Angiotensin in Critical Care

This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency Medicine 2018. Other selected articles can be found online at https://www.biomedcentral.com/collections/annualupdate2018. Further information about the Annual Update in Intensive Care and Emergency Medicine is available from http://www.springer.com/series/8901.


Background
Hypotension is a key feature of shock and strongly correlated with the development of multisystem organ failure. Multiple studies have highlighted that even short durations of hypotension are harmful [1,2]. In a retrospective analysis of 33,000 non-cardiac surgical patients, Walsh et al. showed that short periods of intraoperative hypotension were associated with a significant increase in the risk of acute kidney injury (AKI), myocardial injury or cardiac complications and mortality [1]. The risk of renal and cardiac injury increased with duration of hypotension and was significant for periods as short as 1-5 min. Similarly, using data from over 57,000 patients undergoing non-cardiac surgery, Salmasi et al. showed that patients with a mean arterial pressure (MAP) less than 65 mmHg during the intraoperative period had a significantly higher risk of myocardial injury and AKI, confirming that hypotension does not need to be severe to affect organ function [2]. On the basis of these and other studies, European and international guidelines for the treatment of shock recommend that a minimum MAP should be maintained at all times and that the target should be at least 65 mmHg [3,4]. Heretofore, the restoration and maintenance of MAP has been accomplished through the judicious use of fluids as well as vasopressors, namely catecholamines and vasopressin analogs. However, patients with sepsis in particular often show marked hyporeactivity to traditionally administered therapies. To date, no vasopressor has consistently been proven to be superior to the others in terms of clinical outcomes [5][6][7]. In 2015, a metaanalysis concluded that in terms of survival, with the exception of noted superiority of norepinephrine over dobutamine, there was insufficient evidence to recommend any vasopressor agent or combination over another [8].
Angiotensin II (Ang II) has emerged as an effective therapy to raise blood pressure in patients with vasodilatory shock [9]. The first reports of Ang II administration in patients with shock date back 50 years, but interest was re-ignited following several small studies and a recent larger randomized controlled trial (RCT) confirming that Ang II was effective at maintaining MAP at target and reducing norepinephrine requirements without an increase in adverse effects [9][10][11]. The following review provides an overview of the physiological effects of angiotensin and summarizes existing data in the literature.

Role of Renin-Angiotensin System
After the discovery of renin in 1898, angiotensinogen and angiotensin-converting enzyme (ACE) were later identified as additional key components of the classical circulating renin-angiotensin system (RAS) [12,13]. Angiotensinogen, the precursor of angiotensin, is an αglycoprotein produced primarily by the liver and released into the systemic circulation where it is converted to angiotensin I (Ang I) under activity by renin ( Fig. 1). Ang I is cleaved into Ang II, predominantly by endothelial-bound ACE in the lungs but also in plasma and the vascular bed of kidneys, heart and brain, and to some extent by chymases stored in secretory granules in mast cells [13,14].
Renin is an enzyme produced by pericytes in the vicinity of the afferent arterioles and cells of the juxtaglomerular apparatus. It is stored in intracellular vesicles and rapidly secreted in response to three stimuli: a decrease in blood pressure as detected by baropressors, a decrease in the sodium concentration delivered to the distal tubules, and activation of the sympathetic nervous system (through β 1 adrenergic receptors). Renin itself has no peripheral receptors and no direct hemodynamic effects [14].
Ang II, an octapeptide, has strong vasopressor properties but its action is terminated by rapid degradation to angiotensin III by angiotensinases located in red blood cells and the vascular beds of most tissues. Ang II is also hydrolized into Ang (1-7) through the actions of ACE 2. It has a half-life in circulation of around 30 s, whereas, in tissue, this may be as long as 15-30 min [15].
In addition to the 'classic' systemic RAS, which regulates blood pressure, fluid and electrolyte homeostasis and preserves volume status and vascular tone, most organs contain a tissue RAS and an intracellular RAS. The tissue RAS is predominantly involved in local cardiovascular regulation and inflammatory processes, including vascular permeability, apoptosis, cellular growth, migration and cell differentiation, and the intracellular RAS participates in intracellular signaling pathways [16].

Physiologic Effects of Angiotensin II
Ang II exerts its effects by binding to specific angiotensin (AT) receptors based on the cell membrane of various cell types: AT-1, AT-2, AT-4 and Mas receptors. In humans, the major physiological effects are mediated by AT-1 receptors located in the kidneys, vascular smooth muscle, lung, heart, brain, adrenals, pituitary gland and liver, and relate to maintenance of hemodynamic stability and fluid and electrolyte regulation ( [14,16]; Fig. 1 and Table 1).
In the healthy adult, the AT-2 receptor is expressed in certain cell types and tissues, such as vascular endothelial cells, distinct areas of the brain, adrenal glands, myometrium and ovaries and selected cutaneous, renal and cardiac structures [17,18]. Although their expression level is often much lower than that of AT-1 receptors, AT-2 receptors have an important role in injury and repair mechanisms and, under conditions such as mechanical injury or ischemia, expression may be increased. There is also good evidence that AT-2 receptors are involved in the regulation of Ang II mediated adrenal catecholamine secretion, for example during sepsis [18]. The main biological effects of the AT-2 receptor are often opposite to the AT-1 receptors with focus on anti-proliferation, vasodilation and anti-inflammation. Stimulation of AT-2 receptors confers protection against an overstimulation of AT-1 receptors: for example, vasoconstriction mediated by the AT-1 receptors can be opposed by the vasodilatory effects of Ang II linked to the AT-2 receptor ( [19]; Fig. 1). AT-2 receptors also play a role in pressure natriuresis, opposing the anti-natriuretic effects of AT-1 receptor activation, and in cardiovascular remodeling following myocardial infarction and hypertension, heart failure and stroke. Finally, in the fetus and neonate, AT-2 receptors are involved in fetal tissue development, neuronal regeneration and cellular differentiation.
The AT-4 receptor is activated by the Ang II metabolite Ang IV, and appears to contribute to the regulation of the extracellular matrix in the central nervous system, as well as modulation of oxytocin release.

Sepsis-Induced Dysregulation of the Renin-Angiotensin System
The natural role of the RAS is to preserve volume status and arterial blood pressure, thereby maintaining the systemic circulation and also the microcirculation. In sepsis, both over-and under-stimulation of the RAS have been reported in patients [20][21][22][23][24][25]. The capacity of ACE and the functionality of angiotensin receptors are key factors that determine whether hemodynamic stability can be achieved and maintained.
ACE is an ectoenzyme that is distributed primarily on the pulmonary capillary endothelium but can also be found in endothelial and renal epithelial cells. ACE molecules are uniformly distributed along the luminal pulmonary endothelial surface including the membrane caveolae [26]. As a result, ACE is directly accessible to blood-borne substrates and able to convert Ang I to Ang II rapidly, but also very susceptible to disease processes that affect the pulmonary vasculature [27].

Effects of Sepsis on Ang II Levels
During sepsis, renin, Ang I and Ang II are usually activated. However, variable and even low plasma levels of Ang II have been reported [20,21]. The reasons are multifactorial. Pre-morbid treatment with an ACE-inhibitor will prevent conversion of Ang I to Ang II. There is also evidence that endotoxin associated with Gram-negative sepsis has potential to deactivate ACE [22]. Additionally, in diseases that affect the pulmonary capillary endothelium, such as acute respiratory distress syndrome (ARDS) and pneumonia, ACE activity is altered at an early stage, resulting in reduced capacity to convert Ang I to Ang II [23,[28][29][30].
Low levels of Ang II and ACE have clinical implications. Zhang et al. measured serial Ang II and ACE concentrations in 58 patients with severe sepsis and showed that the cohort with low levels exhibited more complications and had a greater risk of dying [20].

Sepsis-Induced Downregulation of Ang II Receptors
Ang II is antagonized by the endogenous vasodilator, nitric oxide (NO), and each has a role in influencing the production and functioning of the other. Several studies have shown that sepsis is associated with downregulation of AT-1 receptors, likely mediated by pro-inflammatory cytokines and NO [31,32]. In addition, reduced activity of the AT-1 receptor associated protein 1 (Arap 1) has been reported [33]. The physiological role of Arap 1 is to support the Stimulation of Na reabsorption and H + excretion in the proximal tubule via the Na/H + exchanger Stimulation of the release of aldosterone, which stimulates the distal tubule and collecting ducts of the kidneys to re-absorb sodium and water Variable effects on glomerular filtration and renal blood flow depending on the physiological and pharmacological setting: i) Constriction of the afferent and efferent glomerular arterioles; although this will tend to restrict renal blood flow, the effect on the efferent arteriole is markedly greater, and as a result, this tends to increase or maintain GFR ii) Constriction of the glomerular mesangium, thereby reducing the area for glomerular filtration iii) Enhanced sensitivity to tubuloglomerular feedback and thereby prevention of excessive rise in GFR iv) Stimulation of local release of prostaglandins, which oppose the effect of Ang II and antagonize renal vasoconstriction trafficking of the AT-1 receptor to the cell membrane. As such, reduced activity of Arap 1 is associated with decreased sensitivity of the AT-1 receptor. Downregulation of AT-2 receptors may also occur during septic shock [18]. The consequences of this process are reduced catecholamine release by the adrenal medulla and attenuation of the responsiveness of blood pressure and aldosterone formation.

Clinical Studies with Angiotensin
Ang II was discovered in the 1930s and has been used in clinical studies since the early 1960s. To date, over 31,000 subjects have been exposed to Ang II either as monotherapy or in combination with catecholamines and non-catecholamine vasopressors in various clinical settings [34].

Prevention of Hypotension During Obstetric Anesthesia
Hypotension is a frequently occurring adverse effect during spinal anesthesia. In the obstetric population where utero-placentary blood flow depends directly on maternal blood pressure and where moderate maternal hypotension is associated with fetal hypoxemia and neurological morbidity, every attempt is made to prevent hypotension [35]. Phenylephrine and ephedrine are often used in clinical practice. Ephedrine was the vasoconstrictor agent of choice in obstetric anesthesia for many years because of its marked increase in utero-placentary blood flow [36]. However, it has fallen out of favor because of its association with lower umbilical artery pH values, likely due to increased fetal metabolic activity [37].
Phenylephrine is a synthetic sympathicomimetic agent that is regarded to be safe in the treatment of regional anesthesia-induced maternal hypotension [35].
Ang II has been shown to cause less vasoconstriction of the utero-placental vascular bed compared with uterine or other systemic vessels [38,39]. In 1994, Ramin et al. randomized 30 healthy pregnant women undergoing elective Cesarean section either to a control group or prophylactic Ang II infusion versus prophylactic ephedrine infusion in order to maintain a diastolic blood pressure 0-10 mmHg above the baseline [40]. In women randomized to Ang II infusion, the maternal Ang II levels were increased nearly fourfold but Ang II levels in the umbilical artery and vein were unchanged. Of note, no one in the Ang II cohort had a recorded umbilical artery blood pH < 7.20 in contrast to 40% of the ephedrine group. Vincent et al. reported similar results in 54 women randomized to Ang II versus ephedrine during spinal anesthesia for elective Cesarean delivery [41]. The umbilical arterial and venous pH and base excess were higher in the angiotensin group compared to women who had received ephedrine, and maternal heart rate was higher in the ephedrine group. The authors concluded that Ang II maintained systolic blood pressure during anesthesia without causing fetal acidosis or increasing maternal heart rate.

Treatment of Hypotension Following ACE Inhibitor Overdose
ACE-inhibitor overdose may result in severe refractory hypotension. Several case reports have highlighted successful treatment with Ang II [42][43][44]. Although in all cases, Ang II was administered in combination with other therapies, including gut decontamination, intravenous fluids, vasopressors and naloxone, there was a profound effect on blood pressure immediately after starting Ang II infusion. Physiologically, it is logical to regard Ang II as a rational treatment for ACEinhibitor induced hypotension.

Treatment of Vasodilatory Shock
The most immediate and critical need of patients with vasodilatory shock is the achievement of hemodynamic stability to prevent multiorgan dysfunction whilst allowing time to treat the underlying etiology. Multiple vasopressors and catecholamines are often needed [45]. Studies using Ang II as a vasopressor for management of shock were originally conducted in the 1960s. Ang II was compared to catecholamines in non-randomized designs and was shown to have comparable effects to norepinephrine [46,47].
In the first RCT, Chawla et al. reported a catecholamine-sparing effect in patients with high output shock treated with Ang II administration [10]. The subsequent Angiotensin for the Treatment of High Output Shock (ATHOS)-3 trial was a phase 3, placebocontrolled, double-blind, multicenter RCT including 321 patients with refractory vasodilatory shock who were randomized to Ang II infusion or placebo [9]. Analysis of the primary efficacy endpoint (defined as the percentage of patients achieving the pre-specified target blood pressure response) was statistically significant (p < 0.0001). Twenty-three percent of the 158 placebo-treated patients had a desired blood pressure response compared to 70% of the 163 patients treated with Ang II. Treatment with Ang II also resulted in a significant decrease in the standard of care vasopressor use, as measured by a change in the cardiovascular Sequential Organ Failure Assessment (SOFA) score at 48 h (− 1.75 versus − 1.28, p = 0.01). No difference in mortality was noted but there were fewer adverse events with Ang II. In a recent systematic review including data from > 31,000 patients, Busse et al. also confirmed that Ang II was safe to be used in humans [34].

Conclusion
The RAS plays a key role in maintaining hemodynamic stability, vascular tone and electrolyte homeostasis. Studies suggest that its physiological regulation is disturbed in sepsis and critical illness, which results in altered ACE functionality, reduced generation of Ang II and downregulation of Ang II receptors. Recent RCTs stipulate that Ang II is an effective and safe treatment for hypotension in patients with refractory vasodilatory shock, allowing for sparing of catecholamines. It may also have a role in cardiogenic, distributive and unclassified shock [48].
Innate to the human body are three molecules (catecholamines, vasopressin and angiotensin) that maintain and regulate BP. The addition of Ang II as a potential tool in the armamentarium against shock offers clinicians the opportunity to provide a 'balanced' approach to vasopressor therapy. The combination of different vasoactive drugs that mimic the natural response to severe vasodilatation and hypotension makes physiological sense [49]. With this approach, the likelihood of hemodynamic recovery is enhanced and toxicity from large doses of monotherapy can be minimized.