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The Myth of Vasopressors and Ischemia

2018-06-11T08:02:01+00:00

Despite the widespread clinical use, and their well-documented life-saving properties, vasopressors are often maligned, accused of causing ischemia to fingers, toes, mesentery, kidneys, and so forth. Not only is the evidence that this happens poor, but, a fear of this dreaded complication can unwarrantedly lead good clinicians to limit or withhold potentially life- and organ-saving medications. This article showcases the importance of end-organ perfusion and explains how vasopressors may in fact be one of the most important therapies in an emergency physician’s armamentarium.

The Myth of Vasopressor Induced End-Organ Ischemia

“Vasopressors work by vasoconstriction, and therefore, they may cause decreased perfusion to key organs, such as bowel, or not-so-key organs, such as the digits.”

The rationale behind this claim is understandable, given the vasoconstriction properties of alpha-agonists and vasopressin receptor agonists. There are many case reports of variable quality out there to support this claim.1–3

But, here’s the thing about vasopressors . . . if you need them, you are already not doing well. Yes, some patients in shock, on vasopressors, develop mesenteric ischemia. But how do we know that the ischemia is due to the vasopressors, and not due to the underlying cause of shock? How do we know that it isn’t due to the preceding hypotension that occurred before fluids and vasopressors were administered?

There may be some circumstances associated with developing ischemia directly from vasopressors, but as it stands, we do not really know what those circumstances are. The best available data would indicate they are far rarer than commonly claimed.4–7

Historical Data: High-Dose Vasopressin and Cirrhosis

There is a historical precedent for ischemic concerns with vasopressors use. In decades past, vasopressin in particular was used in high doses (18-20 units/hour!) to reduce portal pressures in patients with cirrhosis. Numerous case reports describe the development of mesenteric ischemia in these patients.8,9 But there are some key differences in these scenarios in addition to the modern use of vasopressors, such as vasopressin.

  1. These cirrhotic patients were not necessarily in shock. Our current use of vasopressors instead is to counterbalance the vasodilation that occurs with distributive shock.
  2. These patients had the severe comorbidity of cirrhosis, which places them already at baseline high-risk category.
  3. The doses of vasopressin commonly used now are 0.01-0.04 units/minute, or up to 2.4 units/hour. In contrast, the cirrhotic patients were treated with nearly 10 times that dose, at 18-20 units/hour.
  4. In many of these cases, vasopressin was injected directly into the superior mesenteric artery (SMA).9 Therefore, the lessons learned regarding the risks of injecting high-dose vasopressin directly into the SMA of a cirrhotic patient do not necessarily apply to using vasopressors to combat septic shock in a general ED population.

More Recent Data: Mixed Results

Searching for recent or more robust studies of vasopressors leading to mesenteric or digital ischemia is surprisingly futile, given the frequency with which vasopressors are invoked as a cause of ischemia. Much of the more recent data are from animal studies. Apparently, giving pigs sepsis and looking at their gut perfusion was all the rage in the mid-aughts. The data are quite mixed, with some indicating ischemia, and others showing improved perfusion.10,11 Human studies are similarly small and varied. A 2016 study in the cardiac surgery literature even shows improvement in non-occlusive mesenteric ischemia with vasopressin.12

More recently in 2017, there was an outcomes study of patients receiving high-dose norepinephrine (≥1 μg/kg/minute for at least an hour) for refractory shock.6 The mean maximum dose for all patients in that study was about 245 mcg/minute, or 3.28 mcg/minute/kg. Despite these incredibly high doses of vasopressors, only 5.7% had digital ischemia and 2.8% had mesenteric ischemia. If the vasopressors were causative, and followed a dose-response curve, one would expect far higher rates of ischemia than reported. It turns out these rates are comparable to the rates of digital and mesenteric ischemia seen in other studies of vasopressors.4,7

Protect the Kidneys: Don’t Forget About Autoregulation

The myth that vasopressors may lead to mesenteric or digit ischemia is one reason why some providers may delay starting vasopressors in the ED. Another myth, however, is finding comfort in hearing that a patient is “mentating well” despite being hypotensive.

Hypotension is a significant problem in the critically ill – and having a patient who is mentating is not sufficiently reassuring. One of the best renal articles for EM physicians and intensivists beautifully explains how we can protect the kidneys in the ED and help our patients for the long-term.13 The kidneys of our older, hypertensive patients, especially those with vascular disease, need a higher pressure to perfuse. When these patients become hypotensive, they can still mentate (autoregulation will shunt blood to the brain even at late stages of critical illness) but their kidneys can be ischemic. Acute kidney injury (AKI) in these patients is a big deal, and is associated with significantly increased morbidity and mortality. Therefore, avoidance of AKI remains one of the key reasons to avoid hypotension.

Similar to concerns regarding mesenteric ischemia, the myth remains that we need to titrate patients off vasopressors to improve renal perfusion. In one of my favorite studies in all of critical care, the investigators compared high (80-85 mmHg) vs low (65-70 mmHg) mean arterial pressures (MAPs) in septic shock.7 They found that randomizing patients with baseline hypertension to a higher target MAP (resulting in higher doses of vasopressors) also resulted in less renal replacement therapy. In other words, keeping the target MAP at 80-85 mmHg with vasopressors was associated with significantly less kidney injury, directly contradicting the idea that vasopressors cause renal ischemia.

Arm of patient with Klebsiella bacteremia and subsequent purpura fulminans. The maximum dose of vasopressors required during her septic shock was 40 mcg/minute of phenylephrine for approximately 8 hours.

 

Purpura Fulminans: Continue Patients on Vasopressors

One final point. Physicians often confuse purpura fulminans, a distinct coagulation disorder associated with sepsis, with ischemia from vasopressors. Biopsy specimens of purpura fulminans demonstrate microthrombi in the distal tissues, arising from sepsis-related protein C dysfunction.5 This is likely the etiology of the irreversible digit, nose, and ear ischemia seen in some cases of septic shock and not from vasoconstriction. The largest study of purpura fulminans (with only 20 patients in each cohort) showed no differences in vasopressor doses between patients with purpura fulminans and those who did not develop the condition.5 Purpura fulminans thus should be treated with heparin and not by withholding vasopressors. Unfortunately, some case reports to this day invoke vasopressors as the etiology – and patients miss out on receiving the proper treatment.

Take-Home Points

  1. Do not be afraid to give patients vasopressors to meet their hemodynamic goals, based on your best available data.
  2. If you see a patient with digital ischemia or mesenteric ischemia, look for other causes rather than assuming it is related to the vasopressors.
  3. For patients in whom you suspect purpura fulminans, they may benefit from anticoagulation while continuing vasopressor treatment.
  4. Do NOT let patients remain persistently hypotensive, even if they are mentating. Their brains may be getting enough blood, but it is not clear that the kidneys are.
1.
Ruffin N, Vasa C, Breakstone S, Axman W. Symmetrical peripheral gangrene of bilateral feet and unilateral hand after administration of vasopressors during septic shock. BMJ Case Rep. 2018;2018. [PubMed]
2.
Phan P, Acharya V, Parikh D, Shad A. A rare case of symmetrical four limb gangrene following emergency neurosurgery. Int J Surg Case Rep. 2015;16:15-18. [PubMed]
3.
Sharma B, Kabra S, Gupta B. Symmetrical peripheral gangrene. Trop Doct. 2004;34(1):2-4. [PubMed]
4.
Russell J, Walley K, Singer J, et al. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med. 2008;358(9):877-887. [PubMed]
5.
Lerolle N, Carlotti A, Melican K, et al. Assessment of the interplay between blood and skin vascular abnormalities in adult purpura fulminans. Am J Respir Crit Care Med. 2013;188(6):684-692. [PubMed]
6.
Auchet T, Regnier M, Girerd N, Levy B. Outcome of patients with septic shock and high-dose vasopressor therapy. Ann Intensive Care. 2017;7(1):43. [PubMed]
7.
Asfar P, Meziani F, Hamel J, et al. High versus low blood-pressure target in patients with septic shock. N Engl J Med. 2014;370(17):1583-1593. [PubMed]
8.
Anderson J, Johnston G. Development of cutaneous gangrene during continuous peripheral infusion of vasopressin. Br Med J (Clin Res Ed). 1983;287(6406):1657-1658. [PubMed]
9.
Berardi R. Vascular complications of superior mesenteric artery infusion with pitressin in treatment of bleeding esophageal varices. Am J Surg. 1974;127(6):757-761. [PubMed]
10.
Krejci V, Hiltebrand L, Sigurdsson G. Effects of epinephrine, norepinephrine, and phenylephrine on microcirculatory blood flow in the gastrointestinal tract in sepsis. Crit Care Med. 2006;34(5):1456-1463. [PubMed]
11.
Malay M, Ashton J, Dahl K, et al. Heterogeneity of the vasoconstrictor effect of vasopressin in septic shock. Crit Care Med. 2004;32(6):1327-1331. [PubMed]
12.
Bomberg H, Groesdonk H, Raffel M, et al. Vasopressin as Therapy During Nonocclusive Mesenteric Ischemia. Ann Thorac Surg. 2016;102(3):813-819. [PubMed]
13.
Abuelo J. Normotensive ischemic acute renal failure. N Engl J Med. 2007;357(8):797-805. [PubMed]
Susan Wilcox, MD

Susan Wilcox, MD

Chief, Division of Critical Care
Department of Emergency Medicine
Massachusetts General Hospital
Chair-Elect, Critical Care Section
American College of Emergency Physicians
Susan Wilcox, MD

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