More Than Surviving Sepsis: Everything Old Is New Again

Because of numerous failed attempts at novel or targeted therapies in sepsis over the past 20 years, investigators have been compelled to step back in time and repurpose old agents, including angiotensin II and ascorbic acid, for the treatment of sepsis and septic shock. Both medications have historically shown promise in animal shock models. However, it was not until the publication of recent clinical investigations in humans that investigators’ interest piqued regarding their use in refractory vasodilatory shock.

ANGIOTENSIN II

Management of distributive shock focuses on early and adequate fluid resuscitation, timely antibiotic administration, and initiation of catecholamine (eg, norepinephrine, epinephrine) and/or noncatecholamine (eg, vasopressin) vasopressor therapy.¹ Given the potential for dose-dependent adverse effects (AEs) from catecholamine-based vasopressor therapy (eg, tachycardia), noncatecholamine therapy has potential clinical benefits.

One promising therapeutic strategy involves using the renin-angiotensin-aldosterone system (RAAS) to generate noncatecholamine vasopressor effects. Angiotensin II binds a number of G-protein coupled receptors, including angiotensin II receptor type 1 (AGTR1), which notably results in vasoconstriction, aldosterone secretion, sodium and water retention, and vasopressin release.²

In 1962, Derrick and colleagues described the use of angiotensin II in 10 patients with shock who were unresponsive to standard catecholamine therapy. The authors commented that angiotensin II consistently increased blood pressure and reduced heart rate with no apparent AEs.³ Despite use in early clinical studies, synthetic human angiotensin II only gained US Food and Drug Administration approval in December 2017 after more robust clinical evaluation.

The Angiotensin II for the Treatment of High-Output Shock (ATHOS-3) trial randomized 344 patients with persistent vasodilatory shock despite at least 25 mL/kg fluid resuscitation in 24 hours and high-dose vasopressor therapy (>0.2 mcg/kg/min of norepinephrine equivalent) for >6 hours to receive titratable angiotensin II vs placebo in addition to background vasopressor therapy. Importantly, patients were excluded if they did not have adequate cardiac function (cardiac index of >2.3 L/min/m2 or central venous oxygen saturation >70% with central venous pressure >8 mm Hg), had active bleeding, or were receiving high-dose glucocorticoid therapy.⁴

Patients included in the ATHOS-3 trial had a high risk of death, as demonstrated by a baseline median acute physiology and chronic health evaluation II score of 28. Significantly more patients in the angiotensin II group (69.9%) achieved the primary end point of mean arterial pressure (MAP) >75 mm Hg or MAP increase of >10 mm Hg from baseline at hour 3 compared with placebo (23.4%; OR, 7.95; 95% CI, 4.76-13.3; P <.001).4 A post hoc analysis demonstrated a significant increase in 28-day survival with angiotensin II (53.2%) versus placebo (29.6%; HR, 0.515; 95% CI, 0.304-0.817; P = .0118).⁵

Based on the findings from this study, the clinician might be eager to incorporate angiotensin II in the treatment of refractory vasodilatory shock. However, important safety issues must be considered. A total of 12.9% of patients receiving angiotensin II experienced an arterial or venous thromboembolic (VTE) event compared with 5.1% in placebo.⁶ Angiotensin II may cause development of thrombotic events through activation of AGTR1, which induces expression of plasminogen activator inhibitor-1 and causes platelet aggregation.² Therefore, patients using angiotensin II should receive concomitant VTE prophylaxis. If there is a contraindication to prophylaxis, the risk—benefit ratio must be considered before initiating therapy with angiotensin II.

Additionally, patients with reduced cardiac output were excluded from the ATHOS-3 study because of concern that pure vasoconstrictor therapy may result in a reflexive bradycardia, thereby worsening cardiac output and potentially increasing mortality.⁷ In general, routine use of invasive cardiac monitoring has declined because of changes in clinical practice. However, patients with vasodilatory shock may progress to low-output states, and the subsequent impact of angiotensin II is unknown. Therefore, invasive cardiac monitoring may be considered in these patients.⁷

Current clinical practice guidelines recommend the addition of vasopressin or epinephrine to first-line vasopressor therapy with norepinephrine.¹ Angiotensin II costs approximately 6 times more than vasopressin per day when given at standard doses for septic shock.² The significant increase in cost must be considered when deciding to use this agent for refractory vasodilatory shock.

Given these concerns, angiotensin II is likely a third-line vasopressor for the treatment of vasodilatory shock at this time. As more real-world, clinical experience is gained with this agent, it may prove to have a niche in shock states with retained cardiac output.

ASCORBIC ACID (VITAMIN C)

In addition to its role in a number of other biochemical interactions, ascorbic acid (vitamin C) serves as a cofactor for the enzymes peptidylglycine β-amidating monooxygenase and dopamine β-hydroxylase, which are responsible for production of vasopressin and norepinephrine in the adrenal gland.⁸ Although vitamin C is endogenously synthesized in most mammals, humans require adequate dietary consumption. Vitamin C deficiency is well described in patients with sepsis and may account for reduced production of these endogenous catecholamines.⁹

Vitamin C deficiency has been shown to play an important role in animal models of sepsis. In 1971, vitamin C—deficient guinea pigs demonstrated a higher mortality compared with a replete cohort in an endotoxin shock model.^10,11 L-gulono-γ-lactone oxidase (GULO) is a pivotal enzyme in the biosynthesis of vitamin C in mice. In a cecal ligation and puncture murine sepsis model, GULO-knockout mice had a reduced survival fraction compared with wild-type mice, but survival was improved in the GULO-knockout cohort that received vitamin C.¹²

Despite these findings, there have been discordant outcomes in human clinical trials of vitamin C. Until recently, few single-center studies demonstrated reductions in sepsis and inflammatory biomarkers, Sequential Organ Failure Assessment (SOFA) scores, and mortality with administration of vitamin C in patients with sepsis.8 In a prospective study of 24 patients with septic shock randomized to vitamin C 50 mg/kg intravenous (IV) daily, 200 mg/kg IV daily, or placebo daily for 4 days, patients receiving either dose of vitamin C had reductions in SOFA scores, C-reactive protein, and procalcitonin.¹³ Another study of 28 patients with septic shock randomized to vitamin C 25 mg/kg IV every 6 hours for 72 hours had significant reductions in dose and duration of vasopressor therapy and 28-day mortality compared with placebo.¹⁴ These results laid the groundwork for future investigations.

Marik and colleagues enrolled 94 patients with severe sepsis or septic shock into a before-and-after study of usual care compared with usual care plus the combination of vitamin C 1.5 g IV every 6 hours (4 days), thiamine 200 mg every 12 hours (4 days), and hydrocortisone 50 mg every 6 hours (7 days, followed by a 3-day taper). A significant reduction in mortality was seen in the control (40.4%) versus intervention (8.5%) groups (P <.001), as well as duration of vasopressor therapy, SOFA scores, need for renal replacement therapy, and increased procalcitonin clearance. Although there were notable limitations, including the observational study design and use of combination therapy with hydrocortisone, a drug known to improve outcomes in septic shock, nearly 60% of patients in the control group also received hydrocortisone, signaling that the intervention effects were not attributable entirely to corticosteroid administration. Because cortisol levels were not reported, it is unknown whether patients had adrenal insufficiency at baseline.¹⁵

Although no safety issues have been identified with high-dose vitamin C to date, questions regarding its place in therapy remain.¹⁵ As of April 10, 2019, there were 28 clinical trials listed on ClinicalTrials.gov for ascorbic acid/vitamin C in sepsis or toxemia.¹⁶ Select ongoing studies are described in the Table.¹⁶ A number of studies will evaluate vitamin C monotherapy, as well as the combination with thiamine and hydrocortisone in severe sepsis and septic shock. A pharmacokinetic evaluation may provide insight on the optimal dosing. The Vitamin C, Thiamine, and Steroids in Sepsis (VICTAS) study is projected to be the most robust evaluation of vitamin C in sepsis treatment, with its randomized, double-blind study design and planned enrollment of 2000 participants.¹⁶ These future studies may elucidate the role of vitamin C as part of the treatment of sepsis and septic shock.

In conclusion, recent clinical data for the use of angiotensin II and vitamin C in patients with septic shock generate optimism for improving clinical outcomes. As we begin to dust off these old therapies, clinicians must realize that future clinical experience and investigations will likely better define their roles in the treatment of septic shock.

Igneri is the critical care clinical pharmacy specialist at Cooper University Health Care in Camden, New Jersey. She earned her PharmD at Rutgers University in Piscataway, New Jersey, and went on to complete her PGY-1 at Temple University Hospital in Philadelphia, Pennsylvania, and PGY- 2 critical care specialty residency at Philadelphia College of Pharmacy at University of the Sciences and Cooper University Hospital.

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