Ashish K. Khanna, MD, FCCP

Hypotension is an often-underestimated adversary. Even brief periods of intraoperative mean arterial pressure (MAP) <65 mm Hg increase the odds of both myocardial ischemia and acute kidney injury in the postoperative period. The threshold may be even higher in the postoperative critically ill population (Khanna, et al. Crit Care Med. 2018;46(1):71). Hypotension that is refractory to high-dose vasopressors is associated with an all-cause mortality of 50% to 80%.

The vasopressor toolbox centers around escalating doses of catecholamines with or without the addition of vasopressin. High-dose catecholamines, albeit a frequent choice, is associated with adverse cardiac events (Schmittinger, et al. Intensive Care Med. 2012;38[6]:950) and is an independent predictor of ICU mortality (Sviri, et al. J Crit Care. 2014;29[1]:157).
 

The evidence behind angiotensin II

Angiotensin II (AT II) is a naturally occurring hormone in the renin-angiotensin-aldosterone (RAA) system that modulates blood pressure through direct arterial vasoconstriction and direct stimulation of the kidneys and adrenal cortex to release vasopressin and aldosterone, respectively.

Positive results from the recent phase 3 trial for AT II have offered hope that this agent would add the needed balance to the current scarcity of vasopressor options (Khanna, et al. N Engl J Med. 2017;377[5]:419). AT II would provide the missing piece in the jigsaw that would allow the intensivist to manage refractory hypotension, while keeping a multimodal vasopressor dosing regimen within therapeutic limits.

Irvine Page and coworkers are credited with most of the initial work on AT II, which they did nearly 70 years ago. Anecdotal use in humans has been reported since the early 1960s (Del Greco, et al. JAMA 1961;178:994). After a prolonged period of quiescence, the Angiotensin II in High-Output Shock (ATHOS) pilot study, which was done in 2014 as a single-center “proof of concept” study of 20 patients, reinvigorated clinical enthusiasm for this agent (Chawla, et al. Crit Care. 2014;18[5]:534). ATHOS demonstrated the effectiveness of AT II at decreasing norepinephrine (NE) requirements of patients in vasodilatory shock (mean NE dose in AT II group 7.4 ug/min vs 27.6 ug/min in placebo, P=.06). These promising results were followed by ATHOS-3, a phase 3, double-blind, multicenter randomized controlled trial of stable human synthetic AT II. This trial was conducted under a special protocol assessment agreement with the US Food and Drug Administration (FDA). A total of 344 patients with predefined criteria for vasodilatory shock were randomized to AT II or placebo as the intention-to-treat population. The primary end-point was a response in MAP by hour 3 of AT II initiation; response was defined as either a MAP rise to 75 mm Hg or an increase in MAP ≥ 10 mm Hg. The primary end-point was reached more frequently in the AT II group than in the placebo group (69.9% AT II vs 23.4% placebo, OR 7.95, 95% CI 4.76-13.3, P<.001). The AT II group had significantly lower cardiovascular sequential organ failure assessment (SOFA) scores at 48 hours and achieved a consistent decrease in background vasopressor doses. Post-hoc data analysis found that the highest benefit was in patients who were AT II deficient (high ratio of AT I:AT II) (Wunderink, et al. Intensive Care Med Exp. 2017;5(Suppl 2):44). The patients who were AT II depleted and received placebo had a higher hazard ratio of death (HR 1.77, 95% CI 1.10-2.85, P=.019), while those who were AT II depleted and received AT II had a decreased risk of mortality (HR 0.64, 95% CI 0.41-1.00, P=.047). The data suggest not only that AT II levels may be predictive of mortality in vasodilatory shock but also that exogenous AT II administration may favorably modulate mortality in this population. Further, a subset data analysis of severely ill patients (APACHE II scores > 30) showed that those who received AT II and standard vasopressors had a significantly lower 28-day mortality compared with patients who only received standard vasopressors (Szerlip, et al. Crit Care Med. 2018;46[1]:3). Considering that the endothelial cells in the lungs and kidneys are locations where AT I is hydrolyzed by angiotensin-converting enzyme (ACE) into AT II, patients receiving ACE-inhibitors and individuals with pulmonary or renal disease are at greatest risk for AT II deficiency. As such, the use of AT II in the extra-corporeal membrane oxygenation (ECMO), post cardiopulmonary bypass, acute respiratory distress syndrome (ARDS), and renal failure populations are of future interest.

 

Is there a downside?

Appropriate caution is necessary when interpreting these outcomes. One criticism that ATHOS-3 received was the use of a MAP goal of 75 mm Hg, a higher value than currently recommended by clinical guidelines, in the first 3 hours of AT II administration. Because this was a phase 3 trial, both the safety and efficacy of the drug were examined. These goals are difficult to accomplish if simultaneously manipulating other variables. Therefore, to isolate the effects of drug efficacy and safety, a higher MAP goal (75 mm Hg) was established to minimize any effect from varying background vasopressor doses during the first 3 hours of the study.

 

Furthermore, ATHOS-3 did find an increase in venous and arterial thromboembolic events in patients who received AT II (13% AT II vs 5% placebo). Previously, a systematic review of over 30,000 patients did not report this increased thromboembolic risk (Busse, et al. Crit Care. 2017;21[1]:324). According to the package insert, all patients receiving AT II should receive appropriate thromboembolic prophylaxis if medically indicated.
 

Where does AT II fit in our algorithm for resuscitation and the vasopressor toolbox?

Data from Wunderink et al indicate a potential mortality benefit in populations who are AT II depleted. However, we can only infer who these patients may be, as no commonly available assay can measure AT I and AT II levels. ATHOS and ATHOS-3 used AT II late during resuscitation, as did the Expanded Access Program (EAP) of the FDA, which gave physicians preliminary access to AT II while it was undergoing FDA review. Using similar inclusion criteria as ATHOS-3, the EAP did not permit patients to receive AT II until doses greater than or equal to 0.2 ug/kg/min of NE-equivalents were reached. In a recently published case report, AT II was successfully used in a patient with septic shock secondary to a colonic perforation (Chow, et al. Accepted for e-publication: A&A Practice. April 2018.). This individual was in vasodilatory shock despite standard resuscitation, 0.48 ug/kg/min of NE, and 0.04 units/min of vasopressin. Methylene blue and hydroxocobalamin had failed to relieve the vasoplegia, and only after the initiation of AT II at 40 ng/kg/min, the patient could be relieved of vasopressors and survived to be discharged from the hospital. In our opinion, best clinical practices would allow for an early multimodal vasopressor regimen that should include AT II at the earliest sign of rapid clinical decline (Jentzer, et al. Chest. 2018. Jan 9. pii: S0012-3692(18)30072-2. doi: 10.1016/j.chest.2017.12.021. [Epub ahead of print]).

Angiotensin II was recently approved by the FDA in December 2017 and is now available on the market for management of vasodilatory shock. This will undoubtedly have a profound impact on the way clinicians treat vasodilatory shock. Previously, we were confined to agents such methylene blue and hydroxocobalamin to rescue patients from profound vasoplegia. However, none of these agents are supported by robust evidence from randomized control trials.

Now, we can openly welcome a new challenger to the campaign, a new hue to the palette of vasopressor colors. This new class of vasopressor makes complete physiological sense and will provide an invaluable tool in our daily battle against sepsis and vasodilatory shock.

Dr. Chow is Assistant Professor, Division of Critical Care Medicine, Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, MD; Dr. Khana is Assistant Professor of Anesthesiology, Staff Intensivist, Vice-Chief for Research, Center for Critical Care, Department of Outcomes Research & General Anesthesiology, Anesthesiology Institute, Cleveland Clinic, Cleveland, OH

Editor’s note

For decades, our options to treat patients with profound vasoplegia have been limited to high-dose catecholamines and vasopressin. Clinicians are often faced with the need to initiate multiple catecholamine agents knowing that these drugs stimulate similar receptors. The recent ATHOS-3 trial introduces AT II as a new option for the management of patients with refractory vasodilatory shock. This drug has a distinct mechanism of action that complements the effect of other vasopressors. Moreover, recent data suggest that this new agent is most beneficial in patients who are AT II deficient. Just like cancer therapies have evolved to precision medicine, will we perhaps face the need to better understand and promptly identify patients with AT II deficiency? For now, we have a new player on our vasopressor team.

Angel Coz, MD, FCCP
Section Editor

Hypotension is an often-underestimated adversary. Even brief periods of intraoperative mean arterial pressure (MAP) <65 mm Hg increase the odds of both myocardial ischemia and acute kidney injury in the postoperative period. The threshold may be even higher in the postoperative critically ill population (Khanna, et al. Crit Care Med. 2018;46(1):71). Hypotension that is refractory to high-dose vasopressors is associated with an all-cause mortality of 50% to 80%.

The vasopressor toolbox centers around escalating doses of catecholamines with or without the addition of vasopressin. High-dose catecholamines, albeit a frequent choice, is associated with adverse cardiac events (Schmittinger, et al. Intensive Care Med. 2012;38[6]:950) and is an independent predictor of ICU mortality (Sviri, et al. J Crit Care. 2014;29[1]:157).
 

The evidence behind angiotensin II

Angiotensin II (AT II) is a naturally occurring hormone in the renin-angiotensin-aldosterone (RAA) system that modulates blood pressure through direct arterial vasoconstriction and direct stimulation of the kidneys and adrenal cortex to release vasopressin and aldosterone, respectively.

Positive results from the recent phase 3 trial for AT II have offered hope that this agent would add the needed balance to the current scarcity of vasopressor options (Khanna, et al. N Engl J Med. 2017;377[5]:419). AT II would provide the missing piece in the jigsaw that would allow the intensivist to manage refractory hypotension, while keeping a multimodal vasopressor dosing regimen within therapeutic limits.

Irvine Page and coworkers are credited with most of the initial work on AT II, which they did nearly 70 years ago. Anecdotal use in humans has been reported since the early 1960s (Del Greco, et al. JAMA 1961;178:994). After a prolonged period of quiescence, the Angiotensin II in High-Output Shock (ATHOS) pilot study, which was done in 2014 as a single-center “proof of concept” study of 20 patients, reinvigorated clinical enthusiasm for this agent (Chawla, et al. Crit Care. 2014;18[5]:534). ATHOS demonstrated the effectiveness of AT II at decreasing norepinephrine (NE) requirements of patients in vasodilatory shock (mean NE dose in AT II group 7.4 ug/min vs 27.6 ug/min in placebo, P=.06). These promising results were followed by ATHOS-3, a phase 3, double-blind, multicenter randomized controlled trial of stable human synthetic AT II. This trial was conducted under a special protocol assessment agreement with the US Food and Drug Administration (FDA). A total of 344 patients with predefined criteria for vasodilatory shock were randomized to AT II or placebo as the intention-to-treat population. The primary end-point was a response in MAP by hour 3 of AT II initiation; response was defined as either a MAP rise to 75 mm Hg or an increase in MAP ≥ 10 mm Hg. The primary end-point was reached more frequently in the AT II group than in the placebo group (69.9% AT II vs 23.4% placebo, OR 7.95, 95% CI 4.76-13.3, P<.001). The AT II group had significantly lower cardiovascular sequential organ failure assessment (SOFA) scores at 48 hours and achieved a consistent decrease in background vasopressor doses. Post-hoc data analysis found that the highest benefit was in patients who were AT II deficient (high ratio of AT I:AT II) (Wunderink, et al. Intensive Care Med Exp. 2017;5(Suppl 2):44). The patients who were AT II depleted and received placebo had a higher hazard ratio of death (HR 1.77, 95% CI 1.10-2.85, P=.019), while those who were AT II depleted and received AT II had a decreased risk of mortality (HR 0.64, 95% CI 0.41-1.00, P=.047). The data suggest not only that AT II levels may be predictive of mortality in vasodilatory shock but also that exogenous AT II administration may favorably modulate mortality in this population. Further, a subset data analysis of severely ill patients (APACHE II scores > 30) showed that those who received AT II and standard vasopressors had a significantly lower 28-day mortality compared with patients who only received standard vasopressors (Szerlip, et al. Crit Care Med. 2018;46[1]:3). Considering that the endothelial cells in the lungs and kidneys are locations where AT I is hydrolyzed by angiotensin-converting enzyme (ACE) into AT II, patients receiving ACE-inhibitors and individuals with pulmonary or renal disease are at greatest risk for AT II deficiency. As such, the use of AT II in the extra-corporeal membrane oxygenation (ECMO), post cardiopulmonary bypass, acute respiratory distress syndrome (ARDS), and renal failure populations are of future interest.

 

Is there a downside?

Appropriate caution is necessary when interpreting these outcomes. One criticism that ATHOS-3 received was the use of a MAP goal of 75 mm Hg, a higher value than currently recommended by clinical guidelines, in the first 3 hours of AT II administration. Because this was a phase 3 trial, both the safety and efficacy of the drug were examined. These goals are difficult to accomplish if simultaneously manipulating other variables. Therefore, to isolate the effects of drug efficacy and safety, a higher MAP goal (75 mm Hg) was established to minimize any effect from varying background vasopressor doses during the first 3 hours of the study.

 

Furthermore, ATHOS-3 did find an increase in venous and arterial thromboembolic events in patients who received AT II (13% AT II vs 5% placebo). Previously, a systematic review of over 30,000 patients did not report this increased thromboembolic risk (Busse, et al. Crit Care. 2017;21[1]:324). According to the package insert, all patients receiving AT II should receive appropriate thromboembolic prophylaxis if medically indicated.
 

Where does AT II fit in our algorithm for resuscitation and the vasopressor toolbox?

Data from Wunderink et al indicate a potential mortality benefit in populations who are AT II depleted. However, we can only infer who these patients may be, as no commonly available assay can measure AT I and AT II levels. ATHOS and ATHOS-3 used AT II late during resuscitation, as did the Expanded Access Program (EAP) of the FDA, which gave physicians preliminary access to AT II while it was undergoing FDA review. Using similar inclusion criteria as ATHOS-3, the EAP did not permit patients to receive AT II until doses greater than or equal to 0.2 ug/kg/min of NE-equivalents were reached. In a recently published case report, AT II was successfully used in a patient with septic shock secondary to a colonic perforation (Chow, et al. Accepted for e-publication: A&A Practice. April 2018.). This individual was in vasodilatory shock despite standard resuscitation, 0.48 ug/kg/min of NE, and 0.04 units/min of vasopressin. Methylene blue and hydroxocobalamin had failed to relieve the vasoplegia, and only after the initiation of AT II at 40 ng/kg/min, the patient could be relieved of vasopressors and survived to be discharged from the hospital. In our opinion, best clinical practices would allow for an early multimodal vasopressor regimen that should include AT II at the earliest sign of rapid clinical decline (Jentzer, et al. Chest. 2018. Jan 9. pii: S0012-3692(18)30072-2. doi: 10.1016/j.chest.2017.12.021. [Epub ahead of print]).

Angiotensin II was recently approved by the FDA in December 2017 and is now available on the market for management of vasodilatory shock. This will undoubtedly have a profound impact on the way clinicians treat vasodilatory shock. Previously, we were confined to agents such methylene blue and hydroxocobalamin to rescue patients from profound vasoplegia. However, none of these agents are supported by robust evidence from randomized control trials.

Now, we can openly welcome a new challenger to the campaign, a new hue to the palette of vasopressor colors. This new class of vasopressor makes complete physiological sense and will provide an invaluable tool in our daily battle against sepsis and vasodilatory shock.

Dr. Chow is Assistant Professor, Division of Critical Care Medicine, Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, MD; Dr. Khana is Assistant Professor of Anesthesiology, Staff Intensivist, Vice-Chief for Research, Center for Critical Care, Department of Outcomes Research & General Anesthesiology, Anesthesiology Institute, Cleveland Clinic, Cleveland, OH

Editor’s note

For decades, our options to treat patients with profound vasoplegia have been limited to high-dose catecholamines and vasopressin. Clinicians are often faced with the need to initiate multiple catecholamine agents knowing that these drugs stimulate similar receptors. The recent ATHOS-3 trial introduces AT II as a new option for the management of patients with refractory vasodilatory shock. This drug has a distinct mechanism of action that complements the effect of other vasopressors. Moreover, recent data suggest that this new agent is most beneficial in patients who are AT II deficient. Just like cancer therapies have evolved to precision medicine, will we perhaps face the need to better understand and promptly identify patients with AT II deficiency? For now, we have a new player on our vasopressor team.

Angel Coz, MD, FCCP
Section Editor

Hypotension is an often-underestimated adversary. Even brief periods of intraoperative mean arterial pressure (MAP) <65 mm Hg increase the odds of both myocardial ischemia and acute kidney injury in the postoperative period. The threshold may be even higher in the postoperative critically ill population (Khanna, et al. Crit Care Med. 2018;46(1):71). Hypotension that is refractory to high-dose vasopressors is associated with an all-cause mortality of 50% to 80%.

The vasopressor toolbox centers around escalating doses of catecholamines with or without the addition of vasopressin. High-dose catecholamines, albeit a frequent choice, is associated with adverse cardiac events (Schmittinger, et al. Intensive Care Med. 2012;38[6]:950) and is an independent predictor of ICU mortality (Sviri, et al. J Crit Care. 2014;29[1]:157).
 

The evidence behind angiotensin II

Angiotensin II (AT II) is a naturally occurring hormone in the renin-angiotensin-aldosterone (RAA) system that modulates blood pressure through direct arterial vasoconstriction and direct stimulation of the kidneys and adrenal cortex to release vasopressin and aldosterone, respectively.

Positive results from the recent phase 3 trial for AT II have offered hope that this agent would add the needed balance to the current scarcity of vasopressor options (Khanna, et al. N Engl J Med. 2017;377[5]:419). AT II would provide the missing piece in the jigsaw that would allow the intensivist to manage refractory hypotension, while keeping a multimodal vasopressor dosing regimen within therapeutic limits.

Irvine Page and coworkers are credited with most of the initial work on AT II, which they did nearly 70 years ago. Anecdotal use in humans has been reported since the early 1960s (Del Greco, et al. JAMA 1961;178:994). After a prolonged period of quiescence, the Angiotensin II in High-Output Shock (ATHOS) pilot study, which was done in 2014 as a single-center “proof of concept” study of 20 patients, reinvigorated clinical enthusiasm for this agent (Chawla, et al. Crit Care. 2014;18[5]:534). ATHOS demonstrated the effectiveness of AT II at decreasing norepinephrine (NE) requirements of patients in vasodilatory shock (mean NE dose in AT II group 7.4 ug/min vs 27.6 ug/min in placebo, P=.06). These promising results were followed by ATHOS-3, a phase 3, double-blind, multicenter randomized controlled trial of stable human synthetic AT II. This trial was conducted under a special protocol assessment agreement with the US Food and Drug Administration (FDA). A total of 344 patients with predefined criteria for vasodilatory shock were randomized to AT II or placebo as the intention-to-treat population. The primary end-point was a response in MAP by hour 3 of AT II initiation; response was defined as either a MAP rise to 75 mm Hg or an increase in MAP ≥ 10 mm Hg. The primary end-point was reached more frequently in the AT II group than in the placebo group (69.9% AT II vs 23.4% placebo, OR 7.95, 95% CI 4.76-13.3, P<.001). The AT II group had significantly lower cardiovascular sequential organ failure assessment (SOFA) scores at 48 hours and achieved a consistent decrease in background vasopressor doses. Post-hoc data analysis found that the highest benefit was in patients who were AT II deficient (high ratio of AT I:AT II) (Wunderink, et al. Intensive Care Med Exp. 2017;5(Suppl 2):44). The patients who were AT II depleted and received placebo had a higher hazard ratio of death (HR 1.77, 95% CI 1.10-2.85, P=.019), while those who were AT II depleted and received AT II had a decreased risk of mortality (HR 0.64, 95% CI 0.41-1.00, P=.047). The data suggest not only that AT II levels may be predictive of mortality in vasodilatory shock but also that exogenous AT II administration may favorably modulate mortality in this population. Further, a subset data analysis of severely ill patients (APACHE II scores > 30) showed that those who received AT II and standard vasopressors had a significantly lower 28-day mortality compared with patients who only received standard vasopressors (Szerlip, et al. Crit Care Med. 2018;46[1]:3). Considering that the endothelial cells in the lungs and kidneys are locations where AT I is hydrolyzed by angiotensin-converting enzyme (ACE) into AT II, patients receiving ACE-inhibitors and individuals with pulmonary or renal disease are at greatest risk for AT II deficiency. As such, the use of AT II in the extra-corporeal membrane oxygenation (ECMO), post cardiopulmonary bypass, acute respiratory distress syndrome (ARDS), and renal failure populations are of future interest.

 

Is there a downside?

Appropriate caution is necessary when interpreting these outcomes. One criticism that ATHOS-3 received was the use of a MAP goal of 75 mm Hg, a higher value than currently recommended by clinical guidelines, in the first 3 hours of AT II administration. Because this was a phase 3 trial, both the safety and efficacy of the drug were examined. These goals are difficult to accomplish if simultaneously manipulating other variables. Therefore, to isolate the effects of drug efficacy and safety, a higher MAP goal (75 mm Hg) was established to minimize any effect from varying background vasopressor doses during the first 3 hours of the study.

 

Furthermore, ATHOS-3 did find an increase in venous and arterial thromboembolic events in patients who received AT II (13% AT II vs 5% placebo). Previously, a systematic review of over 30,000 patients did not report this increased thromboembolic risk (Busse, et al. Crit Care. 2017;21[1]:324). According to the package insert, all patients receiving AT II should receive appropriate thromboembolic prophylaxis if medically indicated.
 

Where does AT II fit in our algorithm for resuscitation and the vasopressor toolbox?

Data from Wunderink et al indicate a potential mortality benefit in populations who are AT II depleted. However, we can only infer who these patients may be, as no commonly available assay can measure AT I and AT II levels. ATHOS and ATHOS-3 used AT II late during resuscitation, as did the Expanded Access Program (EAP) of the FDA, which gave physicians preliminary access to AT II while it was undergoing FDA review. Using similar inclusion criteria as ATHOS-3, the EAP did not permit patients to receive AT II until doses greater than or equal to 0.2 ug/kg/min of NE-equivalents were reached. In a recently published case report, AT II was successfully used in a patient with septic shock secondary to a colonic perforation (Chow, et al. Accepted for e-publication: A&A Practice. April 2018.). This individual was in vasodilatory shock despite standard resuscitation, 0.48 ug/kg/min of NE, and 0.04 units/min of vasopressin. Methylene blue and hydroxocobalamin had failed to relieve the vasoplegia, and only after the initiation of AT II at 40 ng/kg/min, the patient could be relieved of vasopressors and survived to be discharged from the hospital. In our opinion, best clinical practices would allow for an early multimodal vasopressor regimen that should include AT II at the earliest sign of rapid clinical decline (Jentzer, et al. Chest. 2018. Jan 9. pii: S0012-3692(18)30072-2. doi: 10.1016/j.chest.2017.12.021. [Epub ahead of print]).

Angiotensin II was recently approved by the FDA in December 2017 and is now available on the market for management of vasodilatory shock. This will undoubtedly have a profound impact on the way clinicians treat vasodilatory shock. Previously, we were confined to agents such methylene blue and hydroxocobalamin to rescue patients from profound vasoplegia. However, none of these agents are supported by robust evidence from randomized control trials.

Now, we can openly welcome a new challenger to the campaign, a new hue to the palette of vasopressor colors. This new class of vasopressor makes complete physiological sense and will provide an invaluable tool in our daily battle against sepsis and vasodilatory shock.

Dr. Chow is Assistant Professor, Division of Critical Care Medicine, Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, MD; Dr. Khana is Assistant Professor of Anesthesiology, Staff Intensivist, Vice-Chief for Research, Center for Critical Care, Department of Outcomes Research & General Anesthesiology, Anesthesiology Institute, Cleveland Clinic, Cleveland, OH

Editor’s note

For decades, our options to treat patients with profound vasoplegia have been limited to high-dose catecholamines and vasopressin. Clinicians are often faced with the need to initiate multiple catecholamine agents knowing that these drugs stimulate similar receptors. The recent ATHOS-3 trial introduces AT II as a new option for the management of patients with refractory vasodilatory shock. This drug has a distinct mechanism of action that complements the effect of other vasopressors. Moreover, recent data suggest that this new agent is most beneficial in patients who are AT II deficient. Just like cancer therapies have evolved to precision medicine, will we perhaps face the need to better understand and promptly identify patients with AT II deficiency? For now, we have a new player on our vasopressor team.

Angel Coz, MD, FCCP
Section Editor