By Samuel Nadler, MD, PhD
Clinical Instructor, University of Washington, Seattle
Shock is a common cause for intensive care unit admission, necessitating rapid treatment of the underlying cause while supporting patients with fluids and vasopressor agents. Typical vasopressor agents include adrenergic agonists and vasopressin. When shock persists despite these interventions, this is labeled refractory shock. While no universal definition exists, most proposed criteria include the failure to reverse hypotension despite high vasopressor administration with ≥ 0.2 mcg/kg/min to 0.5 mcg/kg/min norepinephrine equivalents.1 (See Table 1.) More specifically, refractory vasodilatory shock as seen in sepsis occurs with relatively preserved or elevated cardiac output but inadequate vascular tone to maintain a mean arterial blood pressure (MAP) ≥ 65 mmHg. In these situations, therapy for refractory vasodilatory shock should be considered and options can include angiotensin II, methylene blue, and hydroxocobalamin, among others. (See Table 2.)
Table 1. Vasopressor Dose Equivalency |
Drug |
Dose |
Norepinephrine Equivalent |
Norepinephrine |
0.1 mcg/kg/min |
0.1 mcg/kg/min |
Epinephrine |
0.1 mcg/kg/min |
0.1 mcg/kg/min |
Phenylephrine |
1 mcg/kg/min |
0.1 mcg/kg/min |
Dopamine |
15 mcg/kg/min |
0.1 mcg/kg/min |
Vasopressin |
0.04 U/min |
0.1 mcg/kg/min |
Reprinted from Chest, volume 154, Jentzer JC, Vallabhajosyula S, Khanna AK, et al, Management of refractory vasodilatory shock, pages 416-426, Copyright 2018, with permission from Elsevier. |
Table 2. Summary of Therapies for Refractory Distributive Shock |
Drug |
Dosing |
Mechanism of Action |
Notes |
Angiotensin II |
20-40 ng/kg/min |
Activates ATII receptor |
ATHOS trials |
Methylene Blue |
1-2 mg/kg bolus or
0.25-1 mg/kg/hr |
Inhibits sGC and inhibits NOS |
Watch for serotonin syndrome, hypoxia |
Hydroxocobalamin |
5 g bolus |
NO scavenger |
Interferes with HD sensors |
Hydrocortisone |
50 mg IV q6 hours or
100 mg IV q8 hours |
Improves response to adrenergic agents |
Increase in blood glucose and infection |
Sodium Bicarbonate |
1-2 mEq/kg |
Improves pH for vasopressor function |
Hypernatremia and hypocalcemia |
IV: intravenous; sGC: soluble guanylyl cyclase; NOS: nitric oxide synthetase; NO: nitric oxide; HD: hemodialysis |
Angiotensin II
Angiotensin II (ATII) is a synthetic analog of the human hormone that binds ATII receptors, leading to vasoconstriction via G-protein coupled mechanism.1 It works in parallel with catecholamines to increase blood pressure. Furthermore, patients with sepsis may have a relative deficit in angiotensin-converting enzyme activity and ATII levels. The half-life of ATII in the circulation is only 30 seconds, but its tissue effects may last up to 30 minutes.2 The benefits of ATII infusion also might normalize physiologic responses to shock by increasing endogenous secretion of catecholamines and vasopressin and potentiating the renin-angiotensin-aldosterone system.
The efficacy of ATII was demonstrated in the ATHOS-3 trial.3 This study randomized 344 patients requiring more than 0.2 mcg/kg/min of norepinephrine or an equivalent dose of another vasopressor to placebo or an infusion of ATII. The primary outcome was an increase in the MAP by 10 mmHg from enrollment or an increase to MAP > 75 mmHg. With ATII infusion, more patients achieved this outcome compared with placebo (66.9% vs. 23.4%; odds ratio, 7.95; P < 0.001). There also were positive secondary outcomes, including lower Sequential Organ Failure Assessment (SOFA) score at 48 hours and decreased need for other vasopressor agents within three hours of infusion. While not statistically significant, there was a trend toward decreased mortality at 28 days (46% vs. 54%, P = 0.12). The most concerning adverse event was an increase in the incidence of venous thromboembolism. A subsequent post-marketing study showed that among the 67% of patients who responded to ATII, there was lower 30-day mortality (41% vs. 25%, P = 0.001).4 This study did not show an increased rate of thrombotic events. With this evidence, ATII was approved for use in the United States by the Food and Drug Administration (FDA) in 2018 for the treatment of distributive shock.
Methylene Blue
Methylene blue (MB) has been used in the prevention and treatment of vasoplegic syndromes during cardiovascular surgery for many years.5 More recently, MB has been evaluated for the treatment of septic and distributive shock.6-8 MB binds to the heme moiety on soluble guanylyl cyclase (sGC) and inhibits the formation of cyclic guanosine monophosphate (cGMP).7 By decreasing cGMP in vascular smooth muscle, vasomotor tone is increased. MB also may serve to inhibit inducible nitric oxide synthetases (iNOs) and scavenge nitric oxide (NO), preventing their vasodilatory effects. The onset of action after an intravenous (IV) dose is within 30-60 minutes, and studies have used doses of 0.25 mg/kg to 2 mg/kg as one-time dosing or continuous infusions. The most common adverse effects are discoloration of tissues and urine, flushing, dizziness, and nausea. It also may precipitate serotonin syndrome, worsen pulmonary hypertension and oxygenation by impairing hypoxemic pulmonary vasoconstriction, and contribute to the development of mesenteric ischemia.
Studies evaluating the efficacy of MB for shock have been summarized previously.7 These studies generally are small observational studies and case reports, although two prospective randomized controlled trials in sepsis have been conducted. Memis et al demonstrated in 30 patients an increased MAP with MB infusion of 0.5 mg/kg/hr for six hours with no change in inflammatory cytokine levels or overall outcomes.9 In a similarly small study, Kirov et al showed MB infusion in patients with septic shock decreased vasopressor need and improved cardiac function without differences in clinical outcomes.10 Both studies included patients already on adrenergic vasopressor agents. Although none of these studies showed an overall effect on mortality, one trial did show a mortality benefit in those patients who responded to MB infusion.8 Thus, in select patients with refractory shock, MB can improve hemodynamics and may improve overall outcomes.
Hydroxocobalamin
Hydroxocobalamin is a precursor to vitamin B12 and is used to treat cyanide toxicity. During these trials, transient hypertension was noted with treatment.11 Hydroxocobalamin acts to scavenge NO and might reverse NO-mediated vasodilation in sepsis. It previously has been shown to improve vasoplegia in cardiac surgery and liver transplantation.12 In vasodilatory shock, results are mixed. Case reports suggest a 5 g infusion of hydroxocobalamin can rescue patients with distributive shock from sepsis.13 Other case series failed to demonstrate significant hemodynamic effects.14 A systematic review comparing hydroxocobalamin and MB found similar effects between the two.15 Hydroxocobalamin increased MAP at one hour greater than MB without a significant difference in mortality. Sacco et al conducted a retrospective analysis of 26 patients with refractory shock treated with hydroxocobalamin and showed significant increases in MAP and decreased norepinephrine need at six and 24 hours.16 Unlike MB, there were no concerns for serotonin syndrome, but there were concerns of increased cost and interference with detectors used in dialysis machines preventing proper function. A randomized trial of hydroxocobalamin specifically for sepsis is ongoing (NCT03783091).
Other Agents
Many other rescue therapies for refractory vasodilatory shock have been evaluated.1 Steroid therapy with hydrocortisone is suggested in the most recent Surviving Sepsis Guidelines as a weak recommendation with moderate quality of evidence.17 Correction of acidosis either with bicarbonate therapy or renal replacement may improve vasopressor efficacy. NO regulators other than MB and hydroxocobalamin have been shown to increase vascular tone and blood pressure but were associated with increased mortality.1 Calcium replacement may improve intracellular vascular signaling. Adjunct therapies with ascorbate and thiamine continue to be evaluated.
Summary
Refractory vasoplegic shock is encountered in patients with severe sepsis and is challenging to treat. Like refractory hypoxemia in acute respiratory distress syndrome (ARDS), rescue therapies exist, although the evidence behind these interventions varies widely. With the ATHOS-3 trial, ATII shows promise in improving blood pressure, decreasing the need for adrenergic vasopressors, and may improve mortality. MB may increase vascular tone in selected patients, and those patients who do respond seem to have improved outcomes. Hydroxocobalamin commonly is used to treat intraoperative vasoplegia and also may have a role in refractory shock with sepsis. The foundation of treatment for distributive shock from sepsis remains appropriate source control, early antibiotics, and judicious fluid administration in addition to pressor support, usually with norepinephrine and vasopressin. When these interventions fail to correct shock, use of adjunct therapies is increasingly available to improve patient outcomes.
REFERENCES
- Jentzer JC, Vallabhajosyula S, Khanna AK, et al. Management of refractory vasodilatory shock. Chest 2018;154:416-426.
- Chawla LS, Busse L, Brasha-Mitchell E, et al. Intravenous angiotensin II for the treatment of high-output shock (ATHOS trial): A pilot study. Crit Care 2014;18:534.
- Khanna A, English SW, Wang XS; ATHOS-3 Investigators. Angiotensin II for the treatment of vasodilatory shock. N Engl J Med 2017;377:419-430.
- Wieruszewski PM, Wittwer ED, Kashani KB, et al. Angiotensin II infusion for shock: A multicenter study of postmarketing use. Chest 2021;159:596-605.
- Ozal E, Kuralay E, Yildirim V, et al. Preoperative methylene blue administration in patients at high risk for vasoplegic syndrome during cardiac surgery. Ann Thorac Surg 2005;79:1615-1619.
- Porizka M, Kopecky P, Dvorakova H, et al. Methylene blue administration in patients with refractory distributive shock — a retrospective study. Sci Rep 2020;10:1828.
- Puntillo F, Giglio M, Pasqualucci A, et al. Vasopressor-sparing action of methylene blue in severe sepsis and shock: A narrative review. Adv Ther 2020;37:3692-3702.
- Naoum EE, Dalia AA, Roberts RJ, et al. Methylene blue for vasodilatory shock in the intensive care unit: A retrospective, observational study. BMC Anestheisology 2022;22:1999.
- Memis D, Karamanlioglu B, Yuksel M, et al. The influence of methylene blue infusion on cytokine levels during severe sepsis. Anaesth Intensive Care 2002;30:755-762.
- Kirov MY, Evgenov OV, Evgenov NV, et al. Infusion of methylene blue in human septic shock: A pilot, randomized, controlled trial. Crit Care Med 2001;29:1860-1867.
- Uhl W, Nolting A, Golor G, et al. Safety of hydroxocobalamin in healthy volunteers in a randomized, placebo-controlled study. Clin Toxicol 2006;44(Suppl 1):17-28.
- Roderique JD, VanDyck K, Holman B, et al. The use of high-dose hydroxocobalamin for vasoplegic syndrome. Ann Thoracic Surg 2014;97:1785-1786.
- Lin Y, Vu TQ. Use of high-dose hydroxocobalamin for septic shock: A case report. A A Pract 2019;12:332-335.
- Ritter LA, Maldarelli M, McCurdy MT, et al. Effects of a single bolus of hydroxocobalamin on hemodynamics in vasodilatory shock. J Crit Care 2022;67:66-71.
- Brokmeier HM, Seelhammer TG, Nei SD, et al. Hydroxocobalamin for vasodilatory hypotension in shock: A systematic review with meta-analysis for comparison to methylene blue. J Cardiothorac Vasc Anesth 2023;37:1757-1772.
- Sacco AJ, Cunningham CA, Kosiorek HE, Sen A. Hydroxocobalamin in refractory septic shock: A retrospective case series. Crit Care Explor 2021;3:1-7.
- Evans L, Rhodes A, Alhazzani W, et al. Surviving sepsis campaign: International guidelines for management of sepsis and septic shock 2021. Intensive Care Med 2021;47:1181-1247.
