Reversal of Vasodilatory Shock: Current Perspectives on Conventional, Rescue, and Emerging Vasoactive Agents for the Treatment of Shock

Jonathan H. Chow, MD; Ezeldeen Abuelkasem, MBBCh, MSc; Susan Sankova, MD; Reney A. Henderson, MD; Michael A. Mazzeffi, MD, MPH; Kenichi A. Tanaka, MD, MSc


Anesth Analg. 2019;130(1):15-30. 

In This Article

Emerging Agents to Treat Vasodilatory Shock

Ascorbic Acid

Ascorbic acid, also referred to as vitamin C, is an emerging therapeutic option for the treatment of septic shock. Like thiamine, ascorbic acid is an essential cofactor in biochemical pathways and is involved in 2 reactions essential for the synthesis of catecholamines.[100] Patients with critical illness have been found to have decreased plasma ascorbic acid levels by up to 70%, which can lead to impaired catecholamine synthesis.[101,102] This forms the rationale for the use of ascorbic acid supplementation in vasodilatory shock.

Pharmacology. Synthesis of NE and Epi is a stepwise process that involves the conversion of L-tyrosine to levodopa (L-DOPA) by tyrosine hydroxylase.[100] O2 and tetrahydrobiopterin are required for this reaction to occur, and ascorbic acid is an essential cofactor in the generation of these 2 molecules. After L-DOPA is generated, it is converted to dopamine, which is then converted to NE by dopamine β-hydroxylase. This reaction again requires O2 and ascorbic acid for the synthesis of NE and Epi to occur.[100] In addition to being an essential cofactor, ascorbic acid also scavenges free radicals, downregulates proinflammatory mediators, and enhances vasopressor receptor sensitivity.[103–105]

Clinical Studies. A phase I RCT of patients with severe sepsis found that high-dose ascorbic acid was safe and significantly increased the rate of SOFA score improvement (slope of regression −0.044 ascorbic acid versus 0.003 placebo, P < .01), while also significantly reducing the plasma concentrations of the proinflammatory markers C-reactive protein and procalcitonin.[102] Another small RCT of septic shock patients found that ascorbic acid decreased the mean dose (7.4 vs 13.8 μg/min, P = .004) and duration of NE (49.6 vs 71.6 hours, P = .007), while also improving 28-day mortality (14.3% vs 62.3%, P = .009) when compared to placebo.[106] The largest study to date was a retrospective before–after, propensity-matched study of 94 consecutive patients in septic shock.[100] Marik et al[100] built on the previous reported benefits of corticosteroids and thiamine and intervened by creating a protocol that consisted of a combination of ascorbic acid (1.5 g every 6 hours for 4 days), hydrocortisone (50 mg every 6 hours for 7 days), and thiamine (200 mg every 12 hours for 4 days). They reported a significant improvement in 72-hour SOFA score (−4.8 treatment versus −0.9 control, P < .001), duration of vasopressor use (18.3 vs 54.9 hours, P < .001), procalcitonin clearance (86.4% vs 33.9%, P < .001), need for RRT (10% vs 33%, P = .02), and hospital mortality (8.5% vs 40.4%, P < .001).[100]

The retrospective, single-center nature of the study, the use of nonconcurrent controls in the before–after design, and the potential selection bias in the intervention arm all limit the generalizability of the results.[100] However, Marik et al's[100] study set the stage for a large North American RCT, the vitamin C, thiamine, and steroids in sepsis (VICTAS) Trial, which is currently ongoing.[107] This multicenter, double-blind, placebo-controlled RCT will provide the evidence that we need to critically evaluate ascorbic acid's role in the treatment of vasodilatory shock.

Angiotensin II

Ang-2 is considered to be a novel treatment for vasodilatory shock, but it has been described as early as the 1930s, and its use has been reported in patients with circulatory shock, distributive shock, and angiotensin-converting enzyme inhibitor (ACE-I) overdose.[108–110] Its Food and Drug Administration (FDA) approval in 2018 has reinvigorated interest in the drug, particularly because it utilizes a pathway distinct from traditional vasoconstrictive agents.[111]

Pharmacology. Ang-2 is a naturally occurring hormone in the renin–angiotensin–aldosterone (RAA) system. Angiotensinogen is produced by the liver and is converted to angiotensin I (Ang-1) after stimulation by renin during conditions of low renal perfusion pressure (Figure 4). Ang-2 is then derived from the hydrolysis of Ang-1 via ACE in the lung and renal endothelium. Ang-2 has a short half-life of only 30 s and directly interacts with other catecholamines and vasopressin.[112–114] It exerts its action on AT1 and angiotensin-type 2 (AT2) receptors.[115] The majority of Ang-2 action is through activation of AT1 receptors on smooth muscle cell membrane (Figure 1). It causes smooth muscle contraction and stimulates release of antidiuretic hormone (ADH) and aldosterone in the adrenal cortex, which increases reabsorption of water.[108]

Figure 4.

Renin–angiotensin–aldosterone system. Renin stimulates the conversion of angiotensinogen to Ang-1 during conditions of low renal perfusion. Via ACE, Ang-1 is converted to Ang-2 primarily in the pulmonary endothelium. Ang-2 then acts on AT1 receptors on smooth muscle cells to cause vasoconstriction. ACE-I inhibits the action of ACE, while ARBs inhibit the binding of Ang-2 to AT1. ACE indicates angiotensin-converting enzyme; ACE-I, ACE inhibitors; Ang-1, angiotensin I; Ang-2, angiotensin II; ARB, angiotensin receptor blocker; AT1, angiotensin-type 1 receptor.

Clinical Data. In 1961, Del Greco and Johnson[116] examined Ang-2 use in 21 patients with shock. This case series reported a return to normotension in 15 of 21 patients without any adverse side effects from its administration. The Angiotensin II for the Treatment of High-Output Shock (ATHOS) trial was the first modern-day clinical trial of Ang-2 and found that it was efficacious as a vasopressor and a catecholamine-sparing agent (Table 2).[112]

In the phase III follow-up RCT, ATHOS-3, 344 patients in vasodilatory shock were randomly assigned to either standard vasopressors (eg, NE, vasopressin, Epi, phenylephrine) plus placebo or standard vasopressors plus Ang-2.[117] Those in the Ang-2 group achieved the target MAP at a significantly higher rate than those in the control group (69.9% Ang-2 versus 23.4% control; OR = 7.95; 95% CI, 4.76–13.3; P < .001; Table 2). Furthermore, those patients randomly assigned to Ang-2 had a greater change in background NE-equivalent dose than those receiving placebo plus standard vasopressors (−0.03 ng kg−1 min−1 Ang-2 versus 0.03 control, P < .001). The study was not powered to detect a mortality benefit, and no association was found in improving all-cause mortality at 28 days (46% mortality Ang-2 versus 54% control; HR = 0.78; 95% CI, 0.57–1.07; P = .12).

There have been several prespecified post hoc analyses of the ATHOS-3 data.[118–120] The first found that critically ill patients with APACHE II scores over 30 who received Ang-2 had significantly improved 28-day mortality compared to patients receiving standard vasopressors alone (51.8% Ang-2 versus 70.8% control; HR = 0.62; 95% CI, 0.39–0.98; P = .037; Table 2).[119] The second found that the subset of patients with AKI requiring RRT not only had improved survival with Ang-2 (53% Ang-2 versus 30% control; HR = 0.52; 95% CI, 0.30–0.87; P = .012) but also had improved rates of liberation from RRT by day 7 (38% Ang-2 versus 15% control; adjusted HR = 2.90; 95% CI, 1.29–6.52; P = .007).[120] These findings are clinically important because, with the exception of NE over dopamine, no single vasopressor has been found to have mortality benefit over another in septic shock.[9,11,26,121]

Finally, patients who were Ang-2 deficient, as measured by higher Ang-1:Ang-2 ratios, were found to have higher mortality than those who were not (Table 2).[118] This higher ratio of Ang-1:Ang-2 suggests an ACE deficiency as the cause of Ang-2 depletion. Those with high ratios and randomly assigned to standard vasopressors also had higher mortality than those randomly assigned to the Ang-2 arm. Administration of Ang-2 appeared to modulate this outcome, because there was a significant treatment effect of Ang-2 on mortality among Ang-2–deficient patients. These data indicate that Ang-1:Ang-2 ratios are not only predictive of mortality, but also that Ang-2 supplementation is capable of decreasing mortality during states of Ang-2 deficiency. ACE, the enzyme that hydrolyzes Ang-1 to Ang-2, is predominantly found in pulmonary vascular endothelial cells (Figure 4).[118] Patients with pulmonary pathology, such as those with influenza, multilobar pneumonia, acute respiratory distress syndrome (ARDS), or those with mechanical bypass of ACE in the pulmonary circulation, as in the case with veno-veno extracorporeal membrane oxygenation (VV-ECMO), may suffer the most from ACE dysfunction and Ang-2 depletion. Whether they may also benefit from Ang-2 administration remains to be seen.

Use of Ang-2 as an early third-line vasopressor, as was done in the ATHOS-3 trial, is intuitive, because α1 receptors are desensitized and internalized with repetitive exposure to NE, Epi, and phenylephrine.[14] This tachyphylaxis is well established at the toxic doses of vasopressors that are commonly used in distributive shock, and a multimodal form of therapy targeting several different receptors may be the most beneficial method to maintain MAP in vasodilatory shock.