An Evidence-Based Approach to Pressors in Shock: Part I
- Jan 29th, 2018
- Sarah Brubaker
Author: Sarah Brubaker, MD (EM Resident Physician, 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.
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.”
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?”
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).
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).
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.
Most providers in the United States do not use weight-based dosing, starting with 2-4 mcg/min and titrating to effect. Several intensivists suggest using weight-based dosing to avoid the adverse effects associated with norepinephrine use (14). Weight-based dosing is based on GFR – GFR <10: 0.2 mcg/kg/min; GFR 10-40: 0.3 mcg/kg/min; GFR >40: 0.4 mcg/kg/min.
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?
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).
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.
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).
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?
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.
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).
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).
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.
– 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!
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