What is a vasopressor?

Contents

What Are Vasopressors?

This class of drugs can be lifesaving in emergency medical situations.

Vasopressors are a group of medicines that contract (tighten) blood vessels and raise blood pressure.

They’re used to treat severely low blood pressure, especially in people who are critically ill.

Very low blood pressure can lead to organ damage and even death.

These drugs can help doctors treat patients who are in shock or are undergoing surgery.

Vasopressors have been used since the 1940s. They’re commonly given in combination with medicines called inotropes (which affect cardiac muscle contraction).

Common Vasopressors

Medicines — including synthetic hormones — that are used as vasopressors include:

  • Norepinephrine
  • Epinephrine
  • Vasopressin (Vasostrict)
  • Dopamine
  • Phenylephrine
  • Dobutamine

Vasopressor Precautions

Vasopressors should only be given under the supervision of a medical professional. These are powerful drugs, and they can be dangerous if used incorrectly.

The medicines may reduce blood flow to some parts of the body.

Vasopressors are commonly given in an emergency situation, but if you can, tell your doctor if you have any of the following conditions before receiving a vasopressor:

  • High blood pressure
  • Diabetes
  • Heart disease
  • Circulation problems
  • A history of blood clots
  • An overactive thyroid (hyperthyroidism)
  • Varicose veins
  • Asthma
  • Allergies to medications

Side Effects of Vasopressors

Tell your doctor if you experience any of the following serious side effects after receiving a vasopressor:

  • Slow or uneven heartbeat
  • Blue lips or fingernails
  • Pain, burning, irritation, or discoloration of the skin
  • Sudden numbness, weakness, or a cold feeling anywhere in your body
  • Trouble breathing
  • Little or no urination
  • Problems with speech, vision, or balance
  • Signs of dangerously high blood pressure (including severe headache, ringing in your ears, blurred vision, confusion, anxiety, chest pain, or seizures)
  • Signs of anaphylaxis, a severe allergic reaction, such as rash, hives, chest tightness, or swelling of the mouth, face, lips, or tongue

If possible, let your doctor know about all prescription, non-prescription, illegal, recreational, herbal, nutritional, or dietary drugs you’re taking before receiving a vasopressor.

Vasopressors and Pregnancy

If possible, let your doctor (or emergency room physician) know if you’re pregnant before receiving a vasopressor.

Your doctor will have to decide whether the benefits of using these drugs outweigh the risks.

Also, talk to your healthcare provider before breastfeeding if you’ve received a vasopressor.

Current use of vasopressors in septic shock

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Levophed

Medical Editor: John P. Cunha, DO, FACOEP

Last reviewed on RxList 3/26/2019

Levophed (norepinephrine bitartrate) is a vasoconstrictor, similar to adrenaline, used to treat life-threatening low blood pressure (hypotension) that can occur with certain medical conditions or surgical procedures. Levophed is often used during or after CPR (cardio-pulmonary resuscitation). Levophed is available in generic form. Tell your doctor if you have serious side effects of Levophed include:

  • dizziness,
  • weakness,
  • headache,
  • slow heart rate,
  • breathing difficulty, or
  • redness and swelling at the injection site.

Serious side effects of Levophed include:

  • pain or burning where the injection is given,
  • sudden numbness/weakness/cold feeling in your body,
  • blue lips or fingernails,
  • urinating less than usual or not at all,
  • trouble breathing,
  • dangerously high blood pressure (severe headache, blurred vision, buzzing in your ears, anxiety, confusion, chest pain, shortness of breath, irregular heartbeats, seizure).

Levophed is diluted in liquid and given continuously into a large vein (IV infusion), as directed by the doctor. Dosage is based on the patient’s condition and response to treatment. Levophed may interact with blood pressure medications, MAO inhibitors, or antidepressants. Tell your doctor all medications you use. During pregnancy, Levophed should be used only if prescribed. It is unknown if this medication passes into breast milk. Consult your doctor before breastfeeding.

Our Levophed (norepinephrine bitartrate) Side Effects Drug Center provides a comprehensive view of available drug information on the potential side effects when taking this medication.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

An Evidence-Based Approach to Pressors in Shock: Part I

Author: Sarah Brubaker, MD (EM Resident, San Antonio TX) // Edited by: Alex Koyfman, MD (@EMHighAK) and Brit Long, MD (@long_brit)

Clinical Case 1:

An 86-year-old man with a history of COPD, CHF, CAD, and ESRD presents to your emergency department via EMS for decreased mental status. When he arrives, he is alert but confused, with a rectal temperature of 102.4F, heart rate of 113, and blood pressure of 75/55. You immediately treat for sepsis, administering a fluid bolus, antipyretics, and broad-spectrum antibiotics. However, you think to yourself, “What if this patient’s blood pressure doesn’t respond to fluids? When should I give pressors? Which pressors should I use?”

The Evidence Behind Pressors

The evaluation and treatment of patients with cardiovascular shock is a cornerstone of emergency care. Unfortunately, the literature behind the use of vasoactive medications in cardiovascular shock is inconsistent. A Cochrane review in 2004 declared “the current available evidence is not suited to inform clinical practice” (1). Since 2004, there has been an impressive amount of research to investigate the use and safety of pressors, including several large, multi-center clinical trials. However, the results continue to be inconsistent and conflicting. An updated Cochrane review in 2016 concluded that, with the exception of an increased risk for arrhythmia associated with dopamine, there is no significant difference in mortality between vasopressors and “evidence of any other differences between any of the six vasopressors examined is insufficient” (2). These findings reflect the underlying complexity of vasopressor use. With that in mind, let’s delve into the literature behind each pressor, so that we can make informed decisions about which pressors are appropriate for patients in circulatory shock.

Resuscitation Goals

Before discussing the specifics of pressor management, it is important to define the goals of pressor therapy. Providers often colloquially describe pressors as agents used to improve blood pressure. However, in medical practice this is an oversimplification, because the goal of pressors is not to restore blood pressure to a specific number, but rather to return blood flow to vital organs and prevent irreversible tissue damage (3). Extensive research has been performed in an attempt to establish the most effective surrogate for end-organ perfusion. However, the majority of these studies have been conducted in patients with shock secondary to sepsis, so it is unclear whether this is generalizable to all categories of shock.

Mean arterial pressure (MAP) is the most commonly used objective measurement. It is generally understood that as MAP decreases, blood flow to vital organs decreases in a linear fashion. Surviving-sepsis campaign guidelines suggest a MAP goal of greater than 65 mm Hg (4). This is based on several prospective randomized control trials that have demonstrated the futility of attempting to achieve MAPs greater than 65 (5-7) (primarily in sepsis) because higher MAP goals were not associated with improved oxygen delivery, decreased lactate, or improved microvascular perfusion. The Sepsis and Mean Arterial Pressure (SEPSISPAM) trial (2014) found that a goal MAP of 80-85 mmHg does not improve mortality compared to a goal of 65-70 mmHg, though in patients with history of chronic hypertension, higher MAP targets were associated with decreased risk of renal dysfunction (8).

Several researchers have questioned whether MAP is truly an adequate marker of end-organ perfusion. For example, patients with chronic hypertension likely require higher MAPs to maintain adequate perfusion, while younger patients or patients with chronic hypotension likely can sustain adequate perfusion at lower MAPs. Therefore, it is important to evaluate other markers of end-organ perfusion during resuscitation. Surviving sepsis guidelines recommend the use of CVP (goal 8-12 mmHg), CvO2 (at least 70%), and UOP (at least 0.5cc/kg/hr) (4). Overall, it is important to monitor MAP in conjunction with other clinical factors (UOP, capillary refill, mental status, etc.) to guide resuscitation.

Vasopressors vs. Inotropes

With this foundation of knowledge, let’s now make the important distinction between vasopressors and inotropes. The goal of any pressor is to restore end-organ perfusion. However, vasopressors and inotropes are meant to achieve this goal by different mechanisms of action. By definition, the goal of vasopressors is to increase afterload via vasoconstriction and increased arterial pressure (12, 13). In contrast, inotropes increase cardiac contractility, thereby improving stroke volume and cardiac output. The most-commonly used agents in the ED are actually “inopressors”(14), a combination of vasopressors and inotropes, because they lead to both increased cardiac contractility and increased peripheral vasoconstriction.

In general, vasopressors are the preferred choice when blood pressure is low secondary to systemic vasodilation or obstruction, such as distributive shock (e.g. sepsis, anaphylaxis) or obstructive shock (e.g. pulmonary embolism, tamponade). It is important to note that by definition, pressors increase afterload (dependent on the specific pressor, dose, and receptors involved). Therefore, especially in patients with underlying cardiac disease, any pure vasopressor can reduce cardiac output. Inotropes are often preferred when there is suspicion for poor cardiac function (e.g. cardiogenic shock, or septic shock in the setting of CHF).

Vasopressin and phenylephrine are “pure pressors,” which work exclusively to increase vasoconstriction with minimal effects on heart rate or cardiac contractility. Although norepinephrine, epinephrine, and dopamine are placed under the categorization of vasopressors, they are actually more accurately described as “inopressors” because they primarily induce vasoconstriction, but also substantially increase cardiac contractility. Dobutamine and milrinone are closer to “pure inotropes” because they lead to improved cardiac function without substantial vasoconstrictive effects, though dobutamine can increase or decrease vasomotor tone and blood pressure.

For the purpose of this discussion, we will discuss norepinephrine, epinephrine, and dopamine under the category “inopressors.” In a future article, we will discuss vasopressin and phenylephrine under the category “vasopressors;” and dobutamine and milrinone under the category “inotropes.”

Inopressors

One benefit of inopressors over other options is the ability to infuse them through a peripheral intravenous line. Although most of the literature on this topic is derived from case studies (15), several recent studies demonstrate the safety of the catecholamine-based pressors when given through a peripheral catheter. In a prospective, observational study performed in 2015, patients were given phenylephrine, norepinephrine, or dopamine through a peripheral catheter for an average duration of 49 hours (16). Only 2% of the patients experienced extravasation, all of which were treated with local phentolamine and subsequently did not sustain tissue injury. Approximately 13% of patients ultimately required transition from peripheral to central intravenous access. A similar study in 2017 corroborated these results (17). Until more rigorous research is performed on the topic, this technique is an acceptable temporizing measure, but central access should be obtained as soon as possible for long-term use (we recommend within 4 hours of beginning the inopressor) and regular reassessment of the extremity and IV line. If using peripheral vasopressors, it is important to place the catheter as proximally as possible (18). If extravasation occurs, use phentolamine 0.1-0.2 mg/kg (maximum 10 mg) subcutaneously at the site of extravasation.

Clinical Case 2:

A 37-year-old male presents to the trauma bay after jumping off a bridge. His initial vital signs are heart rate 56, blood pressure 70/50, respiratory rate 30, and temperature 96.5F. His GCS is 14. He is alert but oriented only to person and place. He complains of severe neck pain. On exam, he has obvious deformities that are consistent with closed fractures of his upper and lower extremities. Upon examination of his spine, you note palpable midline tenderness and step-offs at multiple levels. Despite the administration of 2 units of packed red blood cells, the patient’s pressure is still 70/50. You decide to start a pressor, but think to yourself, “Which pressor should I choose?”

Norepinephrine

MECHANISM OF ACTION

Norepinephrine primarily stimulates alpha-1 and alpha-2 receptors, acting as a balanced venous and arterial vasoconstrictor. Norepinephrine also results in a small amount of beta-1 agonism, thereby producing a modest inotropic effect. Its effect on the arterial system (theoretically) leads to increased coronary blood flow and afterload, while its effect on the venous system effectively mobilizes the physiologic venous reserve, offering increased preload (19-21).

ADVERSE EFFECTS

Norepinephrine is considered safer than both epinephrine and dopamine. A systematic review published in 2015 demonstrated an absolute risk reduction of 11% compared to dopamine (due to dopamine’s arrhythmogenic effects, which are discussed below), with a number needed to treat of 9 (22). The same study found norepinephrine superior in improving central venous pressure, urinary output, and arterial lactate levels compared to epinephrine, phenylephrine, and vasopressin. However, norepinephrine was not associated with a mortality benefit or improved hemodynamic endpoints. In addition, several studies have demonstrated that while norepinephrine increases MAP and cardiac index, it may not improve end-organ flow (as measured by splanchnic circulation) (23).

Although norepinephrine is largely considered to be the safest inopressor, it still carries a risk of toxicity to cardiac myocytes, cardiac arrhythmias, and peripheral vasoconstriction leading to tissue ischemia (21).

INDICATIONS

Because norepinephrine is considered to be a “balanced pressor,” it is arguably the most popular pressor in the ED. It is the first-line pressor choice in distributive shock, including both neurogenic (24, 25) and septic shock (4). Although previous guidelines included epinephrine as an alternative first-line agent for septic shock, the most recent Surviving Sepsis Campaign guidelines, published in 2016, recommend norepinephrine as the only first-line pressor (4).

Norepinephrine is considered first-line in cardiogenic shock with profound hypotension (systolic blood pressure less than 70 mm Hg) (26, 27). It should be used in conjunction with dobutamine in patients with cardiogenic shock and blood pressure higher than 70 mm Hg who fail to respond to dobutamine.

DOSING

Norepinephrine has a rapid onset of action, so the effects should be seen within minutes, and the dose can be titrated every 2-5 minutes.

Clinical Case 3:

A 22-year-old female with no past medical history presents to your emergency department with extreme shortness of breath after being stung a bee just prior to arrival. She is in moderate respiratory distress, speaking only in 1-2 word phrases. Her respiratory rate is 42, oxygen saturation is 94%, heart rate is 123, and blood pressure is 84/52. On exam, you note moderate stridor, oropharyngeal swelling, diffuse expiratory wheezes, and a diffuse urticarial rash. You treat her with intramuscular epinephrine, in addition to intravenous steroids, diphenhydramine, 2L LR, and ranitidine. The patient’s respiratory status improves, but she remains hypotensive and tachycardic. What’s the next step?

Epinephrine

MECHANISM OF ACTION

Epinephrine stimulates beta-1 and beta-2 receptors, resulting in substantially more inotropic effects than norepinephrine. Due to its beta-agonism, epinephrine greatly increases heart rate and stroke volume, with a small amount of bronchodilation. Epinephrine also has a moderate stimulatory effect on alpha-1 receptors, leading to modest peripheral vasculature effects. At lower doses, epinephrine acts primarily as a beta-1 agonist; at higher doses, it acts primarily as an alpha-1 agonist (21).

ADVERSE EFFECTS

Epinephrine is associated with an increased risk of tachycardia and lactic acidosis (28). Although the exact cause for the lactic acidosis is unknown (likely due to enhanced beta agonism triggering lactic acid production and release), no studies demonstrate increased mortality or serious adverse events associated with epinephrine use (28, 29); this increase may not be related to tissue hypoperfusion. Although the lactic acidosis is transient (30, 31), with unknown clinical significance, this does make it more difficult use lactate as a marker of the patient’s response to treatment.

INDICATIONS

Due to its potential for deleterious effects, current Surviving Sepsis Campaign guidelines recommend using epinephrine as a second-line agent, after norepinephrine (4). This can be used with norepinephrine if cardiac contractility is decreased on US. However, in emergent situations, epinephrine is commonly used as a “push-dose pressor” or in a “dirty epi drip” because it is most readily available and easiest to find. These topics are beyond this scope of this article, but see http://www.emdocs.net/push-dose-pressors/ for more information.

In 2016, a multinational, prospective randomized control trial (RCT) of 219 patients with cardiogenic shock found epinephrine to be independently associated with increased 90-day mortality and worsened renal function compared to dobutamine and norepinephrine (32). These results have not yet been validated by further studies. However, due to these findings, in addition to known increased incidence of arrhythmogenic events associated with epinephrine, it should be used with extreme caution in cases of cardiogenic shock.

Due in part to its stimulatory effect on beta-2 receptors leads to bronchodilation, epinephrine is widely regarded as the first-line agent for anaphylactic shock (33).

DOSING

The current guidelines for anaphylactic shock recommend an initial bolus of 0.1 mg (1:10,000) over 5 minutes, followed by an infusion of 2-15 mcg/min. However, several studies have demonstrated increased incidence of adverse events associated with intravenous epinephrine. One study in 2015 found adverse cardiovascular events with 10% of IV bolus doses, compared to 1% of intramuscular doses (34).

For the same reasons as those discussed for norepinephrine, weight-based dosing is probably ideal. In the setting of septic shock, start epinephrine at 0.05 mcg/kg/min (generally 3-5 mcg/min) and titrate by 0.05 to 0.2 mcg/kg/min every 10 minutes. The maximum drip rate for epinephrine is 2 mcg/kg/min (140 mcg/min in a 70 kg patient).

Keep epinephrine’s dose-dependency in mind: doses of 1-10 mcg/min predominantly activate beta-1 receptors, while doses greater than 10 mcg/min begin to primarily affect alpha-1-mediated vasoconstriction.

Clinical Case 4:

An 83-year-old male with unknown past medical history is brought to your emergency department via EMS. Family called EMS because the patient is normally ambulatory and active, but has been increasingly somnolent and diffusely weak for the past several days. His initial vital signs reveal a rectal temperature of 101.4F, heart rate of 99, and blood pressure of 68/42. You immediately treat for sepsis, administering a fluid bolus, antipyretics, and broad-spectrum antibiotics. His blood pressure fails to improve after these interventions, so you initiate a norepinephrine drip and titrate it to 20 mcg/min. The patient’s blood pressure is now 82/58. You prepare to initiate a second pressor. Which one should you choose?

Dopamine

MECHANISM OF ACTION

Dopamine is the natural precursor of norepinephrine and epinephrine. Its effects are dose-dependent. In low doses, dopamine almost exclusively stimulates the dopaminergic receptors, which leads to renal vasodilation and ultimately results in increased renal blood flow and GFR. It is important to note that at low doses, dopamine has no pressor effects. In fact, it causes a small amount of vasodilation and can slightly lower the blood pressure. Due to its physiologic effects, low-dose dopamine was initially thought to reduce rates of kidney failure. However, the ANZICS trial (2000) studied 328 patients with early renal dysfunction who were given low-dose dopamine or placebo. The study failed to demonstrate improved renal function with dopamine use (35).

In moderate doses, beta-1 agonism predominates, which leads to increased cardiac contractility and heart rate. At high doses, alpha-1 adrenergic effects predominate, which leads to arterial vasoconstriction and increased blood pressure.

ADVERSE EFFECTS

Dopamine has largely fallen out of favor, due to several large, multi-center studies that demonstrate increased morbidity associated with its use. The SOAP trial (2006) found dopamine to be independently associated with increased mortality in shock (36). The SOAP II trial (2010) 2010 failed to demonstrate increased mortality with dopamine use, but it did find significantly higher rates of dysrhythmias in the setting of dopamine use, with a number needed to harm of 9 (37). Several smaller studies have also demonstrated increased arrhythmic events. In addition, several studies have posited that dopamine may have negative effects on cellular function, leading to immunosuppression (38). A meta-analysis in 2015 also found evidence to suggest increased mortality associated with dopamine use compared to norepinephrine (39).

INDICATIONS

Dopamine was once considered first-line for septic and cardiogenic shock, but recent studies have overwhelmingly demonstrated increased adverse events with dopamine compared to other pressors. Therefore, dopamine use has largely fallen out of favor. Dopamine is now only indicated as a rescue medication when shock is refractory to other medications. Some sources continue to recommend dopamine as a first-line agent for neurogenic shock (as an alternative to norepinephrine), given its combined cardiac and peripheral effects (24).

DOSING

Start the dopamine infusion at 2 mcg/kg/min and titrate to a maximum dose of 20 mcg/kg/min. Keep in mind dopamine’s distinct dose-dependent effects: at less than < 5 mcg/kg/min, vasodilation in the renal vasculature predominates; between 5-10mcg/kg/min, beta-1 adrenergic effects predominate; > 10 mcg/kg/min, alpha-1 adrenergic effects predominate.

INOPRESSOR SUMMARY

– All the inopressors are catecholamine derivatives, with varying levels of alpha, beta, and dopaminergic stimulation. Therefore, inopressors stimulate both vasoconstriction and cardiac activity.

– Norepinephrine has the most favorable safety profile. Therefore, norepinephrine has largely become the pressor of choice for distributive and obstructive shock.

– Epinephrine is first-line for anaphylactic shock.

– Dopamine has largely fallen out of favor, and its use should be avoided except as an adjunctive agent in refractory shock.

Stay tuned for the second part of this article coming soon, which will discuss pure vasopressors and pure inotropes, with a summary of how to choose each pressor based on category of shock!

References/Further Reading

  1. Mullner M, Urbanek B, Havel C, Losert H, Waechter F, Gamper G. Vasopressors for shock. Cochrane Database Syst Rev. 2004;3.
  2. Gamper G, Havel C, Arrich J, Losert H, Pace NL, Müllner M, et al. Vasopressors for hypotensive shock. The Cochrane Library. 2016.
  3. Dünser MW, Takala J, Brunauer A, Bakker J. Re-thinking resuscitation: leaving blood pressure cosmetics behind and moving forward to permissive hypotension and a tissue perfusion-based approach. Critical care. 2013;17(5):326.
  4. Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock: 2016. Intensive care medicine. 2017;43(3):304-77.
  5. LeDoux D, Astiz ME, Carpati CM, Rackow EC. Effects of perfusion pressure on tissue perfusion in septic shock. Critical care medicine. 2000;28(8):2729-32.
  6. Bourgoin A, Leone M, Delmas A, Garnier F, Albanèse J, Martin C. Increasing mean arterial pressure in patients with septic shock: effects on oxygen variables and renal function. Critical care medicine. 2005;33(4):780-6.
  7. Jhanji S, Stirling S, Patel N, Hinds CJ, Pearse RM. The effect of increasing doses of norepinephrine on tissue oxygenation and microvascular flow in patients with septic shock. Critical care medicine. 2009;37(6):1961-6.
  8. Asfar P, Meziani F, Hamel J-F, Grelon F, Megarbane B, Anguel N, et al. High versus low blood-pressure target in patients with septic shock. New England Journal of Medicine. 2014;370(17):1583-93.
  9. Investigators P. A randomized trial of protocol-based care for early septic shock. N Engl J Med. 2014;2014(370):1683-93.
  10. Investigators A, Group ACT. Goal-directed resuscitation for patients with early septic shock. N Engl J Med. 2014;2014(371):1496-506.
  11. Mouncey PR, Osborn TM, Power GS, Harrison DA, Sadique MZ, Grieve RD, et al. Trial of early, goal-directed resuscitation for septic shock. New England Journal of Medicine. 2015;372(14):1301-11.
  12. Hollenberg SM. Vasoactive drugs in circulatory shock. American journal of respiratory and critical care medicine. 2011;183(7):847-55.
  13. Ellender TJ, Skinner JC. The use of vasopressors and inotropes in the emergency medical treatment of shock. Emergency medicine clinics of North America. 2008;26(3):759-86.
  14. Weingart S 2014;Pageshttps://emcrit.org/emcrit/vasopressor-basics/.
  15. Loubani OM, Green RS. A systematic review of extravasation and local tissue injury from administration of vasopressors through peripheral intravenous catheters and central venous catheters. Journal of critical care. 2015;30(3):653. e9-. e17.
  16. Cardenas‐Garcia J, Schaub KF, Belchikov YG, Narasimhan M, Koenig SJ, Mayo PH. Safety of peripheral intravenous administration of vasoactive medication. Journal of hospital medicine. 2015;10(9):581-5.
  17. Medlej K, Kazzi AA, Chehade AEH, Eldine MS, Chami A, Bachir R, et al. Complications from Administration of Vasopressors Through Peripheral Venous Catheters: An Observational Study. The Journal of Emergency Medicine. 2017.
  18. Brewer JM, Puskarich MA, Jones AE. Can Vasopressors Safely Be Administered Through Peripheral Intravenous Catheters Compared With Central Venous Catheters? Annals of emergency medicine. 2015;66(6):629-31.
  19. Monnet X, Jabot J, Maizel J, Richard C, Teboul J-L. Norepinephrine increases cardiac preload and reduces preload dependency assessed by passive leg raising in septic shock patients. Critical care medicine. 2011;39(4):689-94.
  20. Persichini R, Silva S, Teboul J-L, Jozwiak M, Chemla D, Richard C, et al. Effects of norepinephrine on mean systemic pressure and venous return in human septic shock. Critical care medicine. 2012;40(12):3146-53.
  21. Stratton L, Berlin DA, Arbo JE. Vasopressors and inotropes in sepsis. Emergency Medicine Clinics. 2017;35(1):75-91.
  22. Avni T, Lador A, Lev S, Leibovici L, Paul M, Grossman A. Vasopressors for the treatment of septic shock: systematic review and meta-analysis. PloS one. 2015;10(8):e0129305.
  23. De Backer D, Creteur J, Silva E, Vincent J-L. Effects of dopamine, norepinephrine, and epinephrine on the splanchnic circulation in septic shock: which is best? Critical care medicine. 2003;31(6):1659-67.
  24. Ploumis A, Yadlapalli N, Fehlings M, Kwon B, Vaccaro A. A systematic review of the evidence supporting a role for vasopressor support in acute SCI. Spinal Cord. 2010;48(5):356-62.
  25. Muzevich KM, Voils SA. Role of vasopressor administration in patients with acute neurologic injury. Neurocritical care. 2009;11(1):112.
  26. Antman EM, Anbe DT, Armstrong PW, Bates ER, Green LA, Hand M, et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1999 Guidelines for the Management of Patients with Acute Myocardial Infarction). Journal of the American College of Cardiology. 2004;44(3):E1-E211.
  27. Senz A, Nunnink L. Inotrope and vasopressor use in the emergency department. Emergency Medicine Australasia. 2009;21(5):342-51.
  28. Mahmoud KM, Ammar AS. Norepinephrine supplemented with dobutamine or epinephrine for the cardiovascular support of patients with septic shock. Indian journal of critical care medicine: peer-reviewed, official publication of Indian Society of Critical Care Medicine. 2012;16(2):75.
  29. Annane D, Vignon P, Renault A, Bollaert P-E, Charpentier C, Martin C, et al. Norepinephrine plus dobutamine versus epinephrine alone for management of septic shock: a randomised trial. Lancet. 2007;370(9588):676-84.
  30. Levy B, Perez P, Perny J, Thivilier C, Gerard A. Comparison of norepinephrine-dobutamine to epinephrine for hemodynamics, lactate metabolism, and organ function variables in cardiogenic shock. A prospective, randomized pilot study. Critical care medicine. 2011;39(3):450-5.
  31. Myburgh JA, Higgins A, Jovanovska A, Lipman J, Ramakrishnan N, Santamaria J, et al. A comparison of epinephrine and norepinephrine in critically ill patients. Intensive care medicine. 2008;34(12):2226.
  32. Tarvasmäki T, Lassus J, Varpula M, Sionis A, Sund R, Køber L, et al. Current real-life use of vasopressors and inotropes in cardiogenic shock-adrenaline use is associated with excess organ injury and mortality. Critical Care. 2016;20(1):208.
  33. Kemp SF, Lockey RF, Simons FER. Epinephrine: the drug of choice for anaphylaxis. A statement of the World Allergy Organization. Allergy. 2008;63(8):1061-70.
  34. Campbell RL, Bellolio MF, Knutson BD, Bellamkonda VR, Fedko MG, Nestler DM, et al. Epinephrine in anaphylaxis: higher risk of cardiovascular complications and overdose after administration of intravenous bolus epinephrine compared with intramuscular epinephrine. The Journal of Allergy and Clinical Immunology: In Practice. 2015;3(1):76-80.
  35. Bellomo R, Chapman M, Finfer S, Hickling K, Myburgh J. Low-dose dopamine in patients with early renal dysfunction: a placebo-controlled randomised trial. Australian and New Zealand Intensive Care Society (ANZICS) Clinical Trials Group. Lancet (London, England). 2000;356(9248):2139-43.
  36. Sakr Y, Reinhart K, Vincent J-L, Sprung CL, Moreno R, Ranieri VM, et al. Does dopamine administration in shock influence outcome? Results of the Sepsis Occurrence in Acutely Ill Patients (SOAP) Study. Critical care medicine. 2006;34(3):589-97.
  37. De Backer D, Biston P, Devriendt J, Madl C, Chochrad D, Aldecoa C, et al. Comparison of dopamine and norepinephrine in the treatment of shock. New England Journal of Medicine. 2010;362(9):779-89.
  38. Oberbeck R, Schmitz D, Wilsenack K, Schüler M, Husain B, Schedlowski M, et al. Dopamine affects cellular immune functions during polymicrobial sepsis. Intensive care medicine. 2006;32(5):731-9.
  39. Pollard S, Edwin SB, Alaniz C. Vasopressor and Inotropic Management Of Patients With Septic Shock. Pharmacy and Therapeutics. 2015;40(7):438.

Vasopressors for Septic Shock (from the Surviving Sepsis Guidelines)

See more from Surviving Sepsis Guidelines*

*PulmCCM is not affiliated with the Surviving Sepsis Campaign.

Vasopressors are provided for septic shock that does not respond to fluid resuscitation. Norepinephrine (Levophed), epinephrine, vasopressin, phenylephrine (Neo-Synephrine), and dopamine are the most commonly used vasopressors for septic shock.

To achieve adequate fluid resuscitation, the Surviving Sepsis Guidelines advise at least 30 ml/kg of crystalloids (1.5-3 liters) be infused for most patients (Grade 1C) in septic shock. Some patients will require more IV fluids; fluid should be aggressively infused for as long as the patient continues to improve hemodynamically (ungraded recommendation). A portion of infused resuscitation fluid can be given as “albumin-equivalent” (Grade 1C).

Vasopressors should be promptly begun in patients in persistent septic shock despite fluid resuscitation; vasopressors can be begun and continued simultaneously with fluid resuscitation, especially in patients with severe hypotension. The Surviving Sepsis Guidelines advise the following:

  • Vasopressors should be begun initially to target a mean arterial pressure of 65 mm Hg (Grade 1C).
  • Norepinephrine (Levophed) should be provided as the first-line vasopressor (Grade 1B).
  • Epinephrine is considered the next-line agent for septic shock after norepinephrine in the Surviving Sepsis Guidelines. When norepinephrine is insufficient to maintain MAP 65 mm Hg, epinephrine should be added to or substituted for norepinephrine (Grade 2B).
  • Vasopressin at 0.03 units/minute is appropriate to use with norephinephrine, either to improve perfusion (increase MAP) or to reduce the required dose of norepinephrine (ungraded recommendation).
  • Vasopressin is not recommended for use as a single vasopressor for septic shock (ungraded recommendation).
  • Vasopressin doses higher than 0.03 – 0.04 units/min are recommended to be reserved only for dire situations of septic shock refractory to standard doses of multiple vasopressors (ungraded recommendation).
  • Dopamine is suggested to not be used as an alternative to norepinephrine in septic shock, except in highly selected patients such as those with inappropriately low heart rates (absolute or relative bradycardia) who are at low risk for tachyarrhythmias (Grade 2C). Dopamine is recommended to not be used in low doses in a so-called renal-protective strategy (Grade 1A).
  • Phenylephrine is recommended to not be used for septic shock, except when 1) septic shock persists despite the use of 2 or more inotrope/vasopressor agents along with low-dose vasopressin; 2) cardiac output is known to be high, or 3) norepinephrine is considered to have already caused serious arrhythmias (Grade 1C).
  • An arterial catheter for hemodynamic monitoring should be placed as soon as practical, if resources are available, for all patients requiring vasopressors (ungraded recommendation).
  • Dobutamine should be tried for patients in septic shock who have low cardiac output with high filling pressures while on vasopressors, or who have persistent evidence of hypoperfusion after attaining an adequate mean arterial pressure and intravascular volume (with or without vasopressors) (Grade 1C).
  • A dobutamine infusion up to 20 mcg/kg/min can be added to any vasopressor(s) in use. Dobutamine is also an appropriate first-line agent in patients with severe sepsis and low cardiac output, with a preserved mean arterial pressure (i.e., who are not in septic shock) (Grade 1C).
  • Dobutamine is recommended not to be used to deliberately raise cardiac output to higher than normal levels in an attempt to improve perfusion (Grade 1B).
Mean Arterial Pressure (MAP) ≥ 65 mm Hg is Not An Absolute

The goal of attaining a mean arterial pressure (MAP) of ≥ 65 mm Hg for patients receiving vasopressors for septic shock is based on very limited evidence. The single research study cited in the Surviving Sepsis Guidelines to support the goal of MAP ≥ 65 mm Hg enrolled only 10 patients. Accordingly, the Surviving Sepsis Guidelines advise that “the optimal MAP should be individualized” during treatment of septic shock — perhaps higher than 65 mm Hg in a patient with hypertension and known atherosclerosis; perhaps lower than 65 mm Hg in a young healthy patient with a baseline normal blood pressure — and that other markers of perfusion such as serum lactate, skin appearance and temperature, urine output, and mental status should supplement the use of mean arterial pressure in all patients.

Why Norepinephrine (Levophed) for Septic Shock Instead of Other Vasopressors?

Norepinephrine (Levophed) is favored as the first-line vasopressor for septic shock in the Surviving Sepsis Guidelines (Grade 1B). Norepinephrine increases mean arterial pressure primarily through vasoconstriction, with little effect on heart rate, stroke volume, and cardiac output; dopamine increases MAP primarily through an increase in cardiac output (by increasing both heart rate and stroke volume). These characteristics make dopamine more likely than norepinephrine to cause potentially harmful tachyarrhythmias.

Norepinephrine and dopamine have been compared directly in at least 6 randomized trials, and less directly in meta-analyses. The Surviving Sepsis Campaign’s own (unpublished) pooled analysis of these trials showed a relative risk for death of 0.91 (0.83-0.99) with the use of norepinephrine compared to dopamine as vasopressor therapy for septic shock. A 2012 meta-analysis including randomized and observational trials also concluded dopamine brings an increased risk for death compared with Levophed as a first-line vasopressor for septic shock.

Epinephrine is suggested as the next-line vasopressor after norepinephrine for septic shock, to be added or substituted if norepinephrine is inadequate (Grade 2B). Epinephrine has been compared to norepinephrine in at least 4 randomized trials, with no increase in the risk for death. Epinephrine may increase lactate concentrations by stimulating skeletal muscles’ aerobic metabolism, thereby interfering with the use of lactate as a marker of perfusion during treatment of septic shock.

Phenylephrine can decrease stroke volume and is recommended to not be used except as salvage therapy, in known high cardiac output states, or if norepinephrine has caused tachyarrhythmias (Grade 1C).

Vasopressin (or its analogue terlipressin) has been compared to norepinephrine as a vasopressor for septic shock in 9 randomized trials (n=963); vasopressin / terlipressin carried a (non-significant) increased risk of death (albeit a lower risk of tachyarrhythmias) compared to norepinephrine.

Guide to Recommendations’ Strengths and Supporting Evidence in the Surviving Sepsis Guidelines:

  • 1 = strong recommendation;
  • 2 = weak recommendation or suggestion;
  • A = good evidence from randomized trials;
  • B = moderate strength evidence from small randomized trial(s) or upgraded observational trials;
  • C = low strength evidence, well-done observational trials with control randomized controlled trials
  • D = very low strength evidence, downgraded controlled studies or expert opinion.

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Introduction with a case

Once upon a time at Genius General Hospital, an elderly man was admitted to the ICU with rapidly progressive cellulitis and tachypnea (1). We admitted him to the ICU despite a normal blood pressure because he looked toxic. Soon after arriving in the unit his blood pressure dropped, so vasopressors were started and lines were inserted.

A few hours later, I was called to his bedside due to refractory hypotension. He was on the maximal dose of three agents according to institutional guidelines (30 mcg/min norepinephrine, 10 mcg/min epinephrine, 0.04 U/min vasopressin), meanwhile phenylephrine was being up-titrated. His blood pressure was 60/30 on a femoral arterial line. It was suggested that he was dying and we should call his family in from the waiting room to say goodbye.

We told his family that things were looking dire, and they did come into the room for what we all anticipated was a last encounter. Meanwhile, we up-titrated his vasopressors to 80 mcg/min norepinephrine and 40 mcg/min epinephrine. His blood pressure steadily improved over the next 15 minutes. Within a few hours we were down-titrating the vasopressors. He eventually made a full recovery.

What is your hospital’s “maximum dose” of vasopressor?

Maximal doses used in clinical studies have ranged between 0.2-5 mcg/kg/min (Dopp-Zemel 2013). Every hospital and pharmacopeia have their own “maximum dose” of vasopressors. For example:

The maximum dose of vasopressors is important for a few reasons:

  • Clinicians may be afraid to titrate above their hospital’s “maximum” dose, lest they run afoul of institutional policy.
  • Failure of the patient to respond to “maximal” doses may be interpreted as meaning that the patient is moribund, with any further therapy being futile.

Theory: What is the maximum effective dose of vasopressors ??

Any drug ought to have a dose-response curve. Such curves indicate that above a certain dose, additional drug will have little effect. This would suggest that a maximal effective dose of vasopressor ought to exist. However, it also implies that higher doses of vasopressor aren’t dangerous (they are merely futile, since all the receptors at this point are fully saturated).

Dose-response curves don’t exist for humans due to ethical concerns. Dose-titration in rats shows that norepinephrine has a nearly linear effect up to a dose of 1.35 mcg/kg/min (Pang 1986). This suggests that commonly used clinical doses aren’t close to saturating all the alpha-receptors.

However, excessive norepinephrine doses could be dangerous within the context of an individual patient’s physiology. Specifically, excessive afterload could threaten to choke off cardiac output (thereby generating an iatrogenic state of vasopressor-induced shock). The norepinephrine dose at which this occurs would reflect several competing factors: cardiac function, volume status, and underlying vasoplagia. Thus, there might not exist any specific norepinephrine dose which would be expected to be detrimental for every patient. The same dose of norepinephrine that would kill one patient (e.g. someone with cardiogenic shock) might be required to keep another patient alive (e.g. someone with profound vasodilation).

Methodology pitfalls: Self-fulfilling prophecies & circular logic

Unfortunately, all available evidence consists of retrospective case series. Before considering the evidence, we must respect its limitations. One way to appreciate this is through the following thought experiments.

Thought experiment #1

  • Imagine that there is a maximal effective dose of norepinephrine, let’s say 30 mcg/min. Any infusion above 30 mcg/min has exactly the same efficacy as 30 mcg/min.
  • Imagine that we have a patient who is going to be hypotensive for one hour, and then her blood pressure will improve. This will happen regardless of vasopressor dose – she simply needs an hour to respond to resuscitation. Let’s imagine how this case could play out in two parallel universes:
  • Universe A: Everyone in this universe believes that the maximal dose of norepinephrine is 30 mcg/min. Consequently, the norepinephrine will be titrated up to 30 mcg/min, but no higher. The patient will be hypotensive for one hour on 30 mcg/min norepinephrine, then her blood pressure will improve. Everyone in this universe concludes that the patient simply needed some time to recover.
  • Universe B: Everyone in this universe believes that there is no maximal dose of norepinephrine. For the hour that the patient is hypotensive, norepinephrine is continually up-titrated. By the end of the hour, the norepinephrine has been increased to a dose of 200 mcg/min and the patient’s blood pressure finally improves. Everyone in this universe concludes that the high dose of norepinephrine caused her blood pressure to improve.

Thought experiment #2

In order to prove that high doses of norepinephrine are truly required, it would be ideal to perform ongoing,repeated dose-titration. For example:

  1. The patient appears to require 200 mcg/min norepinephrine to achieve a MAP >65mm.
  2. If the norepinephrine is decreased to 150 mcg/min this immediately causes hypotension, which immediately resolves when the norepinephrine is increased to 200 mcg/min. There is an obvious causal relationship between adjusting the norepinephrine dose and the blood pressure, which is reproduced several times.

In this scenario, it would be reasonable to conclude that the high dose of norepinephrine is actually needed. However, even in this situation it’s possible to fool yourself. For example, let’s perform the following thought experiment:

  • Imagine that the maximal dose of norepinephrine is 30 mcg/min. Any higher dose has no additional effect.
  • The patient’s blood pressure is oscillating between 55 mm and 75 mm. These oscillations are due to the patient’s intrinsic physiology; they have absolutely nothing to do with the vasopressor dose.
  • The nurse is titrating the norepinephrine up and down between 100-200 mcg/min, based on the blood pressure.
  • The resulting pattern will show that whenever the vasopressor dose is decreased, the blood pressure soon falls. Alternatively, then the vasopressor dose is increased, the blood pressure soon increases (graph above). This would seem to indicate that the vasopressor dose is driving the blood pressure. Of course, in this thought experiment we already know that this is purely a temporal correlation which is generated by the way the nurse is titrating the medication.

Thought experiment #3: The self-fulfilling prophecy

Imagine that some patients require very high doses in order to survive. Unfortunately, in one country it is incorrectly believed that the maximum dose of norepinephrine is 30 mcg/min. Any patient who fails to respond to 30 mcg/min is deemed to be moribund, leading to withdrawal of care. Consequently, no patient ever receives >30 mcg/min of norepinephrine. This creates a self-fulfilling prophesy that the maximum dose of norepinephrine is 30 mcg/min.

Clinical evidence

So, it’s possible for retrospective case reports to be easily confounded. That said, this is the best data that we have, so let’s take a look at it.

Auchet et al 2017

This is a retrospective single-ICU French study of septic patients requiring >1 ug/kg/min vasopressor between 2008-2013. 106 patients required this dose, making up 15% of all patient treated for septic shock. The most commonly used treatment was norepinephrine monotherapy. On average, high-dose vasopressor was required for 84 hours. 28-day mortality was 60%. Among survivors, the maximum rate was on average 2.3 ug/kg/min. The average norepinephrine dose was fairly predictive of death (area under the AUC curve 0.76). 6% of patients suffered digital or limb necrosis.

Martin et al. 2015

This is a retrospective single-ICU French study of septic shock patients admitted from 2009-2013. In-hospital mortality of all 324 septic shock patients was 48%, which is rather high. 84 patients (one quarter) received a maximal dose of norepinephrine >1 mcg/kg/min, of whom 90% died.

Sviri et al. 2014

This is a retrospective single-center Israeli study of patients receiving vasopressors in a medical ICU between 2008-2010. 166 patients who received norepinephrine or epinephrine were included, of whom 51 received high-dose vasopressors (defined as >40 mcg/min). In-hospital mortality among all patients receiving any vasopressor dose was extraordinarily high at 75%. Vasopressor dose was fairly predictive of death (AUC 0.779). High-dose vasopressor use was associated with a 90% in-hospital mortality.

Brown et al. 2013

This is a retrospective study involving five US hospitals between 2005-2010 describing patients requiring high-dose vasopressor (defined as >1 ug/kg/min norepinephrine or equivalent doses of other vasopressors)(2). 443 patients were included, of whom 241 had septic shock. 90-day mortality was high in the entire group (83%) as well as the subgroup with septic shock (80%). Digital or limb necrosis occurred in only 8% of surviving patients. Vasopressor dose correlated with increased mortality as shown above.

Dopp-Zemel et al. 2013

This is a retrospective single-ICU study from the Netherlands between 2007-2009 involving 113 patients treated with >0.9 mcg/kg/min norepinephrine. 28-day mortality was 66%. A norepinephrine dose above 2.22 mcg/kg/min was associated with 100% mortality, but this is statistically insignificant due to the very low number of patients treated with this dose (n=3).

Caution about using high-dose vasopressors

The above studies show a strong correlation between high-dose vasopressors and mortality. This is probably because the need for high-dose vasopressors correlates with greater disease severity, not because high-dose vasopressors cause mortality. Nonetheless, the need for high-dose vasopressors should never be taken lightly. This is generally a treatment of last resort. Whenever high-dose vasopressors are needed, meticulous evaluation is needed (ideally including echocardiography) with particular attention to the following questions:

  • Is blood pressure truly that low? Consider placement of a femoral or axillary arterial catheter to transduce central arterial pressure.
  • Is there a role for volume resuscitation or inotropic support? Some patients who respond poorly to norepinephrine may do better with epinephrine (see: epinephrine challenge).
  • Is there occult right ventricular failure that could be treated (e.g. with pulmonary vasodilation)?
  • Is there low cardiac output and impaired perfusion (e.g. mottling)? In that case, additional vasoconstriction may simply aggravate matters.
  • Is there a failure of surgical source control or incorrect antibiotic selection?
  • Is the patient on adequate adjunctive therapy (stress-dose steroid, possibly thiamine/ascorbate)?
  • Is there a pH abnormality that merits correction (e.g. treatment of hyperchloremic metabolic acidosis with bicarbonate)?
  • Is there autoPEEP or elevated intra-abdominal pressure which is impairing venous return?
  • Is the patient on any medications which may be reducing the blood pressure (e.g. propofol, dexmedetomidine)?
  • Is there clinically significant hypocalcemia?
  • Published series suggest that it’s not uncommon for septic patients to require high-dose vasopressors (above ~1 mcg/kg/min norepinephrine).
  • Vasopressor dose is moderately predictive of mortality. However, no particular vasopressor dose is 100% specific for death. For example, patients can survive despite requiring extremely high doses (e.g. >2 mcg/kg/min).
  • The concept of a “maximum dose” of vasopressors should be discouraged, as this appears to be a myth. Limiting vasopressor dosage below an arbitrary rate could prevent successful resuscitation of the sickest patients.
  • High-dose vasopressors are a treatment of last resort. In this situation, treatable causes of hypotension should be aggressively sought and corrected.
Related
  • Epinephrine challenge (PulmCrit)
  • Vasopressor basics (EMCrit)
  • Norepinephrine (Deranged Physiology blog)

Acknowledgement: Thanks to Dr. Gilman Allen for thoughtful comments on this post.

Notes
  1. Someone will probably ask: how do you get septic from cellulitis? Basically two ways: either necrotizing fasciitis or Group A streptococcal infection with toxic shock syndrome (and often bacteremia). This was the latter. Toxic shock syndrome is actually fairly common with invasive group A strep infections (more on this here).
  2. One weakness of this study is that it considered 1 mcg of norepinephrine to be equivalent to 2.2 mcg of phenylephrine. In contrast, most modern studies seem to use a conversion whereby 1 mcg of norepinephrine is equivalent to 10 mcg of phenylephrine. A 1-2.2 conversion rate of phenylephrine could artificially inflate the “effective norepinephrine” dose.
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Josh is the creator of PulmCrit.org. He is an associate professor of Pulmonary and Critical Care Medicine at the University of Vermont. Social Me

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An Evidence-Based Approach to Pressors in Shock: Part II

This is the second article in a discussion about the use of pressors in circulatory shock. Part I discussed basic guidelines for pressor management, in addition to specific literature regarding “inopressors” (norepinephrine, epinephrine, and dobutamine). Part II will discuss “pure inotropes” (dobutamine and milrinone) and “pure vasopressors” (vasopressin and phenylephrine).

Pure Inotropes

Inotropes work primarily to increase cardiac output; they increase stroke volume by improving cardiac contractility, as opposed to vasopressors, which increase blood pressure by increasing peripheral resistance (1). Inotropes can lead to peripheral vasodilation and have a variable effect on blood pressure; their use often results in hypotension. For this reason, inotropes should only be used in patients after complete fluid resuscitation. In addition, increased cardiac contractility leads to increased myocardial oxygen consumption (2), which can result in increased in-hospital mortality (3) and risk for myocardial infarction (1). Because inotrope use is rife with complications, research is currently underway in an attempt to find alternative options (4, 5).

There are only two inotropes frequently used in the United States: dobutamine and milrinone. Levosimendan is a calcium-channel sensitizer with equivalent efficacy to the dopamine and milrinone, and possibly lower morbidity and mortality (6). It is used in several European countries, but it is not FDA-approved for use in the United States. Therefore, this article will focus on dobutamine and milrinone.

Clinical Case #1:

A 79-year-old female with a history of CHF presents to your emergency department in acute respiratory distress. Her vital signs are: heart rate 104, blood pressure 84/58, respiratory rate 45, and oxygen saturation 84%. Exam reveals decreased lung sounds with diffuse crackles bilaterally, in addition to 2+ pitting edema to the knees. Bedside cardiac ultrasound demonstrates marked global hypokinesis. You give a dose of IV Lasix and initiate BiPAP. Several minutes after initiation of these treatments, the patient’s blood pressure is 75/45. You are unable to wean the patient off BiPAP, so you decided to continue positive pressure ventilation while starting a pressor. Which pressor should you use?

Dobutamine

MECHANISM OF ACTION

Dobutamine is a synthetic catecholamine derivative (7) that stimulates beta-1 and beta-2 receptors (7, 8), at approximately a 3:1 ratio (9). At high doses (greater than 15 ug/kg/min), dobutamine also becomes a mild alpha-1 agonist. Because it primarily stimulates beta-1 receptors, dobutamine confers predominantly inotropic effects, with less pronounced chronotropic effects.

Dobutamine’s stimulation of beta-2 receptors can result in peripheral vasodilation, though the magnitude of this effect is variable (1). Therefore, dobutamine can lead to decreased blood pressure in some (but not all) patients. Due to its vasodilatory effects, dobutamine has been shown to improve capillary perfusion independent of changes in blood pressure and cardiac index (10).

As a catecholamine analog, dobutamine may be used through a peripheral catheter (7). However, central access is strongly preferred.

ADVERSE EFFECTS

Dobutamine was developed in an attempt to decrease the rates of myocardial ischemia associated with epinephrine and dopamine use. However, despite minimal chronotropic effects, studies have demonstrated increased myocardial oxygen demand and malignant arrhythmias (8, 11, 12). Although these adverse events typically occur at doses higher than 15 ug/kg/min, they can happen at any dose. Dobutamine use was found to substantially increase mortality at 180 days when compared with placebo in the CASINO study (13).

As noted above, many patients experience hypotension associated with dobutamine use. It should be used with caution in patients with systolic blood pressure less than 90 mmHg. In addition, dobutamine use often requires concomitant inopressor/vasopressor use. For this reason, dobutamine should only be used in patients with adequate fluid resuscitation (14).

It is important to note that dobutamine’s onset of action is 1-2 minutes (2), and the half-life is also approximately 2 minutes. Therefore, negative effects of dobutamine are theoretically rapidly reversible. In addition, dobutamine infusions lasting longer than 72 hours can lead to pharmacologic tolerance (1).

INDICATIONS

Surviving sepsis campaign guidelines recommend the use of dobutamine in patients with septic shock who display evidence of decreased cardiac output in the presence of adequate preload (15). This includes patients with known decreased ejection fracture and those who are persistently hypotensive despite adequate fluid administration and use of vasopressors.

Current ACC/AHA guidelines recommend using dobutamine as a first-line agent in management of hypotension associated with acute myocardial infarction (9, 16). However, because dobutamine can lower blood pressure, it should only be used if systolic blood pressure is between 70-100 mmHg, with norepinephrine ready (or already infusing) as well. Dobutamine is typically recommended as the first line agent in cardiogenic shock (17), but this is not a strong recommendation because several studies have demonstrated benefits to norepinephrine in this setting (18, 19). If dobutamine is used as a first-line agent, then norepinephrine should be second-line or already infusing, followed by milrinone.

DOSING

Dobutamine can be started at 2 mcg/kg/min and titrated to effect, with a maximum dose of 20 mcg/kg/min.

Clinical Case #2:

You are treating a 79-year-old female in acute decompensated heart failure. You have given a dose of IV Lasix and initiated BiPAP. You are currently attempting to provide positive pressure ventilation while using pressors to maintain hemodynamic stability. You previously initiated a dobutamine drip, and then added norepinephrine. However, despite escalating doses of both pressors, the patient’s hemodynamic status does not improve. What can do you do now?

Milrinone

MECHANISM OF ACTION

Milrinone is a phosphodiesterase-3 (PDE3) inhibitor. PDE3 is present in cardiac myocytes and vascular smooth muscles; it ultimately leads to cardiac smooth muscle relaxation and peripheral vasoconstriction (1, 9). Therefore, PDE3 inhibition results in potent inotropy, in addition to diastolic relaxation and vasodilation. This leads to reduced preload, afterload, and systemic vascular resistance (SVR). In addition to increased cardiac contractility, this results in improved cardiac output. Milrinone has no beta-adrenergic activity, resulting in minimal chronotropic effects.

ADVERSE EFFECTS

Because milrinone decreases preload (and therefore often leads to hypotension), it should only be used in patients who have undergone appropriate fluid resuscitation (8). In addition, the use of milrinone often necessitates concurrent vasopressor administration. The OPTIME-CHF study, an RCT involving 951 patients with systolic heart failure who did not require inotropic support, demonstrated increased rates of sustained hypotension and dysrhythmias (20).

Because milrinone is metabolized in the kidneys, it should be avoided in patients with renal disease (1).

In addition, milrinone has a substantially longer half-life compared to the other pressors. Because its half-life is approximately 1-2 hours (8), milrinone’s adverse effects can last for several hours. Milrinone should never be given as a bolus, and it should be slowly titrated from the lowest starting dose.

INDICATIONS

There are few studies directly comparing milrinone and dobutamine, so the exact indication for milrinone is unclear. However, because milrinone exerts its effects via PDE inhibition, it bypasses the catecholamine pathway. Therefore, it is recommended for use in patients with daily beta-blocker use and in patients with long-standing heart failure who have developed resistance to catecholamine derivatives (8).

Due to PDE’s vasodilatory effect on pulmonary vasculature, one would expect an advantage in patients with pulmonary hypertension (1). However, the use of milrinone in this setting has not been thoroughly studied.

DOSING

The starting dose of milrinone should ideally be chosen based on that patient’s renal function. The general range is 0.25-0.75 mcg/kg/min. Avoid its use in patients with creatinine clearance less than 50 mL/min. Because of its long onset of action and half-life, milrinone should be titrated every 2 hours (or slower, in the presence of renal disease).

Pure Inotrope Summary

-Inotropes have traditionally been avoided due to their increased risk of arrhythmia and myocardial ischemia.

-Inotropes are indicated in septic shock when there is evidence of decreased cardiac function (echocardiogram with evidence of decreased ejection fraction, failure of blood pressure to improve with pressors, known CHF).

-Inotropes are first-line for cardiogenic shock.

-Dobutamine is generally preferred over milrinone, but milrinone is preferred in patients who take daily beta-blockers.

Clinical Case #3:

An 86-year-old man with a history of COPD, CHF, CAD, and ESRD presents to your emergency department via EMS for decreased mental status. When he arrives, he is alert but confused, with a rectal temperature of 102.4F, heart rate of 113, and blood pressure of 75/55. You immediately treat for sepsis, administering a fluid bolus, antipyretics, and broad-spectrum antibiotics. His hemodynamic status does not improve, so you initiate a norepinephrine drip. You titrate to 20 mcg/min, with minimal effect. You decide to initiate a second pressor. Which one should you choose?

Pure Vasopressors

Vasopressin

MECHANISM OF ACTION

Vasopressin is an endogenously released hormone (also known as anti-diuretic hormone) that directly stimulates vasopressin receptors, located in the kidneys, to selectively constrict the efferent arterioles of the glomeruli. There are also vasopressin receptors on the peripheral vasculature, which directly stimulate vasoconstriction. It is believed that vasopressin also causes coronary and cerebral vasodilation (21).

Based on its mechanism of action, one would expect vasopressin to improve GFR. Several small RCTs and case studies have investigated this supposition, and each demonstrates improved renal function with vasopressin use (21-23). However, the VANISH trial (2016), which was the first large-scale RCT to compare the renal effects of vasopressin versus norepinephrine, failed to demonstrate a statistically significant difference between number of kidney-failure-free days for the first month after randomization (24). However, patients in the vasopressin group were less likely to require dialysis while hospitalized. Therefore, there is currently not enough evidence to suggest a renal-protective effect associated with vasopressin use.

ADVERSE EFFECTS

There was once concern that vasopressin increases the risk of cardiac arrest. However, several studies have since disproven this belief. Most notably, two large, multicenter trials demonstrated equivalent mortality and complication rates between both vasopressin and norepinephrine. The first large RCT to investigate vasopressin, the VASST trial (2008), found lower mortality in the vasopressin group (26.5%) compared to the norepinephrine group (35.0%) in “less severe septic shock,” but equivalent mortality in “more severe septic shock” (25). The rates of adverse events were equivalent in both groups. The VANISH trial (2016) corroborated these findings.

Although serious adverse event rates were equivalent between both vasopressin and norepinephrine, vasopressin increases the risk of digital ischemia more significantly than the catecholamine derivatives. In addition, the risk of digital ischemia increases dramatically when epinephrine and vasopressin are given in combination (26).

It is important to note that because previous studies regarding the safety of peripheral intravenous access for pressors did not include vasopressin (27), there is not enough evidence to support the use of vasopressin through a peripheral intravenous line. In addition, unlike catecholamine derivatives, vasopressin does not have an antidote if extravasation does occur.

INDICATIONS

It has been proposed that vasopressin deficiency leads to the vasodilation associated with septic shock (28), as demonstrated by the vasopressin depletion that occurs with the progression of shock (29). Therefore, vasopressin was historically a first-line pressor for septic shock. However, current surviving sepsis guidelines recommend vasopressin as a second-line agent, after norepinephrine (15). Several studies have demonstrated similar efficacy between vasopressin and norepinephrine (30, 31). In addition, the VASST and VANISH trials demonstrate similar complication and mortality rates between vasopressin and the catecholamine derivatives. Therefore, vasopressin may become more highly recommended as further studies continue to support its use. However, at this time it is unclear which patients may benefit from vasopressin use. Vasopressin may be preferable to epinephrine in incidences of hyperkinetic cardiac function, severe tachycardia, and renal failure. Due to its increased risk for digital ischemia, it may be best to avoid vasopressin in patients with known peripheral vascular disease or other such risk factors.

It has been proposed that because vasopressin leads to coronary vasodilation, it may be a preferable agent in cardiogenic shock. One retrospective study in 2005 demonstrated favorable hemodynamic effects associated with vasopressin use, compared to norepinephrine (32). However, studies on this subject are contradictory, with several retrospective studies demonstrating increased mortality in vasopressin use during cardiogenic shock (33). There are few RCTs investigating vasopressin use in cardiogenic shock.

Because vasopressin may not lead to pulmonary vasoconstriction, it may be an ideal pressor choice in hypotension secondary to pulmonary hypertension. While a small number of studies in limited clinical scenarios have proposed the superiority of vasopressin in this setting (34), there have only been case reports on the topic (35). Therefore, there is not enough literature to support vasopressin’s routine use in pulmonary hypertension.

Some intensivists have suggested using epinephrine and vasopressin in combination, in an attempt to minimize the deleterious effects of both pressors while harnessing the strength of each. In theory, epinephrine has fewer peripheral effects, but would stimulate cardiac contraction, while vasopressin would improve renal microcirculation. However, this is not a well-established practice.

DOSING

Because vasopressin is an endogenous hormone with a limited number of receptors, there is no utility to titrating vasopressin. Therefore, vasopressin is used at a set dose of 0.04 U/min, regardless of weight.

Clinical Case #4:

A 37-year-old male presents to the trauma bay after jumping off a bridge. His initial vital signs are heart rate 56, blood pressure 70/50, respiratory rate 30, and temperature 96.5F. His GCS is 14. He is alert but oriented only to person and place. He complains of severe neck pain. On exam, he has obvious deformities that are consistent with closed fractures of his upper and lower extremities. Upon examination of his spine, you note palpable midline tenderness and step-offs at multiple levels. Despite the administration of 2 units of packed red blood cells, the patient’s pressure is still 70/50. You initiate a norepinephrine drip and titrate to 20 mcg/min, but the patient’s capillary refill is still delayed and the blood pressure is only 80/54. You decide to initiate a second pressor. What should you choose?

Phenylephrine

MECHANISM OF ACTION

Phenylephrine is a pure alpha-1 agonist. It primarily affects large arterioles, with little effect on terminal arterioles (36, 37). In addition, because phenylephrine is solely an alpha agonist, it does not confer any inotropic effects.

ADVERSE EFFECTS

Because phenylephrine is a pure vasopressor, it induces substantial increases in arterial and venous tone, without concomitant increases in cardiac function. This leads to rapid changes in MAP and baroreflex-mediated bradycardia (8), in addition to digital ischemia and possibly end-organ hypoperfusion. Several studies have demonstrated worsened cardiac function associated with phenylephrine use (37, 38).

INDICATION

Phenylephrine is no longer recommended in septic shock. In addition, it should also be avoided in other forms of shock. Phenylephrine’s role should ideally be limited to rapidly correcting vasodilatory hypotension, such as is seen in medication-overdose (8). In addition, it may be indicated in neurogenic shock, if the patient is known to have normal cardiac function. However, due to the possibility of reflex bradycardia, phenylephrine should only be initiated as an adjunct to norepinephrine (39, 40).

DOSING

Phenylephrine can be initiated at 100-180 mcg/min initially, then titrated to 40-60 mcg/min as a maintenance dose. Boluses of 50-200 mcg can be used every 20 minutes as needed.

Pure Vasopressor Summary

-Pure vasopressors increase peripheral vasoconstriction, with minimal effects on heart rate and cardiac contractility.

-Current guidelines suggest using vasopressin as a second-line agent for septic shock, after norepinephrine.

-Vasopressin has a myriad of potential uses, including cardiogenic shock and pulmonary hypertension, but currently there is not enough literature to support its use in these settings.

–Vasopressin is associated with a high risk for digital ischemia, especially when used in combination with epinephrine.

-Phenylephrine should never be used in isolation, due to high risk for reflex bradycardia.

-Phenylephrine use should generally be avoided, but it may be useful as an adjunct to norepinephrine in neurogenic shock.

To bring everything together in an easy-to-use format, emDocs has a downloadable summary chart here: Inopressor Summary_chart

Further Reading/References

  1. Francis GS, Bartos JA, Adatya S. Inotropes. Journal of the American College of Cardiology. 2014;63(20):2069-78.
  2. Bayram M, De Luca L, Massie MB, Gheorghiade M. Reassessment of dobutamine, dopamine, and milrinone in the management of acute heart failure syndromes. The American journal of cardiology. 2005;96(6):47-58.
  3. Abraham WT, Adams KF, Fonarow GC, Costanzo MR, Berkowitz RL, LeJemtel TH, et al. In-hospital mortality in patients with acute decompensated heart failure requiring intravenous vasoactive medications: an analysis from the Acute Decompensated Heart Failure National Registry (ADHERE). Journal of the American College of Cardiology. 2005;46(1):57-64.
  4. Teerlink JR, Clarke CP, Saikali KG, Lee JH, Chen MM, Escandon RD, et al. Dose-dependent augmentation of cardiac systolic function with the selective cardiac myosin activator, omecamtiv mecarbil: a first-in-man study. The Lancet. 2011;378(9792):667-75.
  5. Sabbah HN, Imai M, Cowart D, Amato A, Carminati P, Gheorghiade M. Hemodynamic properties of a new-generation positive luso-inotropic agent for the acute treatment of advanced heart failure. The American journal of cardiology. 2007;99(2):S41-S6.
  6. De Luca L, Colucci WS, Nieminen MS, Massie BM, Gheorghiade M. Evidence-based use of levosimendan in different clinical settings. European heart journal. 2006;27(16):1908-20.
  7. Senz A, Nunnink L. Inotrope and vasopressor use in the emergency department. Emergency Medicine Australasia. 2009;21(5):342-51.
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