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Angiotensin II for septic shock treatment

An update

Griffiths, Carrie L. PharmD, BCCCP; Jackson, Matthew R.; Hoke, Tanner J.; Hertel, Kristie A. MSN, RN, CCRN, ACNP-BC

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doi: 10.1097/01.CCN.0000546307.15415.e6
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The prevalence of sepsis is rising. According to the CDC, more than 1.7 million individuals develop sepsis each year in the US. Of these, about 270,000 die. Of those patients who die in the hospital, 1 in 3 will die from sepsis.1 The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) defines sepsis as “a life-threatening organ dysfunction caused by a dysregulated host response to infection.”2 Sepsis-3 defines septic shock as “a subset of sepsis in which underlying circulatory and cellular/metabolic abnormalities are profound enough to substantially increase mortality.”2 Diagnostic criteria for septic shock include a serum lactate level greater than 2 mmol/L (18 mg/dL) and use of therapy with vasopressor agents to maintain a mean arterial pressure (MAP) of at least 65 mm Hg despite adequate volume resuscitation.2 Mortality for sepsis is 26% at 90 days and increases to 42% if the patient progresses to septic shock.2 The most profound clinical finding with septic shock is hypotension, which leads to hypoperfusion. Hypoperfusion can cause serious complications, such as acute kidney injury, myocardial injury, and increased mortality.3

The most recent treatment recommendation for patients with suspected sepsis is to begin initial treatment within 1 hour of presentation to the treatment center.4 Initial sepsis treatment starts with obtaining a serum lactate level. If the initial lactate level is greater than 2 mmol/L, the level should be remeasured in 2 to 4 hours to guide resuscitation. Lactate can be used as a surrogate marker of tissue hypoperfusion. If the patient is hypotensive or has a lactate level greater than 4 mmol/L, fluid resuscitation with crystalloids should immediately be infused intravenously at 30 mL/kg.4 After initial fluid resuscitation, fluid administration should be reassessed to determine if the patient will remain responsive because some evidence indicates sustained positive fluid balance may be harmful to patients in the ICU.4 If the lactate level is greater than 2 mmol/L, blood cultures should be obtained immediately before starting broad-spectrum antibiotics. One or more empiric broad-spectrum antibiotics covering all the most likely pathogens should be administered intravenously as soon as possible. Antibiotic treatment should not be delayed while awaiting blood cultures. If initial fluid resuscitation does not restore BP, then vasopressors should be administered with a goal of achieving a MAP of at least 65 mm Hg.4

Patients with hypotension despite the use of multiple high doses of vasopressors have a 30-day all-cause mortality exceeding 50%.5 This high mortality and increased prevalence of sepsis require new treatment options for catecholamine-resistant septic shock.

A closer look at angiotensin II

In December 2017, the FDA approved angiotensin II (Giapreza), a new therapy option for the treatment of septic shock. Angiotensin II has been studied for the treatment of shock since 1962.6 Angiotensin II is a key component in the renin-angiotensin-aldosterone system (RAAS). The RAAS consists of five main components: renin, angiotensinogen, angiotensin-converting enzyme (ACE), angiotensin—specifically angiotensin I and II, and aldosterone. Renin is synthesized and stored in its inactive form in the kidneys but does not have a direct effect on hemodynamics. Renin is then activated in the bloodstream through various mechanisms. Three stimuli elicit the rapid secretion of renin from the kidneys:

  • activation of the sympathetic nervous system
  • decreased sodium concentrations delivered to the distal tubules
  • a decrease in BP detected by baroreceptors.

Angiotensin II is the main functional unit of the RAAS and has strong vasopressor properties. (See Control of BP by RAAS.) Angiotensin II begins as angiotensinogen. Renin then converts angiotensinogen to angiotensin I. Endothelial-bound ACE, located primarily in the lungs, cleaves angiotensin I to angiotensin II. (See Angiotensin II pathway.) Angiotensin II acts by binding to specific angiotensin receptors on cell membranes to exert its vasoconstrictive effects. The AT1 receptors, located in many organs throughout the body, are the primary receptors in humans that mediate physiologic effects, such as maintenance of hemodynamic stability as well as fluid and electrolyte regulation. AT2 receptors are found in much lower concentrations compared with AT1. AT2 receptors are expressed in cardiac structures, renal structures, areas of the brain, adrenal glands, and vascular endothelial cells. AT2 receptors have important roles in mechanical injury, ischemia, injury and repair mechanisms, and, most notably, pressure natriuresis.7

Angiotensin II also stimulates synthesis and secretions of aldosterone through activation of AT1 receptors located in the adrenal cortex. Aldosterone is then produced and secreted from vascular smooth muscle cells or epithelial cells in the renal tubule. Aldosterone exerts its effects by binding to mineralocorticoid receptors that in turn promote transcription of genes that regulate fluid and electrolyte balance. Aldosterone modulates extracellular volume and BP by promoting water retention, sodium reabsorption, as well as potassium and magnesium loss.7 This process assists in maintaining a normal arterial BP range.

Renin, angiotensin I, and angiotensin II are usually activated in patients with sepsis; however, the plasma levels of angiotensin II are unpredictable and may even be decreased compared with normal levels.9 A study conducted by Zhang and colleagues showed that patients with sepsis in the mortality group also had low levels of angiotensin II and ACE.10 The mechanism of angiotensin II makes it a plausible treatment option to help increase MAP and decrease the required dose of catecholamines in patients with septic shock.

Current vasopressor therapy in septic shock

The 2016 Surviving Sepsis Campaign (SSC) International Guidelines for Management of Sepsis and Septic Shock recommend immediate hemodynamic support to combat the rapid decline in tissue perfusion that is an inherent complication of sepsis and septic shock.11 The 2018 SSC bundle recommends that initial resuscitation from sepsis-induced hypoperfusion be with at least 30 mL/kg of an I.V. crystalloid within 1 hour of recognition of sepsis.4 Albumin is suggested in addition to crystalloids for initial resuscitation to prevent the use of large amounts of crystalloids in patients with severe hypoperfusion.11 It is not until after the patient is receiving or has received adequate fluid resuscitation that if there is no response or an inadequate response to the patient's hemodynamic parameters is seen, vasopressor and/or inotropic therapy is incorporated into treatment within the first hour.4 Selection of a vasoactive medication is largely due to their respective mechanisms of action and receptor activity. Norepinephrine's affinity for alpha-1-adrenergic receptors and minimal affinity for beta-1-adrenergic receptors in the heart suggest that it will work to increase systemic vascular resistance, and thus BP, with little effect on cardiac output, making it an ideal and recommended first-line vasopressor option.11,12 Vasoactive agents are typically given to obtain a target MAP of at least 65 mm Hg. If this target is not met with norepinephrine alone, vasopressin or epinephrine is typically added to the treatment regimen. Vasopressin may also be added to norepinephrine monotherapy to decrease norepinephrine use. Dopamine can be used as an alternative to norepinephrine in patients with low risk of tachydysrhythmias or bradycardia. Phenylephrine may be a useful vasoactive medication in septic shock when norepinephrine has caused dysrhythmias in a patient or when use of the aforementioned therapies has failed to reach the target MAP.11 In cases of persistent hypoperfusion in which a patient has not responded to an adequate fluid challenge in addition to a vasoactive medication, dobutamine is recommended. The use of I.V. corticosteroids such as hydrocortisone is recommended in patients exhibiting further signs of persistent hypoperfusion.11

Control of BP by RAAS
Angiotensin II pathway7,8

Supportive measures in the treatment of sepsis and septic shock include blood glucose control, stress ulcer prophylaxis, nutrition support, and venous thromboembolism (VTE) prophylaxis. Of particular note, VTE prophylaxis should be initiated in all patients with severe sepsis or septic shock.11 Low-molecular-weight heparin (LMWH) is typically recommended over low-dose unfractionated heparin for VTE prophylaxis if the patient has no contraindications to LMWH. Nonpharmacologic options are available and recommended, such as sequential compression devices or compression stockings, when pharmacologic prophylaxis is contraindicated.11

Achieving FDA approval

The ATHOS-3 (Angiotensin II for the Treatment of High-Output Shock) trial was conducted to obtain approval of angiotensin II by the FDA.13 The ATHOS-3 trial was a phase 3, randomized, double-blind, placebo-controlled trial. Patients enrolled in the study were age 18 years and older with vasodilatory shock despite high-dose vasopressor infusion therapy and I.V. volume resuscitation of a minimum of 25 mL/kg over 24 hours. Patients were randomized into two groups: placebo and angiotensin II at 20 nanograms/kg/min.

Participants were stratified based on a MAP of less than 65 mm Hg or greater than or equal to 65 mm Hg and an Acute Physiology and Chronic Health Evaluation II (APACHE II) score of less than 30, 31 to 40, or 41 or greater with a max score being 71. The study had 321 participants; 163 participants received angiotensin II, and 158 received a placebo. The average age of participants was 64, and the median APACHE II score was 28. The leading cause of shock was sepsis, experienced by 80% of the participants. The primary outcome was to raise the MAP by 10 mm Hg or raise the MAP to greater than 75 mm Hg within 3 hours. This outcome was achieved by 69.9% of the participants receiving angiotensin II and 23.4% of the participants receiving placebo. In addition, participants in the angiotensin II arm had lower requirements for catecholamine infusions than participants in the placebo arm.13

Angiotensin II (Giapreza) was approved by the FDA on December 21, 2017. Angiotensin II is a vasoconstrictor used to increase BP in adults and is indicated for adults with septic or other distributive shock.14 The mechanism of action of angiotensin II is unique compared with other vasopressors as described above. Angiotensin II is individually titrated to effect for each patient. In the ATHOS-3 trial, patients had a median time of 5 minutes to reach the target MAP in the angiotensin II arm.13 Baseline serum levels of angiotensin II were similar to levels 3 hours after I.V. infusion, but treatment serum levels of angiotensin I were reduced by about 40%. The half-life after I.V. administration of angiotensin II is less than 1 minute. Angiotensin II is metabolized in plasma, erythrocytes, and many major organs by aminopeptidase A and ACE 2 to angiotensin III and angiotensin-(1-7), respectively.14

Angiotensin II is available in vials of 2.5 mg/mL and 5 mg/2 mL.14 Angiotensin II must be diluted in 0.9% sodium chloride to a concentration of 5,000 nanograms/mL or 10,000 nanograms/mL prior to administration as an I.V. infusion. Angiotensin II administration is recommended through a central line.14 Consult the full prescribing information for complete dosage and administration recommendations.14

Drug interactions, warnings, and precautions

The only drug interactions with angiotensin II known to date are with concomitant use of ACE inhibitors, which can increase the response to angiotensin II and angiotensin II receptor blockers (ARBs), which may decrease the response to angiotensin II.14 Although no contraindications have been reported, the ATHOS-3 trial showed that angiotensin II can cause life-threatening thrombotic and embolic events (13% vs. 5% compared with placebo). The prevalence of events such as deep vein thrombosis has led to the warnings and precautions associated with angiotensin II. One of the warnings states prophylactic treatment for VTE should be used whenever angiotensin II is administered. Other notable adverse reactions of note from the ATHOS-3 trial were an increase in infection and delirium.13

Busse and colleagues conducted a systematic review of safety on angiotensin II in 1,124 studies that included 31,281 participants receiving angiotensin II. The review concluded the most prominent adverse reactions included headache, chest pressure, orthostatic symptoms, and exacerbation of asthma and heart failure. The only fatal adverse reaction reported was one case of cerebral hemorrhage.15

There is little evidence of angiotensin II use in patients with certain disease states, such as liver failure, asthma requiring inhaled bronchodilators if not mechanically ventilated, history of or acute mesenteric ischemia, active bleeding, a lifespan of less than 12 hours, and an absolute neutrophil count of less than 1,000 cells/mm3. Other populations in which angiotensin II should not be used include patients receiving more than 500 mg daily of hydrocortisone or equivalent glucocorticoid medication as a standing dose, patients who are pregnant or breastfeeding, and pediatric patient populations.13

A post hoc analysis of the ATHOS-3 trial and the outcomes of 105 patients (angiotensin II n = 45; placebo n = 60) with acute kidney injury requiring renal replacement therapy (RRT) was recently conducted. It showed that 28-day survival was 53% (95% CI: 38%-67%) in the angiotensin II group and 30% (95% CI: 19%-41%) in the placebo group (P = .012). The rate of RRT liberation within 7 days was greater in the angiotensin II group as 38% (95% CI: 25%-54%) of patients in the angiotensin II group discontinued RRT compared to the 15% (95% CI: 8%-27%) of patients in the placebo group that discontinued RRT (P = .007). Analysis also revealed that a MAP response was achieved in 53% (95% CI: 38%-68%) of patients in the angiotensin II group and 22% (95% CI: 12%-34%) of patients in the placebo group (P = .001).16

Additional research concerning the timing and sequence of angiotensin II administration is warranted and could impact its incorporation as a standard of care for treatment in septic shock.

Nursing considerations

Sepsis has remained a prevalent diagnosis for patients admitted to the ICU.17 Understanding the physiology of sepsis as well as knowledge of the current guidelines for treatment is essential for all ICU nurses. This fundamental knowledge base allows early identification of sepsis and the ability to anticipate and be prepared to treat the patient. Timely administration of medications and completion of interventions for a patient with sepsis is paramount to their recovery.18

The hallmark of septic shock is hypoperfusion with end organ dysfunction. Patients with sepsis will present with alterations in their hemodynamic assessment as the body attempts to compensate for its physiologic derangement brought on by a systemic response to a pathogen. Vital signs will indicate tachypnea along with tachycardia and, in later stages of sepsis, hypotension indicating septic shock. As clinicians at the bedside, nurses need to be diligent in their clinical observations of the patient. Early identification of sepsis results in improved outcomes.17 Urinary output via a urinary drainage catheter should be monitored closely as hypoperfusion of the kidneys would present as decreased hourly output. The neurologic system is extremely sensitive to changes in perfusion and a change in mental status, including minor restlessness or anxiety, is an early indication of hypoperfusion. Assessment of skin temperature and color is an additional reference for how adequately the patient is being perfused. Close bedside observation with communication of abnormalities to medical providers by nurses assists in early identification of sepsis along with evaluation of ongoing management effectiveness of treatment strategies.

Treating the cause of septic shock, source control, and ensuring optimal treatment is the primary goal for a patient with septic shock.4,11 If the cause of septic shock is not identified, then a persistent septic state can lead to end organ failure and death.4,11 Timely administration of antibiotics is essential for patients with bloodstream infections, pneumonia, urinary tract infections, and others. Surgical intervention is required for source control in patients with soft-tissue infections, intra-abdominal infections, and other infections. Monitoring of surgical wounds and early identification of possible indications for return to surgery are responsibilities of the nursing staff in conjunction with the surgical team. Cultures should be evaluated daily for speciation and susceptibility to assure the patient is receiving the appropriate antibiotic therapy.11

Management of a patient with sepsis begins with fluid resuscitation.18 Large bore I.V. access is required for successful fluid resuscitation. Nurses should anticipate the need for central venous access and be prepared to assist the medical provider with insertion. In addition, to allow rapid infusion of fluids for resuscitation, central access is required in most institutions for administration of vasoactive medications, which are the next steps if hypoperfusion persists despite fluid resuscitation. Central venous access allows for the trending of central venous pressure to assist with fluid management as well as access for obtaining and monitoring venous blood gas samples. Placement of an arterial line for frequent blood sampling and continuous BP monitoring should be anticipated and prepared for by the nurse.

There is a wide range of vasoactive medications that can be used for the management of a patient with septic shock. Clinical nurses are required to understand the physiologic effects of each medication along with possible adverse reactions. The newest vasoactive medication in the management of sepsis is angiotensin II. Clinical nurses need to be aware that angiotensin II has a very short onset period with required titration to adjust the doses of other vasoactive medications to maintain a goal MAP between 65 to 75 mm Hg.13 The nurse should monitor the patient closely after starting the infusion of angiotensin II to ensure appropriate titration and the down titration of other vasoactive agents.14 Careful setup of I.V. angiotensin II is imperative because most vasoactive infusions are dosed as micrograms/kilogram/minute. However, angiotensin II is dosed in nanograms/kilogram/minute.14 Clinical nurses will need to know how to convert nanograms to micrograms because most infusion pumps will not be preprogrammed for nanograms/kilogram/minute. Angiotensin II is administered by I.V. infusion using an infusion pump, preferably through a central line. Assess the patient's response to angiotensin II by monitoring the BP and titrating the drug every 5 minutes by prescribed weight-based increments to achieve the target BP. Downward titration of angiotensin II occurs after the dose of catecholamines, norepinephrine and/or epinephrine, has been weaned to minimal doses or has been weaned to off.19 Before starting a patient on angiotensin II, nurses should be aware of all the medications the patient was taking at home as well as all medications during hospitalization, including the use of ACE inhibitors and ARBs because these drugs may affect the patient's responsiveness to an angiotensin II infusion.14,19

The incidence of sepsis has increased significantly over the last two decades. Morbidity and mortality related to sepsis continue to be profound despite new treatment options. Early identification and treatment remains the best option for decreasing the healthcare cost and sepsis-associated morbidity and mortality. Nurses in all areas of practice must remain knowledgeable regarding current guidelines for identification and treatment of patients with sepsis.


Angiotensin II has been studied for many years and has consistently shown to increase MAP. This medication adds a new mechanism of action to the vasopressor arsenal that is already used for septic shock. Angiotensin II should be reserved for patients in septic shock who do not respond to high doses of catecholamines and vasopressin.


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    angiotensin II; AT1 receptors; AT2 receptors; hypoperfusion; renin-angiotensin-aldosterone system; sepsis; septic shock; vasopressor therapy

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