endogenous and infused catecholamines, vasopressin, and RAS system hormones (e.g., angiotensin II) can occur in any cause of shock but especially septic shock. Variable hormone responsiveness in septic shock is due in part to variable: 1) intravascular volume, 2) endothelial permeability, 3) hormone levels, and 4) responsiveness to hormones because of decreased receptor expression, for example, the G protein-coupled adrenergic α1 (vasoconstriction) and β2 (vasodilation) receptors, vasopressin V1a receptor (vasoconstriction) and the angiotensin II receptor type I receptor (ATI) (vasoconstriction). Tolerance to norepinephrine is commonly due to decreased adrenergic α1 receptor expression (1). Additional causes of variable vasopressor responsiveness include genomics and pharmacogenomics of norepinephrine (2) and angiotensin II (3) (age, underlying conditions, and medications (e.g., angiotensin receptor blockers [ARBs] and angiotensin-converting enzyme [ACE] inhibitors) and severity of sepsis and shock. We previously interrogated angiotensin-related axis genes (ACE, angiotensin II receptor type 1, and angiotensin II type 1 receptor-associated protein [AGTRAP], a negative regulator of angiotensin II receptor type 1). Only AGTRAP variants were associated with septic shock mortality (3) so these AGTRAP variants could also modulate response to infused angiotensin II. The dilemma for clinicians is that too little or too much vasopressor support carries adverse consequences. However, it is often difficult to accurately identify vasopressors and specifically angiotensin II responders. Accordingly, there would be great clinical applicability if one could measure “actionable” hormones or related substances that accurately predict vasopressor responsiveness. In this issue of Critical Care Medicine, See et al (4) report a relevant study. In their single-center preplanned study (n = 40 plus 80 matched controls who received other vasopressors) of the acute renal effects of angiotensin II management in shock (ARAMIS) RCT of angiotensin II infusion versus alternative vasopressors in vasodilatory shock (60% septic shock) (5), high renin levels were linearly associated with higher angiotensin II infusion dose indicating responsiveness to angiotensin II. High renin levels were also associated with the use of ARBs (Supplement Figs. 3 and 4 in [4])—but not ACE inhibitors—and with increased acute kidney injury and renal replacement therapy (RRT: indicated by decreased days alive and free of RRT [5,6]. Other factors associated with increased angiotensin II infusion dose were norepinephrine dose (a positive association) and arterial pH (a negative association). Acidosis decreases responsiveness to vasopressin (7) and apparently angiotensin II too. The study hypothesis by See et al (4) is sound, the methods are clear, and the interpretation and discussion of the results are a pleasure to read. The topic is highly relevant because clinicians are trying to decide when and how to use infused angiotensin II in vasodilatory shock, especially septic shock. The authors help clinicians with their strong discussion of the pharmacokinetic and pharmacodynamic differences between ARBs and ACE inhibitors. The study by See et al (4) illuminates one mechanism of vasopressor hyporesponsiveness—circulating renin levels—indicating that the RAS modulates response to vasopressors. With further study, serum renin levels could become a candidate “predictive” biomarker. A predictive biomarker is defined as a biomarker that predicts the need for or dose of a drug such as angiotensin II. Clinicians should take note that the use of ARBs was associated with increased renin levels, acute kidney injury, and RRT use. Separately, acute COVID-19 RCT evidence suggests that modulating the RAS system increases acute kidney injury and hypotension. RCTs of ARBs in acute COVID-19 were done because the SARS-CoV-2 virus decreases ACE2 expression. ACE2 converts the vasopressor angiotensin II to the vasodilating peptide angiotensin I-7. So, ACE2 down-regulation could increase angiotensin II levels and induce organ injury by excessive vasoconstriction, increased permeability (8) and inflammation (9). The REMAP Community Acquired Pneumonia ARBs RCT showed that the use of ARBs in acutely hospitalized COVID-19 patients increased acute kidney injury (10) and other RCTs indicated an increased risk of hypotension (11). Accordingly, in the study by See et al (4), it would be helpful to know whether the frequency of serious adverse events other than acute kidney injury, differed in number or type between ARB-exposed and non-ARB-exposed patients. There may be sex differences in response to ARBs because the ACE2 gene resides on the X chromosome. We showed sex differences in response to ARBs, specifically a greater response in males to ARBs (12). Unfortunately, the sample size of the study by See et al (4) is too small to evaluate sex differences in renin levels and response to angiotensin II. Perhaps, renin and other RAS peptide levels could have been used to better determine ARBs dose in these COVID-19 RCTs to mitigate risks of acute kidney injury and hypotension. In multivariable analysis, arterial lactate at ICU admission and recent exposure to an RAS inhibitor were independently associated with increased baseline renin levels. Thus, renin levels likely increased in response to: 1) shock as indicated by higher lactate levels and 2) recent RAS inhibitor use, which would tend to decrease angiotensin II levels by ACE inhibitors or decrease response to angiotensin II by blocking the angiotensin II receptor type 1 by ARBs. The difference in angiotensin II infusion rate between ARB-exposed and non-ARB-exposed was quite large at 40 versus 20 ng/kg2/min2, nicely confirming their hypothesis and aligning with the expected pharmacology of angiotensin II infusion. After accounting for baseline renin levels and multiple measurements per patient, angiotensin II infusion was associated with a 56% decrease in renin levels at 24 hours. There was greater normalization of renin levels during angiotensin II infusion in the no RASi subgroup than in the ARB subgroup, concordant with the rest of the main results. Supplemental Figure 4 in (4) illustrates so differential responses according to RASi exposure. There has been remarkable consistency of median serum renin levels from three different studies (Angiotensin II for the Treatment of High-Output Shock-3 [13] [172 pg/mL], ARAMIS [181 pg/mL], and Vitamin C, Thiamine, and Steroids in Sepsis [VICTAS] [14] [189 pg/mL]) indicating that serum renin levels may be a robust and accurate biomarker in patients with shock. In a recent post hoc analysis of VICTAS (14) baseline serum renin levels were directly associated with mortality. There are of course safety considerations with angiotensin II infusion in cardiac patients. A pilot RCT of angiotensin II versus noradrenaline in cardiac surgery patients (angiotensin-2 to reduce acute kidney injury [15]) found no significant harm in this population. In the ARAMIS trial (5), patients receiving angiotensin II were less likely to have a troponin increase compared with noradrenaline controls (8% vs. 22%, p = 0.04), also suggesting cardiac safety of angiotensin II infusion. Thus, See et al (5) considered it unlikely that cardiac surgery patients are at higher risk of SAEs with angiotensin II infusion. Indeed, it is possible patients with a history of cardiac dysfunction or myocardial infarction (with or without prior RAS inhibitor exposure) could be one subgroup for which angiotensin II therapy may be beneficial. Strengths of the study by See et al (4) include the careful post hoc approach that took advantage of a well-conducted RCT of angiotensin II in vasodilatory shock. I see great value in such post hoc analyses of RCTs because RCTs mitigate a key source of bias present in nonrandomized designs, indication bias because the treatment was randomized. However, results from See et al (4) must be considered hypothesis-generating and require further hypothesis-testing designed trials. Another strength was the careful technical measurement by immunoassay of renin levels as a window to RAS. This is important because of the instability of ex vivo RAS peptide levels such as the angiotensins. The renin assay is more stable and less at risk of technical variability compared with the measurement of circulating angiotensin I, I-7, and II levels. The authors explained that renin levels are “predictive” biomarkers for response to angiotensin II infusion. In general, predictive biomarkers have greater clinical utility than prognostic biomarkers because predictive biomarkers are “actionable”—in this case indicating patients with high renin levels required double the angiotensin II dose. There are, however, some limitations to the study by See et al (4). First, the number of ACE inhibitor patients was small and limited interpretation but the authors wisely emphasized that throughout. Cardiac dysfunction due to prior heart failure or acute myocardial infarction could increase the risk of angiotensin II infusion and could alter renin levels significantly. Such patients were not excluded in the ARAMIS RCT. Although excess vasopressor dose appeared to increase mortality in observational cohorts, an RCT of two different mean arterial pressure targets found no increased mortality in the lower target group that had higher norepinephrine doses (16). In summary, the conclusion of the study by See et al (4) is sound that there is an association between baseline renin levels and peak angiotensin II infusion dose to achieve an a priori mean arterial pressure target. This conclusion is augmented by the cumulative angiotensin II dose sensitivity analysis that led to similar conclusions. The field would benefit from a well-designed hypothesis-testing study to drive the potential clinical utility of renin levels in vasodilatory hypotension and shock.

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