The effect of angiotensin II on blood pressure in patients with circulatory shock: a structured review of the literature

Circulatory shock is a life-threatening condition with a high risk of multi-organ failure and death and a paucity of treatment options [1]. Catecholamines and vasopressin are often required to achieve an adequate blood pressure (BP), sometimes at the risk of adverse events, including peripheral and splanchnic ischemia, dysrhythmias, and organ dysfunction [2‐5]. To date, no specific vasopressor has been shown to improve outcomes [6‐8]. A 2015 meta-analysis by Zhou et al. concluded that other than the superiority of norepinephrine over dobutamine, no vasopressor outperformed any other with respect to mortality [9]. Two recent randomized controlled trials have renewed interest in angiotensin II (Ang II) for circulatory shock [10, 11]. In both of these studies, Ang II was hypothesized to increase mean arterial pressure (MAP) in patients with circulatory shock, as an adjunctive therapy to catecholamines and vasopressin standard-of-care therapy.

Ang II is a naturally occurring octapeptide that increases BP through various mechanisms, including vasoconstriction of peripheral vessels, potentiation of antidiuretic hormone (ADH) and adrenocorticotropin hormone (ACTH) release, and direct actions on postganglionic sympathetic fibers [12]. Following its discovery in the 1930s, Ang II has been administered to humans clinically and experimentally [13‐18]. Considerable literature surrounds the clinical and experimental use of Ang II [19]. However, to our knowledge, no systematic evaluation has associated Ang II administration with improved BP in hypotensive states.

The search in Ovid, MEDLINE, Embase, and PubMed retrieved 3743 potentially relevant abstracts, of which 95 articles were eligible for a more detailed evaluation. After full text evaluation, another 71 were excluded. Of the remaining 24 studies, two were RCTs, nine were case-control studies, and 13 were case reports. Details are shown in Fig. 1.

Administration of Ang II in patients with hypotension appears to be associated with an increase in BP. The effect was seen in patients with shock of different etiologies, including distributive, cardiogenic, and other subtypes. Doses ranged from 15 ng/kg/min to bolus therapy of 1500 mcg. Ang II also appears to be associated with an increase in BP in patients with angiotensin-converting enzyme (ACE) inhibitor overdose and in patients on chronic dialysis. The pressor effect of Ang II was variable, ranging from a decrease in MAP of 8 mmHg to an increase in SBP of 250 mmHg in all patients. Nonetheless, the weighted means remained fairly consistent among the total cohort and subgroups (Table 6). Sensitivity analyses following exclusion of ATHOS-3 and cardiac arrest patients yielded results similar to the primary analyses. Sensitivity analyses according to the quality of studies were not substantially different, but did reflect a trend toward more robust results in poorer quality studies.

The two included RCTs demonstrated an improvement of BP by only 6.0 mmHg (8.7%) and 12.5 mmHg (18.9%) [10, 11]. However, this was achieved in the context of a concomitant decrease in catecholamine doses [10] or as part of a protocolized BP endpoint which included titration of Ang II to a target MAP increase of 10 mmHg [11]. As such, comparisons to other studies is challenging. Nonetheless, the catecholamine-sparing effect and BP effect in these studies are consistent with the conclusion contained herein.

The consistent BP increase from Ang II may be explained in teleological terms. Ang II is a molecule innate to human physiology and, along with catecholamines and vasopressin, helps maintain BP throughout a variety of conditions. Its widely described effects include direct vasoconstriction of peripheral vessels, potentiation of water reabsorption as part of the renin-angiotensin-aldosterone system (RAAS), and interaction with other endogenous pressors (catecholamines and vasopressin). It is produced via multiple pathways throughout various tissue types and has important autocrine and paracrine functions, including participation in the cellular lifecycle and immune regulation [42]. The ubiquity of Ang II, its precursors and derivatives, and its receptors underlie a complex, highly evolved, homeostatic system of BP regulation. For example, RAAS activation during longstanding cardiovascular disease increases BP to maintain perfusion, but it also potentiates cardiac remodeling to withstand this increased BP [43]. Ang II also helps regulate and maintain glomerular filtration, especially during periods of reduced renal perfusion [44, 45].

Since its discovery in the 1930s, Ang II has been reported in over 31,000 humans in 1124 studies [19]. In the mid-1960s, intravenous Ang II was administered to pregnant women for preeclampsia evaluation [15, 16]. It has also been used in patients with a multitude of diseases, including circulatory shock [17, 24, 40, 41, 46] and ACE inhibitor overdose [20‐22]. The 2014 ATHOS RCT highlighted the catecholamine-sparing effect of Ang II in patients with distributive shock [10]. Results of the recently completed ATHOS-3 study have confirmed its beneficial effect and safety in patients with distributive shock refractory to conventional vasopressor therapy [11].

Importantly, Ang II has been implicated as contributing to cardiac pathophysiology. Activation of the RAAS is associated with ventricular remodeling both at the site of infarct and remotely after myocardial ischemia [47]. Ang II also increases sympathoexcitation, which leads to hypertension and other cardiovascular diseases [48], and it upregulates peptides causing fibrogenesis, chemotaxis of fibroblasts, and scar formation in the healing heart [49]. ACE concentrations within myocardial tissue correlate with tissue collagen levels, and processes like fibrogenesis may cause further ACE accumulation in areas of cardiac remodeling [47]. Due to its ability to mitigate adverse myocardial remodeling, ACE inhibition has become the standard of care for patients with congestive heart failure [50]. Despite inhibition, however, patients with congestive heart failure can have elevated Ang II levels, which are associated with worse morbidity and mortality [51, 52]. Long-term effects of intravenous Ang II on cardiovascular health are unknown.

The cardiogenic shock population deserves special mention because of its exclusion from the two aforementioned RCTs [10, 11]. Scant data describe ACE or Ang II levels in patients with cardiogenic shock, though increased levels of Ang II and downregulation of Ang II receptors have been reported in other forms of shock [42, 53, 54]. Patients with cardiogenic shock may have a relative deficiency of Ang II, based on similar pathogenic mechanisms. While many studies in this review predate the widespread use of ACE inhibitors, the effect of Ang II in the five patients evaluated in the ACE-inhibition era [i.e., occurring after practice changes as a result of Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS) and Studies of Left Ventricular Dysfunction (SOLVD) trials] suggest a potential role in patients on ACE inhibition who present with cardiogenic shock [55, 56]. Notably, four of the five patients had premorbid ACE inhibitor use, while information was unavailable for the remaining patient. The profound effect seen in these five patients (83.9% increase from baseline BP) suggests that administration of exogenous Ang II may restore the RAAS effect on BP. While exposure to angiotensin receptor blocker (ARB) therapy was noted in in the study by Khanna et al., the impact of ARB therapy was not specifically investigated [11]. In fact, the effect of Ang II on patients pre-treated with ARB therapy may be difficult to predict owing to heterogeneity in pharmacodynamics and pharmacokinetics of ARB therapy [56‐58]

Eighteen patients included in this analysis had an initial BP of 0 mmHg, suggesting a condition of cardiac arrest. The pressor effect seen in these patients ranged from no change in BP (no ROSC) to an increase of 250 mmHg. The mean effect was 107.3 mmHg in patients with ROSC. Although cardiac arrest in these patients cannot be verified, their successful resuscitation suggests a potential role of Ang II to achieve ROSC. Ang II has not been described specifically for cardiac arrest, but a 2016 porcine cardiac arrest study examined Ang II levels with and without ACE inhibitor pretreatment [59]. Angiotensin (1–7) and Ang II levels increased in all animals after ROSC, though the effect on Ang II was muted in the ACE inhibitor-treated group and survival did not differ between groups. It should be noted that Wang et al. hypothesize that ACE inhibition, rather than an increase in Ang II, is beneficial in a cardiac arrest situation due to amelioration of ischemia-reperfusion injury in the myocardium as shown in a pig model. Nonetheless, the manipulation of the RAAS system in cardiac arrest may be a potential target for future investigation, as ischemia-reperfusion injury would be predicted to happen in all therapies for resuscitation, including catecholamines (which are the current standard of care). The mechanisms surrounding a potential benefit of Ang II in cardiac arrest are only speculative but may include: (a) maintenance of adequate systemic BP to vital organs [60], (b) manipulation of intracellular calcium levels leading to increased inotropy [61, 62], (c) potentiation of catecholamines [63, 64], and (d) increased afterload for enhancement of coronary perfusion [65]. Our observations are hypothesis-generating and require further properly constructed RCTs to elucidate the role of Ang II in cardiac arrest.

To our knowledge, this is the only analysis to thoroughly review the association of Ang II with increases in BP in patients with circulatory shock. The systematic selection of studies, the reproducibility of search results, and careful extraction of data support the comprehensiveness of the analysis. The consistent observed pressor effect over a wide variety of patients with different clinical conditions over a 66-year period (1961–2017) adds credence to the generalizability of the results.

This analysis has a number of weaknesses, including the lack of quality data. Only two of 24 studies analyzed were RCTs, with other studies being case-control and case-study formats. As such, the lack of a comparator to Ang II limits our ability to conclude causality. Of the 353 patients included in the analysis, 163 were from one source, potentially leading to a skewed effect [11]. However, this one source was a well-designed RCT, lending credibility to the results. Additionally, the risk of publication bias exists, as we were unable to identify any papers reporting lack of effect in patients treated with Ang II. Most studies were designed to address research questions either unrelated or tangentially related to the pressor effect of Ang II. Nonetheless, included in this analysis are 51 patients in the two RCTs who received Ang II but did not respond, as well as 30 nonresponders in the case-control analyses and case studies. The inclusion of nonresponders, in our opinion, mitigates publication bias. The quality and heterogeneity of data (e.g., BP variably reported as MAP, SBP, or DBP, and some BP reported graphically or qualitatively as “normal”) limit robust quantitative analysis. However, this heterogeneity was expected, and the a priori primary endpoint was designed specifically to account for this. We chose a simple, easy-to-identify, frequently reported endpoint (BP) so as to be able to include as many data points as possible. The specific effect of Ang II may also be questioned, as many studies described its BP effect in association with the co-administration of other vasoactive medications (e.g., norepinephrine, epinephrine, and amrinone). However, this approach mirrors clinical management of shock, in which multiple agents are often used. Moreover, Ang II was evaluated in the ATHOS-3 study as a therapeutic adjunct to other drugs, including catecholamines and vasopressin, which may add legitimacy to our results [11]. In both RCTs included herein, doses of catecholamines and vasopressin were controlled, allowing for clear elucidation of the isolated effect of Ang II. In further analysis, the observed BP effects in a vast majority of the patients analyzed herein can be attributed to or associated with Ang II alone, with only a handful of patients (n = 9) responding to a combination of medications including Ang II. Much of the analysis contained herein is derived from fairly old data. Ten of the 24 studies were published in the 1960s, while two were published in the 1980s, and ten in the 1990s. Only two studies (the two RCTs) have been published since the year 2000. As such, the standard of care for many disease states may be substantially different today. For example, ARB therapy is only described in the study by Khanna et al., despite the common use of this class of medication currently. ARB therapy may significantly affect the clinical response to Ang II, the effects of which remain unknown. Finally, as part of our comprehensive search, we deliberately omitted non-English language sources, and may have inadvertently omitted relevant English-language sources.

In conclusion, Ang II appears to be associated with an increase in BP in patients with circulatory shock. The effect was robust, with increases in excess of 70 mmHg in SBP and 14 mmHg in MAP from the entire patient cohort, and remained observable in shock of various etiologies, including distributive, cardiogenic, and other circulatory shock. Observations in patients with cardiogenic shock and with ACE inhibitor use suggests a potential role for Ang II in patients with ACE depletion, either from acute ACE inhibitor overdose or as part of chronic heart disease management. Moreover, a role for Ang II in patients with cardiac arrest may warrant further exploration. More research, including well-designed randomized, controlled analyses are required to answer these questions.